Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation

Summary

It has been observed that elderly patients with nonvalvular atrial fibrillation (NVAF) benefit from standard [an international normalised ratio (INR) goal of 2.0–3.0] oral anticoagulant treatment (OAT). The hypothesis that lower-intensity anticoagulation therapy can offset the higher bleeding risk in this population has never been tested in an ‘ad hoc’ clinical trial. Patients over 75 years of age with NVAF were randomised to receive warfarin to maintain the INR at 1.8 (range 1.5–2.0) or at a standard target of 2.5 (range 2.0–3.0). There were 135 patients in the low-intensity and 132 in the standard-intensity groups. During a mean follow-up lasting 5.1 years, 59 primary outcome events (thromboembolism and major haemorrhage) were recorded, 24 (3.5 per 100 patient-years) in the low-intensity group and 35 (5.0 per 100 patient-years) in the standard-intensity group (HR=0.7, 95% CI 0.4–1.1, p=0.1). The reduction in the primary endpoint was mainly due to a diminution in major bleedings (1.9 vs. 3.0 per 100 patient-years; HR=0.6, 95% CI 0.3–1.2, p=0.1). The median achieved INR value was 1.86 in the low-intensity and 2.24 in the standard-intensity group (p<0.001). The frequency of INR testing was 26.1 ± 13.5 vs. 24.3 ± 11.6 days, p<0.0001). In this exploratory study we observed a low rate of stroke and major bleeding in elderly patients (>75) being managed in an anticoagulation clinic for primary stroke prevention with low-intensity anticoagulation (INR 1.5–2.0). However, further trials are needed to confirm the hypothesis generated by the present study.

Keywords

Clinical trials - oral anticoagulants - stroke - prevention - thrombosis

• References

• 1 Furberg CD, Psaty BM, Manolio TA. et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994; 74: 236-241.
• 2 Cardiogenic brain embolism.. Cerebral Embolism Task Force. Arch Neurol 1986; 43: 71-84.
• 3 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987; 147: 1561-1564.
• 4 Aronow WS, Ahn C, Gutstein H. Prevalence of atrial fibrillation and association of atrial fibrillation with prior and new thromboembolic stroke in older patients. J Am Geriatr Soc 1996; 44: 521-523.
• 5 Yamanouchi H, Tomonaga M, Shimada H. et al. Nonvalvular atrial fibrillation as a cause of fatal massive cerebral infarction in the elderly. Stroke 1989; 20: 1653-1656.
• 6 Lin HJ, Wolf PA, Kelly-Hayes M. et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27: 1760-1764.
• 7 Longstreth Jr., WT, Bernick C, Fitzpatrick A. et al. Frequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study. Neurology 2001; 56: 368-375.
• 8 Halperin JL, Hart RG. Atrial fibrillation and stroke: new ideas, persisting dilemmas. Stroke 1988; 19: 937-941.
• 9 Kempster PA, Gerraty RP, Gates PC. Asymptomatic cerebral infarction in patients with chronic atrial fibrillation. Stroke 1988; 19: 955-957.
• 10 Petersen P, Madsen EB, Brun B. et al. Silent cerebral infarction in chronic atrial fibrillation. Stroke 1987; 18: 1098-1100.
• 11 Mant J, Hobbs FD, Fletcher K. et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493-503.
• 12 Fuster V, Ryden LE, Cannom DS. et al.; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines. Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol 2006; 48: 854-906.
• 13 Friberg L, Hammar N, Ringh M. et al. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J 2006; 27: 1954-1964.
• 14 Hylek EM, D’Antonio J, Evans-Molina C. et al. Translating the Results of Randomized Trials into Clinical Practice: The Challenge of Warfarin Candidacy Among Hospitalized Elderly Patients With Atrial Fibrillation. Stroke 2006; 37: 1075-1080.
• 15 Pradhan AA, Levine MA. Warfarin use in atrial fibrillation: A random sample survey of family physician beliefs and preferences. Can J Clin Pharmacol 2002; 9: 199-202.
• 16 Gage BF, Boechler M, Doggette AL. et al. Adverse Outcomes and Predictors of Underuse of Antithrombotic Therapy in Medicare Beneficiaries With Chronic Atrial Fibrillation. Stroke 2000; 31: 822-827.
• 17 Rosendaal FR. The Scylla and Charybdis of oral anticoagulant treatment. N Engl J Med 1996; 335: 587-589.
• 18 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: 540-546.
• 19 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: 1019-1026.
• 20 Fang MC, Chang Y, Hylek EM. et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 745-752.
• 21 The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990; 323: 1505-1511.
• 22 Hart RG. Anticoagulation for nonrheumatic atrial fibrillation. N Engl J Med 1997; 336: 441-442.
• 23 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: 433-437.
• 24 Pengo V, Barbero F, Biasiolo A. et al. Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment. Thromb Haemost 2003; 89: 760-764.
• 25 Ridker PM, Goldhaber SZ, Danielson E. et al.; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-1434.
• 26 Buller HR, Prins MH. Secondary prophylaxis with warfarin for venous thromboembolism. N Engl J Med 2003; 349: 702-704.
• 27 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. J Am Med Assoc 2001; 285: 2864-2870.
• 28 Palareti G. A guide to oral anticoagulant therapy. Italian Federation of Anticoagulation Clinics. Haemostasis 1998; 28 (Suppl. 01) 1-46.
• 29 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
• 30 Pengo V, Legnani C, Noventa F. et al. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost 2001; 85: 418-422.
• 31 Fang MC, Go AS, Hylek EM. et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006; 54: 1231-1236.
• 32 Garcia D, Hylek E. Stroke prevention in elderly patients with atrial fibrillation. Lancet 2007; 370: 460-461.
• 33 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
• 34 Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638.
• 35 The Amadeus Investigators. Comparison of idraparinux with vitamin K antagonists for
• 36 prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008; 371: 315-321.
• 37 The ACTIVE Writing Group on behalf of the ACTIVE Investigators.. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fi brillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903-1912.
• 38 Yamaguchi T. Optimal Intensity of Warfarin Therapy for Secondary Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation. A Multicenter, Prospective, Randomized Trial. Stroke 2000; 31: 817-821.
• 39 Hellemons BSP, 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. Br Med J 1999; 319: 958-964.
• 40 Crowther MA, Ginsberg JS, Julian J. et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349: 1133-1138.
• 41 Finazzi G, Marchioli R, Brancaccio V. et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3: 848-853.
• 42 Torn M, van der Meer FJ, Rosendaal FR. Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism. Arch Intern Med 2004; 164: 668-673.
• 43 Kortke H, Korfer R. International normalized ratio self-management after mechanical heart valve replacement: is an early start advantageous?. Ann Thorac Surg 2001; 72: 44-48.
• 44 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-428.
• 45 Perez-Gomez F, Salvador A, Zumalde J. et al. Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial. Eur Heart J 2006; 27: 960-967.
• 46 Wyse DG, Waldo AL, DiMarco JP. et al.; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825-1833.
• 47 Boos CJ, Lip GY. Novel therapies for the prevention of stroke. Expert Opin Investig Drugs 2004; 13: 1615-1630.
• 48 O’Donnell M, Agnelli G, Weitz JI. Emerging therapies for stroke prevention in atrial fibrillation. Eur Heart J 2005; 7: C19-27.
• 49 Hylek EM, Evans-Molina C, Shea C. et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.