- Email: [email protected]
Randomized clinical trials of antithrombotic therapy in atrial fibrillation: Update 2003
Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 1 2003
Randomized Clinical Trials of Antithrombotic Therapy in Atrial Fibrillation: Update 2003 ROBERT
G. H A R T ,
LESLY
A. P E A R C E ,
and SANTIAGO
RESTREPO
San Antonio, Texas and Minot, North Dakota
ABSTRACT Atrial fibrillation is a prevalent risk marker for preventable stroke. To date, 20 randomized clinical trials involving 13;843 participants have assessed antithrombotic therapies for prevention of stroke in atrial fibrillation. Here, these trials are considered, along with 8 additional randomized trials involving an additional 20,000 patients that are underway. These trials provide a ~vealth of solid evidence on which to individualize patient management to prevent stroke. A formerly neglected cause of major stroke, atrial fibrillation is now the focus of intensive clinical research aimed at stroke prevention. Keywords: stroke, atrial fibrillation, antiplatelet agents, anticoagulants, antithrombotic agents, clinical trials.
of antithrombotic agents for stroke prevention in AF (Tables 1 and 2). In 1999, we published an analysis of the first 16 randomized clinical trials of antithrombotic therapy involving 9,874 patients with nonvalvular atrial fibrillation (AF). 24 Since then, 4 additional clinical trials that included nearly 4,000 participants have been published, and 8 more are currently underway. Here, we list all 28 completed or ongoing randomized clinical trials focusing on antithrombotic therapies to prevent stroke in AF, discuss selected recent trials, and provide our perspective on this rapidly evolving area of clinical research.
By the early 1980s, it was clear from epidemiological, case-control and autopsy studies that atrial fibrillation (AF) unassociated with mitral valvular disease (ie, nonvalvular AF) was a strong, independent risk factor for stroke. Based on the presumed pathogenesis of embolism of stasis-precipitated thrombi from the left atrial appendage, it seemed likely that antithrombotic therapies would be efficacious for stroke prophylaxis. However, concern about whether elderly AF patients would tolerate such therapies without prohibitive bleeding mandated randomized clinical trials to define the overall benefits and risks. In May 1985, the first patient was randomized in the Stroke Prevention in Atrial Fibrillation (SPAF) pilot trial (a 67-year-old hypertensive man assigned aspirin and who later died from myocardial infarction during the course of the trial). Since then, more than a score of randomized clinical trials performed by investigators throughout the world have solidly established the value
Methods Randomized trials were identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group supplemented by contact with investigators working in the area.
From the Department of Medicine (Neurology) MC 7883, University of Texas Health Scienee Center, San Antonio, TX.
Results
Address reprint/requests to Robert G. Hart, MD, Department of Medicine (Neurology)MC 7883, Universityof Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: [email protected].
We identified 20 randomized trials including 13,843 participants whose results have been published or presented (Table 1). Most emanated from either Europe (n = 12) or North America (n = 6). Six U'ials involyed
9 2003 Elsevier Inc. All rights reserved.
1528-9931/03/0301-0004530.00/0 doi:10.1053/scds.2003.00010
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Table 1. Randomized Trials of Antithrombotic Therapy in Atrial Fibrillation: Published Trials* Trial
1. Copenhagen AF, Aspirin, Anticoagulation (AFASAK) I (1989)(1) 2. Boston Area Anticoagulation Trial for AF (BAFTA) (1990)(2) 3. Stroke Prevention in AF (SPAF) I (1991)(3) 4. Canadian AF Anticoagulation (CAFA) (1991)(4) 5. Stroke Prevention in Nonrbeumatic AF (SPINAF) (1992)(5) 6. European AF Trial (EAFT)(1993)(6) 7. Harenberg et al. (1993)(7) 8. Stroke Prevention in AF (SPAF) II (1994)(8) 9. Stroke Prevention in AF (SPAF) III (1996)(9) 10. Studio Italiano Eibrillazione Atriale (SIFA) (1997)(10) 11. European Stroke Prevention Study (ESPS) II (1997)(11)
N
Interventions
1007 420 1330 378 571 1007 75 1100 1044 916 429
