Deep Venous Thrombosis Anthony J. Comerota, MD, FACS, FACC OVERVIEW (…of treatment) Anthony J. Comerota, MD, FACS, FACC Director, Jobst Vascular Center Adjunct Professor of Surgery, University of Michigan

Anthony J. Comerota, MD, RVT DISCLOSURES Anthony J. Comerota, MD, RVT Consulting Fees Aastrom, Cook Medical, Covidien, Bristol-Myers Squibb, sanofi-aventis U.S. LLC, Talecris Biotherapeutics, Inc. Honoraria Bristol-Myers Squibb, Covidien, Otsuka, sanofi-aventis U.S. LLC, Servier, ZymoGenetics Grants/Contracted Research Aastrom Biosciences, Inc., Abbott Vascular, Baxter Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, BSN, Colorado Prevention Center, CVRx, ev3, Inc., Lombard Medical, Medtronic CardioVascular, Inc., National Institutes of Health, Pfizer, sanofi-aventis U.S. LLC, Schering-Plough Corp. / Merck & Co., Inc., Talecris Biotherapeutics, Inc.

Acute Deep Venous Thrombosis - Treatment - Not all DVTs are the same!

Acute DVT Management ACCP 2008 Initial anticoagulation Immobilization Duration of anticoagulation Intensity of long-term anticoagulation Compression stockings

Early Anticoagulation Long-Term Anticoagulation Acute DVT ACCP 2008 Early Anticoagulation “Initial Treatment” Objectives Prevent: • Thrombus extension • Embolization • Recurrent DVT Early Late Long-Term Anticoagulation Objectives • Reduce recurrence

Importance of Early Therapeutic Rx Acute DVT Importance of Early Therapeutic Rx Recurrent VTE* PTT <1.5x (24 hrs.) 24.5% (15:1) PTT >1.5x 1.6% <0.001 * • most occur > 4 weeks, • association with poor initial response not appreciated by attending MDs Hull, RD et al NEJM 1990

Duration of Initial Heparin Acute DVT Background: Anticoagulation Duration of Initial Heparin Two randomized trials: Proximal DVT Result IV UFH x 5-7 days is as effective as IV UFH x 14 days… …provided adequate long-term anticoagulation Gallus A S et al Lancet 1986;2:1293 Hull R D et al NEJM 1990;322:1260

Initial Anticoagulation Acute DVT Background: Anticoagulation Initial Anticoagulation SQ LMWH (Grade 1A) IV UFH (Grade 1A) Monitored SQ UFH (Grade 1A) Weight adjusted SQ UFH (Grade 1A) SQ Fondaparinux (Grade 1A) …at least 5 days overlap with VKA, and …INR ≥ 2.0 for 24 hours 2008 Kearon C et al CHEST 2008;133:4545

Anticoagulation…how long? Acute DVT Duration of Anticoagulation Anticoagulation…how long? Studies have shown… …the longer the better!

Anticoagulation for DVT 4 Weeks vs. 3 Months: Study Design 406 Proximal DVT (venogram) 3 mos. better than 4 weeks 4 Weeks Anticoagulation IPG Positive (N=192) Negative (N=214) All patients receiving 3 months of anticoagulation who had recurrence had continuing risk factors Anticoagulation (8 Weeks) Randomize Placebo (N=105) Anticoag x 8 Wks (N=109) Recurrence @ 8 wks @ 11 mos 8.6% 11.5% vs. 0.9% 6% P =.009 P =.3 Levine MN et al Thromb Haemost 1995; 74: 6061

Anticoagulation for VTE 6 Weeks vs. 6 Months: Study Design Multicenter, randomized trial 1st episode VTE (DVT-790; PE-107) 6 weeks vs. 6 months oral anticoagulation Endpoints: Recurrence @ 2 yrs Bleeding Schulman S et al NEJM 1995; 332:1661

Anticoagulation for VTE 6 Weeks vs. 6 Months: Results at 2 Years Odds Ratio Recurrence P-Value All 18.1% 9.5% 2.1 <.001 6 mos. better than 6 weeks Month 0-1.5 0.7% 0.9% — — Month 1.5-6 9.5% 0.4% — — Month 6-24 7.9 8.1 — — Major Bleed 0.2 1.1 0.2 0.23 Schulman S et al NEJM 1995; 332:1661

3 mos vs. Indefinite Anticoagulation Anticoagulation for Acute DVT Duration of Warfarin: Randomized Trial 3 mos vs. Indefinite Anticoagulation Study Stopped @ Interim Analysis! Percent per Patient Year Endpoint 3 Mos >1 Year RRR P-value Recurrent VTE 24.1 1.3 95% <0.001 Major Bleed 3.8 - 0.09 (non-fatal) Indefinite better than 3 months (more bleeding) Kearon C et al NEJM 1999;340;901

Low-Intensity vs. Placebo Acute DVT Intensity of Anticoagulation Low-Intensity vs. Placebo Long-Term Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism (INR 1.5 - 2.0 vs. Placebo) Ridker PM, Goldhaber SZ, Danielsen E, et al and the PREVENT Investigators New England Journal of Medicine 2003; 348:15

