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. 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; J. L. Blackshear; R. G. Hart; J. H. McAnulty; R. McBride; S. P. Kelsy; D. E. Levy; J. D. Marsh; K. M.A. Welch; J. R. Marler; M. D. Walker

doi:10.1016/S0140-6736(96)03487-3

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, R. G. Hart, J. H. McAnulty, R. McBride, S. P. Kelsy, D. E. Levy, J. D. Marsh, K. M.A. Welch, J. R. Marler, M. D. Walker

Research output: Contribution to journal › Article › peer-review

1114 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	633-638
Number of pages	6
Journal	The Lancet
Volume	348
Issue number	9028
DOIs	https://doi.org/10.1016/S0140-6736(96)03487-3
State	Published - Sep 7 1996

ASJC Scopus subject areas

General Medicine

Access to Document

10.1016/S0140-6736(96)03487-3

Cite this

Blackshear, J. L., Baker, V. S., Rubino, F., Safford, R., Lane, G., Flipse, T., Malouf, J., Thompson, R., Webel, R., Flaker, G. C., Young, L., Hess, D., Friedman, G., Burger, R., McAnulty, J. H., Coull, B. M., Marchant, C., Timberg, J., Janzik, C., ... Walker, M. D. (1996). 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. The Lancet, 348(9028), 633-638. https://doi.org/10.1016/S0140-6736(96)03487-3

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. / Blackshear, J. L.; Baker, V. S.; Rubino, F. et al.
In: The Lancet, Vol. 348, No. 9028, 07.09.1996, p. 633-638.

Research output: Contribution to journal › Article › peer-review

Blackshear, JL, Baker, VS, Rubino, F, Safford, R, Lane, G, Flipse, T, Malouf, J, Thompson, R, Webel, R, Flaker, GC, Young, L, Hess, D, Friedman, G, Burger, R, McAnulty, JH, Coull, BM, Marchant, C, Timberg, J, Janzik, C, Giraud, G, Halperin, B, Kron, J, Wynn, M, Raitt, M, Anderson, DC, Asinger, RW, Newburg, SM, Fifield, J, Bundlie, SR, Koller, RL, Tarrel, RD, Dick, C, Haugland, JM, Jorgensen, CR, Leonard, AD, Kanter, MC, Solomon, DH, Zabalgoitia, M, Mego, D, Carter, JE, Boyd, SY, Boop, BS, LaLonde, D, Modlin, R, Logan, WR, Green, BJ, Hamilton, WP, Mezei, L, Riggio, S, Feldman, G, Hayward, A, Strauss, R, Anderson, W, Grover, J, McKenzie, M, Hart-McArthur, P, Gramberg, M, Houston, H, Halperin, JL, Rothauf, EB, Weinberger, JM, Goldman, ME, Laupacis, A, Chan, KL, Bourque, P, Biggs, J, Ives, A, Feinberg, WM, Kern, KB, Pennock, GD, Fenster, PE, Huerta, BJ, Ohm, J, Dittrich, HC, Kerridge, C, Keen, W, Swenson, M, Kopecky, SL, Litin, SC, Wiebers, DO, Holland, AE, Brown, RD, Khandheria, BK, Meissner, I, Tucker, KR, Rothbart, R, Torelli, J, Schmidt, J, Murray, D, Ruzich, RS, Loutfi, H, Appleton, C, Ingall, T, Carlson, L, Wilson, D, Dunn, M, Nolte, B, Edwards, C, Dick, A, Price, LA, Janosik, DL, Bjerregaard, P, Quattromani, A, Schiller, L, Labovitz, A, Burch, C, Parks, BJ, Thompson, D, Berarducci, L, Carey, S, Vigil, A, Falk, R, Battinelli, N, McNeil, M, Davidoff, R, Bernard, S, Bergethon, P, Fiori, L, Albers, G, Atwood, E, Clark, J, Tong, D, Yenari, M, Froelicker, V, Lutsep, H, Hock, NH, Quaglietti, S, Kemp, S, Alpert, MA, Rothrock, JF, Hupp, CH, Massey, CV, Hamilton, WJ, Miller, VT, Fox, J, Kronmal, RA, McBride, R, Nasco, E, Pearce, LA, Fletcher, K, Koehler, J, Hart, RG, Sherman, DG, Talbert, RL, Heberling, PA, Kajzer, C, Bovill, E, Geffken, D, Cornell, E, Nightingale, S, Blackshear, JL, Hart, RG, McAnulty, JH, McBride, R, Kelsy, SP, Levy, DE, Marsh, JD, Welch, KMA, Marler, JR & Walker, MD 1996, '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', The Lancet, vol. 348, no. 9028, pp. 633-638. https://doi.org/10.1016/S0140-6736(96)03487-3

@article{b23fcacf69034630baae01eaac856307,

title = "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",

abstract = "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.",

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

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",

year = "1996",

month = sep,

day = "7",

doi = "10.1016/S0140-6736(96)03487-3",

language = "English (US)",

volume = "348",

pages = "633--638",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "9028",

}

TY - JOUR

T1 - Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation

T2 - Stroke prevention in Atrial Fibrillation III Randomised Clinical Trial

AU - Blackshear, J. L.