warfarin?, aspirin, placebo warfarin?, control warfarin?, aspirin?, placebo warfarin, placebo warfarin?, placebo warfarint, aspirin, placebo LMW-heparin, control warfarin, aspirin warfarin?, LD-warfarin + aspirin warfarin, indobufen aspirin, dipyridamole, aspirin + dipyridamole, placebo warfarin, LD-warfarin, aspirin, LD-warfarin + aspirin warfarin, LD-warfarin warfarin, LD-warfarin, aspirin aspirin daily, aspirin qod, placebo aspirin (2 dosages), placebo warfarin (2 intensities) warfarin, warfarin + aspirin ximelagatran (3 dosages), warfarin ximelagatran, warfarin
12. Copenhagen AF, Aspirin, Anticoagulation (AFASAK) II (1998)(12)
677
13. Minidose Warfarin in Nonrbeumatic AF (1998)(13) 14. Prevention of Arterial Thromboembolism in AF (PATAF) (1999)(14) 15. Low-dose aspirin, stroke, AF CLASAF) (1999)(15) 16: United Kingdom TIA (UK-TIA)(1999)(16) 17. Japanese Nonvalvular AF Embolism Secondary Prevention (2000)(17) 18. Fhiindione Fibrillation Auriculaire Aspirin Contraste Spontane (FFAACS) (2001)(18) 19. Stroke Prevention using an Oral Thrombin Inhibitor in AF (SPORTIF) II (2001)(19) 20. Stroke Prevention using an Oral Thrombin Inhibitor in AF (SPORTIF) III (2003)(20)
303 729 285 49 115 157 257 3410
*In order of year of publication; AF = atrial fibrillation, LMW = low-molecular weight, LD = low-dose, qod = every other day. In the EAFT and PATAF, a variety of oral vitamin K antagonists were used in addition to warfarin. ?Indicates a statistically significant result reported for efficacy.
> 1,000 participants, with one mega-trial ( S P O R T I F III) i n c l u d i n g 3,410 participants. E x c l u d i n g these six large trials (8,898 participants), the n u m b e r of participants in the r e m a i n i n g 14 trials averaged 353 (range 49-916); their results were frequently inconclusive. M o s t trials studied oral v i t a m i n K inhibitors or aspirin in various dosages/intensities, but other antiplatelet agents (dipyridamole, i n d o b u f e n ) and anticoagulants (low-molecularweight heparin, an oral t h r o m b i n inhibitor) were also assessed. F i v e trials had a d o u b l e - b l i n d design,4,5,11,15,16 with three others i n c l u d i n g on-site potential stroke e v e n t assessment b y neurologists u n a w a r e of treatment allocat i o n to m i n i m i z e bias. 3,8,9 The last four published trials, perhaps less w e l l - k n o w n , are discussed in m o r e detail below. T h e goal o f the Japanese N o n v a l v u l a r Atrial Fibrillation E m b o l i s m Secondary Prevention Trial was to corn-
pare two target intensities of warfarin anticoagulation: target I N R 1.5 to 2.1 versus I N R 2.2 to 3.5.17 Based on retrospective studies, it was hypothesized that the lower I N R range w o u l d be better tolerated by Japanese patients and that efficacy for stroke p r e v e n t i o n w o u l d be similar. A c h i e v e d INRs were 1.9 versus 2.3 w h e n the study was stopped at an interim analysis because o f a perceived excess of major bleeding in those given m o r e intensive anticoagulation (6 vs. 0 m a j o r hemorrhages, P = .01). The risk of major hemorrhage was u n u s u a l l y high (6.6% per year) in A F patients with a m e a n age of 67 years g i v e n c o n v e n t i o n a l intensity anticoagulation, possibly because of the high rates observed d u r i n g short-term follow-up, race-specificity, or the play of chance. Too few strokes occurred to m e a n i n g f u l l y assess the relative efficacies of the two target intensities of anticoagulation. In short, this trial showed that lower intensity anticoag-
Table 2. Randomized Trials of Antithrombotic Therapy in Atrial Fibrillation: Unpublished and Ongoing Trials* Trial
1. Swedish AF Trial (SAFT)(21) 2. Stroke Prevention Using an Oral Thrombin Inhibitor in AF (SPORTIF) V (22) 3. Japan AF Stroke Prevention Trial (JAST) 4. NASPEAF (Spain) 5. Birmingham AF Treatment in the Aged (BAFTA) (23) 6. Hong Kong 7. AF Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE)-W 8. AF Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE)-A
N
Intervention
Anticipated Results
668 3922 895 901t (1240) (200) (6500) (7500)
LD-warfarin, control ximelagatran, warfarin aspirin, control triflusal, warfarin, both warfarin, aspirin warfarin, clopidogrel warfarin, clopidogrel + aspirin clopidogrel + aspirin, aspirin
2003 2003 2003 2004 2006 ? 2006-7 2006-7
*AF = atrial fibrillation, LD = low-dose. Numbers in parentheses are anticipated recruitment in ongoing trials. ?311 additional participants had mitral stenosis.
