Venous thrombosis, Manifestations, Diagnosis and

TherapySam Schulman, MD

Incidence of VTE

Estimated to affect 350,000 to 600,000 Americans annually

Contributing to at least 100,000 deaths per year

Will increase with ageing population

Incidence by race

0

50

100

150

200

250

300

Race

WhiteAfrican AmericanHispanicAsian/Pacific

Idiopathic DVT per 1,000,000 older than 18

White RH. Ann Intern Med 1998

Copyright 2003 American Heart Association

White, R. H. Circulation 2003;107:I-4-I-8

Annual incidence of VTE among residents of Worcester MA 1986, by age and sex

Age

Sex

Worcester: No signif difference Young age: more women; old age: more

men (Silverstein and others) California database: women 78 and men 63

per 100,000

Copyright 2001 BMJ Publishing Group Ltd.

Boulay, F. et al. BMJ 2001;323:601-602

Seasonal variation

Metabolic syndrome Of all components in the metabolic

syndrome abdominal obesity is the only component significantly associated with VTE (LITE-study and Troms Study)

Steffen LM et al. J Thromb Haemost 2009;7:746-51. Borch KH et al. J Thromb Haemost 2009;7:739-45.

HRT on the other hand

The Netherlands

Trends in different age categories

USA

Hersh AL et al. JAMA 2004;291:47-53Faber A et al. Br J Clin Pharmacol 2005;60:641-7)

And smoking

Danish registry study 1993-97 (n=57,000) with adjustments for sex, alcohol, BMI, physical activity and HRT.

HR females: 1.52 (95% CI, 1.15-2.00) HR males: 1.32 (95% CI, 1.00-1.74)

Severinsen MT et al. J Thromb Haemost 2009;7:1297-1303

Incidence of DVT and PE

0

10

20

30

40

50

60

70Pe

rcen

t

No autopsy Autopsy

DVTPE

White RH. Circulation. 2003;107:I-4

Unprovoked or provoked

Mateo J. Thromb Haemost 1997Cushman M. Thromb Haemost 2001Heit JA. Arch Intern Med 2002White RH. Circulation 2003

01020304050607080

EMETstudy

Cushman Olmsted California

UnprovokedProvoked

Hospitalized vs outpatient

Worcester community-based study: 1,897 with validated VTE.

73.7% developed VTE as outpatients. 27% occurred in patients already hospitalized for

other disease.

Spencer FA. Thromb Haemost 2008 & 2009.

Thrombophilia and riskDefect Antithrombin Protein C Protein S FVL FII mut

Prevalence, %

0.02 0.4-4.0 0.7-2.3 2-10 2-4

Risk for VTE

10 4-5 4-5 4-5 3-4

Thrombo-phlebitis

Not ?

Homozy-gote form

Often lethal Neonatal purpura fulminans Risk for VTE x 30-140

Risk for VTE is moderate

Prevalence of VTE is predicted to double by 2050

VTE = venous thromboembolismDeitelzweig SB et al. Am J Haematol 2011;86:21720

15

YearVTE cases per 100 000:

2002

2003

2004

2005

2006

2008

2010

2015

2020

2025

2030

2035

2040

2045

2050

317

341

371

401

422

426

432

453

478

505

527

544

556

563

567

Adu

lts 1

8 ye

ars

and

olde

r with

VTE

in U

SA (m

illio

ns)

0

0.5

1

1.5

2

2002 2003 2004 2005 2006 2008 2010 2015 2020 2025 2030 2035 2040 2045 2050

Typical case

36 y.o. lady with pain in the R calf x 3d Previously healthy Went for a long walk last weekend Was on COC for 10 years, stopped at age

28, restarted 3 months ago. Physical: Tender calf, no edema or SOB

DVT most common symptoms

Deep leg pain Unilateral swelling Increased temperature, tenderness, redness Phlegmasia cerulea dolens

Severe pain, cyanosis Phlegmasia alba dolens

Severe pain, edema, pallor

Reduction of imaging diagnostics Use Wells score and D-dimer

Only if low score + neg D-dimer will result in No imaging

D-dimer: Not useful In generally ill patients Shortly after surgery Differential vs cellulitis Very elderly (>80) Long duration of symptoms

Reduction of imaging diagnostics Use Wells score and D-dimer

Only if low score + neg D-dimer will result in No imaging

D-dimer: Not useful In generally ill patients Shortly after surgery Differential vs cellulitis Very elderly (>80) Long duration of symptoms

Active cancer 1Paralysis, recent immob 1Recently bedridden >2 d 1Localized tenderness 1Calf swelling >3 cm 1Unilat pitting edema 1Collateral superf. veins 1Previous documented DVT 1Alt. Dx at least as likely -2

2 p likely

Analysis of 5 studies of sympt calf DVT without treatment (Rhigini et al 2006): Progression proximally in 25 of 353 (7%)

RCT whole leg vs. 2-point CUS in patients with non-low clin probability or D-dimer

Whole-leg 2-pointN 257 264DVT on CUS 99 (38%) 59 (23%)

VTE during 3 months

2 (1.2%) 4 (2.0%)

Gibson NS, et al. J Thromb Haemost. 2009;7:2035-2041.

