Idiopathic DVT: How long to treat? Population-based or Personalized

Marc Zumberg Associate Professor

Division of Hematology/Oncology March 2012

Disclosures

•  Consultant –  Johnson and Johnson Pharmaceuticals

•  Speakers bureau and Consultant – Amgen – GlaxoSmithKline

Goals

•  Understand the complexities of decision making concerning length of therapy for idiopathic DVT

•  Understand the risks for recurrent VTE, as well as bleeding

•  Understand the potential benefits of a personalized, risk adapted approach to decision making

Facts •  Incidence of venous thrombosis 1-3/1000/yr

–  Common in elderly, nearly 1%/yr –  1 in 20 individuals experience a VTE in their lifetime

•  One person is diagnosed with a blood clot every minute –  900,000 cases/year in USA –  60,000-300,000 fatalities per year

•  40% of cases are considered idiopathic –  Initial thromboembolic event is the strongest single

predictor for recurrent VTE Rosendall. Hematology. 2005

Bauer. JAMA. 2011. 305 Rodger. Blood Reviews. 2010:171-8

www.clotconnect.org

Recurrence risk is greatest with an idiopathic VTE

Idiopathic

Other risks Surgery

Surgery

Baglin T. Lancet. 2003 Aug 16;362(9383):523-6

Prandoni, P. et al. Haematologica 2007;92:199-205 Goldhaber. Circulation. 2011;123:664-7

Incidence of recurrent thromboembolism in patients with idiopathic (unprovoked) and secondary VTE

Boutitie F et al. BMJ 2011;342:bmj.d3036 ©2011 by British Medical Journal Publishing Group

Incidence of recurrent thromboembolism in patients

with idiopathic (unprovoked) and secondary VTE

Pooled patient date from 7 studies comparing recurrence rates of provoked vs. idiopathic VTE

Case •  51 year-old previously healthy male seeks consultation

for anticoagulation recommendations

–  Idiopathic femoral vein clot and has completed 3 months of warfarin

–  Tolerating well with mostly therapeutic INR values –  No prior or family history of thrombosis –  Up to date on PSA testing and colonoscopy –  Nl cbc, electrolytes, LFTs

Do I need to stay on this medicine ??

Risks versus Benefits

Patient Preference

Clotting Bleeding

Risks versus Benefits

Clotting Bleeding

1-12% per year and highest in the first 3 months -rate of ICH approx 1%/yr

Case fatality rate of approx 10-13% Bleeding rates are decreased after the first 3 months

Recurrence rate in the first year 5-15%

Recurrence rate at 8 years approx 45%

Case fatality rate approx 4-12%

Coumadin decreases risk by 80-90%

Goldhaber, Circulation. 2011; 123:664-7

Rodger. Blood Reviews 24. 2010: 171-8

Kearon. J Thromb Thombolysis, 2011. 31:295-300

Bounameaux. Hematology 2008. 252-8

Length of Therapy

Bauer. JAMA. 2011. 305 (13): 1336-45

Long term anticoagulant therapy may simply delay recurrence compared to short

term therapy

Idiopathic DVT: A chronic disease Length of Therapy

•  3 months of anticoagulation better then < 3 months •  3 months no worse than 6-12 months

– Treats acute episode optimally – Recurrence rate is high whenever anticoagulation is

stopped

•  The real question should be 3 months vs. indefinite anticoagulation

Kearon. J Thromb Thrombolysis 2011. 31:295-300

Population based guidelines: ACCP 2004-2012

Bounameaux. Hematology. 2010: 252-258 Kearon. Chest. 2008 Jun;133(6 Suppl):454S-545S. Guyatt. Chest. 2012 141(2): 22S

This recommendation attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy.

Bauer. Hematology. 2010. 210-215

ECASA

Risk factors for recurrent VTE

•  Male gender •  Obesity •  PE vs. DVT, proximal vs. distal •  Elevated D-dimer after discontinuing

anticoagulation •  Failure to recanalize leg veins •  Thrombophilia •  Family History

Goldhaber. Circulation. 2011; 123:664-7

Gender

McRae. Lancet. 2006; 368(9533):371-8

Gender

Douketis. BMJ. 2011. 342. preprint

Location

Douketis. Am J Med. 2001. 110:515-9 Donadini Thrombolysis 2011. 31:301-5 Bauer. Hematology. 2010. 210-215

Patients with symptomatic PE are 3X more likely to recur with PE than DVT

Eichinger, S. et al. Arch Intern Med 2008;168:1678-1683.