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Seminarsin Cerebrovascular Diseasesand StrokeVol. 3 No. 1 March 2003
ulation is probably safer than higher intensity for Japanese AF patients, but no firm conclusions can be drawn about overall benefit versus risk because of the small number of stroke events and brief follow-up. The FFAACS trial compared warfarin alone (achieved INR 2.3) versus warfarin plus aspirin in 157 AF patients, mean age of 74 years and with hypertension or other additional risk factors for stroke. 18 The trial was stopped early because of poor recruitment combined with lack of funding. At that point, only a handful of strokes and major hemorrhages had occurred; minor hemorrhages were more frequent in those assigned to the combination of warfarin plus aspirin. Of note, the observed rate of major bleeding (1.4% per year) among older French AF patients was lower than that reported in the Japanese trial discussed above, despite similar mean achieved INRs, although the confidence intervals for the rates overlapped widely because of the small numbers of events. The SPORTIF II pilot trial tested three dosages of a novel oral direct thrombin inhibitor, ximelagatran, versus adjusted-dose warfarin in 257 AF patients. 19 Ximelagatran was well tolerated, and this initial experience prompted two large phase III trials. SPORTIF III was conducted in Europe, Asia and Australasia, randomizing 3,410 moderate and high risk AF patients to oral ximelagatran 36 mg twice daily versus adjusted-dose warfarin (target INR 2 to 3). 22 Ximelagatran met preset criteria for equivalence compared with high-quality anticoagulation, with a strong trend toward superiority for reducing stroke and with comparably low rates of major hemorrhage. Liver function test abnormalities were reported in about 6% of those given ximelagatran. 2~ Results of the companion double-blinded SPORTIF V carried-out in North America involving 3,900 participants should be available in late 2003 and will importantly supplement these preliminary results of SPORTIF III. In addition to these 20 published/presented trials, eight randomized trials are underway (Table 2) It is anticipated that over 20 thousand participants with AF wilt be involved and include 3 mega-trials comparing adjusteddose warfarin to ximelagatran and to combined antiplatelet therapy (clopidogrel plus aspirin). The Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) trial is of particular interest, as AF patients who are age 75 years or older will be randomly assigned to receive adjusted-dose warfarin (target INR 2.5) versus aspirin (75 mg/d)73 The risks and benefits of warfarin (target INR 2-4.5) versus aspirin (325 mg/d) had been assessed in the early 1990s among 385 AF patients in the SPAF II randomized trial, 8 in which an intolerably high rate of intracranial hemorrhage and frequent treatment dropouts combined to make stroke rates during anticoagulation comparable to those during aspirin (Fig 1). BAFTA includes four important design differences that will make it of special importance in reas-
S P A F I1: Results 12 "c" 10 "-"
8
0r
6
e-
>
ua
Age > 75yrs ~- p=NS 7
4
0
Aspirin Warfarin
Fig. 1. Combined rates of ischemic (gray) and hemorrhagic (red) strokes according to antithrombotic therapy assignment (vertical lines are 95% CIs) among participants over age 75 years in the SPAF II trial.
sessing the value of warfarin versus aspirin: better control of anticoagulation using INRs, a target INR that is lower, safer but efficacious, better control of hypertension (impacting the rate of anticoagulation-associated intracerebral hemorrhage), and execution by general practice physicians in "real-life" clinical circumstances.