AU - Baker, V. S.

AU - Rubino, F.

AU - Safford, R.

AU - Lane, G.

AU - Flipse, T.

AU - Malouf, J.

AU - Thompson, R.

AU - Webel, R.

AU - Flaker, G. C.

AU - Young, L.

AU - Hess, D.

AU - Friedman, G.

AU - Burger, R.

AU - McAnulty, J. H.

AU - Coull, B. M.

AU - Marchant, C.

AU - Timberg, J.

AU - Janzik, C.

AU - Giraud, G.

AU - Halperin, B.

AU - Kron, J.

AU - Wynn, M.

AU - Raitt, M.

AU - Anderson, D. C.

AU - Asinger, R. W.

AU - Newburg, S. M.

AU - Fifield, J.

AU - Bundlie, S. R.

AU - Koller, R. L.

AU - Tarrel, R. D.

AU - Dick, C.

AU - Haugland, J. M.

AU - Jorgensen, C. R.

AU - Leonard, A. D.

AU - Kanter, M. C.

AU - Solomon, D. H.

AU - Zabalgoitia, M.

AU - Mego, D.

AU - Carter, J. E.

AU - Boyd, S. Y.

AU - Boop, B. S.

AU - LaLonde, D.

AU - Modlin, R.

AU - Logan, W. R.

AU - Green, B. J.

AU - Hamilton, W. P.

AU - Mezei, L.

AU - Riggio, S.

AU - Feldman, G.

AU - Hayward, A.

AU - Strauss, R.

AU - Anderson, W.

AU - Grover, J.

AU - McKenzie, M.

AU - Hart-McArthur, P.

AU - Gramberg, M.

AU - Houston, H.

AU - Halperin, J. L.

AU - Rothauf, E. B.

AU - Weinberger, J. M.

AU - Goldman, M. E.

AU - Laupacis, A.

AU - Chan, K. L.

AU - Bourque, P.

AU - Biggs, J.

AU - Ives, A.

AU - Feinberg, W. M.

AU - Kern, K. B.

AU - Pennock, G. D.

AU - Fenster, P. E.

AU - Huerta, B. J.

AU - Ohm, J.

AU - Dittrich, H. C.

AU - Kerridge, C.

AU - Keen, W.

AU - Swenson, M.

AU - Kopecky, S. L.

AU - Litin, S. C.

AU - Wiebers, D. O.

AU - Holland, A. E.

AU - Brown, R. D.

AU - Khandheria, B. K.

AU - Meissner, I.

AU - Tucker, K. R.

AU - Rothbart, R.

AU - Torelli, J.

AU - Schmidt, J.

AU - Murray, D.

AU - Ruzich, R. S.

AU - Loutfi, H.

AU - Appleton, C.

AU - Ingall, T.

AU - Carlson, L.

AU - Wilson, D.

AU - Dunn, M.

AU - Nolte, B.

AU - Edwards, C.

AU - Dick, A.

AU - Price, L. A.

AU - Janosik, D. L.

AU - Bjerregaard, P.

AU - Quattromani, A.

AU - Schiller, L.

AU - Labovitz, A.

AU - Burch, C.

AU - Parks, B. J.

AU - Thompson, D.

AU - Berarducci, L.

AU - Carey, S.

AU - Vigil, A.

AU - Falk, R.

AU - Battinelli, N.

AU - McNeil, M.

AU - Davidoff, R.

AU - Bernard, S.

AU - Bergethon, P.

AU - Fiori, L.

AU - Albers, G.

AU - Atwood, E.

AU - Clark, J.

AU - Tong, D.

AU - Yenari, M.

AU - Froelicker, V.

AU - Lutsep, H.

AU - Hock, N. H.

AU - Quaglietti, S.

AU - Kemp, S.

AU - Alpert, M. A.

AU - Rothrock, J. F.

AU - Hupp, C. H.

AU - Massey, C. V.

AU - Hamilton, W. J.

AU - Miller, V. T.

AU - Fox, J.

AU - Kronmal, R. A.

AU - McBride, R.

AU - Nasco, E.

AU - Pearce, L. A.

AU - Fletcher, K.

AU - Koehler, J.

AU - Hart, R. G.

AU - Sherman, D. G.

AU - Talbert, R. L.

AU - Heberling, P. A.

AU - Kajzer, C.

AU - Bovill, E.

AU - Geffken, D.

AU - Cornell, E.

AU - Nightingale, S.

AU - Blackshear, J. L.

AU - Hart, R. G.

AU - McAnulty, J. H.

AU - McBride, R.

AU - Kelsy, S. P.

AU - Levy, D. E.

AU - Marsh, J. D.

AU - Welch, K. M.A.

AU - Marler, J. R.

AU - Walker, M. D.

N1 - 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

PY - 1996/9/7

Y1 - 1996/9/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=9544248668&partnerID=8YFLogxK

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U2 - 10.1016/S0140-6736(96)03487-3

DO - 10.1016/S0140-6736(96)03487-3

M3 - Article

C2 - 8782752

AN - SCOPUS:9544248668

SN - 0140-6736

VL - 348

SP - 633

EP - 638

JO - The Lancet

JF - The Lancet

IS - 9028

ER -

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

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