Low-dose warfarin in atrial fibrillation leads to more thromboembolic events without reducing major bleeding when compared to adjusted-dose

Summary

The use of warfarin with a range INR of 2.0-3.0 is recommended in prevention of stroke for nonvalvular atrial fibrillation (AF) patients, in particular those older than 75 years. The risk of bleeding that is associated with this range of INR has led to evaluate lower ranges (low-dose or fixed minidose) in terms of risks and benefits. A meta-analysis of all randomized controlled trials evaluating ‘low-intensity’ ‘minidose’ or ‘low-dose anticoagulant’ treatment for prevention of thromboembolic events in AF was conducted by two independent reviewers. Study quality was evaluated in a blinded fashion. Four original studies were retrieved. Outcome events were determined in various treatment groups: ischemic stroke, systemic embolism, thromboses (ischemic stroke, systemic embolism or myocardial infarction), vascular death, major hemorrhage and hemorrhagic death. Results obtained with a random effects model were expressed as a common relative risk. Adjusted-dose warfarin compared with lower dose warfarin (INR ≤1.6) in 2108 randomised patients significantly reduced the risk of any thrombosis: Relative risk (RR): 0.50 (95% CI; 0.25 to 0.97).The RR was 0.46 (95%CI ; 0.2 to 1.07) for ischemic stroke. Inversely lower dose did not statistically decrease the risk for major hemorrhage compared to adjusted-dose: RR adjusted-dose vs lower dose: 1.23 (95% CI ; 0.67-2.27). The RR was 0.97 (95 % CI 0.27-3.54) for hemorrhagic death. Our meta-analysis showed that adjusted-dose compared with low-dose or minidose warfarin therapy (INR ≤1.6) was more effective to prevent ischemic thromboembolic events in patients with atrial fibrillation.

Keywords

Atrial fibrillation - thrombosis - warfarin - low-dose

• References

• 1 Petersen P, Boysen G, Godtfredsen J. et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrilllation. The Copenhagen AFASAK study. Lancet 1989; 01: 175-9.
• 2 Petersen P, Kastrup J, Helweg-Larsen S. et al. Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Arch Intern Med 1990; 150: 819-21.
• 3 The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11.
• 4 Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991; 84: 527-39.
• 5 Connolly SJ, Laupacis A, Gent M. et al. for the CAFA Study Coinvestigators. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18: 349-55.
• 6 Ezekowitz MD, Bridgers SL, James KE. et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992; 327: 1406-12.
• 7 Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687-91.
• 8 Hart RG, Benavente O, McBride R. et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation : a meta-analysis. Ann Intern Med 1999; 131: 492-501.
• 9 Desbiens NA. Deciding on anticoagulating the oldest old with atrial fibrillation: insights from cost-effectiveness analysis. J Am Geriatr Soc 2002; 50: 863-9.
• 10 Levine MN, Raskob G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S-121S.
• 11 Pengo V, Legnani C, Noventa F. et al. Oral anticoagulant therapy in patients with non-rheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost 2001; 85: 418-22.
• 12 Moher D, Cook DJ, Eastwood S. et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354: 1896-900.
• 13 Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation Embolism Secondary Prevention Cooperative Study Group. Stroke 2000; 31: 817-21.
• 14 Cucherat M, Boissel JP, Leizorovicz A. et al. EasyMA: a program for the meta-analysis of clinical trials. Comput Methods Programs Biomed 1997; 53: 187-90.
• 15 Chalmers TC, Smith H, Blackburn B. et al. A method for assessing the quality of a randomized control trial. Control Clin Trials 1981; 02: 31-49.
• 16 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-8.
• 17 Gullov AL, Koefoed BG, Petersen P. et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158: 1513-21.
• 18 Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. Arch Intern Med 1999; 159: 1322-8.
• 19 Hellemons BS, Langenberg M, Lodder J. et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 1999; 319: 958-64.
• 20 Pengo V, Zasso A, Barbero F. et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: 433-7.
• 21 American Geriatrics Society Clinical Practice Committee. The use of oral anticoagulants (warfarin) in older people. American Geriatrics Society guideline. J Am Geriatr Soc 2002; 50: 1439-45.
• 22 Fuster V, Rydén LE, Asinger RW. et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: 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). Eur Heart J 2001; 22: 1852-923.
• 23 Beyth RJ, Quinn L, Landefeld CS. A multi-component intervention to prevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Ann Intern Med 2000; 133: 687-95.
• 24 Fihn SD, McDonell M, Martin D. et al. Risk factors for complications of chronic anti-coagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: 511-20.
• 25 Hylek EM, Skates SJ, Sheehan MA. et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-6.
• 26 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: 1019-26.
• 27 Ridker PM, Goldhaber SZ, Danielson E. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-34.