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V enousThromboEmbolism (VTE) Deep Vein Thrombosis – DVT Pulmonary Embolism – PE Dr. Mudi Misgav The National Hemophilia & Thrombosis center

Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

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Page 1: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

VenousThromboEmbolism (VTE)

Deep Vein Thrombosis ndash DVT Pulmonary Embolism ndash PE

Dr Mudi Misgav

The National Hemophilia amp Thrombosis center

Topics

Treatment options

Treatment duration

Cancer associated VTE (CAT)

Medical patients

VTE treatment

AC Thrombolysis PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

תיאור מקרה בריא 25בן

כאב שמתחיל בסובך שמאל

והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של

-פנייה לחדר מיון

Fem-Pop DVT

The probability of DVT (DVT in 3months FU)

ge 3 High (49)

1 2 Intermediate (143)

le 0 low (32)

Modified Wellrsquos criteria

Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999

Previously documented DVT 1

The probability of DVT ge 2 DVT likely

le 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 2: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Topics

Treatment options

Treatment duration

Cancer associated VTE (CAT)

Medical patients

VTE treatment

AC Thrombolysis PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

תיאור מקרה בריא 25בן

כאב שמתחיל בסובך שמאל

והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של

-פנייה לחדר מיון

Fem-Pop DVT

The probability of DVT (DVT in 3months FU)

ge 3 High (49)

1 2 Intermediate (143)

le 0 low (32)

Modified Wellrsquos criteria

Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999

Previously documented DVT 1

The probability of DVT ge 2 DVT likely

le 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 3: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

VTE treatment

AC Thrombolysis PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

תיאור מקרה בריא 25בן

כאב שמתחיל בסובך שמאל

והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של

-פנייה לחדר מיון

Fem-Pop DVT

The probability of DVT (DVT in 3months FU)

ge 3 High (49)

1 2 Intermediate (143)

le 0 low (32)

Modified Wellrsquos criteria

Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999

Previously documented DVT 1

The probability of DVT ge 2 DVT likely

le 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 4: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

תיאור מקרה בריא 25בן

כאב שמתחיל בסובך שמאל

והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של

-פנייה לחדר מיון

Fem-Pop DVT

The probability of DVT (DVT in 3months FU)

ge 3 High (49)

1 2 Intermediate (143)

le 0 low (32)

Modified Wellrsquos criteria

Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999

Previously documented DVT 1

The probability of DVT ge 2 DVT likely

le 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 5: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

The probability of DVT (DVT in 3months FU)

ge 3 High (49)

1 2 Intermediate (143)

le 0 low (32)

Modified Wellrsquos criteria

Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999

Previously documented DVT 1

The probability of DVT ge 2 DVT likely

le 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 6: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Recurrent VTE

NEJM 1992

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 7: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Chart1

20
67

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
AC
UFH+AC
Page 8: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Sheet1

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
AC UFH+AC
20 67
Page 9: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 10: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 11: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 12: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Prothrombin

Fibrinogen Fibrin

Va

TF

Extrinsic pathway

Intrinsic pathway

Xa

VIIa

Oral DXa Inhibitor

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Thrombin (IIa)

Oral DTI Dabigatran (Pradaxa)

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 13: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Acute VTE treatment studies

RE-COVER (I+II) (dabigatran)

bull DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bull DVT (2010) bull PE (2012)

AMPLIFY (apixaban)

bull DVT-PE (2013)

HOKUSAI VTE (edoxaban)

bull DVT-PE (2013)

27023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 14: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

DOAC

Pradaxa (Dabigatran)

Re-Cover UFHLMWH for ~10d

Pradaxa 150mg BID

Xarelto (rivaroxaban)

Einstein Dosing 15mg BID

for 21d follow by 20mg OD

Eliquis (Apixaban

Amplify Dosing 10mg BID for 7 days follow by

5mg BID

The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 15: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Events DOAC ENX-VKA

Rec VTE 204 226

MB+CRNMB 734 977

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 16: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

Odds ratio meta-analysis plot [fixed effects]

02 05 1 2

HOKUSAI 082 (058 116)

AMPLIFY 083 (058 120)

EINSTEIN PE 114 (074 175)

EINSTEIN DVT 069 (044 109)

RECOVER II 108 (062 189)

