VenousThromboEmbolism (VTE) Deep Vein Thrombosis – DVT Pulmonary Embolism – PE

Dr. Mudi Misgav

The National Hemophilia & Thrombosis center

http://newsnetwork.mayoclinic.org/files/2014/01/DVT.jpg

Topics

Treatment options

Treatment duration

Cancer associated VTE (CAT)

Medical patients

VTE treatment

AC Thrombolysis PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC – 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)

≥ 3 High (49%)

1 / 2 Intermediate (14.3%)

≤ 0 low (3.2%)

Modified Well’s criteria

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

Previously documented DVT 1

The probability of DVT ≥ 2 DVT likely

≤ 1 DVT Unlikely

Recurrent VTE

NEJM 1992

Chart1

AC

UFH+AC

20

6.7

Sheet1

ACUFH+AC

206.7

Chest 2010

Chest 2010

Anti-coagulation

LMWH vitK antagonist DOAC

“Traditional” 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)

• DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

• DVT (2010) • PE (2012)

AMPLIFY (apixaban)

• DVT-PE (2013)

HOKUSAI VTE (edoxaban)

• DVT-PE (2013)

27,023 patients

DOAC

Pradaxa (Dabigatran)

Re-Cover UFH/LMWH for ~10d

Pradaxa 150mg B.I.D

Xarelto (rivaroxaban)

Einstein Dosing: 15mg B.I.D

for 21d follow by 20mg O.D

Eliquis (Apixaban

Amplify Dosing: 10mg B.I.D for 7 days follow by

5mg B.I.D

* The comparator warfarin

Events DOAC ENX-VKA

Rec VTE 2.04 % 2.26%

MB+CRNMB 7.34% 9.77%

Main outcomes

Odds ratio meta-analysis plot [fixed effects]

0.2 0.5 1 2

HOKUSAI 0.82 (0.58, 1.16)

AMPLIFY 0.83 (0.58, 1.20)

EINSTEIN PE 1.14 (0.74, 1.75)

EINSTEIN DVT 0.69 (0.44, 1.09)

RECOVER II 1.08 (0.62, 1.89)

RECOVER I 1.06 (0.63, 1.78)

combined [fixed] 0.90 (0.76, 1.06)

odds ratio (95% confidence interval)

Rec. Symptomatic adjudicated VTE OR = 0.89 (0.76 – 1.06) FIXED MODEL

= Non-inferiorityיעילות זהה

MB+CRNMB OR = 0.70 (0.54 – 0.90) RANDOM MODEL

Odds ratio meta-analysis plot [random effects]

0.2 0.5 1 2

HOKUSAI 0.80 (0.69, 0.93)

AMPLIFY 0.42 (0.33, 0.53)

EINSTEIN PE 0.90 (0.74, 1.08)

EINSTEIN DVT 1.00 (0.78, 1.29)

RECOVER II 0.61 (0.44, 0.86)

RECOVER I 0.61 (0.44, 0.85)

combined [random] 0.70 (0.54, 0.90)

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 >>

Lancet 2012

NNT = 8.7 NNH = 11.2

Events CDT Standard Rx P

Ilio-femoral V. (6m) 65.9% 47.4% 0.012

PTS - 6m 30.3% 32.2% 0.77

PTS – 24m 41.1% 55.6% 0.047

Bleeding M+CRNM 8.9% 0%

CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (P

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 > Seventeen RCTs with 1103 Pt. > There was no significant effect on mortality > Systemic thrombolysis and CDT had similar effectiveness.

Thrombolysis for acute deep vein thrombosis -

Cochrane Database Nov-16

Main results (long term 6m-5y)

> PTS significantly less (RR 0.66, P < 0.0001, NNT-4)

> Complete clot lysis (RR 2.44; P = 0.002)

> Bleeding complications (RR 2.23; P = 0.0006).

IVC-ilio-Fem deep vein thrombosis 10.4.18

Mostly occluded

IVC-ilio-Fem deep vein thrombosis 10.4.18

More than 50% patency

692 pts with acute prox. DVT

PCDT N= 337

SOC N=355

• Pharmaco-mechanic catheter directed thrombolysis • Standard of care

ATTRACT study

Inclusion criteria DVT symptom duration < 14d

NEJM 2017

Events PCDT Standard Rx P PTS all types 46.7% 48.2% 0.56 Severe PTS 17.9% 23.7% 0.035 Recurrent VTE 12.5% 8.5% 0.09

All bleeding 4.5% 1.70% 0.049 Major bleeding 1.7% 0.3% 0.049

Primary outcome – PTS (6-24m)

