Controversies in Anticoagulation and …impak.sgim.org/userfiles/file/AMHandouts/AM05/handouts/...Controversies in Anticoagulation and Thromboembolism Amir Jaffer, MD Scott Kaatz,

Controversies in Anticoagulation and Thromboembolism Amir Jaffer, MD Scott Kaatz, DO

This pre-course is conducted by members of the Anticoagulation/Thromboembolism Interest Group. We hope that the interactive format will spur audience discussion. We are fortunate to have many leaders and world experts in this field involved to help us improve the care of our patients. Summary: • Orthopedists disagree on how long hip arthroplasty patients should receive

postoperative Venous Thromboembolism (VTE) prophylaxis. • Intensivists differ on which patients with pulmonary embolism should be treated with

thrombolysis. • Hospitalists are sometimes uncertain of the optimal duration of warfarin therapy for

patients with idiopathic DVT. • Hematologists debate on which patients need a hypercoagulable work-up in patients

with venous thromboembolic disease. • Cardiologists vacillate regarding which patients with atrial fibrillation should be

anticoagulated. Out of this chaos of multiple specialties managing different aspects of thromboembolic disease comes the critical role of general internists both inside the hospital and in their practices to orchestrate the care of their patients. Five brief cases representing these controversies will be presented during this precourse. Each case will be followed by a query of the audience by the facilitator for their opinions and feedback regarding their position. Each case will then be followed by two presentations with each speaker presenting their position. The speakers are all members of the Anticoagulation and Thromboembolism Interest Group and the facilitators are senior members who will facilitate the discussion. This pre-course is designed to be very lively and highly interactive. Learning Objectives: 1. Be aware of the strength of evidence supporting new guidelines for the duration of

venous thromboembolism in patients undergoing hip replacement surgery. 2. Understand the limitations of the evidence for thrombolysis in patients with sub-

massive pulmonary embolism. 3. Become familiar with the considerable evidence to guide the duration of warfarin

therapy for patients with idiopathic venous thromboembolism. 4. Learn about the pitfalls in conducting a hypercoagulable work-up 5. Appreciate the tools available to internists to risk stratify patients with atrial

fibrillation to help them make an informed decision regarding anticoagulation.

Duration Topic Presenters

5 minutes Introduction/rules of engagement Scott Kaatz 2 minutes How long should prophylaxis be

used in patients undergoing hip replacement surgery? Query the audience.

Scott Kaatz

10 minutes 10 days Peter Kaboli 10 minutes 28 days Rich White 10 minutes Audience questions Scott Kaatz 2 minutes Should thrombolysis be used in

patients with sub massive PE? Query the audience.

Amir Jaffer

10 minutes Yes Tracy Minichiello 10 minutes No Pungi Dorasamy 10 minutes Audience questions Amir Jaffer 2 minutes How long should a patient with

idiopathic DVT be treated with warfarin? Query the audience.

Scott Kaatz

10 minutes 6 months Andrew Dunn 10 minutes Indefinitely Rebecca Beyth 10 minutes Audience questions Scott Kaatz 30 minutes Break 2 minutes Should a patient with idiopathic DVT

undergo a hypercoagulable work up? Query the audience.

Amir Jaffer

10 minutes Yes Matt Eisen 10 minutes No Doug Einstadter 10 minutes Audience questions Amir Jaffer 2 minutes A 64-year-old female patient with

atrial fibrillation and hypertension, would you anticoagulate? Query the audience.

Scott Kaatz

10 minutes Yes Steven Cohn 10 minutes No Brian Gage 10 minutes Audience questions Scott Kaatz 5 minutes Closing remarks Amir Jaffer

References How long should prophylaxis be used in patients undergoing hip replacement surgery? 1. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course

of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158:1525-31.

2. Heit JA, Elliott CG, Trowbridge AA, Morrey BF, Gent M, Hirsh J. Ardeparin

sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 2000; 132:853-61.

3. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent

venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. Patient Care Management 2001; 83-A:336-45.

4. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against

venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358:9-15.

5. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of

immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Archives of Internal Medicine 2003; 163:2518-24.

6. Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin

(enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. New England Journal of Medicine 1996; 335:696-700.

7. Silbersack Y, Taute BM, Hein W, Podhaisky H. Prevention of deep-vein

thrombosis after total hip and knee replacement. Low-molecular-weight heparin in combination with intermittent pneumatic compression. Journal of Bone & Joint Surgery - British Volume 2004; 86:809-12.

8. Best AJ, Williams S, Crozier A, Bhatt R, Gregg PJ, Hui AC. Graded compression

stockings in elective orthopaedic surgery. An assessment of the in vivo performance of commercially available stockings in patients having hip and knee arthroplasty. Journal of Bone & Joint Surgery - British Volume 2000; 82:116-8.

9. Anonymous. Prevention of pulmonary embolism and deep vein thrombosis with

low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295-302.

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White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998 Jul 27;158(14):1525-31. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000 Dec 14;343(24):1758-64. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003 Sep;90(3):446-55. White RH, Henderson MC. Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin Pulm Med. 2002 Sep;8(5):365-71. Should thrombolysis be used in patients with sub massive PE? Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism, A meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2002 Dec 9-23;162(22):2537-41 PMID: 12456225 Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. CHEST 1997;111:1241-1245. Goldhaber SZ. Thrombolysis in submassive pulmonary embolism. J Thromb Haemost. 2004 Aug;2(8):1473-4 PMID: 15304059 Meneveau N, Ming LP, Seronde MF, Mersin N, Schiele F, Caulfield F, Bernard Y, Bassand JP. In-hospital and long-term outcome after sub-massive and massive pulmonary embolism submitted to thrombolytic therapy.Eur Heart J. 2003 Aug;24(15):1447-54 PMID: 12909074 Konstantinides S. Thrombolysis in submassive pulmonary embolism? Yes. J Thromb Haemost. 2003 Jun;1(6):1127-9. PMID: 12871305 Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcome-based meta-analysis.Arch Intern Med. 2002 Dec 9-23;162(22):2537-41. PMID: 12456225

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Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002 Oct 10;347(15):1143-50. PMID: 12374874 Goldhaber SZ. Thrombolysis for pulmonary embolism.N Engl J Med. 2002 Oct 10;347(15):1131-2. PMID: 12374871 Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J.Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J AM Coll Cardiol. 1997;3-:1165-1171 PMID: 9350909 Goldhaber SZ, Visani L, De Rosa M.Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) Lancet. 1999 Apr 24;353(9162):1386-9. PMID: 10227218 Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism.Chest. 2004 Apr;125(4):1539-45. PMID: 15078772 The urokinase pulmonary embolism trial. A national cooperatieve study. Circulaiton 1973;47:108-111 Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993 Feb 27;341(8844):507-11. PMID: 8094768 Konstantinides S, Tiede N, Geibel A, Olschewski M, Just H, Kasper W. Comparison of alteplase versus heparin for resolution of major pulmonary embolism.Am J Cardiol. 1998 Oct 15;82(8):966-70. PMID: 9794353 Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, Iversen S, Redecker M, Kienast J, Just H, Kasper W. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.Circulation. 1997 Aug 5;96(3):882-8. PMID: 9264496

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Meneveau N, Ming LP, Seronde MF, Mersin N, Schiele F, Caulfield F, Bernard Y, Bassand JP. In-hospital and long-term outcome after sub-massive and massive pulmonary embolism submitted to thrombolytic therapy.Eur Heart J. 2003 Aug;24(15):1447-54. PMID: 12909074 Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation. 2003 Nov 4;108(18):2191-4. PMID: 14597581 La Vecchia L, Ottani F, Favero L, Spadaro GL, Rubboli A, Boanno C, Mezzena G, Fontanelli A, Jaffe AS. Increased cardiac troponin I on admission predicts in-hospital mortality in acute pulmonary embolism. Heart. 2004 Jun;90(6):633-7. PMID: 15145864 Blackmon JR, Sautter RD, Wagner HN et al. Urokinase Pulmonary Embolism Trial: Phase 1 results. JAMA 1970; 214: 2163-72 Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: Alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicentre study 2. J Am Coll Cardiol 1992; 20:520 Levine M, Hirsh J, Weitz J, et al. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest 1990; 98:1473 PIOPED Investigators. Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED Investigators. Chest 1990; 98: 1473-9 Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus Alteplase compared with Heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347: 1143-1150 Goldhaber SZ, Kessler CM, Heit JA, et al. Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicentre trial. J Am Coll Cardiol 1992; 20:24 Dalen JE The uncertain role of thrombolytic therapy in the treatment of pulmonary embolism [editorial]. Arch Intern Med. 2002;162:2521-2523 Goldhaber SZ, Haire WD, Feldstein ML et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing RV function and pulmonary perfusion. Lancet 1993;341: 507-11 Ribeiro A, Lindmarker P, et al. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 134: 479-87

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Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with aacute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000; 101: 2817 Vieillard-Baron A, Page B, Augarde R et al. Acute cor pulmonale in massive pulmonary embolism: incidence echocardiographic pattern, clinical implications and recovery rate. Intensive Care Med 2001; 27: 1481-6 Hamel E , Pacouret G, Vincentelli D, et al. Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation: results from a 128-patient monocenter registry. Chest 2001; 120: 120-5 Turpie AGG, Levine MN, Hirsh J, et al. Tissue plasminogen-activator versus heparin in deep venous thrombosis. Chest 1990; 97:172S Tapson VF, Witty LA. Massive pulmonary embolism: Diagnostic and therapeutic strategies. Clin Chest Med 1995; 16: 329-340 Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicentre registry. Circulation 1997; 96:882-8 Goldhaber SZ, Visani L, De Rosa M. Acute Pulmonary Embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) Lancet 1999; 353:1386-1389 Should a patient with idiopathic DVT undergo a hypercoagulable work up? Auerbach AD. Cost-effectiveness of testing for hypercoagulability and effects on treatment strategies in patients with deep vein thrombosis. Am J Med 2004; 116(12): 816-28 [PMID: 15178497] Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003 Aug 16;362(9383):523-6. [PMID: 12932383] Bauer KA, Rosendaal FR, Heit JA. Hypercoagulability: too many tests, too much conflicting data. Hematology (Am Soc Hematol Educ Program). 2002;:353-68. [PMID: 12446432] Bauer KA. The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications. Ann Intern Med 2001;135:367-373 [PMID: 11529700] Crowther MA. Congenital Thrombophilic States Associated with Venous Thrombosis: A Qualitative Overview and Proposed Classification System. Ann Intern Med 2003;138:128-134 [PMID: 12529095]

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Deitcher SR. Hypercoagulable state testing and malignancy screening following venous thromboembolic events. Vasc Med 2003; 8(1): 33-46 [PMID: 12866610] Feero WG. Genetic thrombophilia. Prim Care 2004; 31(3): 685-709, xi [PMID: 15331254] Greaves M, Baglin T. Laboratory testing for heritable thrombophilia: impact on clinical management of thrombotic disease annotation. Br J Haematol. 2000 Jun;109(4):699-703. [PMID: 10929018] Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Investigation and management of heritable thrombophilia. Br J Haematol. 2001 Sep;114(3):512-28. [PMID: 11552975] Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost. 1999 May;81(5):684-9. [PMID: 10365737] Murin S, Marelich GP, Arroliga AC, Matthay RA. Hereditary thrombophilia and venous thromboembolism. Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1369-73. [PMID: 9817680] Perry SL. Clinical and laboratory evaluation of thrombophilia. Clin Chest Med 2003; 24(1): 153-70 [PMID: 12685062] Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [PMID: 12601075] A 64-year-old female patient with atrial fibrillation and hypertension, would you anticoagulate? Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110(16):2287-92. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med. 2003;139(12):1009-17.

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Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349(11):1019-26. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in Collaboration With the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol. 2001;38(4):1231-66. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1 Suppl):108S-121S. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention. Ann Intern Med. 1999;131(9):688-95. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. Jama. 1999;281(19):1830-5. Monette J, Gurwitz JH, Rochon PA, Avorn J. Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. J Am Geriatr Soc. 1997;45(9):1060-5. Man-Son-Hing M, Laupacis A, O'Connor A, et al. Warfarin for atrial fibrillation. The patient's perspective. Arch Intern Med. 1996;156(16):1841-8. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford M. Validation of Clinical Classification Schemes for Predicting Stroke: Results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. Oct 19 2004;110:2287-2292. Go AS, Hylek EM, Chang Y, ...Singer D. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. Nov 26 2003;290:2685-2692. Caro JJ, Flegel KM, Orejuela ME, Kelley HE, Speckman JL, Migliaccio-Walle K. Anticoagulant prophylaxis against stroke in atrial fibrillation: effectiveness in actual practice. Cmaj. 1999;161:493-497. Birman-Deych E, Nilasena DS, Radford MJ, Gage BF. Real-World

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Effectiveness of Warfarin Therapy for Stroke Prevention in Medicare Beneficiaries of All Races. Poster session 3; poster #23.

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1

Extended Duration Prophylaxis after Hip Arthroplasty- Yes

RICHARD H. WHITE, MDPROFESSOR OF MEDICINE

UC DAVIS

Arguments:

• Hospitalization for THA is short (4-5 days).

• Most VTE cases become manifest after hospital discharge.

• Asymptomatic VTE can begin very late after discharge.

• Extended prophylaxis is effective.• Immobility-obesity contribute to

Arch Intern Med. 1998 Jul 27;158(14):1525-31 Time of VTE Outcomes after Total Hip Surgery

Primary Total Hip(N=19,586)

Outcome

133 (0.7%)During the initial hospitalization, n (%)

94 (0.5%)During rehabilitation hospitalization, n (%)

329 (1.7%)†Requiring readmission, n (%)

Thrombosis can Begin Late after Discharge

Among patients who had a negative venogram 7 to 10 days after total hip arthroplasty,

20% had a demonstrable clot 21 days later.

Planes A, et al. Lancet. 1996;348(9022): 224-8.

Extended Prophylaxis Is Needed

• Symptomatic VTE < 3 months of surgery was = 3.2%; 1.1% occurred while receiving prophylaxis in the hospital and 2.2% occurred during about 80 days of discharge (no prophylaxis)

• Fatal PE occurred in 0.1% of patients:0 04% while in the hospital and

Douketis, JD, Eikelboom, et al Short-duration prophylaxis against VTE: a meta-analysis investigating symptomatic outcomes. Arch Intern Med 2002;162

2

Extended Prophylaxis is Effective

• Extended prophylaxis reduced the frequency of

- Asymptomatic DVT by 51% from 19.6 to 9.6% - Symptomatic VTE by 62% from 3.3 to 1.3%- Symptomatic PE by 57% from 0.62

Eikelboom, et al Extended-duration prophylaxis against VTE after THAmeta-analysis of the randomised trials. Lancet 2001;358,9-15

Conclusions Regarding Extended Prophylaxis

• An additional 3 weeks of LMWH therapy after the first 7 to 10 days of prophylaxis will reduce the frequency of symptomatic VTE by close to two thirds after major orthopedic surgery, such as THA.

• Indirect evidence suggests that, compared with LMWH, efficacy of extended

h l i ft hi l t i

Kearon. Chest. 2003;124:386S-392S

Warfarin for Extended Prophylaxis

P=0.02

0.7 (0.5-1.0)

176 (29.7%)

66 (22.2%)

Yes

1.0-referent

416 (70.3%)

231 (77.8%)

No

PORControlsCasesWarfarin prophylaxis

White RH, eta l Predictors of rehospitalization for symptomatic VTE afterTHA. N Engl J Med. 2000 Dec 14;343(24):1758-64.

0.040.6 (0.4 –1.0)Warfarin post-discharge

0.160.7 (0.5 - 1.1)Body mass index ≥ 25 §

< 0.0010.3 (0.2 - 0.6) Body mass index < 25 ‡

Pneumatic compression

NS1.0 (0.8-1.1)Hospital Prophylaxis

0.031.8 (1.1 - 2.9)Body Mass Index

0.0013.4 (1.7 – 7.0)History of thromboembolism

0.0070.7 (0.5 – 0.9)Ambulating before second day

0.022.1 (1.1 – 3.9)Age > 85

P ValueOdds Ratio ± 95% CI

Variable

Conclusions:

• To reduce the incidence of VTE, extended prophylaxis is needed for the majority of patients undergoing THA.

• Extended prophylaxis (4-6 weeks) is effective.