RECOVER I 106 (063 178)

combined [fixed] 090 (076 106)

odds ratio (95 confidence interval)

Rec Symptomatic adjudicated VTE

OR = 089 (076 ndash 106) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 17: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

MB+CRNMB

OR = 070 (054 ndash 090) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

02 05 1 2

HOKUSAI 080 (069 093)

AMPLIFY 042 (033 053)

EINSTEIN PE 090 (074 108)

EINSTEIN DVT 100 (078 129)

RECOVER II 061 (044 086)

RECOVER I 061 (044 085)

combined [random] 070 (054 090)

odds ratio (95 confidence interval)

בטיחות עדיפה

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337 261128 60 404 148515 148 409642 36129
80-84 94 497 189135 75 826 90799 169 279934 60371
gt=85 123 690 178261 47 758 62005 170 240266 70755
ALL 683 8858052 596 7709737 12790 16567789
7710 7730 7720
15-19 600
20-24 1243
25-29 1432
30-34 2356
35-39 2820
40-44 4046
45-49 4798
50-54 6958
55-59 7824
60-64 13656
65-69 19756
70-74 31526
75-79 36129
80-84 60371
gt=85 70755
15-19 15-19 15-19
20-24 20-24 20-24
25-29 25-29 25-29
30-34 30-34 30-34
35-39 35-39 35-39
40-44 40-44 40-44
45-49 45-49 45-49
50-54 50-54 50-54
55-59 55-59 55-59
60-64 60-64 60-64
65-69 65-69 65-69
70-74 70-74 70-74
75-79 75-79 75-79
80-84 80-84 80-84
gt=85 gt=85 gt=85
Page 18: Thrombophilia & cardiovascular diseaseDeep Vein Thrombosis – DVT . Pulmonary Embolism PE – Dr. Mudi Misgav . The National Hemophilia & Thrombosis center ... Standard Rx . P . Severe

VTE - Treatment

Vitamin K antagonist

UFH or LMWH

Initial (0 to ~7days)

Extended (~3 months to indefinite)

Long-term (~7 days to ~3 months)

Phases of anticoagulation

LMWH Dabigatran Rivaroxaban Apixaban Edoxaban

Rivaroxaban Apixaban

Kearon C et al Chest 2012

VTE - Treatment

AHJ 2018

VTE - Treatment

AHJ 2018

תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת

-לחדר מיון פנייה לכל אורכה

Ilio-Fem DVT

Treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

Thrombolysis for Deep vein Thrombosis

Not to decrease mortality

Not to prevent recurrence

To prevent Post-thrombotic syndrome

Post Thrombotic Syndrome

209 pt randomly assigned to control 108 or CDT 101

iliofemoral DVT within 21 days

FU for 24 months gtgt

Lancet 2012

NNT = 87 NNH = 112

Events CDT Standard Rx P

Ilio-femoral V (6m) 659 474 0012

PTS - 6m 303 322 077

PTS ndash 24m 411 556 0047

Bleeding M+CRNM 89 0

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)

No better QOL

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

The rationale for the use of thrombolysis for DVT is

to prevent long-term complications related to poor

venus function including PTS and ulceration

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

gt PTS significantly less (RR 066 P lt 00001 NNT-4)

gt Complete clot lysis (RR 244 P = 0002)

gt Bleeding complications (RR 223 P = 00006)

IVC-ilio-Fem deep vein thrombosis 10418

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10418

More than 50 patency

692 pts with acute prox DVT

PCDT N= 337

SOC N=355

bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration lt 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 467 482 056

Severe PTS 179 237 0035

Recurrent VTE 125 85 009

All bleeding 45 170 0049

Major bleeding 17 03 0049

Primary outcome ndash PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 179 237 0035

- Ileo-femoral DVT 184 282

- femoro-popliteal DVT 171 181

Results Summary

Compared with MB rates

Events NNT NNH

Severe PTS 172 714

- Ileo-femoral DVT 102 714

- femoro-popliteal DVT 100 714

Risk-Benefit ratio

High NNT - The average number of patients who need to be treated to prevent one bad outcome