Discussion A score of randomized clinical trials testing antithromboric therapies in AF patients have been published since 1989 providing a wealth of solid evidence on which to base patient management. These multiple trials from multiple investigator groups around the world testing a variety of antithrombotic regimens reflect the general health and vigor of the international stroke research community during the past decade. Adjusted-dose warfarin reduces stroke by about 60% compared with no antithrombotic therapy for most AF patients, while aspirin reduces stroke by about 20%. 24 Compared with aspirin, adjusted-dose warfarin reduces stroke by about 45% based on a recent pooled analysis of individual patient data from 6 randomized trials (the best available evidence). 2s There is no convincing evidence favoring one dosage of aspirin over another; the trial reporting the largest stroke reduction used 325 mg/d. 3 Regarding the optimal intensity of anticoagulation with oral vitamin K antagonists, achieved INRs between 1.6 to 3.0 markedly reduce stroke in AF patients; the only trial directly comparing two different intensities (the
Clinical Trials in Atrial Fibrillation Japanese trial discussed above) was inconclusive because of a paucity of patients and events. 17 The two trials reporting the largest stroke reduction had estimated mean achieved INRs of about 2.1.2,5 F o l l o w i n g the "first generation" antithrombotic trials in A F , there r e m a i n e d a persistent need for agents that were m o r e efficacious than aspirin and that w e r e safer and m o r e easily a d m i n i s t e r e d than a d j u s t e d - d o s e warfarin. Clinical trials of low, fixed-dose warfarin that did not p r o l o n g the INR, alone or c o m b i n e d with aspirin, failed to demonstrate sufficient efficacy for treatment of h i g h - r i s k A F patients. Clinical trials now u n d e r w a y ( S P O R T I F III and V , A C T I V E , N A S P E A F ) continue to explore alternatives m e e t i n g these i needs. The impressive relative risk reduction in stroke by adjusted-dose warfarin does not imply a clinically important benefit for all (or even most) A F patients. The intrinsic stroke risk in A F patients varies 20-fold. M a n y low risk A F patients do not substantially benefit from warfarin, and these patients can be reliably identified76 High risk A F patients (particularly those with prior stroke or TIA) have particularly large relative and absolute stroke rate reductions by warfarin because of the preponderance of cardioembolic stroke events. 24-26 Choice of antithrombotic prophylaxis should not (and should never) be based on relative risk reduction, but rather on the best estimate of the absolute benefits for individual patients. Because antiplatelet and anticoagulant agents have been proven to benefit most A F patients, future trials must compare novel antithrombotic regimens to active therapy, rather than to no treatment, to be ethical, in our view. Several recent trials have been designed as equivalence/noninferiority comparisons with adjusted-dose warfarin. Such designs generally call for larger sample sizes and are consequently more expensive. W h a t is the relevant clinical margin of equivalence? Estimates vary by medical subspecialists and among A F patients themselves. More needs to be known to apply the results of these equivalence trials optimally. F r o m a neglected cause of major ischemic stroke, A F has become the focus of a score and more clinical trials during the past decade, with further advances on the horizon. Efficacious antithrombotic prophylaxis has been firmly established for millions of people harboring this dysrhythmia.
Acknowledgment Supported by a research grant (UO1-NS 38,529) from the National Institute of Neurological Disorders and Stroke, U.S. Public Health Service.
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References 1. Petersen P, Boysen G, Godtffedsen J, et al: Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1:175-179, 1989 2. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators: The effect of low-dose warfarin on the risk of stroke in nonrheumatic atrial fibrillation. N Engl J Med 323:1505-1511, 1990 3. Stroke Prevention in Atrial Fibrillation Investigators: The Stroke Prevention in Atrial Fibrillation Study: Final results. Circulation 84: 527-539, 1991 4. Connolly SJ, Laupacis A, Gent M, et al: Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 18:349-355, 1991 5. 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 327:1406-1412, 1992 6. Emopean Atrial Fibrillation Trial Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. Lancet 342:12551262, 1993 7. Harenberg J, Weuster B, Pfitzer M, et al: Prophylaxis of embolic events in patients with atrial fibrillation using low molecular weight heparin. Semin Thromb Hemost 19:116121, 1993 (suppl 1) 8. Stroke Prevention in Atrial Fibrillation Investigators: Warfarin vs. aspirin for prevention of thromboembolism in atrial fibrillation. Lancet 343:687-691, 1994 9. Stroke Prevention in Atrial Fibrillation Investigators: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 348:633-638, 1996 10. Morocutti C, Amablie G, Fattapposta F, et al: Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke 28: 1015-1021, 1997 11. Diener HC, Lowenthal A: Antiplatelet therapy to prevent stroke: Risk of brain hemorrhage and efficacy in atrial fibrillation. J Neurol Sci 153:112, 1997 12. Gullov AL, Koefoed BG, Petersen P, et al: Mini-dose warfarin and aspirin in atrial fibrillation. Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study (AFASAK 2). Arch Int Med 158:1513-152l, 1998 13. 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 82:433-437, 1998 14. Hellemons BS, Langenberg M, Lodder J, et al: Primary prevention of arterial thromboembolism in nonrheumatic atrial fibrillation in primary care: Randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 319:958-964, 1999 15. Posada IS, Barriales V for the LASAF Pilot Study Group:
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17.
18.
19.
20.