• We need studies to better define patients at high-risk for VTE, which likely include patients with prior VTE, i bilit b it d d d

Tracy Minichiello, M.D.Assistant Professor of Medicine

Director, UCSF Thrombosis & Anticoagulation Services

Department of MedicineUniversity of California, San Francisco

Thrombolysis in Submassive Pulmonary Embolism

3

Mortality in Pulmonary Embolism

• Case fatality rate of PE 15% at 3 months despite standard thearpy

• In-hospital mortality 30% in patients with hemodynamic instability

Goldhaber Lancet 1999; Kasper J AM Coll Cardiol 1997

Thrombolysis and Massive Pulmonary Embolism

• Established treatment for massive PE – Recent meta-analysis supports use of

thrombolysis in patients with hemodynamic instability

Wan Circulation 2004

Thrombolysis vs. Heparin in PE: Recurrent PE/Death all comers


If massive PE: risk 9 4% vs. 19.0% (thrombolysis vs heparin)OR 0.45, 95% CI 0.22 to 0.92; NNT=10

Thrombolysis for Non-massive PE- 1st 12 Hours

• Reduced pulmonary artery pressure

• Decreased RV dilation

• Reduced radiographic evidence of PE

UPET, Circulation 1973 Konsatantinides Am J Cardiol 1998 Fam N Engl J Med 2002

Thrombolysis in Non-massive PE and Mortality

4.1%3164.6%305

2.2%1383.4%118Konstantinides

3%1003.8%105t-PA

9%787%82UPET

Mortality(heparin)

nMortality (lysis)

ntrial

Dalen, J Thromb Haemost 2003

Predictors of Poor Long Term Outcome in PE

• PA systolic pressure > 50mm HG• Echo evidence of RV dysfunction/dilation• >30% obstruction of pulmonary vascular • Elevated BNP• Increased troponin

Liu, Chin Med J 2003

4

BNP Levels According to Clinical Outcome

Kucher N et al Circulation 2003

Relationship Between TnIConcentration and Mortality

La Vechia, L. Heart. 2004

RV Dysfunction and Mortality

0.49.3706Total

04.6162Grifoni

012.8126Ribeiro

0.912.6317Kasper

04.3101Goldhaber

Nl RV Function

RV Dysfunction

Patients

Source

Kreitt JW Chest 2004

Thrombolysis and Pulmonary Embolism-MAPPET

Kasper J Am Coll Cardiol 1997

ns2 (0.4%)2 (1.2%)ICH

0.001103 (18.7%)13 (7.7%)Recurrent PE

0.01661 (11%)8 (4.7%)death

P value

Heparin n=550

Lysisn=169

event

Copyright restrictions may apply.

Agnelli, G. et al. Arch Intern Med 2002

Meta-analysis of Thrombolysis and Pulmonary Embolism Thrombolysis for Submassive Pulmonary

Embolism

• RCT of thrombolysis vs. heparin therapy for submassive PE

• 118 received heparin + altepase, 138 received heparin +placebo

• Primary outcome combined endpointof “escalation of therapy” and mortality

Konstantinides N Engl J Med 2002

5

Thrombolysis for Submassive Pulmonary Embolism

• Acute PE without hemodynamiccompromise plus– RV dysfunction on ECHO– Pulmonary hypertension on ECHO

or right heart cath– New RV strain on ECG


Defining Submassive Pulmonary Embolism

• PE without evidence of hemodynamicinstability, plus – Echocardiographic evidence of RV dysfunction– Subclinical impending right heart failure– Clinical evidence of pulmonary hypertension or

right ventricular dysfunction

Thrombolysis for Submassive Pulmonary Embolism

• Exclusion– major surgery/ biopsy(7days) – major trauma (10 days)– CVA/TIA or CNS trauma (6 months).– GI bleed (3 months)– uncontrolled hypertension– a known bleeding disorder– known diabetic retinopathy


Event Free Survival

Konstantinides, S. et al. N Engl J Med 2002

In-hospital Clinical Events


Thrombolysis and Pulmonary Embolism-Bleeding risk

Kanter CHEST 1997

0.7-4.11.96/312total

0.3-3.31.34/312Nonfatal

0.08-2.30.62/312Fatal

95% CI%NoICH

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Addressing Critiques of Thrombolysis in Submassive Pulmonary Embolism

• Cost prohibitive– Should consider potential long term impact of

therapy• No decrease in recurrent PE or mortality

benefit– Study used broad definition of submassive PE

• Increased major bleeding– Risk low in carefully selected patients

Thrombolysis and Pulmonary Embolism-Conclusions

• Clinical studies may be used to identify patients with PE at higher risk of adverse outcomes

• Thrombolysis may prevent clinical deterioration in selected patients

• Thrombolysis should be reserved for patients at low bleeding risk

• Future research should address efficacy of thrombolysis in more carefully selected patients; long term impact should be assessed

THE END

Thrombolysis for Pulmonary EMbolism

• Despite early improvements in hemodynamics perfusion no difference in mortality at 1-2 weeks time when compared to heparin

Base-Line Characteristics of the Study Patients


Thrombolysis and Pulmonary Embolism

• 14% reduction in combined endpoint of escalation of therapy and death


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ThrombolysisThrombolysis in in SubmassiveSubmassivePulmonary embolism? Pulmonary embolism? NO!NO!

Dr P Dorasamy MBChB FCP FCCP FRCPC

Internist / PulmonologistAssociate ProfessorMcMaster University

Hamilton Health SciencesO t i C d

Submassive PE

Definiton

• Acute PE with evidence of RV dysfunction but hemodynamicallystable

Thrombolysis in Submassive PE

– Mortality– Morbidity– Complications– Cost

Case study

• 71 yr old male; 25 pack year smoker• Presented with sudden onset dyspnea• HR 100 RR 22 BP 100/60 ; no clinical DVT• Chest hyperinflated with decreased breath

sounds• Heart sounds normal• ECG• CXR• ECHO

• Spiral CT chest• V/Q scan• Treatment1. Oxygen2. Heparin3. Bronchodilators

• Course1. Responded well to therapy2. Repeat CT

ThrombolysisThrombolysis in Pulmonary in Pulmonary EmbolismEmbolism

• Benefit in Massive PE established

• Benefits documented by angiography, perfusion scans and echocardiography

• Thrombolytics have not been shown to have a significant mortality or morbidity benefit in acute PE

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Disadvantages of Thrombolytics

• Increased major bleeding complications

• Increased cost

Randomized trials of Heparin vs Thrombolytic therapy in hemodynamically stable PE patients

4.1%3164.6%305TOTAL

2.2%1383.4%118rt - PAKonstantinides [6]

3%1003.8%105rt - PArt – PA trials [2-5]

9%787%82UrokinaseUPET [1]

MortalityNo. heparinMortalityNo. treatedLytic agentReport

1. Blackmon et al JAMA 1970; 214: 2163-722. Dalla-Volta et al J Am Coll Cardiol 19923. Goldhaber et al Lancet 19934. Levine et al Chest 19905. PIOPED Investigators - Chest 1990

6. Konstantinides et al NEJM 2002


• Recurrent PE is the principal cause of death in hemodynamically stable PE patients

• Thrombolysis will decrease mortality only if it decreased the rate of recurrent PE


• In studies where recurrent PE has been documented by follow-up lung scans or pulmonary angiograms, there has been no difference between patients treated with thrombolytics or heparin (JAMA 1970; J Am Coll Cardiol 1992; Chest 1990; NEJM 2002)

• Patients with hemodynamically stable PE, mortality with heparin therapy is < 5% (Dalen Arch Int Med 2002)

• Thrombolytics are not appropriate in these patients

Mortality in PE• Patients with submassive PE have a higher

mortality ( approx. 50% of all PE patients have RV dysfunction) (Goldhaber Lancet 1993)

• Mortality in patients with RV dysfunction was 4% vs 0.9% in those without RV dysfunction (RVD)

1. Am Heart J 1997 (Ribeiro et al)2. Circulation 2000 ( Grifoni et al)3. Intensive Care Med 2001 ( Vieillard-Baron et al)

• In 719 PE patients who were hemodynamically stable, mortality in those with RVD was 10% vs 4.1% in those without RVD (Konstantinides et al Circulation 1997)

Mortality in PE

• Hamel et al Chest 2001 reported from a French registry of 153 patients with massive PE treated consecutively with either Heparin or a thrombolytic; non-randomised; matched for right ventricular dysfunction, age, lung scans and the presence of cardiac or respiratory disease

• Mortality in 64 pts. treated with thrombolysiswas 6% vs 0% in those treated with heparin

• No difference in rate of recurrence of PE

9

Mortality in PEMortality in PE

• Mortality in 118 pts. randomised to receive alteplase + heparin (3.4%) vs 138 pts. on heparin alone (2.2%)

• Primary end-point was in-hospital death or “clinical deterioration requiring an escalation of treatment”



• Escalation of treatment occurred in 24.6% of patients in the heparin group vs 10.2% in the alteplasegroup ( P = 0.004)

• Secondary thrombolysis occurred in 23% in the heparin group vs 7.6% in the alteplase group ( P = 0.001)

• Primary indication for secondary thrombolysis was “worsening of clinical symptoms, particularly dyspnea”.

• Mortality in 118 pts. randomised to receive alteplase+ heparin (3.4%) vs 138 pts. on heparin alone (2.2%)

• 106/138 pts. in heparin group avoided complications and excessive cost of thrombolytic treatment

ThrombolysisThrombolysis in PE patients with in PE patients with shockshock

• No randomized clinical trials comparing heparin to thrombolytic therapy in patients with massive PE complicated by shock

• Because of high mortality (30%) in PE patients with shock, thrombolysis is considered

• Shock present in 10% of patients diagnosed with PE

Impact of Impact of ThrombolysisThrombolysis on on morbidity in PEmorbidity in PE

• In patients who survive acute PE, morbidity may be due to unresolved pulmonary embolic obstruction, or to recurrent PE

• Thrombolytic therapy increases the early resolution rate of pulmonary embolic obstruction as assessed by repeat lung scans or pulmonary angiograms 24 h after therapy. BUT the degree of resolution 24 h after thrombolytic therapy is incomplete

Morbidity in PEMorbidity in PE

• The Urokinase PE trial (UPET)(JAMA 1970)

Percent resolution by lung scan after therapy

77.2%78.8%1 year

56.2%55.4%2 weeks

8.3%24.1%24 h

HeparinUrokinaseTime since treatment

10

Recurrence in PE after treatmentRecurrence in PE after treatment

• Follow-up scans at 24 h after r-tPA treatment also demonstrated incomplete resolution (Lancet 1993, Chest 1990)

• Incidence of Recurrence in UPET

6%7%2, 5, 14

HeparinUrokinaseDays after treatment


• Konstantinides et alRate of recurrence after Alteplase vs Heparin (using lung scan, spiral CT or pulmonary angiogram)

2.9%3.4%

HeparinAlteplase

Complications of Complications of ThrombolysisThrombolysis

• High rates of bleeding occur despite modification of dose, type of agent, rate of administration and care in avoiding arterial and venepunctures

21.9% vs 7.8%(t-PA vs Heparin)

Konstantinides[2]

2.2%8.4%Levine [1]

Fatal hemorrhageMajor bleeding

1. Clin Chest Med 19952. Circulation 1997


• Intracranial hemorrhage constitutes the most serious and lethal complication of thrombolytic therapy

Incidence of ICH in PE patients treated with thrombolytic therapy

2.1%981TOTAL

0118Konstantinides et al [3]

3.0%304Goldhaber et al [2]

2.1%559Dalen et al 1997 [1]

Incidence of ICHPatients (n)Report

1. Arch Int Med 1997 2. Lancet 1999 (ICOPER) 3. NEJM 2002

Cost of Cost of ThrombolyticThrombolytic therapytherapy

• Drug cost: US$ 2974 for 100 mg ofAlteplase (Univ. Med Center Tucson, AZ 2003)

• Cost of treating bleeding complications

• Additional cost of treating the 50% ofpatients who are hemodynamically stable but with RVD

SUMMARY

• There is insufficient evidence that thrombolysis benefits patients with submassive PE

• Studies demonstrate no mortality benefit and no difference on recurrence rates when compared to heparin

• There is a significant risk of hemorrhage, including ICH

• The cost of treatment is high and unjustifiable

11

Duration of Anticoagulation for Treatment of Acute VTE

Andrew Dunn, MD, FACPDirector, General Medicine Anticoagulation Service

Mount Sinai Medical CenterNew York, NY

SGIM PRECOURSEMay 11, 2005

A 48 year-old female presents with 4 days of right leg pain and swelling. An ultrasound confirms the presence of a right LE DVT.

Treatment with outpatient LMWH and warfarin is begun. LMWH is discontinued when the INR is therapeutic on day #6.

The patient does not have h/o VTE, had no recent surgery or trauma, and is not on OCP or HRT. There is no family history of VTE. A thrombophilia work-up is negative.

How long will you treat the patient with warfarin?

48 year-old female with idiopathic right LE DVT

• 6 months

• 12 months

• Lifelong

• 3 months

• Even longer

• Indefinitely

• 2 years

Expert opinion?

48 year-old with first idiopathic DVT

Buller HR. Chest. 2004;126:401S-428S.

“For patients with a first episode of idiopathic DVT, we recommend treatment with a VKA for at least 6 to 12 months.”

“We suggest that patients with first-episode idiopathic DVT be considered for indefinite anticoagulant therapy.”

What Is Worse?

+

Extended OAC for First VTE3 months vs 24 months

Kearon C. NEJM. 1999;340:901-7.

All patients received 3 months of standard treatment

Randomized to:Additional 24 months OAC (INR goal 2-3) or placebo

Study terminated early (mean f/u 10 months)

12

Standard Extended

Recurrent VTE

Fatal PE

Major Bleeding

1 (1)

0 (0) 3 (4)

1 (1) 0 (0)

17 (27) P<.001

P=.09

P=NS

Kearon C. NEJM. 1999;340:901-7.

Extended OAC for First VTE

n=79 n=83

Extended OAC for First DVT3 months vs 1 year

Agnelli G. NEJM. 2001;345:165-9.

…and lets look 1 year (or more) later

Agnelli G. NEJM. 2001;345:165-9.

3 months 1 year

Recurrent VTE

Recurrent VTE(months 3-12)

Major Bleeding

21 (16)

2 (1.5) 4 (3)

11 (8) 4 (3)

21 (16)

P=NS

P=NS

P=NS

Average f/u 38 months


Extended OAC Duration Treatment of PE

Agnelli G. Ann Intern Med. 2003;139:19-25.

3 months OAC for acute PE vs

6 months (transient risk factor) or 12 months (idiopathic)

Followed for average of 3 years.

Italian study, 19 hospitals.

N = 326

3 months Extended

Recurrent VTETotal group, n (%)

15/165 (9.1)18/369 (11.2) P=NS

PE Treatment3 months vs Extended Duration


Recurrent VTEIdiopathic

11/90 (12.2)11/91 (12.1) P=NS

All but 1 recurrence occurred after OAC discontinued

Long-term Low-Intensity Warfarin for Prevention of Recurrent VTE

PREVENT

Ridker PM. NEJM. 2003:348:1425-34.

Low-intensity Warfarin (INR 1.5-2.0) indefinitely vs Placebo

All received standard treatment (mean 6.5 months)N=508

Average follow-up 2.1 years.

Trial terminated early

13

Ridker PM. NEJM. 2003:348:1425-34.

PREVENT

Standard LI OAC

Recurrent VTEn (% per person-years)

Major Bleedingn (%)

14 (2.6)

2 (2) 5 (3)

37 (7.2)

P=NS

P<.01

Deathn (%)

8 (2) 4 (3) P=NS

Low-Intensity Warfarin vs Conventional-Intensity Warfarin for Prevention of Recurrent VTE

ELATE

Kearon C. NEJM. 2003:349:631-9.

Warfarin target INR 2-3 (standard intensity OAC)

Warfarin target INR 1.5-1.9 (low-intensity OAC)

N=738Average follow-up 2.4 years

INR 2-3 INR 1.5-1.9


Major Bleedingn (% per person-years)

16 (1.9)

8 (0.9) 9 (1.1)

6 (0.7)

P=NS

P<.05

ELATE

Kearon C. NEJM. 2003:349:631-9.

