Research Article| Volume 6, ISSUE 5, P341-353, July 1997

The stroke prevention in atrial fibrillation III study: Rationale, design, and patient features

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      Clinical trials have consistently shown warfarin's high degree of efficacy for stroke prevention in patients with nonvalvular atrial fibrillation (AF). However, aspirin therapy may be sufficient for large subgroups of low-risk AF patients. In addition, many elderly AF patients cannot receive or sustain adjusted-dose warfarin because of bleeding (minor and major), drug interactions, and other disutility. For such patients, a safer and easier to administer anticoagulation regimen is desirable. The Stroke Prevention in Atrial Fibrillation (SPAF) III Study has two components, based on stratification of patients as high-risk or low-risk for thromboembolism. In high-risk patients, adjusted-dose warfarin (INR 2.0 to 3.0) is compared with low-intensity, fixed-dose warfarin (INR 1.2 to 1.5 initial dose adjustment) plus aspirin (325 mg/d) in a randomized trial. Patients categorized as low-risk all receive aspirin 325 mg/d and are followed-up to assess the reliability and durability of the risk stratification scheme. Medications are administered open-label. Primary events (ischemic strokes and systemic emboli) are assessed by a local neurologist and verified by an Events Committee, neither having knowledge of assigned treatment. Transesophageal echocardiography is obtained at entry, when possible. High-risk criteria for the 1,044 patients in the randomized trial (mean age,=72 years) are impaired left ventricular function (45%), systolic blood pressure >160 mm Hg (32%), prior thromboembolism (38%), and female gender over age 75 years (24%). The mean INR is 2.4 for adjusted-dose and 1.3 for fixed-dose warfarin, with mean daily doses of 3.9 mg and 2.1 mg, respectively. Compared with high-risk patients, those categorized as low-risk (n=892) are younger (mean age, 67 years; P<.001), with lower mean systolic blood pressures, (P<.001), and less ischemic heart disease (P<.001), but similar diastolic blood pressures. Given the large variation in stroke rate among AF patients, blanket recommendations for antithrombotic prophylaxis of all AF patients are not optimal. Patient age, gender, left ventricular function, and systolic blood pressure may be useful markers of the inherent thromboembolic risk and may influence selection of antithrombotic therapy to prevent stroke in AF patients.

