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
Authors: 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, David C Hess, G. Friedman, R. Burger, J. H. McAnulty, B. M. Coull, C. Marchant, J. Timberg, C. Janzik, G. Giraud, B. 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, S. P. Kelsy, D. E. Levy, J. D. Marsh, K. M.A. Welch, J. R. Marler, M. D. Walker
Journal: The Lancet (1996)

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.1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, 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.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% Cl 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.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.