CONCLUSIONS FROM RCTs

• Warfarin works when you are on it

• When you stop warfarin, there is a “catch-up” phenomenon

• If you are treating long-term or indefinite, you are treating lifelong

• If you are going to stop eventually, 6 months reasonable choice

• Major bleeding doesn’t happen in large RCTs

Without OAC, the recurrence rate is ~10% over the first year, then about 5% per year, and starts to wane.

Long-term recurrence rate = 30% over 8 years.

You have a 70% chance of being event free and requiring no medication or monitoring.

You have a 30% chance of a recurrent event, in which case you will need lifelong OAC.

Prandoni P. Annals Intern Med. 1996;125:1-7.

Unless you’re dead.

How Often is Recurrent VTE Fatal?

Schulman S. NEJM. 1995;332:1661-5.

Duration of Anticoagulation Trial Study Group (DURAC)

6 weeks vs 6 months. F/U for 2 years.N = 498.

VTE recurrence 18% vs 9% (6 months superior).

Of 123 recurrences, 5 fatal (4%).

14

Risk of Fatal Recurrent VTE

Long-term follow-up study355 patients with first DVT


9 of 78 (11%) recurrences were fatal.

Analysis of California Discharge Database - VTE diagnoses


Murin S. Thromb Haem. 2002;88:407-14

N = 71,25051,233 DVT21,625 PE

If initial dx DVT, relative risk of hospitalization for DVT = 2.7

If initial dx PE, relative risk of hospitalization for PE = 4.2

Review of 25 studies of treatment of DVT or PE


Douketis JD. JAMA. 1998;279:458-62

Of patients with initial DVT, fatality rate of recurrence 9% (15/171).

Of patients with initial PE, fatality rate of recurrence 26% (19/72).

IF IT DOESN’T KILL YOU…

IT DOESN’T MAKE YOU STRONGER


Post-thrombotic syndrome at 8 years after DVT - 30%

Best predictor of PTS: Ipsilateral recurrent DVT

Bleeding Risk from OAC

Randomized trials – small (~1%)

Real life – not so small, (range debatable)

Outpatient Bleeding Risk Index (OBRI)

Beyth RJ. Am J Med. 1998;91-99.

Index derived in a retrospective cohort of 556 patients.

Prospective validation in outpatients starting warfarin at a different hospital.

OVERALL - Major bleeding occurred in 87/820 outpatients (6.5%/yr).

• Age 65 years or greater• History of gastrointestinal bleeding• History of stroke• One or more from: DM, recent MI, hct <30%, creatinine >1.5.


Cumulative incidence at 48 monthsLow risk (n=80) 3% (0.8% per year)Intermediate-risk (n=166) 12% (3% per year)High-risk (n=18) 53% (13% per year)

15

How often is it fatal?

Linkins L. Ann Intern Med. 2003;139:893-901.

META-ANALYSIS

Bleeding from OAC

33 studies examining 4374 patient-years

Case-fatality rate 13.4%

If on OAC >3 months, case fatality rate 9.1%

BALANCING THE FATALITY RISKS

DVT MAJOR BLEEDING

Recurrence rate over 8-10 years30%

Case-fatality rate 5%

Mortality from recurrent VTE1.5%

Major Bleed rate/year 0.8 - 3%


Mortality from major bleed0.6 – 2.4%

Major Bleed over 8 years 6 - 24%

without warfarin with warfarin


DVT MAJOR BLEEDING

Recurrence rate over 8-10 years12%



Major Bleed rate/year 0.5% MAYBE!!!!!


Mortality from major bleed0.4% MAYBE!!!!

Major Bleed over 8 years 4%

If on low-dose warfarin

Total Mortality1.0%

THE BOTTOM LINE48 year-old female first idiopathic DVT

• 30% chance of recurrence long-term

• If recurs can treat lifelong

• If doesn’t recur, you saved 50 years of warfarin and decreased the risk of fatal and nonfatal bleeding

• A great opportunity to involve the patient in shared decision-making

• There is a 70% chance of no recurrence

Should a Patient with Idiopathic DVT Undergo a Hypercoagulable Work-Up?

An Argument in Favor of Testing

Matt Eisen, MDSGIM 28th Annual Meeting

Precourse PM015/11/05

Why Test for Thrombophilia?

Thrombophilia:• Is common among patients with VTE• Increases the relative risk of recurrent VTE• May influence patient management

16

How Common are Hypercoagulable Conditions?

Prevalence of Hypercoagulable States

N/A14%2-7%Anticardiolipin antibodies

N/A5-15%0-3%Lupus anticoagulant

N/A10-25%5-10%Hyperhomocysteinemia

4-8%1%0.02%Antithrombin deficiency

3-13%1-2%N/AProtein S deficiency

6-8%3%0.2-0.4%Protein C deficiency

18%6%1-3%Prothrombin G20210A

50%20%3-7%Factor V Leiden

Thrombophilicfamilies

Patients with 1st

VTEGeneral

populationHypercoagulable

state

Deitcher SR, et al. Vasc Med 2003;8(1):33-46

Increasing Prevalence

Prevalence of Hypercoagulable States

0.06%African or Asian

2.7%Caucasian

Prothrombin G20210A

0.05%African or Asian

0.4%Asian American

1.2%Native American

1.2%African American

2.2%Hispanic American

4.8%Caucasian

Factor V Leiden

General populationHypercoagulable state

Perry SL, et al. Perry SL, et al. ClinClin Chest MedChest Med 2003;24(1):1532003;24(1):153--7070

Prevalence ofHypercoagulable States

Key points:

• Testing will identify thrombophilia in 24-37% of patients with VTE

• Selective testing increases the likelihood of positive findings

How Much Risk is Associated with Hypercoagulable Conditions?

Relative Risk of VTE

2-410Anticardiolipin antibodies

1-32.5Hyperhomocysteinemia

1.5-320Antithrombin deficiency

1.5-35Protein S deficiency

1.5-36.5Protein C deficiency

2-5N/AFVL and G20210A

1-52.8Prothrombin G20210A

480Homozygous

1-47Heterozygous

Factor V Leiden

Relative risk of recurrenceRelative risk of 1st VTEHypercoagulable state

Bates SM, et al. Bates SM, et al. N N EnglEngl J MedJ Med 2004;351:2682004;351:268--277277

17

How Might the Presence of Thrombophilia Affect Patient

Management?

Duration of Therapy

Consider extended anticoagulation in patients with 1st idiopathic VTE and:• Homozygous factor V leiden or prothrombin

gene mutation• Combined heterozygous defects• Protein C or S deficiency• Antithrombin deficiency• Antiphospholipid antibodies

Intensity/Monitoring of Therapy

In patients with antiphospholipid antibody syndrome:• Consider higher target INR• Consider monitoring by chromogenic

factor X assay

Other Therapies

In patients with hyperhomocysteinemia:

• Consider giving folate / B6 / B12 and monitoring for improvement in serum homocysteine

Screening Family Members

Finding of thrombophilia has implications for:

• Decision to use OCPs• Decision to use HRT• Management of pregnancy

Feero WG. Prim Care 2004;31(3):685-709,xi

18

Bauer KA. Hematology (Am Soc Hematol Educ Program) 2002:353-68

What are the Costs of Hypercoagulable Testing?

Costs of Testing

• Cost estimates range from $250 - $1,000 for “standard panel”

• One published cost-effectiveness study using Markov model¹ concluded:

testing for hypercoagulable disorders in pts with idiopathic DVT followed by 2 years of anticoagulation in affected pts is cost-effective

¹Auerbach AD. Am J Med 2004;116(12):816-28

The Case Against Routine Testing for Hypercoagulability

Doug Einstadter, MD, MPHCWRU at MetroHealth Medical Center

SGIM 28th Annual Meeting New Orleans, LA

May 11, 2005

Background

• A cause of thrombosis can be identified in more than 80% of patients with VTE.

• From 24 to 37% of all VTE is due to inherited thrombophilia.

• Testing for thrombophilia has become increasingly common.

• Should testing after VTE be routine?

Commonly Requested Tests

• Antithrombin• Protein C, Protein S• Factor V Leiden• Prothrombin 20210A• Dysfibrinogenemia• Hyperhomocysteinemia• Factor VIII, IX, XI, TAFI• APC resistance without Factor V Leiden

19

Potential Reasons to Test

• To determine optimal duration of therapy• To determine optimal intensity of therapy• To identify and recommend prophylaxis for

asymptomatic family members during:– High risk situations– Pregnancy, oral contraceptive use, HRT

• “Need to know” (intellectual curiosity)

Assumptions Underlying a Decision to Test

1. Presence of identified thrombophilia predicts greater risk of recurrence.

2. More intense treatment for those with thrombophilia leads to better outcomes.

3. Family members of patients with VTE and thrombophilia are at increased risk.

4. Prophylactic treatment of family members leads to improved outcomes.

Does the Literature Support the Assumptions for Testing?

Is Risk of RecurrentVTE Increased?

• The overall risk of recurrent VTE in patients with and without thrombophilia is similar

Lancet 2003; 362: 523Lancet 2003; 362: 523--2626

HR 1.50 [95% CI 0.82–2.77]; p=0.187

Risk of Recurrent VTE with and without Identified Thrombophilia


• The overall risk in patients with and without thrombophilia is similar

• Risk for patients with and without heterozygous Factor V Leiden or G20210A is similar; risk in patients with homozygous Factor V Leiden probably is increased

20

Thromb Haemost 1999; 81: 684–9

Risk of Recurrent VTE in Relation to Factor V Leiden G1691A Status

Pro

porti

on fr

ee o

f rec

urre

nt e

vent

p < 0.05 for Homozygote vs. Heterozygote or Non-carriers


• The overall risk in patients with and without thrombophilia is similar

• Risk for patients with and without heterozygous Factor V Leiden or G20210A is similar; risk in patients with homozygous Factor V Leiden probably is increased

• The risk in patients with combinations of thrombophilia is not well defined

• Other, as yet unidentified deficiencies may also affect risk

Duration of Therapy• Treatment for six months provides a good

balance of risks and benefits. • Longer duration of treatment (up to 3 years)

reduces recurrence, but increases hemorrhage risk for all patients.

• Prolonged duration of treatment for those with identified thrombophilia alone is not supported by the literature.

Intensity of Therapy• Target INR of 2.5 is recommended for VTE

• Higher intensity indicated in those patients with thrombosis despite a therapeutic INR (regardless of identified thrombophilia)

• There is no evidence to support the routine use of higher intensity regimens for patients with identified thrombophilia

Thrombosis Prevention

• There is no evidence to support primary prophylaxis of asymptomatic family members found to have thrombophilia.

• All patients, regardless of thrombophilia status, should receive prophylaxis during periods of high risk.

Effect on Contraceptive, HRT and Pregnancy Advice

• To prevent 1 oral contraceptive related death due to PE requires screening more than 2 million women for Factor V Leiden.

• There is little evidence to quantitate risk of VTE associated with HRT in asymptomatic women with thrombophilia.

• No evidence that risk : benefit ratio favors prophylaxis in pregnant asymptomatic carriers of Factor V Leiden, G20210A, or other deficiencies

21

Summary

• The current evidence does not support indiscriminate testing for thrombophilia

• Testing for heritable thrombophilia is unlikely to change the clinical management of individual patients

• Over-testing may result in increased anxiety, false reassurance, or treatment related adverse events

Stroke Prevention in AF

“To Anticoagulate or Not to Anticoagulate”

Steven L. Cohn, MD, FACPChief – Division of General Internal Medicine

Director – Medical Consultation ServiceClinical Professor of Medicine

SUNY Downstate

AF, Stroke, & AnticoagulationFactors in Decision-Making

• Risk factors for stroke with AF– At age 64 w/o risk factors (with increasing age)– With hypertension

• Risk of stroke with/without therapy– ASA vs warfarin (vs no medication)

• Risk of major bleeding– Intracranial, retroperitoneal, GI

• Patient vs physician concerns/preferences

Definitions of Stroke Risk

No high-risk features; no history of hypertension

History of hypertension; no high-risk features

Women age >75 years; Systolic BP >160 mm Hg; LV dysfunction

Stroke Prevention in Atrial Fibrillation

Age <65 years; no high-risk features

Age 65-75 years; diabetes; CAD; thyrotoxicosis

Age >75 years; history of hypertension; LV dysfunction; more than 1 intermediate risk factor

American College of Chest Physicians

Age <65 years; no high-risk features

Age ≥65 years; history of hypertension; CAD; diabetes

Atrial Fibrillation Investigators

Low RiskIntermediate

RiskHigh RiskSource

Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231. 2001;38:1231--1265.1265.

Stroke Risk in New-onset AFACP/AAFP Guidelines


Moderate5.9 (4.6-7.3)3

High8.5 (6.3-11.1)4

High12.5 (8.2-17.5)5

High18.2 (10.5-27.4)

6

Low1.9 (1.2-3.0)0

Moderate4.0 (3.1-5.1)2Low2.8 (2.0-3.8)1

CHADS2Risk Level

Adjusted Stroke Rate† (95% CI)

CHADS2*Score

*Assessment of the following comorbidities: CHF, *Assessment of the following comorbidities: CHF, hypertensionhypertension, age , age ≥≥75, and diabetes 75, and diabetes (1 point each), history of stroke or TIA (2 points each). (1 point each), history of stroke or TIA (2 points each). †Expected rate of stroke per 100 patient-years.Snow et al. Ann Intern Med. 2003;139:1009-1017.

Warfarin

Stroke risk : 64 year-old woman with HTN

2.4-4.3

0.4-1.7

2.5-3.8

1.8-4.0

1.1-2.52.7-4.5

Stroke rate with ASA

2.3-4.0

2.0-3.8

3.5-4.34.9-8.1

Stroke rate with no Rx

IntermediateFramingham

LowCHADS2

HighACCP

IntermediateSPAF

IntermediateHigh

AFI

Risk category

Study

22

Guidelines for Stroke PreventionACC/AHA/ESC

*Risk factors for thromboembolism include HF, LVEF 35%, and history of hypertension.Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231. 2001;38:1231--1265.1265.

IOral anticoagulation(INR 2.5-3.5 or higher may be appropriate)

Rheumatic heart disease(mitral stenosis)

Prosthetic heart valvesPrior thromboembolismPersistent atrial thrombus on TEE

IOral anticoagulation (INR 2-3)

HFLVEF ≤35%.ThyrotoxicosisHypertension

IIIb

I

Oral anticoagulation (INR 2-3)Addition of aspirin, 81-162 mg dailyis optional

Oral anticoagulation (INR ≈2)

Age greater than or equal to 60 yearsWith diabetes mellitus or CAD

Age greater than or equal to 75 years,especially women

IAspirin (325 mg daily)Age greater than or equal to 60 yearsNo risk factors*

IAspirin (325 mg daily)Age less than 60 yearsHeart disease but no risk factors*

IAspirin (325 mg daily) or no therapy

Age less than 60 yearsNo heart disease (lone AF)

Grade of Recommendati

onAntithrombotic TherapyPatient Features

Expected Stroke Rate in AFEffect of Risk Factors and Age

*No data on aspirin therapy.*No data on aspirin therapy.RF = risk factors: RF = risk factors: hypertensionhypertension, diabetes, prior TIA, or stroke., diabetes, prior TIA, or stroke.Ezekowitz et al. Ezekowitz et al. JAMA.JAMA. 1999;281:18301999;281:1830--1835.1835.

0

5

10

15

-- RFRF -- RFRF -- RFRF+ RF+ RF + RF+ RF + RF+ RF

Age (years)Age (years)

Stro

kes

per Y

ear (

%)

Stro

kes

per Y

ear (

%)

WarfarinWarfarinPlaceboPlacebo AspirinAspirin

>75>756565--7575<65<65

10%10%

4%4%

12%12%

**

1.7%1.7%

3.5%3.5%

1.7%1.7%

**

5.7%5.7%

1.4%1.4%1.1%1.1%

4.3%4.3%

1.7%1.7%

**

4.9%4.9%

1%1% 1%1%**

Aspirin vs PlaceboReduction of Risk of Thromboembolism

in AFAFASAK IAFASAK I

SPAF ISPAF I

EAFTEAFT

ESPS IIESPS II

LASAFLASAF

UKUK--TIATIA

All trials=6All trials=6

Relative Risk Reduction (95% CI)Relative Risk Reduction (95% CI)

100100 5050 00 --5050 --100100AspirinAspirin

Hart et al. Hart et al. Ann Intern MedAnn Intern Med. 1999;131:492. 1999;131:492--501.501.