Do we have to treat distal DVT?

PE most common symptoms

Pleuritic pain 65% Dyspnea 20% Syncope 10% Hemoptysis fewDifferentialsRTI, MI, pericarditis, musculoskeletal

disorders

Suspected PEWells clinical prediction score for PEPrevious PE or DVT +1.5Heart rate > 100/min +1.5Recent surgery or immobilization +1.5Clinical signs of DVT +3Alternative diagnosis less likely than PE +3Hemoptysis +1Cancer +1Dichotomized ruleUnlikely < 4Likely > 4

Wells PS et al. Thromb Haemost. 2000;83:416-20

Clinical probability assessment

Low orintermediate High

Ddimer

Below cutoff Abovecutoff

CUS1 orMDCTA 2

Negative 3 Positive

Noanticoagulanttherapy Anticoagulanttherapy

Can my PE-patient in ER go home?

Pulmonary Embolism Severity Index (PESI) Age 1 p / yr SBP 110 20 p Cancer 30 p RR>30 20 p CHF 10 p Temp

Simplified PESI Retrospective analysis of RIETE registry

Age >80 1 p History of Cancer 1 p Chron cardiopulmonary dis. 1 p Pulse >110 1 p SBP

Simplified PESI result

Jimnez D et al. Arch Intern Med. 2010;170:1383-9

Generally same treatment for DVT and PE (=VTE): UFH iv weight adjusted (bolus 80 U/kg,

infusion at 18 U/kg/h)* UFH s.c. 250 U/kg bid* UFH s.c. 17,500 U bid* UFH s.c. 333 U/kg 1st dose, then 250 U/kg bid

without monitoring LMWH s.c. without monitoring Fondaparinux s.c. 7.5 2.5 mg daily Rivaroxaban 15 mg BID x 3 w, then 20 mg/d

* Monitored to keep anti-Xa at 0.3-0.7 IU/mL at 6 h for s.c. 1B

Initial standard anticoagulation

FIDO-Study

Copyright restrictions may apply.Kearon C, et al. JAMA. 2006;296:935-942.

Clinical Outcomes During the Study Period

UFH 250 U/kg bid vs LMWH 100 IU/kg bid

Event UFH LMWH

Recurrence 3.8% 3.4%

Maj Bleed 1.7% 3.4%

Any Bleed 8.3% 8.5%

Death 5.2% 6.3%

FIDO protocol vs. severe RF

CrCl 30 mL/min 1st dose = 333 IU/kg Then 250 IU/kg q 12 h

CrCl

Is LMWH the best treatment?Meta-analysis of 23 studies

Outcome Studies Odds ratio 95% CIVTE overallRecurrenceInitial treatment period 15 0.68 0.48-0.97At 3 months 13 0.68 0.53-0.88At 6 months 6 0.68 0.48-0.96At end of follow-up 18 0.68 0.55-0.84Major hemorrhage 19 0.57 0.39-0.83Death at end of F-U 18 0.76 0.62-0.92Proximal DVT aloneRecurrence at end of F-U 9 0.57 0.44-0.75Major hemorrhage 8 0.50 0.29-0.85Death 8 0.62 0.46-0.84

van Dongen CJ, et al. Cochrane Database Syst Rev. 2004;CD001100. 2B

Fondaparinux an alternative ?Primary efficacy outcome - 3 mon

Fondaparinux (N=1098) LMWH (N=1107)Matisse DVTFatal PE 5 (0.5 %) 5 (0.5 %) Non-fatal PE or DVT 38 (3.5 %) 40 (3.6 %)Total symptomatic recurrent VTE 43 (3.9 %) 45 (4.1 %)

-0.15 % = 3.5%0 1.5%-1.8%

Fondaparinux - LMWH (95 % CI )

AT

I S SE

M ... .

. ..

Dose: 7.5 mg s.c. daily100 kg: 10 mg

Fondaparinux

LMWH 1.2%

1.1%

3.0%

2.6%

0% 2% 4% 6% 8%

Major Bleeding Non-major Bleeding

3.7 %

4.2 %

Primary safety outcome - initially

1A

T 17 h, longer with renal function

Extensive acute proximal DVT Symptoms 1 year

Low risk of bleeding Expertise and resources available Can reduce acute symptoms and risk of post-thrombotic syndrome

2C

Catheter-directed thrombolysis

The CaVenT study

200-patient RCT with 2-y follow-up Interim surrogate endpoint data published Outcome Cath Standard PN= 50 53Iliofem patency 64% 35.8% .004Venous obstruction 20% 49.1% .004Femoral insuffic 60% 66% .53

Enden T, et al. J Thromb Haemost. 2009;7:1268-1275.