Plegmasia cerulea Dolens Painful Blue edema

Venous gangrena

Thrombolysis

65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 85

HR - 125min

RR - 34 min

Temp - 37cdeg

Arterial O2 - 96

Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)

le 4 PE Unlikely gt 4 PE likely

TampH 2000

Fibrinolysis

Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients

bull Elderly

bull Malignancy

bull Recent surgery

bull Renal insufficiency

bull Inflammation

bull Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of gt 95

Suspected PE ndash Hemodynamically stable patients

le 4 PE Unlikely gt 4 PE likely

Treatment

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC ndash Anticoagulation

Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2

High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15

Anti-coagulation

LMWH vitK antagonist DOAC

ldquoTraditionalrdquo treatment

Or

תיאור מקרה

שבוע לאחר טיסה מיפן 50בן

גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי

קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65

HR - 125min

RR - 34min

Temp - 37cdeg

Arterial O2 - 93

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk gtgt Class I lt 66 class II 66-85

High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125

Eur Heart J (2014)

Classification of patients with acute PE based on early mortality risk

RV dysfunction

Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Eur Heart J 2014

Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days

NEJM 2014

PE with RV dysfunction

Randomization to standard treatment or thrombolysis

NNT = 33 NNH = 20

NEJM 2014

Guidelines

Thrombosis Canada

Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit

American college of chest physician (ACCP)

In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)

In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)

Thrombolysis

DVT

ilio-Fem DVT

PE

High risk PE

VTE - Treatment Aims To prevent short and long-term sequelae

Short term prevent clot extension and PE

Long Term

Post-thrombotic syndrome

Chronic thromboembolic

Pulmonary hypertension

PREVENTION of recurrence

For how long

How long to treat Transient risk factor

Unprovoked proximal DVT

VTE ndash treatment duration

VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor

Treatment with anticoagulation for 3 months (Grade 2B)

ACCP guidelines CHEST 20122016

High Risk

5 Annually

S Shulman NEJM 1995

The Duration of Anticoagulation Trial Study Group (DURAC)

Unprovoked proximal DVT

A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE

17 (27Y)

1 (13Y)

Kearon C NEJM 1999

Recurrent VTE

Provoked

Surgery

06 Non surgical

3

Unprovoked

Non cancer related

6 Cancer related

15

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox DVTPE) provoked by surgery 5

3 months (any bleeding risk)

VTE (prox DVTPE) provoked by non surgical transient risk factor

6

3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor

7

At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8

Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)

VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE

9 10

Indefinite (any bleeding risk)

Any DVT or PE and active cancer 11

ACCP 2016 revised recommendations

Gender age obesity smoking

Comorbidity (cancer)

Unprovoked or extensive thrombosis

Recurrent VTE

Residual vein thrombosis post treatment

Thrombophilia

Other predictors (D dimer)

Risk factors for recurrent VTE

PROLONG study NEJM 2006

Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44

D-dimer

VTE predictors ModelSource

Male D dimer extent VTE Vienna Model Circulation 2010

Male D dimer age (lt50) hormone related VTRE DASH JTH 2012

Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008

VTE prediction models

bull Thrombophilia and residual vein thrombosis also studied

bull NO clear consensus about any of the above

httpwwwmeduniwienacatusergeorgheinzedvpm

Aspirin Vs Placebo

The Aspirin for the Prevention of Recurrent Venous Thrombosis

trial (WARFASA for warfarin followed by aspirin or placebo)

The Aspirin to Prevent Venous Thromboembolism (ASPIRE)

WARFASA NEJM 2012 ASPIRE NEJM 2012

VTE ndash Extended Treatment

Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events

Statistically significant

Apixaban for extended treatment of venous Thromboembolism

NEJM 2013

METHODS

Randomized double-blind

Two doses of apixaban 25 mg and 5 mg with placebo

Patients with VTE who had completed 6 to 12 months of AC

regarding the continuation or cessation of AC Clinical equipoise

The study drugs were administered for 12 months

RESULTS - 1

Placebo (829) 5mg (813) 25mg (840)

