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

J. L. Blackshear, V. S. Baker, F. Rubino, R. Safford, G. Lane, T. Flipse, J. Malouf, R. Thompson, R. Webel, G. C. Flaker, L. Young, D. Hess, G. Friedman, R. Burger, J. H. McAnulty, B. M. Coull, C. Marchant, J. Timberg, C. Janzik, G. GiraudB. Halperin, J. Kron, M. Wynn, M. Raitt, D. C. Anderson, R. W. Asinger, S. M. Newburg, J. Fifield, S. R. Bundlie, R. L. Koller, R. D. Tarrel, C. Dick, J. M. Haugland, C. R. Jorgensen, A. D. Leonard, M. C. Kanter, D. H. Solomon, M. Zabalgoitia, D. Mego, J. E. Carter, S. Y. Boyd, B. S. Boop, D. LaLonde, R. Modlin, W. R. Logan, B. J. Green, W. P. Hamilton, L. Mezei, S. Riggio, G. Feldman, A. Hayward, R. Strauss, W. Anderson, J. Grover, M. McKenzie, P. Hart-McArthur, M. Gramberg, H. Houston, J. L. Halperin, E. B. Rothauf, J. M. Weinberger, M. E. Goldman, A. Laupacis, K. L. Chan, P. Bourque, J. Biggs, A. Ives, W. M. Feinberg, K. B. Kern, G. D. Pennock, P. E. Fenster, B. J. Huerta, J. Ohm, H. C. Dittrich, C. Kerridge, W. Keen, M. Swenson, S. L. Kopecky, S. C. Litin, D. O. Wiebers, A. E. Holland, R. D. Brown, B. K. Khandheria, I. Meissner, K. R. Tucker, R. Rothbart, J. Torelli, J. Schmidt, D. Murray, R. S. Ruzich, H. Loutfi, C. Appleton, T. Ingall, L. Carlson, D. Wilson, M. Dunn, B. Nolte, C. Edwards, A. Dick, L. A. Price, D. L. Janosik, P. Bjerregaard, A. Quattromani, L. Schiller, A. Labovitz, C. Burch, B. J. Parks, D. Thompson, L. Berarducci, S. Carey, A. Vigil, R. Falk, N. Battinelli, M. McNeil, R. Davidoff, S. Bernard, P. Bergethon, L. Fiori, G. Albers, E. Atwood, J. Clark, D. Tong, M. Yenari, V. Froelicker, H. Lutsep, N. H. Hock, S. Quaglietti, S. Kemp, M. A. Alpert, J. F. Rothrock, C. H. Hupp, C. V. Massey, W. J. Hamilton, V. T. Miller, J. Fox, R. A. Kronmal, R. McBride, E. Nasco, L. A. Pearce, K. Fletcher, J. Koehler, R. G. Hart, D. G. Sherman, R. L. Talbert, P. A. Heberling, C. Kajzer, E. Bovill, D. Geffken, E. Cornell, S. Nightingale, J. L. Blackshear, J. L. Halperin, R. G. Hart, A. Laupacis, J. H. McAnulty, R. McBride, S. P. Kelsy, D. E. Levy, J. D. Marsh, K. M A Welch, J. R. Marler, M. D. Walker

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Background Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. Methods 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening ≤ 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrolment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. Findings The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% CI 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Interpretation Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.

Original languageEnglish (US)
Pages (from-to)633-638
Number of pages6
JournalThe Lancet
Issue number9028
StatePublished - Sep 7 1996

Bibliographical note

Funding Information:
This study was supported by grant (R01 NS 24224) from the Division of Stroke and Trauma, National Institute for Neurological Disorders and Stroke, Bethesda, MD, USA


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