Intensity of Anticoagulation Acute DVT Intensity of Anticoagulation Placebo (n = 253) Warfarin (n = 255) RRR P-value Recurrent DVT Major Bleed Death Composite 14.6% 0.8% 0.32% 16.2% 5.5% 1.9% 0.16% 8.6% 62% -253% 50% 48% <0.001 0.25 0.26 0.01 Indefinite low-intensity anticoagulation better than 3-6 months for idiopathic VTE Ridker PM, et al NEJM 2003; 348:15

Low-Intensity vs. Conventional Acute DVT Intensity of Anticoagulation Low-Intensity vs. Conventional Randomized, blinded study 738 pts - 1st unprovoked VTE Randomized after 3 months anticoag. Low-intensity – INR 1.5-1.9 Conventional – INR 2.0-3.0 Endpoints: Recurrence Death Bleeding Follow-up 2.4 yrs Kearon et al NEJM 2003;349:631

Low-Intensity vs. Conventional Acute DVT Intensity of Anticoagulation Low-Intensity vs. Conventional Results @ 2.4 yrs No/100 person yr Low (N=369) Conventional (N=369) Hazard Ratio P-value Recurrent VTE 1.9 0.7 2.8 0.03 Death 1.9 0.9 2.1 0.09 Major bleed 1.1 0.9 1.2 0.76 Kearon et al NEJM 2003;349:631

Duration of Anticoagulation Acute DVT: First-Time DVT ACCP 2008 Duration of Anticoagulation Transient risk: Recommend VKA for 3 mos. over shorter periods (Grade 1A) Unprovoked DVT: VKA for at least 3 mos. (Grade 1A)…then eval. for risk/benefit of continued Rx (1C) Isolated distal DVT, rec. 3 mos. (2B) For proximal DVT in patients at low risk for bleeding, rec. “long-term” (1A) 2008 First Slide after Title Slide only (or first slide with title)! Use only once. Kearon C et al CHEST 2008;133:4545

Acute DVT: Unprovoked DVT CHEST 2008 VKA to target INR – 2.5 for all treatment durations (Grade 1A) For patients with strong preference for less INR testing after 1st 3 mos., rec. low-intensity [INR 1.5 - 1.9] over stopping VKA (Grade 1A) Recommend “against high-intensity” VKA therapy [INR 3.1 - 4.0] (Grade 1A) 2008 First Slide after Title Slide only (or first slide with title)! Use only once.

Acute DVT : Recurrent (Unprovoked) Duration of Anticoagulation 6 Months vs. Indefinite Results @ 4 yrs 6 mos (N=111) Indefinite (N=369) RR P-value Recurrent VTE 21% 3% 8.0 <.001 Death 14% 9% 1.7 0.21 Major bleed 3% 9% 0.3 0.0084 Schulman S et al NEJM 1997;336:393

Duration of Anticoagulation Acute DVT: Recurrent (Unprovoked) ACCP 2008 Duration of Anticoagulation For Recurrent DVT Recommend long-term, indefinite Rx (Grade 1A) For patients on long-term Rx, reassess risk/benefit at periodic intervals 2008 First Slide after Title Slide only (or first slide with title)! Use only once. Kearon C et al CHEST 2008;133:4545

LMWH vs. Coumadin: Results VTE in Cancer Patients LMWH vs. Coumadin: Results Dalteparin (N=338) Coumadin (N=338) Hazard Ratio P-Value Recurrent VTE 8% 15.8% 0.48 0.002 Major Bleed 6% 4% ― 0.27 Mortality 39% 41% ― 0.53 Lee AY et al NEJM 2003;349:146

Acute DVT: Cancer CHEST 2008 DVT and Cancer 2008 Recommend LMWH for the first 3 - 6 mos. (Grade 1A) Recommend subsequent Rx with VKA or LMWH indefinitely or until cancer is resolved (Grade 1C) 2008 First Slide after Title Slide only (or first slide with title)! Use only once.

Acute DVT ACCP 2008 DVT and Ambulation 2008 Recommend early ambulation in preference to initial bed rest (Grade 1A) 2008 First Slide after Title Slide only (or first slide with title)! Use only once. Kearon C et al CHEST 2008;133:4545

Immobilization vs. Ambulation Acute DVT ACCP 2008 Immobilization vs. Ambulation Randomized trials (N=5) Observational studies (N=3) Result Early ambulation with compression shows: 1. Faster resolution of pain 2. More rapid resolution of swelling 3. No increased risk of PE Kearon C et al CHEST 2008;133:4545

Postthrombotic Syndrome Acute DVT: Compression Stockings ACCP 2008 Randomized Trials Lancet 1997;349:759 <.01 51% 24% 49% 55% 21% 47% P-value RRR Stocking Control Postthrombotic Syndrome Prandoni P (N=194) (N=170) Patho Hemst Thromb 2002;32(suppl 2):72 Brandjes DP

Compression Stockings Acute DVT: Compression Stockings ACCP 2008 Compression Stockings “…we recommend the use of an elastic compression stocking with an ankle gradient of 30-40mmHg pressure…for a minimum of 2 years” …GRADE 1A… 2008 First Slide after Title Slide only (or first slide with title)! Use only once.

Acute DVT ACCP 2008 Summary More aggressive recommendations for management of acute DVT…strategy of thrombus removal Emphasize need for: Early therapeutic anticoagulation Long-term anticoagulation for unprovoked DVT and cancer patients Good compression (30-40mmHg) Early ambulation 2008 First Slide after Title Slide only (or first slide with title)! Use only once. Kearon C et al CHEST 2008;133:4545

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