22% (2%22% (2%--38%) 38%)

Anticoagulation in AFStroke Risk Reductions


Warfarin BetterWarfarin Better Control BetterControl Better

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

100%100% 50%50% 00 --50%50% --100%100%

AggregateAggregate

Reduction of stroke

RRR 62%

Reduction of Reduction of strokestroke

RRR 62% RRR 62%

Reduction ofall-cause mortality

RRR 26%

Reduction ofReduction ofallall--cause mortality cause mortality

RRR 26%RRR 26%

Warfarin Versus AspirinEffect of Risk Stratification on Stroke

Reduction

*For stratification schemes; *For stratification schemes; ††Calculations are based on a 40% relative risk reduction with Calculations are based on a 40% relative risk reduction with adjustedadjusted--dose warfarin over aspirin from metadose warfarin over aspirin from meta--analysis. The authors suspect that this analysis. The authors suspect that this overestimates the benefit of warfarin therapy in lowoverestimates the benefit of warfarin therapy in low--risk patients and importantly risk patients and importantly underestimates it for highunderestimates it for high--risk patients.risk patients.Hart. Hart. Ann Intern MedAnn Intern Med. 1999;131:688. 1999;131:688--695.695.

40 †25 †10Secondary prevention24 †42 †6High risk12833Moderate risk42501Low risk

Primary prevention*n%Risk Stratification

Number of Strokes

Prevented Yearly per 1000 Given

Warfarin

Number Needed to be Treated for

1 y to Prevent 1 Stroke

Treatment With Warfarin Instead of Aspirin

Annual Stroke Rate

With Aspirin Therapy

Severity of the Neurologic Deficit at Discharge and 30-Day Mortality

Rates

Hylek et al. Hylek et al. N Engl J MedN Engl J Med. 2003;349:1019. 2003;349:1019--1026.1026.

6161524Total 30-day mortality2325No neurologic sequelae

55384936Minor stroke, neurologic deficit that did not prevent independent living

38443637Major stroke, neurologic deficit that prevented independent living

4678Severe stroke, total dependence

19614Fatal in-hospital stroke%Severity and outcome of stroke

INR ≥2(N=71)

INR <2(N=117

)

Aspirin

(N=160)

None(N=248

)Variable

Warfarin

23

Patient Concerns About AF

0

20

40

60

80

100

Stroke Death Major Bleeding

InconvenienceMinor Side

Effects

Cost

ManMan--SonSon--Hing et al. Hing et al. Arch Intern Med.Arch Intern Med. 1996;156:18411996;156:1841--1848.1848.

Perc

ent

Perc

ent

91%

38%

13%9%

2% 5%

Physician Concerns About Warfarin for Stroke Prevention

in AF

0

20

40

60

80

Risk of Fall

History of GI Bleed

History of Non-CNS

Bleed

History of CV Hemorrhage

Monette et al. Monette et al. J Am Geriatr SocJ Am Geriatr Soc. 1997;45:1060. 1997;45:1060--1065.1065.

47% benefits of warfarin greatly 47% benefits of warfarin greatly outweigh risksoutweigh risks

34% benefits slightly outweigh risks34% benefits slightly outweigh risks19% risks outweigh benefits19% risks outweigh benefits

Frequently Cited ContraindicationsFrequently Cited Contraindications

Perc

ent

Perc

ent

Bleeding Rates in AF Patients Taking Warfarin

Meta-analysis

2 (0.4%/y)

12(2.1%/y)

2.0-3.0SPAF III

*2.6%/y2.0-3.0Pengo et al0.3%/y1.1%/y2.0-3.0Gullov et al

1 (0.2%)6 (1.3%)2.0-3.5Morocutti et al

06(2.3%)1.4-2.8Ezekowitz et al

2 (1.1%)5 (2.7%)2.0-3.0Connolly et al1 (0.5%)8(3.8%)1.5-2.7BAATAF

*1.7%/y2.0-3.5SPAFFatalMajor†Target

INRSource

*No data available. *No data available. ††Defined as intracranial or retroperitoneal bleeding, or bleedingDefined as intracranial or retroperitoneal bleeding, or bleeding that resulted that resulted in death, hospitalization, or transfusion.in death, hospitalization, or transfusion.Levine et al. Levine et al. ChestChest. 2001;119:108S. 2001;119:108S--121S.121S.

BleedingBleeding

0.00.20.40.60.81.01.21.41.61.82.0

Intracranial Hemorrhage During Long-Term Anticoagulation With

Warfarin

*PV=prosthetic valves.*PV=prosthetic valves.Levine et al. Levine et al. ChestChest. 2001;119:108S. 2001;119:108S--121S.121S.

ICH

%/Y

ear

ICH

%/Y

ear

Fihn Fihn (AF)(AF)

INRINR<3.0<3.0

INRINR<3.0<3.0

Fihn Fihn (>75)(>75)

Turpie Turpie (PV*)(PV*)

SPAF SPAF ((≤≤75)75)

SPAF SPAF (AF)(AF)

PengoPengo(PV*)(PV*)

SPAF SPAF ((>>75)75)

SPAF SPAF III (AF)III (AF)

INRINR2.02.0--4.54.5

INRINR2.02.0--3.03.0 INRINR

2.52.5--3.53.5

INRINR3.03.0--4.54.5

INRINR2.02.0--4.54.5

INRINR2.02.0--4.54.5

Warfarin for AF

Samsa et al. Arch Intern Med. 2000;160:967-973.

INR Above INR Above TargetTarget

6%6%

Subtherapeutic INR Subtherapeutic INR 13%13%

INR inINR inTarget RangeTarget Range

15%15%

No WarfarinNo Warfarin65%65%

Adequacy of Anticoagulation inAdequacy of Anticoagulation inPatients With AF in PrimaryPatients With AF in Primary--Care PracticeCare Practice

N=660

174440CAFA

155629SPINAF

0.67326AFASAK

9838BAATAF

% Time Above Target Range

% Time In Target Range

% Time Below Target Range

Range of Anticoagulation Adequacy*

*Percent of time in range.*Percent of time in range.BAATAF. BAATAF. N Engl J Med.N Engl J Med. 1990;323:15051990;323:1505--1511; Connolly et al. 1511; Connolly et al. J Am Coll Cardiol.J Am Coll Cardiol.1991;18:3491991;18:349--355; Ezekowitz et al. 355; Ezekowitz et al. N Engl J Med.N Engl J Med. 1992;327:14061992;327:1406--1412; Petersen et al. 1412; Petersen et al. LancetLancet. 1989;1:175. 1989;1:175--179.179.

24

Survival Following Ischemic Stroke

Warfarin vs Aspirin*

Prob

abili

ty o

f Sur

viva

lPr

obab

ility

of S

urvi

val

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.00.000 55 1010 1515 2020 2525 3030

Days After AdmissionDays After Admission

PP=.002=.002††

Warfarin, INR Warfarin, INR ≥≥22AspirinAspirin

Warfarin, INR Warfarin, INR <2<2

NoneNone

*Warfarin/aspirin therapy was administered before or during occurrence of stroke.††The P value refers to the overall difference among the groups.Hylek et al. N Engl J Med. 2003;349:1019-1026.

Summary• Risk factors place this patient in an intermediate –

high risk category for risk of stroke.• Stroke risk ranges from 2-5% without therapy.• Aspirin reduces stroke risk to 0.5-4%.• Warfarin reduces stroke risk to 1.7%.• Risk of major bleeding with warfarin is 1-3% in

general. Risk of ICH in this patient is 0.5%. • Risk of major bleeding with ASA is 1-2% overall.• If patient preference favors avoiding stroke

despite inconvenience and risk of bleeding, anticoagulate with warfarin – otherwise too close too call.

64 year-old woman w/ Afib and HTN

Brian F. Gage, MD, [email protected]

Associate Professor of Medicine,Washington University, St. Louis

No conflicts of interest

Background

• Over 2 million Americans have atrial fibrillation

• Without antithrombotic therapy their stroke rate is increased 4- to 5-fold

• Stroke is the leading cause of adult disability and the third most common cause of death in Americans

CHADS2

• Congestive Heart Failure (1 pt.)• Hypertension (1 pt.)• Age>75 (1 pt.)• Diabetes (1 pt.)• Stroke History (2 pts.)

With 1 point, expect 2.2 (95% CI: 1.6-3.1) strokes/100 pt-yrs ASA (Gage et al. Circulation 2004)

25

Efficacy in Clinical Trials• In randomized, controlled trials warfarin

reduced ischemic stroke rate by 65% (hazard ratio 0.35) compared to no antithrombotic therapy

HOWEVER: • Trials excluded over 90% of patients

- Esp. patients with contraindications to warfarin (e.g. neuropsychiatric disease, poor compliance, risk for falls)

• Patients in trials are followed more meticulously than in real-life settings

34% (25%-43%)Retrospective CohortNo2005Birman…Gage

69% (0%-91%)Prospective CohortNo?1999JJ Caro et al

64% (42%-78%)Case-controlYes2003Go, Hylek…Singer

51% (39%-60%)Retrospective CohortYes2003Go, Hylek…Singer

EffectivenessDesignAC Clinic?YearAuthors

Effectiveness of Warfarin Therapy for Stroke Prevention in Practice

Subjects and Data Source for Birman-Deych…Gage study

• Subjects: National sample of 23,657 Medicare beneficiaries hospitalized between 04/01/1998 and 03/31/1999 with Atrial Fibrillation

• Data Sources:– Medical chart review (baseline hospitalization) to confirm

the presence of AF and stroke risk factors

– Medicare claims records (baseline and follow-up) for warfarin Rx and validated ICD-9-CM claims for stroke

• For details see poster #23 at session 3, “Real-world effectiveness of warfarin therapy for stroke prevention in Medicare beneficiaries of all races”

0

0.2

0.4

0.6

0.8

1

Go, Hyle

k…Singer

Go, Hyle

k…Singer

JJ Caro

et al

Birman-

Deych…Gage

RR

R W

arfa

rin

for

Stro

ke P

reve

ntio

n

>100088NNT

2.31.22.3Total*

0.80.40.1ICH*

1.50.772.2Strokes*

Warfarin/no ACWarfarin/ACASAEvent

*Events per 100 pt-years

Number Needed to Tx (NNT)

Based on effectiveness of 15% for ASA; 41% for warfarin

Conclusions

• For patients with a CHADS2 score of 1, the decision to prescribe warfarin depends on:– The effectiveness of warfarin in the clinical setting– The risk of bleeding (esp. ICH) in the clinical

setting– The patient’s preferences for taking warfarin vs.

ASA– Possibly other side-effects of these antithrombotic

therapies (e.g. increased osteoporosis?, prevention of MI)

Arguments Against the Prolonged Out-of-Hospital Prophylaxis for ALL Patients with Total Hip Arthroplasty (THA)

One size does not fit all: There is a range of potential risk from relatively low to very high post-discharge

o Unfortunately there is no well-validated method to predict reliably who will have a VTE event There are ~300,000 THA procedures performed annually in the US, so What is the rate of Symptomatic VTE after hospitalization for THA without extended prophylaxis?

• White et al, Arch Int Med 1998: 2-3% at 30-90 days1 • Heit et al, Ann Int Med June 2000: 2.2% at 120 days2 • Comp et al, JBJS 2001: 3.8% at 120 days3 • Eikelboom et al, Lancet July 2001 Meta-analysis4

o Symptomatic VTE rate from 9 studies 3.3% in controls (58/1,744) o 1.3% in treatment groups (12/1,954)

ARR = 2.0% NNT = 50 (PE NNT = 250) O.R. 0.38 (.24-.61)

What is the rate of HIT and Major Bleeding?

• Warkentin et al Arch Int Med 20035 (<50% fall in plt count from post-operative peak) 0.6% with LMWH in orthopedic patients

• Major Bleeding rate (transfusion, wound hematoma requiring surgery, etc) 0.2-1.4% (best guess is ~0.5%)

• Combined HIT and Major Bleeding Rate of ~1.0% Balancing reductions in symptomatic events with adverse events, the overall ARR with out of hospital LMWH prophylaxis will be ~1.0%. Patient Compliance Issues In one of the first studies to suggest out-of-hospital LMWH prophylaxis was effective in THA6, injections were administered by a study nurse, ensuring compliance. In a follow-up LMWH trial2, patients self-administered and were included if they received at least 50% of their injections, which is more reflective of actual clinical practice. My Approach: All patients get prophylaxis of surgeon’s choice at the time of THA, preferably multi-modal

• LMWH for most patients without contraindication and who agree to out-of-hospital injections if needed (considering both cost and convenience)

• Warfarin for patients who would prefer out of hospital prophylaxis with pills and blood tests, if out of hospital prophylaxis warranted.

• Pneumatic devices intra-op and post-op until ambulatory7 • TED hose, if they fit properly, during hospitalization and 4 weeks after discharge8 • ASA in hospital and at discharge for 4 weeks if no warfarin or LMWH, since ASA has been

shown to reduce the rate of fatal PE.9 • Prolonged out of hospital prophylaxis only for those who are at the highest risk based upon risk

factors. Unfortunately, there is no validated way to predict who is at this highest risk because the number of out of hospital VTE events is very small and would take an extremely large study, or a very well-done administrative data study.

• More studies are needed to determine cost-effectiveness and clinical effectiveness

Peter Kaboli, MD, MS [email protected] Iowa City VAMC and University of Iowa

References: 1. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of

thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158:1525-31.

2. Heit JA, Elliott CG, Trowbridge AA, Morrey BF, Gent M, Hirsh J. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 2000; 132:853-61.

3. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. Patient Care Management 2001; 83-A:336-45.

4. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358:9-15.

5. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Archives of Internal Medicine 2003; 163:2518-24.

6. Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. New England Journal of Medicine 1996; 335:696-700.

7. Silbersack Y, Taute BM, Hein W, Podhaisky H. Prevention of deep-vein thrombosis after total hip and knee replacement. Low-molecular-weight heparin in combination with intermittent pneumatic compression. Journal of Bone & Joint Surgery - British Volume 2004; 86:809-12.

8. Best AJ, Williams S, Crozier A, Bhatt R, Gregg PJ, Hui AC. Graded compression stockings in elective orthopaedic surgery. An assessment of the in vivo performance of commercially available stockings in patients having hip and knee arthroplasty. Journal of Bone & Joint Surgery - British Volume 2000; 82:116-8.

9. Anonymous. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295-302.

Peter Kaboli, MD, MS [email protected] Iowa City VAMC and University of Iowa

Richard H. White, MD UC Davis Q: How long should prophylaxis be used in patients undergoing hip replacement surgery or other high risk surgical procedures?-

The case for extended prophylaxis. ____________________________________________________________________________ Before one can make a rational decision, you have to ask: What is the incidence and timing of thromboembolic events after surgery? REF 1 White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998 Jul 27;158(14):1525-31.

Outcome

Primary Total Hip (N=19,586)

Thromboembolic event by time of diagnosis:

During the initial hospitalization, n (%) 133 (0.7%)

During rehabilitation hospitalization, n (%) 94 (0.5%)

Requiring readmission, n (%) 329 (1.7%)†

P<0.01 Over 50% of all VTE events in the first 90 days occurred after discharge!

The next question is: Does extended prophylaxis make a difference? Does it reduce the incidence

EF 2

of symptomatic events? R . White RH, Gettner S, Newman JM, Trauner KB, Romano PS.

sm after

edicare patients undergoing THR in California. Case control study. 300 patients readmitted

Table 2. Results of Bivariate Analysis of Thromboprophylaxis Variables.

Predictors of rehospitalization for symptomatic venous thromboembolitotal hip arthroplasty. N Engl J Med. 2000 Dec 14;343(24):1758-64. Mwith VTE vrs 600 controls who did not develop VTE, matched on hospital where surgery was performed.