73 (88) 14 (17) RR 02

14 (17) RR 019

Rec VTE or VTE-related death

4 (05) 1 (01) 2 (02) Major bleeding

22 (27) 35 (43) 27 (32) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Compared with ASA both 20-mg and 10-mg rivaroxaban reduced

the RR of recurrent VTE by about 70

The rates of M and and CRNMB were low and similar to those with ASA

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators

Extended phase

Compared to warfarin

RE-MEDY Dabigatran

Compared to placebo

EINSTEIN EXT Rivaroxaban

AMPLIFY EXT Apixaban

2 doses

RE-SONATE Dabigatran

RE-SONATE RE-MEDY

(dabigatran)

bull N=4199

EXT-EINSTEIN (rivaroxaban)

bull N=1196

AMPLIFY-EXT (apixaban)

bull N=2486

4 trials with 7881 patients

vs placebo

vs warfarin 18

13

13 73

vs placebo

vs warfarin 101

56

46 20

Warfarin ASA (100mg) Placebo

25 5 mg

Amplify Ext (Eliquis)

10 20mg 20mg

EINSTEIN EXT EINSTEIN CHOICE (Xarelto)

Less bleeding

150mg

Re-Sonate Re-Medy (Pradaxa)

Secondary prevention of VTE

Armand Trousseau

Cancer associated thrombosis (CAT) is unique

VTE is multifactorial

Cancer (more cancer burden ndash more VTE)

Treatment (chemoRx biological Rx)

Hospital (immobilization central lines)

Patient (morbidity thrombophilia)

High rate of recurrent despite treatment

High rate of bleeding events on adequate treatment

53336

27336

RR = 048 (030-077)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (66) 5107 RECOVER

1124 (136) 8281 EINSTEIN

534 (99) 5395 AMPLIFY

771 (93) 8292 HOKUSAI

2764 (102) 27075 sum

RE-COVER (I+II) (dabigatran)

bullDVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

bullDVT (2010) bullPE (2012)

AMPLIFY (apixaban)

bullDVT-PE (2013)

HOKUSAI VTE (edoxaban)

bullDVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10

HOKUSAI 050 (010 205)

EINSTEIN 058 (016 196)

AMPLIFY 056 (008 301)

RECOVER 094 (017 517)

combined [fixed] 061 (032 115)

odds ratio (95 confidence interval)

Rec Symptomatic VTE

OR = 061 (032 ndash 115) FIXED MODEL

Cancer patients

Major bleeding OR = 066 (036 ndash 121) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

001 01 02 05 1 2 5 10 100

HOKUSAI 154 (029 1015)

EINSTEIN 044 (016 112)

AMPLIFY 045 (004 323)

RECOVER 128 (021 896)

combined [fixed] 066 (036 121)

odds ratio (95 confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D gt Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial gt Apixaban Vs SOC

Edoxaban for the treatment of VTE in patients with Cancer

Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial

NEJM 2018

Edoxaban for the treatment of VTE in patients with Cancer

Edoxaban - CAT

Cancer patients

NEJM 2018

Edoxaban

M + CRNMB HR 14 p-004

Rec VTE HR 071 p-009

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018)

A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

8 4 (HR 043)

18 11

Rec VTE () Rec Rate

6 4 Major Bleeding

13 (HR 376) 4 CRNMB

75 70 Survival

DOAC in Cancer patients Rivaroxaban

SELECT D (JCO 2018) - Bleeding

3-fold relative increase in CRNMB with rivaroxaban

Deacrease in reccurent VTE but there was an increase in bleeding

Most bleed in the rivaroxaban arm were from the GI tract

Rivaroxaban (Pt 203)

Dalteparin (Pt 203)

Therapy Outcome

__ Rec VTE ()

Bleeding

Prophylaxis in medical patients

Muscle Pump Venous Insufficiency

Venous Function

Valve Thrombosis

Circulatory Stasis

ATVB 2012

Blood Flow Oxygen Tension Endothelial Activation

diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF

Formation of Thrombosis

Padua Score

Score 4 =lt High risk

DOAC ndash prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013)

Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d

Rivaroxaban (Pt 2938)

Enoxaparin (Pt 2993)

Therapy VTE

78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()

131 (44) RR 077 P = 002 175 (57) Up to 35d ()

111 (28 Plt0001)

164 (41 Plt0001)

10d gt 49 (12)

35d gt 67 (17) Major + CRNMB

Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d

Apixaban (Pt 2211)

Enoxaparin (Pt 2284)

Primary outcome

27 306 At 30d

047 RR 258 P=004 019 Major bleeding

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

DOAC ndash prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011)