Seminarsin Cerebrovascular Diseasesand Stroke Vol. 3 No. 1 March 2003 Alternate-day dosing of aspirin in atrial fibrillation. Am Heart J 138:137-143, 1999 Benavente O, Hart R, Koudstaal P, et al: Antiplatelet therapy for preventing stroke in patients with atrial fibrillation and no previous history of stroke or transient ischemic attacks, in Warlow C, Van Gijn J, Sandercock P (eds): Stroke Module of the Cochrane Database of Systematic Reviews. Oxford, The Cochrane Collaboration, 2003, pp; CD-ROM available from BMJ Publishing Group (London) Yamaguchi T for Japanese Nonvalvular Atrial Fibrillation Embolism Secondary Prevention Cooperative Study Group: Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation. Stroke 31:817-821, 2000 Lechat P, Lardoux H, Mallet A, et al: Anticoagulant (flunidone)-aspirin combination in patients with high risk atrial fibrillation. A randomized trial (Fluindone, Fibrillation Auriculaire, Aspirin et Contrast Spontane, FFAACS). Cerebrovasc Dis 12:245-252, 2001 Petersen P: Long-term treatment of patients using the new oral direct thrombin inhibitor ximelagatran versus warfarin in moderate to high stroke risk patients with atrial fibrillation. J Neurol Sci 187:S124, 2001 (suppl I) Halperin JL: SPORTIF III results presented at the session
21.
22.
23.
24.
25.
26.
on Late-Breaking Clinical Trials, American College of Cardiology Annual Meeting. Chicago, IL, April 2, 2003 Edvardsson N, Juul-Moller S, Omblus R, et al: Effects of low-dose warfarin and aspirin versus no treatment on stroke in a medium-risk patient population with atrial fibrillation. J Intern Med 2003 (in press) Executive Steering Committee on behalf of the SPORTIF 111 and V Investigators: Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: Rationale, objectives and design of a pair of clinical trials and baseline patient characteristics (SPORTIF HI and V). Am Heart J 2003 (in press) Mant J, Richards S, Fitzmaurice D, et al: RCT of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly (aged 75 or over) primary care population. Cerebrovas Dis 13:79, 2002 (suppl 3) Hart RG, Benavente O, McBride R, et al: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 131:492-501, 1999 van Walraven C, Hart RG, Singer DE, et al: Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: An individual patient metanalysis. JAMA 288:2441-2448, 2002 Hart RG, Halperin JL, Pearce LA, et al: Key lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann tnt Med 2003 (in press)
Randomized Clinical Trials of Antithrombotic Therapy in Atrial Fibrillation: Update 2003 ROBERT
G. H A R T ,
LESLY
A. P E A R C E ,
and SANTIAGO
RESTREPO
San Antonio, Texas and Minot, North Dakota
ABSTRACT Atrial fibrillation is a prevalent risk marker for preventable stroke. To date, 20 randomized clinical trials involving 13;843 participants have assessed antithrombotic therapies for prevention of stroke in atrial fibrillation. Here, these trials are considered, along with 8 additional randomized trials involving an additional 20,000 patients that are underway. These trials provide a ~vealth of solid evidence on which to individualize patient management to prevent stroke. A formerly neglected cause of major stroke, atrial fibrillation is now the focus of intensive clinical research aimed at stroke prevention. Keywords: stroke, atrial fibrillation, antiplatelet agents, anticoagulants, antithrombotic agents, clinical trials.
of antithrombotic agents for stroke prevention in AF (Tables 1 and 2). In 1999, we published an analysis of the first 16 randomized clinical trials of antithrombotic therapy involving 9,874 patients with nonvalvular atrial fibrillation (AF). 24 Since then, 4 additional clinical trials that included nearly 4,000 participants have been published, and 8 more are currently underway. Here, we list all 28 completed or ongoing randomized clinical trials focusing on antithrombotic therapies to prevent stroke in AF, discuss selected recent trials, and provide our perspective on this rapidly evolving area of clinical research.
By the early 1980s, it was clear from epidemiological, case-control and autopsy studies that atrial fibrillation (AF) unassociated with mitral valvular disease (ie, nonvalvular AF) was a strong, independent risk factor for stroke. Based on the presumed pathogenesis of embolism of stasis-precipitated thrombi from the left atrial appendage, it seemed likely that antithrombotic therapies would be efficacious for stroke prophylaxis. However, concern about whether elderly AF patients would tolerate such therapies without prohibitive bleeding mandated randomized clinical trials to define the overall benefits and risks. In May 1985, the first patient was randomized in the Stroke Prevention in Atrial Fibrillation (SPAF) pilot trial (a 67-year-old hypertensive man assigned aspirin and who later died from myocardial infarction during the course of the trial). Since then, more than a score of randomized clinical trials performed by investigators throughout the world have solidly established the value
Methods Randomized trials were identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group supplemented by contact with investigators working in the area.