March 2017

Events PCDT Standard Rx P

Severe PTS 17.9% 23.7% 0.035

- Ileo-femoral DVT 18.4% 28.2%

- femoro-popliteal DVT 17.1% 18.1%

Results Summary

* Compared with MB rates

Events NNT NNH

Severe PTS 17.2 71.4

- Ileo-femoral DVT 10.2 71.4

- femoro-popliteal DVT 100 71.4

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 ? 65

תיאור מקרה

שלושה חודשים לאחר התחלת גלולות , 29בת

מתארת כאב פליאוריטי וקוצר נשימה

BP - 120 / 85

HR - 125/min

RR - 34 / min

Temp. - 37c°

Arterial O2 - 96%

Diagnosis of PE Modified Well’s criteria for Pulmonary Embolism (PE)

≤ 4 PE Unlikely > 4 PE likely

T&H 2000

Fibrinolysis

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

• Elderly

• Malignancy

• Recent surgery

• Renal insufficiency

• Inflammation

• Second and third trimester of a normal pregnancy

D-dimer test

dDimer negative predictive value of > 95 %

Suspected PE – Hemodynamically stable patients

≤ 4 PE Unlikely > 4 PE likely

Treatment ?

VTE treatment

AC PMCDT

Pharmaco-mechanical catheter directed thrombolysis

AC – Anticoagulation

Low risk: Class I < 66, class II 66-85 >> 30d mortality 1-2%

High risk: Class III 86-105, IV 106 -125 , V 125 >> 30d mortality 3-15%

Anti-coagulation

LMWH vitK antagonist DOAC

“Traditional” 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 - 125/min

RR - 34/min

Temp. - 37c°

Arterial O2 - 93%

Suspected PE with shock or Hypotension

Suspected PE with shock or Hypotension

Echocardiography

Diagnosis of PE

http://circ.ahajournals.org/content/120/22/2269/F2.large.jpg

Chest CTA ( Computed tomography angiography)

Diagnosis of PE

Low risk >> Class I < 66, class II 66-85

High risk >> Class III 86-105 Class IV 106 -125 Class V > 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 0.9 CTA Increased end-diastolic RV / LV diameter ratio 0.9

Markers of myocardial injury

Elevated cardiac troponin I or T Elevated BNP

PresenterPresentation NotesPE ¼ pulmonary embolism; PESI ¼ Pulmonary embolism severity index; RV ¼ right ventricular; sPESI ¼ simplified Pulmonary embolism severity index.aPESI Class III to V indicates moderate to very high 30-day mortality risk; sPESI ≥1 point(s) indicate high 30-day mortality risk.bEchocardiographic criteria of RV dysfunction include RV dilation and/or an increased end-diastolic RV–LV diameter ratio (in most studies, the reported threshold value was 0.9 or1.0); hypokinesia of the free RV wall; increased velocity of the tricuspid regurgitation jet; or combinations of the above. On computed tomographic (CT) angiography (four-chamberviews of the heart), RV dysfunction is defined as an increased end-diastolic RV/LV (left ventricular) diameter ratio (with a threshold of 0.9 or 1.0).cMarkers of myocardial injury (e.g. elevated cardiac troponin I or -T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriureticpeptide concentrations in plasma).dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock.ePatients in the PESI Class I–II, 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-riskcategory. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index.

Eur Heart J 2014

PresenterPresentation NotesPE ¼ pulmonary embolism; PESI ¼ Pulmonary embolism severity index; RV ¼ right ventricular; sPESI ¼ simplified Pulmonary embolism severity index.aPESI Class III to V indicates moderate to very high 30-day mortality risk; sPESI ≥1 point(s) indicate high 30-day mortality risk.bEchocardiographic criteria of RV dysfunction include RV dilation and/or an increased end-diastolic RV–LV diameter ratio (in most studies, the reported threshold value was 0.9 or1.0); hypokinesia of the free RV wall; increased velocity of the tricuspid regurgitation jet; or combinations of the above. On computed tomographic (CT) angiography (four-chamberviews of the heart), RV dysfunction is defined as an increased end-diastolic RV/LV (left ventricular) diameter ratio (with a threshold of 0.9 or 1.0).cMarkers of myocardial injury (e.g. elevated cardiac troponin I or -T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriureticpeptide concentrations in plasma).dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock.ePatients in the PESI Class I–II, 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-riskcategory. 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 …. where the short-term mortality is >15%. 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

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 – treatment duration

VTE – 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 2012/2016

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 (2.7%/Y)

1 (1.3%/Y)