Death related to VTE PE symptomatic DVT or asymptomatic prox DVT

CONCLUSIONS

An extended course of thromboprophylaxiswith apixaban was not

Superior to a shorter course with enoxaparin

Apixaban was associated with significantly more major bleeding

Events than was enoxaparin

Q

mudimisgavshebagovil

Thank you

DOAC for anti-phospholipid syndrome

ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)

ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA

Standard of treatment gtgt LMWH or Warfarin

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42

Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation

Eligible patients Thrombotic APS and at least one VTE (No arterial events)

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Results 57 patients were assigned to rivaroxaban and 59 to warfarin

No thrombotic events were seen in either group during 6 months

Low risk patients

DOAC for anti-phospholipid syndrome RAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

Thrombin Generation

DOAC for anti-phospholipid syndrome TRAPS study

Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without

SLE a randomised controlled open-label phase 23 non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

ldquoAny disorder (inherited or acquired) associated with increased

tendency to venous thrombosisrdquo

Egeberg 1963

0

200

400

600

800

1000

1200DVT PE ALL

Silverstein MD Arch Int Med 1998

Olmsted county Minnesota

Age as risk factor for VTE

011000 11000

81000

תרשים1

DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243

PE

PE

DVT

DVT

VTE

VTE

DVT
PE
ALL

Malignancy bull Cancer bull Cancer therapy

AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology bull MPD bull PNH

Trauma bull Trauma bull Surgery

bull Varicose veins

Hormones related

bull Estrogen OC bull HRT bull Estrogen RM

Immobilization bull Sitting bull Travel (Car Train) bull Long flights

Acute illness bull Heart Resp failure bull Stroke MI

bull Pregnancy bull Obesity bull Aging

bull Venous Catheter

Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S

Inherited Thrombophilia

11

156

217

7765

34725108

0

5

10

15

20

25

Controls

FVLPTM PS PC

FVLPTM ++

Combined AT

Relative Risk for 1st VTE in carriers

Rates per 1000Y

27 48

02 04

002

Blood 20091135314

Unaffected (no defect)

AT

PC

PS

PT

FVL

FVL PT mutation Most carriers remain asymptomatic

PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic

High vs low risk thrombophilia

Screening for genetic thrombophilia

Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the

initial 3m of anticoagulation

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following provoked VTE

A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode

of unprovoked VTE in a patient with low bleeding risk and willingness to continue

therapy

If a patient with unprovoked VTE and low bleeding risk is planning to stop

anticoagulation test for thrombophilia if test results would change this decision

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia

A family history of VTE confers an excess risk of thrombosis counseled

regarding use of prophylaxis in high risk situations

J Thromb Thrombolysis 2016

Screening for genetic thrombophilia

diams Unprovoked VTE

diams Recurrent VTE

diams Positive family history

diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)

diams Reccurrent early pregnancy fetal loss (APLA)