From the Department of Medicine (Neurology) MC 7883, University of Texas Health Scienee Center, San Antonio, TX.
Results
Address reprint/requests to Robert G. Hart, MD, Department of Medicine (Neurology)MC 7883, Universityof Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: [email protected].
We identified 20 randomized trials including 13,843 participants whose results have been published or presented (Table 1). Most emanated from either Europe (n = 12) or North America (n = 6). Six U'ials involyed
9 2003 Elsevier Inc. All rights reserved.
1528-9931/03/0301-0004530.00/0 doi:10.1053/scds.2003.00010
38
Clinical Trials in Atrial Fibrillation
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Hartet al
39
Table 1. Randomized Trials of Antithrombotic Therapy in Atrial Fibrillation: Published Trials* Trial
1. Copenhagen AF, Aspirin, Anticoagulation (AFASAK) I (1989)(1) 2. Boston Area Anticoagulation Trial for AF (BAFTA) (1990)(2) 3. Stroke Prevention in AF (SPAF) I (1991)(3) 4. Canadian AF Anticoagulation (CAFA) (1991)(4) 5. Stroke Prevention in Nonrbeumatic AF (SPINAF) (1992)(5) 6. European AF Trial (EAFT)(1993)(6) 7. Harenberg et al. (1993)(7) 8. Stroke Prevention in AF (SPAF) II (1994)(8) 9. Stroke Prevention in AF (SPAF) III (1996)(9) 10. Studio Italiano Eibrillazione Atriale (SIFA) (1997)(10) 11. European Stroke Prevention Study (ESPS) II (1997)(11)
N
Interventions
1007 420 1330 378 571 1007 75 1100 1044 916 429
warfarin?, aspirin, placebo warfarin?, control warfarin?, aspirin?, placebo warfarin, placebo warfarin?, placebo warfarint, aspirin, placebo LMW-heparin, control warfarin, aspirin warfarin?, LD-warfarin + aspirin warfarin, indobufen aspirin, dipyridamole, aspirin + dipyridamole, placebo warfarin, LD-warfarin, aspirin, LD-warfarin + aspirin warfarin, LD-warfarin warfarin, LD-warfarin, aspirin aspirin daily, aspirin qod, placebo aspirin (2 dosages), placebo warfarin (2 intensities) warfarin, warfarin + aspirin ximelagatran (3 dosages), warfarin ximelagatran, warfarin
12. Copenhagen AF, Aspirin, Anticoagulation (AFASAK) II (1998)(12)
677
13. Minidose Warfarin in Nonrbeumatic AF (1998)(13) 14. Prevention of Arterial Thromboembolism in AF (PATAF) (1999)(14) 15. Low-dose aspirin, stroke, AF CLASAF) (1999)(15) 16: United Kingdom TIA (UK-TIA)(1999)(16) 17. Japanese Nonvalvular AF Embolism Secondary Prevention (2000)(17) 18. Fhiindione Fibrillation Auriculaire Aspirin Contraste Spontane (FFAACS) (2001)(18) 19. Stroke Prevention using an Oral Thrombin Inhibitor in AF (SPORTIF) II (2001)(19) 20. Stroke Prevention using an Oral Thrombin Inhibitor in AF (SPORTIF) III (2003)(20)
303 729 285 49 115 157 257 3410
*In order of year of publication; AF = atrial fibrillation, LMW = low-molecular weight, LD = low-dose, qod = every other day. In the EAFT and PATAF, a variety of oral vitamin K antagonists were used in addition to warfarin. ?Indicates a statistically significant result reported for efficacy.