Kaplan-Meier estimates of the risk of recurrent venous thromboembolism in patients according to categories of body mass

index (BMI)

HR-1.6 (95% CI, 1.1-2.4) (P = .02) among obese individuals

D-dimer: PROLONG Study

Palareti G. N Engl J Med. 2006 Oct 26;355(17):1780-9.

D-dimer: Meta-analysis

Douketis J. Ann Intern Med. 2010 Oct 19;153(8):523-31

D-dimer and Recurrence

Bauer, K. A. JAMA 2011;305:1336-1345

• 7 studies • 1888 patients • All completed at least 3 months of anticoagulation

Thrombophilia

Among patients with first episode of idiopathic DVT approximately 50% have an identifiable

inherited thrombophilic disorder

Cushman, Hematology. 2005 (1) 452

Christiansen, S. C. et al. JAMA 2005;293:2352-2361.

Recurrence Rates for Prothrombotic Laboratory Abnormalities in 474 Patients

Ho, W. K. et al. Arch Intern Med 2006;166:729-736.

Risk of recurrent venous thromboembolism (VTE) and heterozygous factor V Leiden (FVL) vs no FVL in reviewed

studies

Ho, W. K. et al. Arch Intern Med 2006;166:729-736.

Risk of recurrent venous thromboembolism (VTE) and heterozygous prothrombin G20210A vs no G20210A in

reviewed studies

Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis

of the lower limbs: The extended DACUS study

Siragusa. American Journal of Hematology 2011 . 86(11). 914-917

Recurrences, no. per 100 person-years: 10.4 (RVT) vs. 1.4 (no RVT)

Residual Thrombosis: a systematic review and meta‐analysis

Carrier M. J Journal of Thrombosis and Haemostasis 2011. 9(6): 1119-1125

Eichinger, S. et al. Circulation 2010;121:1630-1636

Nomogram to compute risk scores and estimate cumulative rates of recurrent VTE

Most important per model Male sex Location of VTE Elevated D-dimer

Rodger, M. A. et al. CMAJ 2008;179:417-426 Donandini. J Thromb Thombolysis 2011. 31:301-5

Risk of recurrent VTE 1.6%/year

Don’t forget bleeding risk

20,000 consecutive patients with acute VTE Higher predicted bleeding risks than previously mentioned values

Bounameaux. Hematology. 2010: 252-258 Ruiz-Gimenez. Thromb Haemost. 2008; 100:26-31

20% low risk, 74% intermediate, 6% high risk

Don’t Forget About Bleeding Risk

Beyth. Am J Med. 1998 Aug;105(2):91-9.

Case •  51 year-old previously healthy male seeks consultation for

anticoagulation recommendations –  Idiopathic femoral vein clot 3 months prior –  Tolerating warfarin well with mostly therapeutic INR values –  No prior or family history of thrombosis –  Up to date on PSA testing and colonoscopy –  Nl cbc, electrolytes, LFTs

•  Additional testing – D-dimer 620 ug/L – Repeat doppler showed resolution of DVT – No thrombophilia testing performed

Case VTE recurrence risk-7% in

first year Bleeding risk- 0.3-2%% in first 3

months

For this patient, continued anticoagulation might be preferred

Conclusions •  Idiopathic VTE is a chronic condition

– Risk of recurrence remains after discontinuation of anticoagulation

– Treat for 3 months at a minimum – Consider indefinite anticoagulation based on:

•  VTE recurrence risk •  Bleeding risk •  Patient preference

•  New oral anticoagulants may change the paradigm •  Extended ECASA therapy may be an option

ASH 2011. Abstract 543

Personalized Medicine: A rational risk adapted approach

Kearon J Throm Haem. 7(suppl 1) 296-300

Computer generated risk assessments ??

What are the benefits of genetic testing

•  Subset of patients are at higher risk for recurrent VTE –  Anticoagulation will substantially reduce this risk –  Testing can help reduce the bleeding risk for those at low risk

•  Improved patient understanding of thrombosis –  Increased understanding improves QOL –  Better done in specialized thrombosis clinics

•  Affords the opportunity for family testing –  Controversial –  Most important to young females considering OCT or pregnancy

Middeldorp. J Thromb Thrombolysis. 2001. 31:275-81

Arguments against genetic testing •  Laboratory error/false diagnosis

–  Protein C, Protein S, AT-III

•  Psychological effects

•  Insurance Issues

•  Often does not change treatment recommendations

–  Idiopathic cases may be anticoagulated long-term no matter what the results

–  Strong reversible provocation likely will receive finite anticoagulation no mater the results

–  Anyone with an initial VTE should receive aggressive prophylactic anticoagulation with all future risks

Middeldorp. J Thromb Thrombolysis. 2011. 31:275-81