Variable No95

P- v

. Cases No. Controls OR (N=297) (N=592) % CI alue

No pneumatic compression

o medical prophylaxis 31 (10.4%) 37 (6.3%) 1.0 0.7 ( .4) P= 27

† 5

Pneum ion and: 47 (1 8%) 99 (1 .7%) 0.6 (0 -1.1) P= 06

parin §

Elasti lic

208 (70%) 417 (70.4%) 1.0 1.0 ( .4) P= 90

charge warfarin

231 (77.8%) 416 (70.3%) 1.0 0.7 ( .0) P=0.02

rfarin

* treated with aspirin. eceived warfarin in addition to heparin during the

tion.§ Includes 3 cases

and: N

Warfarin alone 48 (16.2%) 80 (13.5%) 0.4-1 0.Regular heparin 7 (2.4%) 6 (1%) 1.4 (0.4-5.3) P=0.58 Enoxaparin‡ 27 (9.1%) 3 (9%) 0.6 (0.3-1.3) P=0.14 atic compress

No medical prophylaxis 5. 6 .3 0.Warfarin 55 (18.5%) 172 (29.1%) 0.4 (0.2-0.7) P<0.001 Regular he 21 (7.8%) 30 (5.1%)

10.8 (0.4-1.9) P=0.63

Enoxaparin ¶ 61 (20.5%) 15 (19.5%) 0.6 (0.3-1.2) P=0.11 c thromboembo

stockings Yes

No 89 (30%) 175 (29.6%) 0.7-1 0.Post-disprophylaxis No

Yes 66 (22.2%) 176 (29.7%) 0.5-1Duration of waprophylaxis, d

Includes patients

32.8 ± 27 20.7 ± 21 P=0.19

† Includes 2 cases and 1 controls who r hospitalization.

ols who received warfarin in addition to enoxaparin during the hospitaliza‡ Includes 5 contrand 12 controls who received warfarin in addition to heparin during the hospitalization. ¶ Includes 2 cases and 8 controls who received warfarin in addition to heparin during the hospitalization.

Multivariate model of predictors of VTE after hospital discharge following THR

Table 3. Results of Multivariate Analysis of Variables Associated with Thromboembolism.*

Variable Odds Ratio ± 95% CI P Value

Age < 75 years 1.0

75-84 1.1 (0.8 - 1.5) 0.71

> 85 2.1 (1.1 – 3.9) 0.02

Female sex 1.4 (1.0 - 1.9) 0.04

Non-white race 0.9 (0.4 – 2.2) 0.84

Ambulating before second day 0.7 (0.5 – 0.9) 0.007

History of thromboembolism 3.4 (1.7 – 7.0) 0.001

Rheumatoid arthritis 0.6 (0.2 - 1.8) 0.38

Body Mass Index 1.8 (1.1 - 2.9) 0.03

Thromboprophylaxis using:

Regular heparin 1.5 (0.8 - 2.7) 0.23

Enoxaparin 0.9 (0.6 - 1.4) 0.70

Warfarin in-hospital only 0.9 (0.6 - 1.4) 0.57

Pneumatic compression †

Body mass index < 25 ‡ 0.3 (0.2 - 0.6) < 0.001

Body mass index ≥ 25 § 0.7 (0.5 - 1.1) 0.16

Warfarin post-discharge 0.6 (0.4 –1.0) 0.04

In this case control study of over 300 patients who had symptomatic VTE after THR, use of warfarin after discharge (no INR data) was a significant predictor of not developing VTE. Lower body mass was a very strong predictor of not developing VTE. In hospital prophylaxis was not a predictor of developing VTE after hospital discharge.

Is the phenomenon of late VTE restricted to patients undergoing THR? REF 3. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003 Sep;90(3):446-55.

PROCEDURE

# cases

Percent

VTE

% VTE post

discharge

Lower Limb Artery Incis,Lower Limb Endarterect 6670 6.0% 14.8% Resection Abdominal Aorta with Replacement 15480 3.7% 17.4% Aorta-Iliac-Femor Bypass + Fem, Pop Resection With Graft 8677 3.5% 20.0% Open Brain Biopsy, Ex Cereb Meningeal Les +Other Brain Excision

6557 3.1% 42.2%

Vasc Shunt & Bypass Nec 22517 3.0% 25.1% Total Hip Replacement 72468 2.9% 58.4% Incise Cerebral Meninges + Other Brain Incision 8479 2.8% 24.3% Above Knee Amputation 4526 2.6% 9.3% Partial Hip Replacement 32251 2.6% 47.1% Open Reduc-Int Fix Femur 50216 2.3% 41.2% Other Craniotomy 2450 2.3% 37.5% Total Knee Replacement 81767 2.2% 31.5% Lobectomy Of Lung + Segment + Pneumonectomy 2081 2.1% 25.0% Small Bowel Resection 8657 2.0% 32.4% Based on the above data, it appears that patients undergoing many procedures remain at risk for VTE after hospital discharge. Is there any other data to support extended prophylaxis? REF 4 .White RH, Henderson MC. Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin Pulm Med. 2002 Sep;8(5):365-71. Other evidence supporting prolonged prophylaxis comes from studies of patients with ASYMPTOMATIC THROMBOIS. In one study (Planes et al) of patients who had a negative venogram 7 to 10 days after total hip arthroplasty, 20% had a demonstrable clot 21 days later. Bergqvist and others have also shown that extended medical thromboprophylaxis using low molecular weight heparin reduces the incidence of asymptomatic VTE after THA.

Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet. 1996;348(9022):224-8.

Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement [see comments]. N Engl J Med. 1996;335(10):696-700.

When deciding on duration of prophylaxis, it does make sense to take into consideration all of the risk factors associated with both thrombosis and bleeding Risk Factor Effect Increasing age esp > 75 Modest increase in risk with age Ethnicity Lower risk in Asian/Pacific Islanders, 2-3 fold;

Modestly lower in Latinos. Prior thromboembolism Definite increase in risk, 2-3 fold Presence of a malignancy Definite increase in risk, 2 fold Delay in ambulation after surgery Modest increase in risk with delay Paraparesis or paraplegia Increased risk, magnitude uncertain Rheumatoid Arthritis ? Lower Risk Left or right sided heart failure, COPD Possibly higher risk Obesity Increase with BMI > 25, 2 fold Cemented vs non-cemented arthroplasty No difference in risk Underlying thrombophilic disorder Probably higher risk, small effect on incidence Hematocrit Possible increase with higher hematocrit Conclusion. If I need a THR and I am over the age of 70, I want 4-6 weeks of anticoagulation prophylaxis.

Extended Duration Prophylaxis Extended Duration Prophylaxis after Hip Arthroplastyafter Hip Arthroplasty-- YesYes

RICHARD H. WHITE, MDRICHARD H. WHITE, MDPROFESSOR OF MEDICINEPROFESSOR OF MEDICINEUC DAVISUC DAVIS

Arguments:Arguments:Hospitalization for THA is short (4Hospitalization for THA is short (4--5 days).5 days).Most VTE cases become manifest after hospital Most VTE cases become manifest after hospital discharge.discharge.Asymptomatic VTE can begin very late after Asymptomatic VTE can begin very late after discharge. discharge. Extended prophylaxis is effective.Extended prophylaxis is effective.ImmobilityImmobility--obesity contribute to VTE riskobesity contribute to VTE risk

a reason extended is needed.a reason extended is needed.

Arch Intern Med. 1998 Jul 27;158(14):1525-31

Time of VTE Outcomes after Total Hip SurgeryTime of VTE Outcomes after Total Hip SurgeryOutcome Primary Total Hip

(N=19,586)

During the initial hospitalization, n (%)

133 (0.7%)

During rehabilitation hospitalization, n (%)

94 (0.5%)

Requiring readmission, n (%) 329 (1.7%)†

Thrombosis can Begin Late after DischargeThrombosis can Begin Late after Discharge

Planes A, et al. Lancet. 1996;348(9022): 224-8.

Among patients who had a negative venogram 7 to 10 days after total hip arthroplasty,

20% had a demonstrable clot 21 days later.

Extended Prophylaxis Is NeededExtended Prophylaxis Is NeededDouketis, JD, Eikelboom, et al Short-duration prophylaxis against VTE:

a meta-analysis investigating symptomatic outcomes. Arch Intern Med 2002;162

Symptomatic VTE < 3 months of surgery was = 3.2%; 1.1% occurred while receiving prophylaxis in the hospital and 2.2% occurred during about 80 days of discharge (no prophylaxis)

Fatal PE occurred in 0.1% of patients:0.04% while in the hospital and 0.06% after leaving the hospital

Extended Prophylaxis is EffectiveExtended Prophylaxis is Effective

Eikelboom, et al Extended-duration prophylaxis against VTE after THAmeta-analysis of the randomised trials. Lancet 2001;358,9-15

Extended prophylaxis reduced the frequency of

- Asymptomatic DVT by 51% from 19.6 to 9.6% - Symptomatic VTE by 62% from 3.3 to 1.3%- Symptomatic PE by 57% from 0.62 to 0.15%

Conclusions Regarding Extended ProphylaxisConclusions Regarding Extended Prophylaxis

Kearon. Chest. 2003;124:386S-392S

An additional 3 weeks of LMWH therapy after the first 7 to 10 days of prophylaxis will reduce the frequency of symptomatic VTE by close to two thirds after major orthopedic surgery, such as THA.

Indirect evidence suggests that, compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin.

Warfarin for Extended ProphylaxisWarfarin for Extended Prophylaxis

White RH, eta l Predictors of rehospitalization for symptomatic VTE afterTHA. N Engl J Med. 2000 Dec 14;343(24):1758-64.

Warfarin prophylaxis

CasesCases ControlsControls OROR PP

No 231 (77.8%) 416 (70.3%) 1.0- referent

Yes 66 (22.2%) 176 (29.7%) 0.7 (0.5-1.0) P=0.02

Variable Odds Ratio ± 95% CI P Value

Age > 85 2.1 (1.1 – 3.9) 0.02

Ambulating before second day

0.7 (0.5 – 0.9) 0.007

History of thromboembolism

3.4 (1.7 – 7.0) 0.001

Body Mass Index 1.8 (1.1 - 2.9) 0.03

Hospital Prophylaxis 1.0 (0.8-1.1) NS

Pneumatic compression

Body mass index < 25 ‡ 0.3 (0.2 - 0.6) < 0.001

Body mass index ≥ 25 § 0.7 (0.5 - 1.1) 0.16

Warfarin post-discharge 0.6 (0.4 –1.0) 0.04

Conclusions:Conclusions:

To reduce the incidence of VTE, extended To reduce the incidence of VTE, extended prophylaxis is needed for the majority of patients prophylaxis is needed for the majority of patients undergoing THA.undergoing THA.

Extended prophylaxis (4Extended prophylaxis (4--6 weeks) is effective.6 weeks) is effective.

We need studies to better define patients at highWe need studies to better define patients at high--risk risk for VTE, which likely include patients with prior VTE, for VTE, which likely include patients with prior VTE, immobilityimmobility--obesity and advanced age.obesity and advanced age.

Thrombolysis in Submassive Pulmonary Embolism

Tracy Minichiello, M.D.Assistant Professor of Medicine

Director, UCSF Thrombosis & Anticoagulation ServicesDepartment of Medicine

University of California, San Francisco

Mortality in Pulmonary Embolism

Case fatality rate of PE 15% at 3 months despite standard thearpyIn-hospital mortality 30% in patients with hemodynamic instability

Goldhaber Lancet 1999; Kasper J AM Coll Cardiol 1997

Thrombolysis and Massive Pulmonary Embolism

Established treatment for massive PE Recent meta-analysis supports use of thrombolysis in patients with hemodynamic instability


Thrombolysis vs. Heparin in PE: Recurrent PE/Death all comers

If massive PE: risk 9 4% vs. 19.0% (thrombolysis vs heparin)OR 0.45, 95% CI 0.22 to 0.92; NNT=10


Thrombolysis for Non-massive PE- 1st 12 Hours

Reduced pulmonary artery pressureDecreased RV dilationReduced radiographic evidence of PE

UPET, Circulation 1973 Konsatantinides Am J Cardiol 1998 Fam N Engl J Med 2002

Thrombolysis in Non-massive PE and Mortalitytrial n Mortality

(lysis)n Mortality

(heparin)UPET 82 7% 78 9%

t-PA 105 3.8% 100 3%

Konstantinides

118 3.4% 138 2.2%

305 4.6% 316 4.1%

Dalen, J Thromb Haemost 2003

Predictors of Poor Long Term Outcome in PE

PA systolic pressure > 50mm HGEcho evidence of RV dysfunction/dilation>30% obstruction of pulmonary vascular Elevated BNPIncreased troponin

Liu, Chin Med J 2003

BNP Levels According to Clinical Outcome

Kucher N et al Circulation 2003

Relationship Between TnIConcentration and Mortality

La Vechia, L. Heart. 2004

RV Dysfunction and MortalitySource Patients RV

DysfunctionNl RV Function

Goldhaber 101 4.3 0

Kasper 317 12.6 0.9

Ribeiro 126 12.8 0

Grifoni 162 4.6 0

Total 706 9.3 0.4

Kreitt JW Chest 2004

Thrombolysis and Pulmonary Embolism-MAPPET

event Lysisn=169

Heparin n=550

P value

death 8 (4.7%) 61 (11%) 0.016

Recurrent PE

13 (7.7%) 103 (18.7%) 0.001

ICH 2 (1.2%) 2 (0.4%) ns

Kasper J Am Coll Cardiol 1997

Meta-analysis of Thrombolysis and Pulmonary Embolism

Agnelli, G. et al. Arch Intern Med 2002

Copyright restrictions may apply.

Thrombolysis for SubmassivePulmonary Embolism

RCT of thrombolysis vs. heparin therapy for submassive PE118 received heparin + altepase, 138 received heparin +placeboPrimary outcome combined endpointof “escalation of therapy” and mortality



Acute PE without hemodynamiccompromise plus

RV dysfunction on ECHOPulmonary hypertension on ECHO or right heart cathNew RV strain on ECG


Defining Submassive Pulmonary Embolism

PE without evidence of hemodynamicinstability, plus

Echocardiographic evidence of RV dysfunctionSubclinical impending right heart failureClinical evidence of pulmonary hypertension or right ventricular dysfunction


Exclusionmajor surgery/ biopsy(7days) major trauma (10 days)CVA/TIA or CNS trauma (6 months).GI bleed (3 months)uncontrolled hypertensiona known bleeding disorderknown diabetic retinopathy


Event Free Survival


In-hospital Clinical Events


Thrombolysis and Pulmonary Embolism-Bleeding risk

ICH No % 95% CI

Fatal 2/312 0.6 0.08-2.3

Nonfatal 4/312 1.3 0.3-3.3

total 6/312 1.9 0.7-4.1

Kanter CHEST 1997

Addressing Critiques of Thrombolysisin Submassive Pulmonary Embolism

Cost prohibitiveShould consider potential long term impact of therapy

No decrease in recurrent PE or mortality benefit

Study used broad definition of submassive PEIncreased major bleeding

Risk low in carefully selected patients

Thrombolysis and Pulmonary Embolism-Conclusions

Clinical studies may be used to identify patients with PE at higher risk of adverse outcomesThrombolysis may prevent clinical deterioration in selected patientsThrombolysis should be reserved for patients at low bleeding riskFuture research should address efficacy of thrombolysis in more carefully selected patients; long term impact should be assessed

THE END

Thrombolysis for Pulmonary EMbolism

Despite early improvements in hemodynamics perfusion no difference in mortality at 1-2 weeks time when compared to heparin

Base-Line Characteristics of the Study Patients


Thrombolysis and Pulmonary Embolism

14% reduction in combined endpoint of escalation of therapy and death


ThrombolysisThrombolysis in in SubmassiveSubmassivePulmonary embolism? Pulmonary embolism? NO!NO!