Kearon C, NEJM 1999

Recurrent VTE

Provoked

Surgery

0.6% Non surgical

3%

Unprovoked

Non cancer related

6% Cancer related

15%

Blood 2014

Treatment VTE scenario Number

3 months VTE (prox. DVT/PE) provoked by surgery 5

3 months. (any bleeding risk)

VTE (prox. DVT/PE) 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. DVT/PE) unprovoked 8

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

VTE (prox. DVT/PE) – 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 w/o AC - 10.9% Abnormal D-dimer with AC – 2% Normal D-dimer - 4.4%

D-dimer

VTE predictors Model/Source

Male, D dimer, extent VTE Vienna Model, Circulation 2010

Male, D dimer, age (65), PTS, D dimer, BMI (>30) HERDOTOO, CMAJ 2008

VTE prediction models

• Thrombophilia and residual vein thrombosis also studied

• NO clear consensus about any of the above !!

http://www.meduniwien.ac.at/user/georg.heinze/dvpm/.

http://www.meduniwien.ac.at/user/georg.heinze/dvpm/http://www.meduniwien.ac.at/user/georg.heinze/dvpm/

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 – 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 2.5 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) 2.5mg (840)

73 (8.8%) 14 (1.7%) RR 0.2

14 (1.7%) RR 0.19

Rec. VTE or VTE-related death

4 (0.5%) 1 (0.1%) 2 (0.2%) Major bleeding

22 (2.7%) 35 (4.3%) 27 (3.2%) M or CRNM

RESULTS - 2

NNT = 14 NNH = 200

NEJM 2017

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism •Jeffrey I. Weitz, M.D., 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 •Jeffrey I. Weitz, M.D., 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)

• N=4199

EXT-EINSTEIN (rivaroxaban)

• N=1196

AMPLIFY-EXT (apixaban)

• N=2486

4 trials with 7,881 patients

vs. placebo

vs. warfarin 1.8%

1.3%

1.3% 7.3%

vs. placebo

vs. warfarin 10.1 %

5.6 %

4.6 % 2.0 %

Warfarin ASA (100mg) Placebo

2.5, 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 – 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

53/336

27/336

RR = 0.48 (0.30-0.77)

NEJM 2003

CLOT

Dalteparin Standard therapy

Cancer patients All patients

335 (6.6%) 5,107 RECOVER

1,124 (13.6%) 8,281 EINSTEIN

534 (9.9%) 5,395 AMPLIFY

771 (9.3%) 8,292 HOKUSAI

2,764 (10.2%) 27,075 ∑

RE-COVER (I+II) (dabigatran)

•DVT-PE (2009+2013)

EINSTEIN (rivaroxaban)

•DVT (2010) •PE (2012)

AMPLIFY (apixaban)

•DVT-PE (2013)

HOKUSAI VTE (edoxaban)

•DVT-PE (2013)

Cancer patients

Odds ratio meta-analysis plot [fixed effects]

0.01 0.1 0.2 0.5 1 2 5 10

HOKUSAI 0.50 (0.10, 2.05)

EINSTEIN 0.58 (0.16, 1.96)

AMPLIFY 0.56 (0.08, 3.01)

RECOVER 0.94 (0.17, 5.17)

combined [fixed] 0.61 (0.32, 1.15)

odds ratio (95% confidence interval)

Rec. Symptomatic VTE

OR = 0.61 (0.32 – 1.15) FIXED MODEL

Cancer patients

Major bleeding OR = 0.66 (0.36 – 1.21) FIXED MODEL

Odds ratio meta-analysis plot [fixed effects]

0.01 0.1 0.2 0.5 1 2 5 10 100

HOKUSAI 1.54 (0.29, 10.15)

EINSTEIN 0.44 (0.16, 1.12)

AMPLIFY 0.45 (0.04, 3.23)

RECOVER 1.28 (0.21, 8.96)

combined [fixed] 0.66 (0.36, 1.21)

odds ratio (95% confidence interval)

Cancer patients

Cancer patients Cancer-associated theombosis (CAT)

NEJM 2018

Select-D > Rivaroxaban Vs Dalteparin JCO 2018

CARAVAGGIO trial > 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 1.4, p-0.04

Rec VTE HR 0.71, p-0.09

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 0.43)

18 11%

Rec VTE (#) Rec. Rate

6% 4% Major Bleeding

13% (HR 3.76) 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

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

Formation of Thrombosis

Padua Score

Score 4 =< High risk

DOAC – prophylaxis in medical patients Rivaroxaban

MAGELLAN (NEJM 2013) Enoxaparin 40mg/d for 10d Vs Rivaroxaban 10mg/d for 35d.