diams Late 2nd or 3rd trimester fetal loss

diams Neonatal purpura fulminant (PC PS) Skin necrosis

The ldquothresholdrdquo concept

  • Slide Number 1
  • Slide Number 2
  • Slide Number 3
  • תיאור מקרה
  • Modified Wellrsquos criteria
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Slide Number 9
  • Slide Number 10
  • Slide Number 11
  • Slide Number 12
  • Slide Number 13
  • Slide Number 14
  • Slide Number 15
  • Slide Number 16
  • Slide Number 17
  • Slide Number 18
  • Slide Number 19
  • תיאור מקרה
  • Slide Number 21
  • Slide Number 22
  • Slide Number 23
  • Slide Number 24
  • Slide Number 25
  • Slide Number 26
  • Slide Number 27
  • Slide Number 28
  • Slide Number 29
  • Slide Number 30
  • ATTRACT study
  • Slide Number 32
  • Slide Number 33
  • Slide Number 34
  • Slide Number 35
  • Slide Number 36
  • תיאור מקרה
  • Diagnosis of PE
  • Slide Number 39
  • Slide Number 40
  • Slide Number 41
  • Slide Number 42
  • Slide Number 43
  • Slide Number 44
  • Slide Number 45
  • תיאור מקרה
  • Slide Number 47
  • Slide Number 48
  • Diagnosis of PE
  • Diagnosis of PE
  • Slide Number 51
  • Slide Number 52
  • Slide Number 53
  • Slide Number 54
  • Slide Number 55
  • Slide Number 56
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • Slide Number 62
  • Slide Number 63
  • Slide Number 64
  • Slide Number 65
  • Slide Number 66
  • Slide Number 67
  • Slide Number 68
  • Slide Number 69
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • Slide Number 74
  • Slide Number 75
  • Slide Number 76
  • Slide Number 77
  • Slide Number 78
  • Slide Number 79
  • Slide Number 80
  • Slide Number 81
  • Cancer associated thrombosis (CAT) is unique
  • Slide Number 83
  • Cancer patients
  • Cancer patients
  • Cancer patients
  • Cancer patients Cancer-associated theombosis (CAT)
  • Edoxaban - CAT
  • Cancer patients
  • Slide Number 90
  • Slide Number 91
  • Slide Number 92
  • Venous Function
  • Valve Thrombosis
  • Circulatory Stasis
  • Slide Number 96
  • Padua Score
  • Slide Number 98
  • Slide Number 99
  • Slide Number 100
  • Slide Number 101
  • Slide Number 102
  • Slide Number 103
  • Slide Number 104
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Thrombophilia
  • Slide Number 111
  • Slide Number 112
  • Inherited Thrombophilia
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
DVT PE
15-19 115 6 175
20-24 294623115578 124324324324 418947439902
25-29 351226415094 143181818182 494408233276
30-34 33190529876 235606820461 567512119221
35-39 325077399381 281967213115 607044612496
40-44 411063153112 404565117349 815628270462
45-49 440065298507 47976054732 919825845828
50-54 592418032787 695776475513 12881945083
55-59 610827754108 78242865463 1393256408739
60-64 1129411764706 1365647592565 2495059357271
65-69 1102678571429 1975555555556 3078234126984
70-74 1736176239182 3152611319587 4888787558769
75-79 1952003874561 3612906834971 5564910709532
80-84 2429045193454 6037140768715 8466185962169
gt=85 2455329448256 7075487012987 9530816461243
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 18 18 1000000 5 5 1000000 23 2000000 1150
20-24 45 41 1097561 10 13 769231 55 1866792 2946
25-29 55 51 1078431 18 18 1000000 73 2078431 3512
30-34 45 46 978261 19 20 950000 64 1928261 3319
35-39 27 35 771429 23 30 766667 50 1538095 3251
40-44 32 47 680851 23 35 657143 55 1337994 4111
45-49 29 51 568627 21 37 567568 50 1136195 4401
50-54 25 49 510204 34 70 485714 59 995918 5924
55-59 29 63 460317 25 59 423729 54 884046 6108
60-64 40 100 400000 44 128 343750 84 743750 11294
65-69 34 95 357895 36 130 276923 70 634818 11027
70-74 47 148 317568 44 213 206573 91 524140 17362
75-79 46 176 261364 34 229 148472 80 409835 19520
80-84 39 206 189320 29 320 90625 68 279945 24290
gt=85 49 275 178182 10 161 62112 59 240294 24553
5600 8850010 3750 7748505 935 165985152169379 5633
15-19 115
20-24 294623115578
25-29 351226415094
30-34 33190529876
35-39 325077399381
40-44 411063153112
45-49 440065298507
50-54 592418032787
55-59 610827754108
60-64 1129411764706
65-69 1102678571429
70-74 1736176239182
75-79 1952003874561
80-84 2429045193454
gt=85 2455329448256
תסחיף ריאתי
נשים גברים כולם
גיל ממ IR PY ממ IR PY ממ PY IR
15-19 8 8 1000000 4 4 1000000 12 2000000 600
20-24 11 10 1100000 12 16 750000 23 1850000 1243
25-29 23 21 1095238 7 7 1000000 30 2095238 1432
30-34 28 29 965517 17 18 944444 45 1909962 2356
35-39 31 40 775000 12 16 750000 43 1525000 2820
40-44 25 37 675676 29 44 659091 54 1334767 4046
45-49 26 45 577778 29 51 568627 55 1146405 4798
50-54 37 73 506849 32 66 484848 69 991698 6958
55-59 27 59 457627 42 99 424242 69 881870 7824
60-64 43 107 401869 59 171 345029 102 746898 13656
65-69 55 154 357143 70 254 275591 125 632733 19756
70-74 64 202 316832 101 489 206544 165 523376 31526
75-79 88 337