Dr P Dorasamy MBChB FCP FCCP FRCPC

Internist / PulmonologistAssociate ProfessorMcMaster University

Hamilton Health SciencesO t i C d

Submassive PEDefiniton

Acute PE with evidence of RV dysfunction but hemodynamicallystable

Thrombolysis in Submassive PE

MortalityMorbidityComplicationsCost

Case study

71 yr old male; 25 pack year smokerPresented with sudden onset dyspneaHR 100 RR 22 BP 100/60 ; no clinical DVTChest hyperinflated with decreased breath soundsHeart sounds normalECGCXRECHO

Spiral CT chestV/Q scanTreatment

1. Oxygen2. Heparin3. Bronchodilators

Course1. Responded well to therapy2. Repeat CT


Benefit in Massive PE established

Benefits documented by angiography, perfusion scans and echocardiography

Thrombolytics have not been shown to have a significant mortality or morbidity benefit in acute PE

Disadvantages of Thrombolytics

Increased major bleeding complications

Increased cost

Randomized trials of Heparin vs Thrombolytic therapy in hemodynamically stable PE patients

Report Lytic agent No. treated Mortality No. heparin Mortality

UPET [1] Urokinase 82 7% 78 9%

rt – PA trials [2-5] rt - PA 105 3.8% 100 3%

Konstantinides [6] rt - PA 118 3.4% 138 2.2%

TOTAL 305 4.6% 316 4.1%

6. Konstantinides et al NEJM 20021. Blackmon et al JAMA 1970; 214: 2163-722. Dalla-Volta et al J Am Coll Cardiol 19923. Goldhaber et al Lancet 19934. Levine et al Chest 19905. PIOPED Investigators - Chest 1990


Recurrent PE is the principal cause of death in hemodynamically stable PE patients

Thrombolysis will decrease mortality only if it decreased the rate of recurrent PE


In studies where recurrent PE has been documented by follow-up lung scans or pulmonary angiograms, there has been no difference between patients treated with thrombolytics or heparin (JAMA 1970; J Am Coll Cardiol 1992; Chest 1990; NEJM 2002)

Patients with hemodynamically stable PE, mortality with heparin therapy is < 5% (Dalen Arch Int Med 2002)

Thrombolytics are not appropriate in these patients

Mortality in PEPatients with submassive PE have a higher mortality ( approx. 50% of all PE patients have RV dysfunction) (Goldhaber Lancet 1993)

Mortality in patients with RV dysfunction was 4% vs 0.9% in those without RV dysfunction (RVD)

1. Am Heart J 1997 (Ribeiro et al)2. Circulation 2000 ( Grifoni et al)3. Intensive Care Med 2001 ( Vieillard-Baron et al)

In 719 PE patients who were hemodynamically stable, mortality in those with RVD was 10% vs 4.1% in those without RVD (Konstantinides et al Circulation 1997)

Mortality in PEHamel et al Chest 2001 reported from a French registry of 153 patients with massive PE treated consecutively with either Heparin or a thrombolytic; non-randomised; matched for right ventricular dysfunction, age, lung scans and the presence of cardiac or respiratory diseaseMortality in 64 pts. treated with thrombolysiswas 6% vs 0% in those treated with heparinNo difference in rate of recurrence of PE


Mortality in 118 pts. randomised to receive alteplase + heparin (3.4%) vs 138 pts. on heparin alone (2.2%)Primary end-point was in-hospital death or “clinical deterioration requiring an escalation of treatment”


Mortality in PEMortality in PEEscalation of treatment occurred in 24.6% of patients in the heparin group vs 10.2% in the alteplasegroup ( P = 0.004)Secondary thrombolysis occurred in 23% in the heparin group vs 7.6% in the alteplase group ( P = 0.001)Primary indication for secondary thrombolysis was “worsening of clinical symptoms, particularly dyspnea”.Mortality in 118 pts. randomised to receive alteplase+ heparin (3.4%) vs 138 pts. on heparin alone (2.2%)106/138 pts. in heparin group avoided complications and excessive cost of thrombolytic treatment

ThrombolysisThrombolysis in PE patients with in PE patients with shockshock

No randomized clinical trials comparing heparin to thrombolytic therapy in patients with massive PE complicated by shock

Because of high mortality (30%) in PE patients with shock, thrombolysis is considered

Shock present in 10% of patients diagnosed with PE

Impact of Impact of ThrombolysisThrombolysis on on morbidity in PEmorbidity in PE

In patients who survive acute PE, morbidity may be due to unresolved pulmonary embolic obstruction, or to recurrent PE

Thrombolytic therapy increases the early resolution rate of pulmonary embolic obstruction as assessed by repeat lung scans or pulmonary angiograms 24 h after therapy. BUT the degree of resolution 24 h after thrombolytic therapy is incomplete

Morbidity in PEMorbidity in PEThe Urokinase PE trial (UPET)(JAMA 1970)

Percent resolution by lung scan after therapy

Time since treatment Urokinase Heparin

24 h 24.1% 8.3%

2 weeks 55.4% 56.2%

1 year 78.8% 77.2%


Follow-up scans at 24 h after r-tPA treatment also demonstrated incomplete resolution (Lancet 1993, Chest 1990)

Incidence of Recurrence in UPET

Days after treatment Urokinase Heparin

2, 5, 14 7% 6%


Konstantinides et alRate of recurrence after Alteplase vsHeparin (using lung scan, spiral CT or pulmonary angiogram)

Alteplase Heparin

3.4% 2.9%


High rates of bleeding occur despite modification of dose, type of agent, rate of administration and care in avoiding arterial and venepunctures

Major bleeding Fatal hemorrhage

Levine [1] 8.4% 2.2%

Konstantinides[2]

21.9% vs 7.8%(t-PA vs Heparin)

1. Clin Chest Med 19952. Circulation 1997


Intracranial hemorrhage constitutes the most serious and lethal complication of thrombolytic therapy

Incidence of ICH in PE patients treated with thrombolytic therapyReport Patients (n) Incidence of ICH

Dalen et al 1997 [1] 559 2.1%

Goldhaber et al [2] 304 3.0%

Konstantinides et al [3] 118 0

TOTAL 981 2.1%

1. Arch Int Med 1997 2. Lancet 1999 (ICOPER) 3. NEJM 2002

Cost of Cost of ThrombolyticThrombolytic therapytherapyDrug cost: US$ 2974 for 100 mg of

Alteplase (Univ. Med Center Tucson, AZ 2003)

Cost of treating bleeding complications

Additional cost of treating the 50% ofpatients who are hemodynamically stable but with RVD

SUMMARY

There is insufficient evidence that thrombolysis benefits patients with submassive PEStudies demonstrate no mortality benefit and no difference on recurrence rates when compared to heparinThere is a significant risk of hemorrhage, including ICHThe cost of treatment is high and unjustifiable

Duration of Anticoagulation for Treatment of Acute VTE

SGIM PRECOURSEMay 11, 2005

Andrew Dunn, MD, FACPDirector, General Medicine Anticoagulation Service

Mount Sinai Medical CenterNew York, NY

A 48 year-old female presents with 4 days of right leg pain and swelling. An ultrasound confirms the presence of a right LE DVT.

The patient does not have h/o VTE, had no recent surgery or trauma, and is not on OCP or HRT. There is no family history of VTE. A thrombophilia work-up is negative.

Treatment with outpatient LMWH and warfarin is begun. LMWH is discontinued when the INR is therapeutic on day #6.

48 year-old female with idiopathic right LE DVT

How long will you treat the patient with warfarin?

• 3 months

• 6 months

• 12 months

• 2 years

• Indefinitely

• Lifelong

• Even longer

48 year-old with first idiopathic DVT

Expert opinion?

“For patients with a first episode of idiopathic DVT, we recommend treatment with a VKA for at least 6 to 12 months.”

“We suggest that patients with first-episode idiopathic DVT be considered for indefinite anticoagulant therapy.”

Buller HR. Chest. 2004;126:401S-428S.

What Is Worse?

+

Extended OAC for First VTE3 months vs 24 months

All patients received 3 months of standard treatment

Randomized to:Additional 24 months OAC (INR goal 2-3) or placebo

Study terminated early (mean f/u 10 months)

Kearon C. NEJM. 1999;340:901-7.

Extended OAC for First VTE

Standardn=79

Extendedn=83

Recurrent VTE 1 (1)17 (27) P<.001

Fatal PE 1 (1) 0 (0) P=NS

Major Bleeding 0 (0) 3 (4) P=.09

Kearon C. NEJM. 1999;340:901-7.


…and lets look 1 year (or more) later

Agnelli G. NEJM. 2001;345:165-9.


Average f/u 38 months

3 months 1 year

Recurrent VTE 21 (16)21 (16) P=NS

Recurrent VTE(months 3-12)

11 (8) 4 (3) P=NS

Major Bleeding 2 (1.5) 4 (3) P=NS

Agnelli G. NEJM. 2001;345:165-9.

Extended OAC Duration Treatment of PE

3 months OAC for acute PE vs

6 months (transient risk factor) or 12 months (idiopathic)

Followed for average of 3 years.

Italian study, 19 hospitals.

N = 326


PE Treatment3 months vs Extended Duration

3 months Extended

Recurrent VTETotal group, n (%)

15/165 (9.1)18/369 (11.2) P=NS

Recurrent VTEIdiopathic

11/90 (12.2)11/91 (12.1) P=NS

All but 1 recurrence occurred after OAC discontinued


Long-term Low-Intensity Warfarin for Prevention of Recurrent VTE

PREVENT

All received standard treatment (mean 6.5 months)N=508

Low-intensity Warfarin (INR 1.5-2.0) indefinitely vs Placebo

Average follow-up 2.1 years.

Trial terminated early

Ridker PM. NEJM. 2003:348:1425-34.

PREVENT

Standard LI OAC


37 (7.2) 14 (2.6) P<.01

Major Bleedingn (%)

2 (2) 5 (3) P=NS

Deathn (%)

8 (2) 4 (3) P=NS

Ridker PM. NEJM. 2003:348:1425-34.

Low-Intensity Warfarin vs Conventional-Intensity Warfarin for Prevention of Recurrent VTE

ELATE

Warfarin target INR 2-3 (standard intensity OAC)

Warfarin target INR 1.5-1.9 (low-intensity OAC)

N=738Average follow-up 2.4 years

Kearon C. NEJM. 2003:349:631-9.

ELATE

INR 2-3 INR 1.5-1.9


16 (1.9)6 (0.7) P<.05

Major Bleedingn (% per person-years)

8 (0.9) 9 (1.1) P=NS

Kearon C. NEJM. 2003:349:631-9.

CONCLUSIONS FROM RCTs

• Warfarin works when you are on it

• When you stop warfarin, there is a “catch-up” phenomenon

• If you are treating long-term or indefinite, you are treating lifelong

• If you are going to stop eventually, 6 months reasonable choice

• Major bleeding doesn’t happen in large RCTs

Without OAC, the recurrence rate is ~10% over the first year, then about 5% per year, and starts to wane.

Long-term recurrence rate = 30% over 8 years.

You have a 70% chance of being event free and requiring no medication or monitoring.

You have a 30% chance of a recurrent event, in which case you will need lifelong OAC. Unless you’re dead.


How Often is Recurrent VTE Fatal?

Duration of Anticoagulation Trial Study Group (DURAC)

6 weeks vs 6 months. F/U for 2 years.N = 498.

VTE recurrence 18% vs 9% (6 months superior).

Of 123 recurrences, 5 fatal (4%).

Schulman S. NEJM. 1995;332:1661-5.


Long-term follow-up study355 patients with first DVT

9 of 78 (11%) recurrences were fatal.



Analysis of California Discharge Database - VTE diagnoses

N = 71,25051,233 DVT21,625 PE

If initial dx DVT, relative risk of hospitalization for DVT = 2.7

If initial dx PE, relative risk of hospitalization for PE = 4.2

Murin S. Thromb Haem. 2002;88:407-14


Review of 25 studies of treatment of DVT or PE

Of patients with initial DVT, fatality rate of recurrence 9% (15/171).

Of patients with initial PE, fatality rate of recurrence 26% (19/72).

Douketis JD. JAMA. 1998;279:458-62

IF IT DOESN’T KILL YOU…

IT DOESN’T MAKE YOU STRONGER

Post-thrombotic syndrome at 8 years after DVT - 30%

Best predictor of PTS: Ipsilateral recurrent DVT



Randomized trials – small (~1%)

Real life – not so small, (range debatable)

Bleeding Risk from OACOutpatient Bleeding Risk Index (OBRI)

Index derived in a retrospective cohort of 556 patients.

Prospective validation in outpatients starting warfarin at a different hospital.

• Age 65 years or greater• History of gastrointestinal bleeding• History of stroke• One or more from: DM, recent MI, hct <30%, creatinine >1.5.

OVERALL - Major bleeding occurred in 87/820 outpatients (6.5%/yr).

Cumulative incidence at 48 monthsLow risk (n=80) 3% (0.8% per year)Intermediate-risk (n=166) 12% (3% per year)High-risk (n=18) 53% (13% per year)

Beyth RJ. Am J Med. 1998;91-99.

Bleeding from OACHow often is it fatal?

META-ANALYSIS

33 studies examining 4374 patient-years

Case-fatality rate 13.4%

If on OAC >3 months, case fatality rate 9.1%

Linkins L. Ann Intern Med. 2003;139:893-901.


DVT MAJOR BLEEDINGwithout warfarin with warfarin

Major Bleed rate/year 0.8 - 3%Recurrence rate over 8-10 years

30% Major Bleed over 8 years 6 - 24%




Mortality from major bleed0.6 – 2.4%

BALANCING THE FATALITY RISKSIf on low-dose warfarin

DVT MAJOR BLEEDING

Major Bleed rate/year 0.5% MAYBE!!!!!Recurrence rate over 8-10 years

12% Major Bleed over 8 years 4%

Case-fatality rate 5% Case-fatality rate

10%


Mortality from major bleed0.4% MAYBE!!!!

Total Mortality1.0%

THE BOTTOM LINE48 year-old female first idiopathic DVT

• 30% chance of recurrence long-term

• There is a 70% chance of no recurrence

• If recurs can treat lifelong

• If doesn’t recur, you saved 50 years of warfarin and decreased the risk of fatal and nonfatal bleeding

• A great opportunity to involve the patient in shared decision-making

Should a Patient with Idiopathic DVT Should a Patient with Idiopathic DVT Undergo a Hypercoagulable WorkUndergo a Hypercoagulable Work--Up?Up?

An Argument in Favor of TestingAn Argument in Favor of Testing

Matt Eisen, MDMatt Eisen, MDSGIM 28SGIM 28thth Annual Meeting Annual Meeting

Precourse PM01Precourse PM015/11/055/11/05

Why Test for Thrombophilia?Why Test for Thrombophilia?

ThrombophiliaThrombophilia::•• Is common among patients with VTEIs common among patients with VTE•• Increases the relative risk of recurrent Increases the relative risk of recurrent

VTEVTE•• May influence patient managementMay influence patient management

How Common are How Common are HypercoagulableHypercoagulable Conditions?Conditions?

Prevalence of Prevalence of HypercoagulableHypercoagulable StatesStates

HypercoagulableHypercoagulablestatestate

General General populationpopulation

Patients with Patients with 11stst VTEVTE

ThrombophilicThrombophilicfamiliesfamilies

Factor V Factor V LeidenLeiden 33--7%7% 20%20% 50%50%

ProthrombinProthrombin G20210AG20210A 11--3%3% 6%6% 18%18%

Protein C deficiencyProtein C deficiency 0.20.2--0.4%0.4% 3%3% 66--8%8%

Protein S deficiencyProtein S deficiency N/AN/A 11--2%2% 33--13%13%

AntithrombinAntithrombin deficiencydeficiency 0.02%0.02% 1%1% 44--8%8%

HyperhomocysteinemiaHyperhomocysteinemia 55--10%10% 1010--25%25% N/AN/A

Lupus anticoagulantLupus anticoagulant 00--3%3% 55--15%15% N/AN/A

AnticardiolipinAnticardiolipinantibodiesantibodies 22--7%7% 14%14% N/AN/A

Increasing Prevalence

Deitcher SR, et al. Vasc Med 2003;8(1):33-46

Prevalence of Prevalence of HypercoagulableHypercoagulable StatesStates

HypercoagulableHypercoagulable statestate General populationGeneral populationFactor V Factor V LeidenLeiden

CaucasianCaucasian 4.8%4.8%

Hispanic AmericanHispanic American 2.2%2.2%

African AmericanAfrican American 1.2%1.2%

Native AmericanNative American 1.2%1.2%

Asian AmericanAsian American 0.4%0.4%

African or AsianAfrican or Asian 0.05%0.05%

ProthrombinProthrombin G20210AG20210A

CaucasianCaucasian 2.7%2.7%

African or AsianAfrican or Asian 0.06%0.06%

Perry SL, et al. Perry SL, et al. ClinClin Chest MedChest Med 2003;24(1):1532003;24(1):153--7070

Prevalence ofPrevalence ofHypercoagulableHypercoagulable StatesStates

Key points:Key points:•• Testing will identify Testing will identify thrombophiliathrombophilia in in

2424--37% of patients with VTE37% of patients with VTE•• Selective testing increases the Selective testing increases the

likelihood of positive findingslikelihood of positive findings

How Much Risk is Associated with How Much Risk is Associated with HypercoagulableHypercoagulable Conditions?Conditions?