> 1,000 participants, with one mega-trial ( S P O R T I F III) i n c l u d i n g 3,410 participants. E x c l u d i n g these six large trials (8,898 participants), the n u m b e r of participants in the r e m a i n i n g 14 trials averaged 353 (range 49-916); their results were frequently inconclusive. M o s t trials studied oral v i t a m i n K inhibitors or aspirin in various dosages/intensities, but other antiplatelet agents (dipyridamole, i n d o b u f e n ) and anticoagulants (low-molecularweight heparin, an oral t h r o m b i n inhibitor) were also assessed. F i v e trials had a d o u b l e - b l i n d design,4,5,11,15,16 with three others i n c l u d i n g on-site potential stroke e v e n t assessment b y neurologists u n a w a r e of treatment allocat i o n to m i n i m i z e bias. 3,8,9 The last four published trials, perhaps less w e l l - k n o w n , are discussed in m o r e detail below. T h e goal o f the Japanese N o n v a l v u l a r Atrial Fibrillation E m b o l i s m Secondary Prevention Trial was to corn-
pare two target intensities of warfarin anticoagulation: target I N R 1.5 to 2.1 versus I N R 2.2 to 3.5.17 Based on retrospective studies, it was hypothesized that the lower I N R range w o u l d be better tolerated by Japanese patients and that efficacy for stroke p r e v e n t i o n w o u l d be similar. A c h i e v e d INRs were 1.9 versus 2.3 w h e n the study was stopped at an interim analysis because o f a perceived excess of major bleeding in those given m o r e intensive anticoagulation (6 vs. 0 m a j o r hemorrhages, P = .01). The risk of major hemorrhage was u n u s u a l l y high (6.6% per year) in A F patients with a m e a n age of 67 years g i v e n c o n v e n t i o n a l intensity anticoagulation, possibly because of the high rates observed d u r i n g short-term follow-up, race-specificity, or the play of chance. Too few strokes occurred to m e a n i n g f u l l y assess the relative efficacies of the two target intensities of anticoagulation. In short, this trial showed that lower intensity anticoag-
Table 2. Randomized Trials of Antithrombotic Therapy in Atrial Fibrillation: Unpublished and Ongoing Trials* Trial
1. Swedish AF Trial (SAFT)(21) 2. Stroke Prevention Using an Oral Thrombin Inhibitor in AF (SPORTIF) V (22) 3. Japan AF Stroke Prevention Trial (JAST) 4. NASPEAF (Spain) 5. Birmingham AF Treatment in the Aged (BAFTA) (23) 6. Hong Kong 7. AF Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE)-W 8. AF Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE)-A
N
Intervention
Anticipated Results
668 3922 895 901t (1240) (200) (6500) (7500)
LD-warfarin, control ximelagatran, warfarin aspirin, control triflusal, warfarin, both warfarin, aspirin warfarin, clopidogrel warfarin, clopidogrel + aspirin clopidogrel + aspirin, aspirin
2003 2003 2003 2004 2006 ? 2006-7 2006-7
*AF = atrial fibrillation, LD = low-dose. Numbers in parentheses are anticipated recruitment in ongoing trials. ?311 additional participants had mitral stenosis.
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Seminarsin Cerebrovascular Diseasesand StrokeVol. 3 No. 1 March 2003
ulation is probably safer than higher intensity for Japanese AF patients, but no firm conclusions can be drawn about overall benefit versus risk because of the small number of stroke events and brief follow-up. The FFAACS trial compared warfarin alone (achieved INR 2.3) versus warfarin plus aspirin in 157 AF patients, mean age of 74 years and with hypertension or other additional risk factors for stroke. 18 The trial was stopped early because of poor recruitment combined with lack of funding. At that point, only a handful of strokes and major hemorrhages had occurred; minor hemorrhages were more frequent in those assigned to the combination of warfarin plus aspirin. Of note, the observed rate of major bleeding (1.4% per year) among older French AF patients was lower than that reported in the Japanese trial discussed above, despite similar mean achieved INRs, although the confidence intervals for the rates overlapped widely because of the small numbers of events. The SPORTIF II pilot trial tested three dosages of a novel oral direct thrombin inhibitor, ximelagatran, versus adjusted-dose warfarin in 257 AF patients. 19 Ximelagatran was well tolerated, and this initial experience prompted two large phase III trials. SPORTIF III was conducted in Europe, Asia and Australasia, randomizing 3,410 moderate and high risk AF patients to oral ximelagatran 36 mg twice daily versus adjusted-dose warfarin (target INR 2 to 3). 22 Ximelagatran met preset criteria for equivalence compared with high-quality anticoagulation, with a strong trend toward superiority for reducing stroke and with comparably low rates of major hemorrhage. Liver function test abnormalities were reported in about 6% of those given ximelagatran. 2~ Results of the companion double-blinded SPORTIF V carried-out in North America involving 3,900 participants should be available in late 2003 and will importantly supplement these preliminary results of SPORTIF III. In addition to these 20 published/presented trials, eight randomized trials are underway (Table 2) It is anticipated that over 20 thousand participants with AF wilt be involved and include 3 mega-trials comparing adjusteddose warfarin to ximelagatran and to combined antiplatelet therapy (clopidogrel plus aspirin). The Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) trial is of particular interest, as AF patients who are age 75 years or older will be randomly assigned to receive adjusted-dose warfarin (target INR 2.5) versus aspirin (75 mg/d)73 The risks and benefits of warfarin (target INR 2-4.5) versus aspirin (325 mg/d) had been assessed in the early 1990s among 385 AF patients in the SPAF II randomized trial, 8 in which an intolerably high rate of intracranial hemorrhage and frequent treatment dropouts combined to make stroke rates during anticoagulation comparable to those during aspirin (Fig 1). BAFTA includes four important design differences that will make it of special importance in reas-
S P A F I1: Results 12 "c" 10 "-"
8
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6
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ua
Age > 75yrs ~- p=NS 7
4
0
Aspirin Warfarin
Fig. 1. Combined rates of ischemic (gray) and hemorrhagic (red) strokes according to antithrombotic therapy assignment (vertical lines are 95% CIs) among participants over age 75 years in the SPAF II trial.