Of 91 in the intervention (PEVI) group, 33 (36%) received thrombolytic therapy via catheter.

Main outcomes at 6 months:

PEVIn=88

Controln=81

P-value

DVT 2 8* 0.04Nonfatal PE

0 3* 0.07

Fatal PE 0 1* 0.3PTS 3 22

CDT/PEVIn=178

Controln=180

P-value

CaVenT 37 55 0.047

TORPEDO 3 22

Follow-up after CDT Balloon-angioplasty and stent for

underlying lesion Alternative to CDT is Pharmacomechanical

Thrombolysis Shortens treatment time

2C

Standard duration of anticoagulation is now 3 m.

Schulman S, et al. N Engl J Med. 1995;332:1661-1665.Kearon C, et al. N Engl J Med. 1999;340:901-906.

6 months? 27 months?

1B

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WODITThis image cannot currently be displayed.

Agnelli, G et al. N Engl J Med. 2001;345:165-169.

No. at risk

Dabigatran 150 mg bid

681 667 651 591 557 503 186

Matching placebo 662 615 586 537 502 461 171

Cumulative Risk of VTE or Unexplained Death

0

2

4

6

8

10

12

0 3 6 9 12 15 18Months since randomization

Estim

ated

cum

ulat

ive

risk

(%)

Treatment period Post-treatment follow-up

Dabigatran 150mg bidMatching placebo

RE-SONATE

Schulman S, et al. N Engl J Med. 2013;368;709-718.

Recurrent DVT after stopping

Patients with unprovoked DVT 3 months Rx 10% first year after (WODIT) 6 months Rx 10% first year after (DURAC) 12 months Rx 10% first year after (WODIT) 24 months Rx 10% first year after (LAFIT)

No difference 3 vs 6 months in patients with proximal DVT or PE in DOTAVK

Pinede L, et al. Circulation. 2001;103:2453-2460.

Decision on long-term at 3 m Long-term treatment for

Unprovoked VTESecond episodeCancer

Unless bleeding risk or adequate monitoring unavailable

2B

Suggestions for duration of VKA

Proximal DVT and permanent risk or PE

3 m 6 m 12 m 24 m Indefinitely

Bleeding, Poorcompliance

Old ageNeeds ASAFemale?

Mildthrombophilicdefect /Second VTE

Third VTE or more,Severe thrombophilia,Severe venous insuff.,Pulmonary hypertension

Patient preferences

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Elevated D-dimer

Management strategy unprovoked VTE

Dx

0 3-6 m +1 m

D-dimer

Pos

Neg Pos 8.9%/yr

Neg Neg 3.5%/yr

Verhovsek M. Ann Intern Med. 2008;149:481-490. Cosmi B, et al. Blood. 2010;115:481-488.

+3 m

Neg Neg Pos 27%/yrNeg Neg Neg 2.9%/yr

D-dimer not in males?

Several studies indicate that males have despite normalization of D-dimer a higher risk of recurrence.

Recurrent VTE after neg-neg D-dimer Men 9.7% Women & no estrogen 5.4% Women with estrogen Rx 0.0%

McRae S et al. Lancet 2006;368:371-8Kearon C et al. ISTH 2013

Recurrences Recurrence rate adds up to about 30% after

8-10 years (Prandoni et al, Heit et al, Schulman et al.)

Prandoni P. Ann Intern Med 1996.Heit JA. Arch Intern Med 2000Schulman S. J Thromb Haemost 2005.

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Index event = DVTN=790

Index event = PEN=107

The DURAC I trial, Sweden 1988-2001Schulman et al. J Thromb Haemost 2006;4:734-42.Murin S. Thromb Haemost 2002.Douketis JD. JAMA 1998

Site of recurrent VTE

Case-fatality

During short-term follow-up 50-100% higher if initial PE.

After discontinuation of Rx: case fatality 3.8 9% (definite-probable vs any fatal PE) or 0.2-0.5 events/100 person-years.

Rates depend on autopsy routines.

Douketis J. Ann Intern Med 2007;147:766-74.

Duration of follow-up and PTSThis image cannot currently be displayed.This image cannot currently be displayed.

Severe PTS 6-week gr 6-mo gr OR (95% CI)Class 5-6 17 (4.2) 16 (3.8) 1.12 (0.57-2.22)

Conclusions

VTE is an increasing problem Several risk scores and risk stratification tools are

available and should be used Diagnostic algorithm for DVT/PE is helpful Many options for treatment of VTE exist Decide at 3-6 months regarding stopping or

indefinite anticoagulation

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