Relative Risk of VTERelative Risk of VTEHypercoagulableHypercoagulable statestate Relative risk of 1Relative risk of 1stst VTEVTE Relative risk of Relative risk of

recurrencerecurrenceFactor V Factor V LeidenLeiden

HeterozygousHeterozygous 77 11--44

HomozygousHomozygous 8080 44

ProthrombinProthrombin G20210AG20210A 2.82.8 11--55

FVL and G20210AFVL and G20210A N/AN/A 22--55

Protein C deficiencyProtein C deficiency 6.56.5 1.51.5--33

Protein S deficiencyProtein S deficiency 55 1.51.5--33

AntithrombinAntithrombin deficiencydeficiency 2020 1.51.5--33

HyperhomocysteinemiaHyperhomocysteinemia 2.52.5 11--33

AnticardiolipinAnticardiolipin antibodiesantibodies 1010 22--44

Bates SM, et al. Bates SM, et al. N N EnglEngl J MedJ Med 2004;351:2682004;351:268--277277

How Might the Presence of How Might the Presence of Thrombophilia Affect Patient Thrombophilia Affect Patient

Management?Management?

Duration of TherapyDuration of Therapy

Consider extended anticoagulation in Consider extended anticoagulation in patients with 1st idiopathic VTE and:patients with 1st idiopathic VTE and:•• Homozygous factor V Homozygous factor V leidenleiden or or

prothrombinprothrombin gene mutationgene mutation•• Combined heterozygous defectsCombined heterozygous defects•• Protein C or S deficiencyProtein C or S deficiency•• AntithrombinAntithrombin deficiencydeficiency•• AntiphospholipidAntiphospholipid antibodiesantibodies

Intensity/Monitoring of TherapyIntensity/Monitoring of Therapy

In patients with In patients with antiphospholipidantiphospholipidantibody syndrome:antibody syndrome:•• Consider higher target INRConsider higher target INR•• Consider monitoring by chromogenic Consider monitoring by chromogenic

factor X assayfactor X assay

Other TherapiesOther Therapies

In patients with In patients with hyperhomocysteinemiahyperhomocysteinemia::•• Consider giving Consider giving folatefolate / B6 / B12 and / B6 / B12 and

monitoring for improvement in serum monitoring for improvement in serum homocysteinehomocysteine

Screening Family MembersScreening Family Members

Finding of Finding of thrombophiliathrombophilia has has implications for:implications for:•• Decision to use Decision to use OCPsOCPs•• Decision to use HRTDecision to use HRT•• Management of pregnancyManagement of pregnancy

Feero WG. Prim Care 2004;31(3):685-709,xi

Bauer KA. Hematology (Am Soc Hematol Educ Program) 2002:353-68

What are the Costs of What are the Costs of HypercoagulableHypercoagulable Testing?Testing?

Costs of TestingCosts of Testing

•• Cost estimates range from $250 Cost estimates range from $250 --$1,000 for “standard panel”$1,000 for “standard panel”

•• One published costOne published cost--effectiveness study effectiveness study using Markov modelusing Markov model¹¹ concluded:concluded:

testing for testing for hypercoagulablehypercoagulable disorders in disorders in pts with idiopathic DVT followed by 2 pts with idiopathic DVT followed by 2 years of anticoagulation in affected pts is years of anticoagulation in affected pts is costcost--effectiveeffective

¹Auerbach AD. Am J Med 2004;116(12):816-28

The Case Against Routine The Case Against Routine Testing for HypercoagulabilityTesting for Hypercoagulability

Doug Einstadter, MD, MPHDoug Einstadter, MD, MPHCWRU at MetroHealth Medical CenterCWRU at MetroHealth Medical Center

SGIM 28SGIM 28thth Annual Meeting Annual Meeting New Orleans, LANew Orleans, LA

May 11, 2005May 11, 2005

BackgroundBackground•• A cause of thrombosis can be identified in A cause of thrombosis can be identified in

more than 80% of patients with VTE.more than 80% of patients with VTE.•• From 24 to 37% of all VTE is due to From 24 to 37% of all VTE is due to

inherited inherited thrombophiliathrombophilia..•• Testing for Testing for thrombophilia thrombophilia has become has become

increasingly common.increasingly common.•• Should testing after VTE be routine?Should testing after VTE be routine?

Commonly Requested Tests Commonly Requested Tests •• AntithrombinAntithrombin•• Protein C, Protein SProtein C, Protein S•• Factor V LeidenFactor V Leiden•• Prothrombin 20210AProthrombin 20210A•• DysfibrinogenemiaDysfibrinogenemia•• HyperhomocysteinemiaHyperhomocysteinemia•• Factor VIII, IX, XI, TAFIFactor VIII, IX, XI, TAFI•• APC resistance without Factor V LeidenAPC resistance without Factor V Leiden

Potential Reasons to TestPotential Reasons to Test

•• To determine optimal duration of therapyTo determine optimal duration of therapy•• To determine optimal intensity of therapyTo determine optimal intensity of therapy•• To identify and recommend prophylaxis for To identify and recommend prophylaxis for

asymptomatic family members during:asymptomatic family members during:–– High risk situationsHigh risk situations–– Pregnancy, oral contraceptive use, HRTPregnancy, oral contraceptive use, HRT

•• “Need to know” (intellectual curiosity)“Need to know” (intellectual curiosity)

Assumptions Underlying a Assumptions Underlying a Decision to TestDecision to Test

1.1. Presence of identified Presence of identified thrombophilia thrombophilia predicts greater risk of recurrence.predicts greater risk of recurrence.

2.2. More intense treatment for those with More intense treatment for those with thrombophilia thrombophilia leads to better outcomes.leads to better outcomes.

3.3. Family members of patients with VTE and Family members of patients with VTE and thrombophilia thrombophilia are at increased risk. are at increased risk.

4.4. Prophylactic treatment of family members Prophylactic treatment of family members leads to improved outcomes.leads to improved outcomes.

Does the Literature Support Does the Literature Support the Assumptions for Testing?the Assumptions for Testing?

Is Risk of RecurrentIs Risk of RecurrentVTE Increased?VTE Increased?

•• The overall risk of recurrent VTE in patients The overall risk of recurrent VTE in patients with and without with and without thrombophilia thrombophilia is similaris similar

HR 1.50 [95% CI 0.82–2.77]; p=0.187

Risk of Recurrent VTE with and Risk of Recurrent VTE with and without Identified without Identified ThrombophiliaThrombophilia

Lancet 2003; 362: 523Lancet 2003; 362: 523--2626


•• The overall risk in patients with and without The overall risk in patients with and without thrombophilia thrombophilia is similaris similar

•• Risk for patients with and without Risk for patients with and without heterozygous Factor V Leiden or G20210A heterozygous Factor V Leiden or G20210A is similar; risk in patients with homozygous is similar; risk in patients with homozygous Factor V Leiden probably is increasedFactor V Leiden probably is increased

Risk of Recurrent VTE in Relation to Risk of Recurrent VTE in Relation to Factor V Leiden G1691A StatusFactor V Leiden G1691A Status

Thromb Haemost 1999; 81: 684–9

Pro

porti

on fr

ee o

f rec

urre

nt e

vent

p < 0.05 for Homozygote vs. Heterozygote or Non-carriers


•• The overall risk in patients with and without The overall risk in patients with and without thrombophilia thrombophilia is similaris similar

•• Risk for patients with and without Risk for patients with and without heterozygous Factor V Leiden or G20210A heterozygous Factor V Leiden or G20210A is similar; risk in patients with homozygous is similar; risk in patients with homozygous Factor V Leiden probably is increasedFactor V Leiden probably is increased

•• The risk in patients with combinations of The risk in patients with combinations of thrombophilia thrombophilia is not well definedis not well defined

•• Other, as yet unidentified deficiencies may Other, as yet unidentified deficiencies may also affect riskalso affect risk

Duration of TherapyDuration of Therapy•• Treatment for six months provides a good Treatment for six months provides a good

balance of risks and benefits. balance of risks and benefits. •• Longer duration of treatment (up to 3 Longer duration of treatment (up to 3

years) reduces recurrence, but increases years) reduces recurrence, but increases hemorrhage risk for all patients.hemorrhage risk for all patients.

•• Prolonged duration of treatment for those Prolonged duration of treatment for those with identified with identified thrombophilia thrombophilia alone is not alone is not supported by the literature.supported by the literature.

Intensity of TherapyIntensity of Therapy•• Target INR of 2.5 is recommended for VTETarget INR of 2.5 is recommended for VTE•• Higher intensity indicated in those patients Higher intensity indicated in those patients

with thrombosis despite a therapeutic INR with thrombosis despite a therapeutic INR (regardless of identified thrombophilia)(regardless of identified thrombophilia)

•• There is no evidence to support the routine There is no evidence to support the routine use of higher intensity regimens for use of higher intensity regimens for patients with identified thrombophiliapatients with identified thrombophilia

Thrombosis PreventionThrombosis Prevention

•• There is no evidence to support primary There is no evidence to support primary prophylaxis of asymptomatic family prophylaxis of asymptomatic family members found to have thrombophilia.members found to have thrombophilia.

•• All patients, regardless of thrombophilia All patients, regardless of thrombophilia status, should receive prophylaxis during status, should receive prophylaxis during periods of high risk.periods of high risk.

Effect on Contraceptive, HRT Effect on Contraceptive, HRT and Pregnancy Advice and Pregnancy Advice

•• To prevent 1 oral contraceptive related To prevent 1 oral contraceptive related death due to PE requires screening more death due to PE requires screening more than 2 million women for Factor V Leiden.than 2 million women for Factor V Leiden.

•• There is little evidence to quantitate risk of There is little evidence to quantitate risk of VTE associated with HRT in asymptomatic VTE associated with HRT in asymptomatic women with thrombophilia. women with thrombophilia.

•• No evidence that risk : benefit ratio favors No evidence that risk : benefit ratio favors prophylaxis in pregnant asymptomatic prophylaxis in pregnant asymptomatic carriers of Factor V Leiden, G20210A, or carriers of Factor V Leiden, G20210A, or other deficienciesother deficiencies

SummarySummary

•• The current evidence does not support The current evidence does not support indiscriminate testing for indiscriminate testing for thrombophiliathrombophilia

•• Testing for heritable Testing for heritable thrombophilia thrombophilia is is unlikely to change the clinical unlikely to change the clinical management of individual patientsmanagement of individual patients

•• OverOver--testing may result in increased testing may result in increased anxiety, false reassurance, or treatment anxiety, false reassurance, or treatment related adverse eventsrelated adverse events

Stroke Prevention in AFStroke Prevention in AF

““To To AnticoagulateAnticoagulate or or Not to Anticoagulate”Not to Anticoagulate”

Steven L. Cohn, MD, FACPSteven L. Cohn, MD, FACPChief Chief –– Division of General Internal MedicineDivision of General Internal Medicine

Director Director –– Medical Consultation ServiceMedical Consultation ServiceClinical Professor of MedicineClinical Professor of Medicine

SUNY DownstateSUNY Downstate

AF, Stroke, & AnticoagulationAF, Stroke, & AnticoagulationFactors in DecisionFactors in Decision--MakingMaking

Risk factors for stroke with AFRisk factors for stroke with AF–– At age 64 w/o risk factors (with increasing age)At age 64 w/o risk factors (with increasing age)–– With hypertensionWith hypertension

Risk of stroke with/without therapyRisk of stroke with/without therapy–– ASA vs warfarin (vs no medication)ASA vs warfarin (vs no medication)

Risk of major bleedingRisk of major bleeding–– Intracranial, retroperitoneal, GIIntracranial, retroperitoneal, GI

Patient vs physician concerns/preferencesPatient vs physician concerns/preferences

Definitions of Stroke RiskDefinitions of Stroke Risk

SourceSource High RiskHigh RiskIntermediate Intermediate

RiskRisk Low RiskLow Risk

Atrial Fibrillation Atrial Fibrillation InvestigatorsInvestigators

Age Age ≥≥6565 years; history of years; history of hypertensionhypertension; CAD; diabetes; CAD; diabetes

Age Age <65 years; <65 years; no highno high--risk featuresrisk features

American College American College of Chest of Chest PhysiciansPhysicians

Age Age >75 years; history >75 years; history of of hypertensionhypertension; LV ; LV dysfunction; more than dysfunction; more than 1 intermediate risk 1 intermediate risk factorfactor

Age Age 6565--75 years; 75 years; diabetes; CAD; diabetes; CAD; thyrotoxicosisthyrotoxicosis

Age Age <65 years; <65 years; no highno high--risk featuresrisk features

Stroke Prevention Stroke Prevention in Atrial in Atrial FibrillationFibrillation

Women age Women age >75 years; >75 years; Systolic BP >160 mm Systolic BP >160 mm HgHg; LV dysfunction; LV dysfunction

History of History of hypertensionhypertension; no ; no highhigh--risk featuresrisk features

No highNo high--risk features; risk features; no history of no history of hypertensionhypertension

Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231. 2001;38:1231--1265.1265.


Stroke Risk in NewStroke Risk in New--onset AFonset AFACP/AAFP GuidelinesACP/AAFP Guidelines

CHADSCHADS22**ScoreScore

Adjusted Stroke RateAdjusted Stroke Rate††

(95% CI)(95% CI)CHADSCHADS22

Risk LevelRisk Level00 1.9 (1.21.9 (1.2--3.0)3.0) LowLow

33 5.9 (4.65.9 (4.6--7.3)7.3) ModerateModerate

44 8.5 (6.38.5 (6.3--11.1)11.1) HighHigh

55 12.5 (8.212.5 (8.2--17.5)17.5) HighHigh

66 18.2 (10.518.2 (10.5--27.4)27.4) HighHigh

11 2.8 (2.02.8 (2.0--3.8)3.8) LowLow

22 4.0 (3.14.0 (3.1--5.1)5.1) ModerateModerate

Warfarin

*Assessment of the following comorbidities: CHF, *Assessment of the following comorbidities: CHF, hypertensionhypertension, age , age ≥≥75, and diabetes 75, and diabetes (1 point each), history of stroke or TIA (2 points each). (1 point each), history of stroke or TIA (2 points each). †Expected rate of stroke per 100 patient-years.Snow et al. Ann Intern Med. 2003;139:1009-1017.

Stroke risk : 64 yearStroke risk : 64 year--old woman with HTNold woman with HTN

StudyStudy Risk categoryRisk category Stroke rate Stroke rate with no Rxwith no Rx

Stroke rate Stroke rate with ASAwith ASA

3.53.5--4.34.3

4.94.9--8.18.11.11.1--2.52.5

2.72.7--4.54.51.81.8--4.04.0

2.52.5--3.83.8

0.40.4--1.71.7

2.42.4--4.34.3

2.02.0--3.83.8

2.32.3--4.04.0

AFIAFI IntermediateIntermediate

HighHighSPAFSPAF IntermediateIntermediate

ACCPACCP HighHigh

CHADSCHADS22 LowLow

FraminghamFramingham IntermediateIntermediate

Guidelines for Stroke PreventionGuidelines for Stroke PreventionACC/AHA/ESCACC/AHA/ESC

Patient FeaturesPatient Features Antithrombotic TherapyAntithrombotic TherapyGrade of Grade of

RecommendationRecommendation

Age less than 60 yearsAge less than 60 yearsNo heart disease (lone AF)No heart disease (lone AF) Aspirin (325 mg daily) or no therapyAspirin (325 mg daily) or no therapy II

Age less than 60 yearsAge less than 60 yearsHeart disease but no risk factors*Heart disease but no risk factors* Aspirin (325 mg daily)Aspirin (325 mg daily) II

Age greater than or equal to 60 yearsAge greater than or equal to 60 yearsNo risk factors*No risk factors* Aspirin (325 mg daily)Aspirin (325 mg daily) II

Age greater than or equal to 60 yearsAge greater than or equal to 60 yearsWith diabetes mellitus or CADWith diabetes mellitus or CAD

Age greater than or equal to 75 years,Age greater than or equal to 75 years,especially womenespecially women

Oral anticoagulation (INR 2Oral anticoagulation (INR 2--3)3)Addition of aspirin, 81Addition of aspirin, 81--162 mg daily162 mg dailyis optionalis optional

Oral anticoagulation (INR Oral anticoagulation (INR ≈≈2)2)

IIIIbIIb

II

HFHFLVEF LVEF ≤≤35%.35%.ThyrotoxicosisThyrotoxicosisHypertensionHypertension

Oral anticoagulation (INR 2Oral anticoagulation (INR 2--3)3) II

Rheumatic heart diseaseRheumatic heart disease(mitral stenosis)(mitral stenosis)

Prosthetic heart valvesProsthetic heart valvesPrior thromboembolismPrior thromboembolismPersistent atrial thrombus on TEEPersistent atrial thrombus on TEE

Oral anticoagulationOral anticoagulation(INR 2.5(INR 2.5--3.5 or higher may be 3.5 or higher may be appropriate)appropriate)

II

*Risk factors for thromboembolism include HF, LVEF 35%, and history of hypertension.Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231. 2001;38:1231--1265.1265.