sessing the value of warfarin versus aspirin: better control of anticoagulation using INRs, a target INR that is lower, safer but efficacious, better control of hypertension (impacting the rate of anticoagulation-associated intracerebral hemorrhage), and execution by general practice physicians in "real-life" clinical circumstances.
Discussion A score of randomized clinical trials testing antithromboric therapies in AF patients have been published since 1989 providing a wealth of solid evidence on which to base patient management. These multiple trials from multiple investigator groups around the world testing a variety of antithrombotic regimens reflect the general health and vigor of the international stroke research community during the past decade. Adjusted-dose warfarin reduces stroke by about 60% compared with no antithrombotic therapy for most AF patients, while aspirin reduces stroke by about 20%. 24 Compared with aspirin, adjusted-dose warfarin reduces stroke by about 45% based on a recent pooled analysis of individual patient data from 6 randomized trials (the best available evidence). 2s There is no convincing evidence favoring one dosage of aspirin over another; the trial reporting the largest stroke reduction used 325 mg/d. 3 Regarding the optimal intensity of anticoagulation with oral vitamin K antagonists, achieved INRs between 1.6 to 3.0 markedly reduce stroke in AF patients; the only trial directly comparing two different intensities (the
Clinical Trials in Atrial Fibrillation Japanese trial discussed above) was inconclusive because of a paucity of patients and events. 17 The two trials reporting the largest stroke reduction had estimated mean achieved INRs of about 2.1.2,5 F o l l o w i n g the "first generation" antithrombotic trials in A F , there r e m a i n e d a persistent need for agents that were m o r e efficacious than aspirin and that w e r e safer and m o r e easily a d m i n i s t e r e d than a d j u s t e d - d o s e warfarin. Clinical trials of low, fixed-dose warfarin that did not p r o l o n g the INR, alone or c o m b i n e d with aspirin, failed to demonstrate sufficient efficacy for treatment of h i g h - r i s k A F patients. Clinical trials now u n d e r w a y ( S P O R T I F III and V , A C T I V E , N A S P E A F ) continue to explore alternatives m e e t i n g these i needs. The impressive relative risk reduction in stroke by adjusted-dose warfarin does not imply a clinically important benefit for all (or even most) A F patients. The intrinsic stroke risk in A F patients varies 20-fold. M a n y low risk A F patients do not substantially benefit from warfarin, and these patients can be reliably identified76 High risk A F patients (particularly those with prior stroke or TIA) have particularly large relative and absolute stroke rate reductions by warfarin because of the preponderance of cardioembolic stroke events. 24-26 Choice of antithrombotic prophylaxis should not (and should never) be based on relative risk reduction, but rather on the best estimate of the absolute benefits for individual patients. Because antiplatelet and anticoagulant agents have been proven to benefit most A F patients, future trials must compare novel antithrombotic regimens to active therapy, rather than to no treatment, to be ethical, in our view. Several recent trials have been designed as equivalence/noninferiority comparisons with adjusted-dose warfarin. Such designs generally call for larger sample sizes and are consequently more expensive. W h a t is the relevant clinical margin of equivalence? Estimates vary by medical subspecialists and among A F patients themselves. More needs to be known to apply the results of these equivalence trials optimally. F r o m a neglected cause of major ischemic stroke, A F has become the focus of a score and more clinical trials during the past decade, with further advances on the horizon. Efficacious antithrombotic prophylaxis has been firmly established for millions of people harboring this dysrhythmia.
Acknowledgment Supported by a research grant (UO1-NS 38,529) from the National Institute of Neurological Disorders and Stroke, U.S. Public Health Service.
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