Rivaroxaban (Pt. 2938)

Enoxaparin (Pt. 2993)

Therapy VTE

78 (2.7%) P = 0.003 for non-inferiority 82 (2.7%) Up to 10d (#)

131 (4.4%) RR 0.77; P = 0.02 175 (5.7%) Up to 35d (#)

111 (2.8%, P 67 (1.7%) Major + CRNMB

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

DOAC – prophylaxis in medical patients Apixaban

ADOPT trial (NEJM 2011) Enoxaparin 40mg/d for 6-14d vs Apixaban 2.5mg b.i.d /d for 30d.

Apixaban (Pt. 2211)

Enoxaparin (Pt. 2284)

Primary outcome

2.7% 3.06% At 30d

0.47% RR 2.58; P=0.04 0.19% Major bleeding

Death related to VTE, PE, symptomatic DVT or asymptomatic prox. DVT

DOAC – 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?

mudi.misgav@sheba.gov.il

mailto:mudi.misgav@sheba.health.co.il

Thank you

DOAC for anti-phospholipid syndrome

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

ACL+ b2GP1 + LAC >> “Triple” APLA

Standard of treatment >> 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 2/3, 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 2/3, 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 2/3, 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 2/3, non-inferiority trial

Lancet 2016

High risk patients

Thrombophilia

“Any disorder (inherited or acquired) associated with increased

tendency to venous thrombosis”