Expected Stroke Rate in AFExpected Stroke Rate in AFEffect of Risk Factors and AgeEffect of Risk Factors and Age

*No data on aspirin therapy.*No data on aspirin therapy.RF = risk factors: RF = risk factors: hypertensionhypertension, diabetes, prior TIA, or stroke., diabetes, prior TIA, or stroke.Ezekowitz et al. Ezekowitz et al. JAMA.JAMA. 1999;281:18301999;281:1830--1835.1835.

0

5

10

15

-- RFRF -- RFRF -- RFRF+ RF+ RF + RF+ RF + RF+ RF

Age (years)Age (years)

Stro

kes

per Y

ear (

%)

Stro

kes

per Y

ear (

%)

WarfarinWarfarinPlaceboPlacebo AspirinAspirin

>75>756565--7575<65<65

10%10%

4%4%

12%12%

**

1.7%1.7%

3.5%3.5%

1.7%1.7%

**

5.7%5.7%

1.4%1.4%1.1%1.1%

4.3%4.3%

1.7%1.7%

**

4.9%4.9%

1%1% 1%1%**

Aspirin vs PlaceboAspirin vs PlaceboReduction of Risk of Thromboembolism in AFReduction of Risk of Thromboembolism in AF

Relative Risk Reduction (95% CI)Relative Risk Reduction (95% CI)

AFASAK IAFASAK I

SPAF ISPAF I

22% (2%22% (2%--38%) 38%)

EAFTEAFT

ESPS IIESPS II

LASAFLASAF

UKUK--TIATIA

All trials=6All trials=6

00

AspirinAspirin100100 5050 --5050 --100100


Anticoagulation in AFAnticoagulation in AFStroke Risk ReductionsStroke Risk Reductions

Warfarin BetterWarfarin Better Control BetterControl Better

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

100%100% 50%50% 00 --50%50% --100%100%

AggregateAggregate

Reduction of stroke

RRR 62%

Reduction of Reduction of strokestroke

RRR 62% RRR 62%

Reduction ofall-cause mortality

RRR 26%

Reduction ofReduction ofallall--cause mortality cause mortality

RRR 26%RRR 26%


Warfarin Versus AspirinWarfarin Versus AspirinEffect of Risk Stratification on Stroke ReductionEffect of Risk Stratification on Stroke Reduction

Treatment With Warfarin Treatment With Warfarin Instead of AspirinInstead of Aspirin

Number Needed Number Needed to be Treated for to be Treated for

1 y to Prevent 1 y to Prevent 1 Stroke1 Stroke

Number of Number of Strokes Strokes

Prevented Prevented Yearly per 1000 Yearly per 1000 Given WarfarinGiven Warfarin

Risk StratificationRisk Stratification %% nnPrimary prevention*Primary prevention*Low riskLow risk 11 250250 44Moderate riskModerate risk 33 8383 1212High riskHigh risk 66 4242 †† 2424 ††

Secondary preventionSecondary prevention 1010 2525 †† 4040 ††

Annual Annual Stroke Rate Stroke Rate

With With Aspirin Aspirin TherapyTherapy

*For stratification schemes; *For stratification schemes; ††Calculations are based on a 40% relative risk reduction with Calculations are based on a 40% relative risk reduction with adjustedadjusted--dose warfarin over aspirin from metadose warfarin over aspirin from meta--analysis. The authors suspect that this analysis. The authors suspect that this overestimates the benefit of warfarin therapy in lowoverestimates the benefit of warfarin therapy in low--risk patients and importantly risk patients and importantly underestimates it for highunderestimates it for high--risk patients.risk patients.Hart. Hart. Ann Intern MedAnn Intern Med. 1999;131:688. 1999;131:688--695.695.

Severity of the Neurologic Deficit at Discharge Severity of the Neurologic Deficit at Discharge and 30and 30--Day Mortality RatesDay Mortality Rates

WarfarinWarfarin

VariableVariableNoneNone

(N=248)(N=248)AspirinAspirin(N=160)(N=160)

INR <2INR <2(N=117)(N=117)

INR INR ≥≥22(N=71)(N=71)

Severity and outcome of strokeSeverity and outcome of stroke %%

Fatal inFatal in--hospital strokehospital stroke 1414 66 99 11

Severe stroke, total dependenceSevere stroke, total dependence 88 77 66 44

Major stroke, neurologic deficit that Major stroke, neurologic deficit that prevented independent livingprevented independent living 3737 3636 4444 3838

Minor stroke, neurologic deficit that Minor stroke, neurologic deficit that did not prevent independent livingdid not prevent independent living 3636 4949 3838 5555

No neurologic sequelaeNo neurologic sequelae 55 22 33 22

Total 30Total 30--day mortalityday mortality 2424 1515 1616 66

Hylek et al. Hylek et al. N Engl J MedN Engl J Med. 2003;349:1019. 2003;349:1019--1026.1026.

Patient Concerns About AFPatient Concerns About AF

0

20

40

60

80

100

Stroke Death Major Bleeding

InconvenienceMinor Side

Effects

Cost

Perc

ent

Perc

ent

91%

38%

13%9%

2% 5%

ManMan--SonSon--Hing et al. Hing et al. Arch Intern Med.Arch Intern Med. 1996;156:18411996;156:1841--1848.1848.

Physician Concerns About Warfarin Physician Concerns About Warfarin for Stroke Prevention in AFfor Stroke Prevention in AF

0

20

40

60

80

Risk of Fall

History of GI Bleed

History of Non-CNS

Bleed

History of CV Hemorrhage

47% benefits of warfarin greatly 47% benefits of warfarin greatly outweigh risksoutweigh risks

34% benefits slightly outweigh risks34% benefits slightly outweigh risks19% risks outweigh benefits19% risks outweigh benefits

Frequently Cited ContraindicationsFrequently Cited Contraindications

Perc

ent

Perc

ent

Monette et al. Monette et al. J Am Geriatr SocJ Am Geriatr Soc. 1997;45:1060. 1997;45:1060--1065.1065.

Bleeding Rates in AF Patients Taking WarfarinBleeding Rates in AF Patients Taking WarfarinMetaMeta--analysisanalysis

SourceSource Target INRTarget INR MajorMajor†† FatalFatalSPAFSPAF 2.02.0--3.53.5 1.7%/y1.7%/y **BAATAFBAATAF 1.51.5--2.72.7 8(3.8%)8(3.8%) 1 (0.5%)1 (0.5%)Connolly et alConnolly et al 2.02.0--3.03.0 5 (2.7%)5 (2.7%) 2 (1.1%)2 (1.1%)Ezekowitz et alEzekowitz et al 1.41.4--2.82.8 6(2.3%)6(2.3%) 00SPAF IIISPAF III 2.02.0--3.03.0 12(2.1%/y)12(2.1%/y) 2 (0.4%/y)2 (0.4%/y)Morocutti et alMorocutti et al 2.02.0--3.53.5 6 (1.3%)6 (1.3%) 1 (0.2%)1 (0.2%)Gullov et alGullov et al 2.02.0--3.03.0 1.1%/y1.1%/y 0.3%/y0.3%/yPengo et alPengo et al 2.02.0--3.03.0 2.6%/y2.6%/y **

BleedingBleeding

*No data available. *No data available. ††Defined as intracranial or retroperitoneal bleeding, or bleedingDefined as intracranial or retroperitoneal bleeding, or bleeding that resulted that resulted in death, hospitalization, or transfusion.in death, hospitalization, or transfusion.Levine et al. Levine et al. ChestChest. 2001;119:108S. 2001;119:108S--121S.121S.

Intracranial Hemorrhage During LongIntracranial Hemorrhage During Long--Term Anticoagulation With WarfarinTerm Anticoagulation With Warfarin

0.00.20.40.60.81.01.21.41.61.82.0

*PV=prosthetic valves.*PV=prosthetic valves.Levine et al. Levine et al. ChestChest. 2001;119:108S. 2001;119:108S--121S.121S.

ICH

%/Y

ear

ICH

%/Y

ear

Fihn Fihn (AF)(AF)

INRINR<3.0<3.0

INRINR<3.0<3.0

Fihn Fihn (>75)(>75)

Turpie Turpie (PV*)(PV*)

SPAF SPAF ((≤≤75)75)

SPAF SPAF (AF)(AF)

PengoPengo(PV*)(PV*)

SPAF SPAF ((>>75)75)

SPAF SPAF III (AF)III (AF)

INRINR2.02.0--4.54.5

INRINR2.02.0--3.03.0 INRINR

2.52.5--3.53.5

INRINR3.03.0--4.54.5

INRINR2.02.0--4.54.5

INRINR2.02.0--4.54.5

Warfarin for AFWarfarin for AF

Adequacy of Anticoagulation inAdequacy of Anticoagulation inPatients With AF in PrimaryPatients With AF in Primary--Care PracticeCare Practice

Samsa et al. Arch Intern Med. 2000;160:967-973.

INR Above INR Above TargetTarget

6%6%

Subtherapeutic INR Subtherapeutic INR 13%13%

INR inINR inTarget RangeTarget Range

15%15%

No WarfarinNo Warfarin65%65%

N=660

Range of Anticoagulation Adequacy*Range of Anticoagulation Adequacy*

% Time Below % Time Below Target RangeTarget Range

% Time In % Time In Target RangeTarget Range

% Time Above % Time Above Target RangeTarget Range

BAATAF 88 8383 99

AFASAK 2626 7373 0.60.6

CAFA 4040 4444 1717

SPINAF 2929 5656 1515

*Percent of time in range.*Percent of time in range.BAATAF. BAATAF. N Engl J Med.N Engl J Med. 1990;323:15051990;323:1505--1511; Connolly et al. 1511; Connolly et al. J Am Coll Cardiol.J Am Coll Cardiol.1991;18:3491991;18:349--355; Ezekowitz et al. 355; Ezekowitz et al. N Engl J Med.N Engl J Med. 1992;327:14061992;327:1406--1412; Petersen et al. 1412; Petersen et al. LancetLancet. 1989;1:175. 1989;1:175--179.179.

Survival Following Ischemic StrokeSurvival Following Ischemic StrokeWarfarin vs Aspirin*Warfarin vs Aspirin*

1.01.0

Prob

abili

ty o

f Sur

viva

lPr

obab

ility

of S

urvi

val

0.90.9

0.80.8

0.70.7

0.60.6

0.00.000 55 1010 1515 2020 2525

PP=.002=.002††

Warfarin, INR Warfarin, INR ≥≥22AspirinAspirin

Warfarin, INR Warfarin, INR <2<2

NoneNone

3030Days After AdmissionDays After Admission

*Warfarin/aspirin therapy was administered before or during occurrence of stroke.††The P value refers to the overall difference among the groups.Hylek et al. N Engl J Med. 2003;349:1019-1026.

SummarySummaryRisk factors place this patient in an intermediate Risk factors place this patient in an intermediate ––high risk high risk category for risk of stroke.category for risk of stroke.

Stroke risk ranges from 2Stroke risk ranges from 2--5% without therapy.5% without therapy.

Aspirin reduces stroke risk to 0.5Aspirin reduces stroke risk to 0.5--4%.4%.

Warfarin reduces stroke risk to 1.7%.Warfarin reduces stroke risk to 1.7%.

Risk of major bleeding with warfarin is 1Risk of major bleeding with warfarin is 1--3% in general. 3% in general. Risk of ICH in Risk of ICH in thisthis patient is 0.5%. patient is 0.5%.

Risk of major bleeding with ASA is 1Risk of major bleeding with ASA is 1--2% overall.2% overall.

If patient preference favors avoiding stroke despite If patient preference favors avoiding stroke despite inconvenience and risk of bleeding, anticoagulate with inconvenience and risk of bleeding, anticoagulate with warfarin warfarin –– otherwise too close too call. otherwise too close too call.

64 year-old woman w/ Afib and HTN

Brian F. Gage, MD, [email protected]

Associate Professor of Medicine,Washington University, St. Louis

No conflicts of interest

Background

• Over 2 million Americans have atrial fibrillation

• Without antithrombotic therapy their stroke rate is increased 4- to 5-fold

• Stroke is the leading cause of adult disability and the third most common cause of death in Americans

CHADS2

• Congestive Heart Failure (1 pt.)• Hypertension (1 pt.)• Age>75 (1 pt.)• Diabetes (1 pt.)• Stroke History (2 pts.)

With 1 point, expect 2.2 (95% CI: 1.6-3.1) strokes/100 pt-yrs ASA (Gage et al. Circulation 2004)

Efficacy in Clinical Trials• In randomized, controlled trials warfarin reduced

ischemic stroke rate by 65% (hazard ratio 0.35)compared to no antithrombotic therapy

HOWEVER: • Trials excluded over 90% of patients

- Esp. patients with contraindications to warfarin (e.g. neuropsychiatric disease, poor compliance, risk for falls)

• Patients in trials are followed more meticulously than in real-life settings

Effectiveness of Warfarin Therapy for Stroke Prevention in Practice

Authors Year AC Clinic? Design Effectiveness

Go, Hylek…Singer 2003 YesRetrospective Cohort 51% (39%-60%)

Go, Hylek…Singer 2003 Yes Case-control 64% (42%-78%)

JJ Caro et al 1999 No?Prospective Cohort 69% (0%-91%)

Birman…Gage 2005 NoRetrospective Cohort 34% (25%-43%)

Subjects and Data Source for Birman-Deych…Gage study

• Subjects: National sample of 23,657 Medicare beneficiaries hospitalized between 04/01/1998 and 03/31/1999 with Atrial Fibrillation

• Data Sources:– Medical chart review (baseline hospitalization) to confirm the

presence of AF and stroke risk factors

– Medicare claims records (baseline and follow-up) for warfarin Rx and validated ICD-9-CM claims for stroke

• For details see poster #23 at session 3, “Real-world effectiveness of warfarin therapy for stroke prevention in Medicare beneficiaries of all races”

0

0.2

0.4

0.6

0.8

1

Go, Hyle

k…Singer

Go, Hyle

k…Singer

JJ Caro

et al

Birman-

Deych…Gage

RR

R W

arfa

rin

for

Stro

ke P

reve

ntio

n

Number Needed to Tx (NNT)

Event ASA Warfarin/AC Warfarin/no AC

Strokes* 2.2 0.77 1.5

ICH* 0.1 0.4 0.8

Total* 2.3 1.2 2.3

NNT 88 >1000*Events per 100 pt-years

Based on effectiveness of 15% for ASA; 41% for warfarin

Conclusions

• For patients with a CHADS2 score of 1, the decision to prescribe warfarin depends on:– The effectiveness of warfarin in the clinical setting– The risk of bleeding (esp. ICH) in the clinical setting– The patient’s preferences for taking warfarin vs. ASA– Possibly other side-effects of these antithrombotic

therapies (e.g. increased osteoporosis?, prevention of MI)

Documents

Controversies in Anticoagulation and …impak.sgim.org/userfiles/file/AMHandouts/AM05/handouts/...Controversies in Anticoagulation and Thromboembolism Amir Jaffer, MD Scott Kaatz,