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

0.1/1000 1/1000

8/1000

תרשים1

15-1915-1915-19

20-2420-2420-24

25-2925-2925-29

30-3430-3430-34

35-3935-3935-39

40-4440-4440-44

45-4945-4945-49

50-5450-5450-54

55-5955-5955-59

60-6460-6460-64

65-6965-6965-69

70-7470-7470-74

75-7975-7975-79

80-8480-8480-84

>=85>=85>=85

DVT

PE

ALL

11.5

6

17.5

29.4623115578

12.4324324324

41.8947439902

35.1226415094

14.3181818182

49.4408233276

33.190529876

23.5606820461

56.7512119221

32.5077399381

28.1967213115

60.7044612496

41.1063153112

40.4565117349

81.5628270462

44.0065298507

47.976054732

91.9825845828

59.2418032787

69.5776475513

128.81945083

61.0827754108

78.242865463

139.3256408739

112.9411764706

136.5647592565

249.5059357271

110.2678571429

197.5555555556

307.8234126984

173.6176239182

315.2611319587

488.8787558769

195.2003874561

361.2906834971

556.4910709532

242.9045193454

603.7140768715

846.6185962169

245.5329448256

707.5487012987

953.0816461243

PE

תסחיף ריאתי

נשיםגבריםכולם

גילמ"מIRPYמ"מIRPYמ"מPYIR

15-1988100000.044100000.012200000.06.00

20-241110110000.0121675000.023185000.012.43

25-292321109523.877100000.030209523.814.32

30-34282996551.7171894444.445190996.223.56

35-39314077500.0121675000.043152500.028.20

40-44253767567.6294465909.154133476.740.46

45-49264557777.8295156862.755114640.547.98

50-54377350684.9326648484.86999169.869.58

55-59275945762.7429942424.26988187.078.24

60-644310740186.95917134502.910274689.8136.56

65-695515435714.37025427559.112563273.3197.56

70-746420231683.210148920654.416552337.6315.26

75-798833726112.86040414851.514840964.2361.29

80-849449718913.5758269079.916927993.4603.71

>=8512369017826.1477586200.517024026.6707.55

ALL683885805.2596770973.71279.01656778.9

77.1077.3077.20

15-196.00

20-2412.43

25-2914.32

30-3423.56

35-3928.20

40-4440.46

45-4947.98

50-5469.58

55-5978.24

60-64136.56

65-69197.56

70-74315.26

75-79361.29

80-84603.71

>=85707.55

PE

DVT

נשיםגבריםכולם

גילמ"מIRPYמ"מIRPYמ"מPYIR

15-191818100000.055100000.023200000.011.50

20-244541109756.1101376923.155186679.229.46

25-295551107843.11818100000.073207843.135.12

30-34454697826.1192095000.064192826.133.19

35-39273577142.9233076666.750153809.532.51

40-44324768085.1233565714.355133799.441.11

45-49295156862.7213756756.850113619.544.01

50-54254951020.4347048571.45999591.859.24

55-59296346031.7255942372.95488404.661.08

60-644010040000.04412834375.08474375.0112.94

65-69349535789.53613027692.37063481.8110.27

70-744714831756.84421320657.39152414.0173.62

75-794617626136.43422914847.28040983.5195.20

80-843920618932.0293209062.56827994.5242.90

>=854927517818.2101616211.25924029.4245.53

560.0885001.0375.0774850.59351659851.5216937956.33

15-1911.5

20-2429.4623115578

25-2935.1226415094

30-3433.190529876

35-3932.5077399381

40-4441.1063153112

45-4944.0065298507

50-5459.2418032787

55-5961.0827754108

60-64112.9411764706

65-69110.2678571429

70-74173.6176239182

75-79195.2003874561

80-84242.9045193454

>=85245.5329448256

DVT

VTE

DVTPE

15-1911.5617.5

20-2429.462311557812.432432432441.8947439902

25-2935.122641509414.318181818249.4408233276

30-3433.19052987623.560682046156.7512119221

35-3932.507739938128.196721311560.7044612496

40-4441.106315311240.456511734981.5628270462

45-4944.006529850747.97605473291.9825845828

50-5459.241803278769.5776475513128.81945083

55-5961.082775410878.242865463139.3256408739

60-64112.9411764706136.5647592565249.5059357271

65-69110.2678571429197.5555555556307.8234126984

70-74173.6176239182315.2611319587488.8787558769

75-79195.2003874561361.2906834971556.4910709532

80-84242.9045193454603.7140768715846.6185962169

>=85245.5329448256707.5487012987953.0816461243

VTE

DVT

PE

ALL

Malignancy • Cancer • Cancer therapy

A.I diseases • IBD, RA, SLE, ITP • Nephrotic syndrome

Acquired Risk Factors for VTE

Hematology • MPD • PNH

Trauma • Trauma • Surgery

• Varicose veins

Hormones related

• Estrogen / OC • HRT • Estrogen RM

Immobilization • Sitting • Travel (Car, Train) • Long flights

Acute illness • Heart / Resp. failure • Stroke / MI

• Pregnancy • Obesity • Aging

• Venous Catheter

PresenterPresentation NotesVTE disease is a healthcare problem that causes significant morbidity and mortalityThis table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE diseaseIn general, almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40%have three or more risk factorsMost 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 disease

Reference1. Geerts WH et al. Chest. 2008;133(Suppl):381S-453S

Inherited Thrombophilia

11

15.6

21.7

7.76.5

3.472.51.08

0

5

10

15

20

25

Contr

ols FVL

PTM PS PC

FVL/P

TM ++

Comb

ined AT

Relative Risk for 1st VTE in carriers

Rates per 1,000/Y

2.7% 4.8%

0.2% 0.4%

0.02%

Blood 2009;113:5314

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

♦ Unprovoked VTE

♦ Recurrent VTE

♦ Positive family history

♦ Unusual site of thrombosis (CSVT, Mesenteric or Portal vv)

♦ Reccurrent early pregnancy fetal loss (APLA)

♦ Late, 2nd or 3rd trimester fetal loss

♦ Neonatal purpura fulminant (PC, PS) / Skin necrosis

The “threshold” concept

Slide Number 1Slide Number 2Slide Number 3תיאור מקרהModified Well’s criteria Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19תיאור מקרהSlide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30ATTRACT studySlide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36תיאור מקרהDiagnosis of PESlide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44Slide Number 45תיאור מקרהSlide Number 47Slide Number 48Diagnosis of PEDiagnosis of PESlide Number 51Slide Number 52Slide Number 53Slide Number 54Slide Number 55Slide Number 56Slide Number 57Slide Number 58Slide Number 59Slide Number 60Slide Number 61Slide Number 62Slide Number 63Slide Number 64Slide Number 65Slide Number 66Slide Number 67Slide Number 68Slide Number 69Slide Number 70Slide Number 71Slide Number 72Slide Number 73Slide Number 74Slide Number 75Slide Number 76Slide Number 77Slide Number 78Slide Number 79Slide Number 80Slide Number 81Cancer associated thrombosis (CAT) is uniqueSlide Number 83Cancer patientsCancer patientsCancer patientsCancer patients �Cancer-associated theombosis (CAT)Edoxaban - CATCancer patientsSlide Number 90Slide Number 91Slide Number 92Venous FunctionValve ThrombosisCirculatory StasisSlide Number 96Padua Score Slide Number 98Slide Number 99Slide Number 100Slide Number 101Slide Number 102Slide Number 103Slide Number 104Slide Number 105Slide Number 106Slide Number 107Slide Number 108Slide Number 109Thrombophilia Slide Number 111Slide Number 112Inherited Thrombophilia Slide Number 114Slide Number 115Slide Number 116Slide Number 117Slide Number 118Slide Number 119Slide Number 120Slide Number 121Slide Number 122Slide Number 123