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        • Atrial Fibrillation Investigators
        Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
        Arch Intern Med. 1994; 154: 1449-1457
        • Albers GW
        Atrial fibrillation and stroke: Three new studies, three remaining question.
        Arch Intern Med. 1994; 154: 1443-1448
        • Wolf PA
        • Abbott RD
        • Kannel WB
        Atrial fibrillation is an independent risk factor for stroke: The Framingham Study.
        Stroke. 1991; 22: 983-988
        • EAFT Study Group
        European Atrial Fibrillation Trial: Secondary prevention of vascular events in patients with nonrheumatic atrial fibrillation and recent transient ischemic attack or minor ischemic stroke.
        Lancet. 1993; 342: 1255-1262
        • Stroke Prevention in Atrial Fibrillation Investigators
        Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Stroke Prevention in Atrial Fibrillation II Study.
        Lancet. 1994; 343: 687-691
        • Stroke Prevention in Atrial Fibrillation Investigators
        The Stroke Prevention in Atrial Fibrillation Study. Final results.
        Circulation. 1991; 84: 527-539
        • Petersen P
        • Boysen G
        Prevention of stroke in atrial fibrillation.
        N Engl J Med. 1990; 323: 482
        • Hart RG
        • Halperin JL
        Atrial fibrillation and stroke: Revisiting the dilemmas.
        Stroke. 1994; 25: 1337-1341
        • Laupacis A
        • Albers G
        • Dunn M
        • Feinberg W
        Antithrombotic therapy in atrial fibrillation.
        Chest. 1992; 102: 426S-433S
        • Matchar D
        Guidelines for medical treatment for stroke prevention.
        Ann Intern Med. 1994; 121: 41-53
        • Barnett HJM
        • Eliasziw M
        • Meldrum H
        Drugs and surgery in the prevention of ischemic stroke.
        N Engl J Med. 1995; 332: 238-248
        • Feinberg WM
        • Blackshear JL
        • Laupacis A
        • Kronmal R
        • Hart RG
        Prevalence, age distribution and gender of patients with atrial fibrillation. Analysis and implications.
        Arch Intern Med. 1995; 155: 469-473
        • Stroke Prevention in Atrial Fibrillation Investigators
        Predictors of thromboembolism in atrial fibrillation. I: clinical features in patients at risk.
        Ann Intern Med. 1992; 116: 1-5
        • Stroke Prevention in Atrial Fibrillation Investigators
        Predictors of thromboembolism in atrial fibrillation. II: echocardiographic features in patients at risk.
        Ann Intern Med. 1992; 116: 6-12
        • Stroke Prevention in Atrial Fibrillation Investigators
        A differential effect of aspirin for the prevention of stroke in atrial fibrillation.
        J Stroke Cerebrovasc Dis. 1993; 3: 181-188
        • Stroke Prevention in Atrial Fibrillation Investigators
        Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation Study.
        J Stroke Cerebrovasc Dis. 1995; 5: 147-157
        • Miller VT
        • Rothrock JF
        • Pearce LA
        • Feinberg WM
        • Hart RG
        • Anderson DC
        Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism.
        Neurology. 1993; 43: 32-36
        • Miller VT
        • Pearce LA
        • Feinberg WM
        • Rothrock JF
        • Anderson DC
        • Hart RG
        Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation.
        Neurology. 1996; 46: 238-240
        • Landefeld CS
        • Beyth RJ
        Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention.
        Am J Med. 1993; 95: 315-328
        • Gottlieb LK
        • Salem-Schatz S
        Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice.
        Arch Intern Med. 1994; 154: 1945-1953
        • Mathiesen T
        • Benediktsdottir K
        • Johnsson H
        • Lindquist M
        • von Holst H
        Intracranial traumatic and nontraumatic hemorrhagic complications of warfarin treatment.
        Acta Neurol Scand. 1995; 91: 208-214
        • Gitter MJ
        • Jaeger TM
        • Petterson TM
        • Gersh BJ
        • Silverstein MD
        Bleeding and thromboembolism during anticoagulant therapy: A population-based study in Rochester, Minnesota.
        Mayo Clin Proc. 1995; 70: 725-733
        • Connolly S for the Atrial Fibrillation Investigators
        Stroke prevention in Atrial Fibrillation II study.
        Lancet. 1994; 343 ([letter]): 1509
        • Hart RG
        • Boop BS
        • Anderson DC
        Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.
        Stroke. 1995; 26: 1471-1477
        • Stroke Prevention in Atrial Fibrillation Investigators
        Committee on Echocardiography. Transesophageal echocardiography in nonvalvular atrial fibrillation: standards for acquisition and interpretation.
        J Am Soc Echocardiogr. 1996; 9: 556-566
        • Poller L
        • McKernan A
        • Thomson JM
        • Elstein M
        • Hirsch PJ
        • Jones JB
        Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery.
        BMJ. 1987; 295: 1309-1312
        • Bern MM
        • Lokich JJ
        • Wallach SR
        • Bothe A
        • Benotti PN
        • Arkin CF
        • Greco FA
        • Huberman M
        • Moore C
        Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized clinical trial.
        Ann Intern Med. 1990; 112: 423-428
        • Fordyce MJF
        • Baker AS
        • Staddon GE
        Efficacy of fixed mini-dose warfarin prophylaxis in total hip replacement.
        BMJ. 1991; 303: 219-220
        • Stein B
        • Fuster V
        • Halperin JL
        • Chesebro JH
        Antithrombotic risk in cardiac disease: an emerging approach based on pathogenesis and risk.
        Circulation. 1989; 80: 1501-1513
        • Turpie AGG
        • Gent M
        • Laupacis A
        • Littour Y
        • Gunstensen J
        • Basile F
        • Klimek M
        • Hirsch J
        A comparison of aspirin with placebo in patients treated with warfarin and heart valve replacement.
        N Engl J Med. 1993; 329: 524-529
        • Chesebro JH
        • Fuster V
        • Elveback LR
        • McGoon DC
        • Pluth JR
        • Puga FJ
        • Wallace RB
        • Danielson GK
        • Orszulak TA
        • Piehler JM
        • Schaff HV
        Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole.
        Am J Cardiol. 1983; 51: 1537-1541
        • Meade TW
        • Wilkes HC
        • Stirling Y
        • Brennan PJ
        • Kelleher C
        • Browne W
        Randomized controlled trial of low-dose warfarin in the primary prevention of ischemic heart disease in men at high risk: design and pilot study.
        Eur Heart J. 1988; 9: 836-843
        • Prichard PJ
        • Kitchingman GK
        • Walt RP
        • Daneshund TK
        • Hawkey CJ
        Human gastromucosal bleeding induced by low dose aspirin, but not warfarin.
        BMJ. 1989; 298: 496
        • Hawthorne AB
        • Mahida YR
        • Cole AT
        • Hawkey CJ
        Aspirin-induced gastric mucosal damage: prevention by enteric coating and relation to prostaglandins synthesis.
        Br J Clin Pharmacol. 1991; 32: 77-83
        • Thompson SG
        • Kienast J
        • Pyke SDM
        • Haverkate F
        • Van de Loo JCW
        Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.
        N Engl J Med. 1995; 332: 635-641
        • Kistler JP
        • Singer DE
        • Millenson MM
        • Bauer KA
        • Gress DR
        • Barzegar S
        Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation.
        Stroke. 1993; 24: 1360-1365
        • Bussey JI
        • Force RW
        • Bianco TM
        • Leonard AD
        Reliance on prothrombin time ratios causes significant errors in anticoagulant therapy.
        Arch Intern Med. 1992; 152: 278-282
        • Landefeld CB
        • Anderson PA
        • Goodnough LT
        • Moir TW
        • Hom DL
        • Rosenblatt MW
        • Goldman L
        The bleeding severity index: validation and comparison to other methods for classifying bleeding complications of medical therapy.
        J Clin Epidemiol. 1989; 42: 711-718
        • Kannell WB
        • Abbott RD
        • Savage DD
        • McNamara P
        Epidemiologic features of chronic atrial fibrillation: The Framingham Study.
        N Engl J Med. 1982; 306: 1018-1022
      1. Feinberg WM, Kronmal RA, Newman A, et al. Thromboembolic risk factors in an elderly population, with artial fibrilation: The Cardiovascualr Health Study. Submitted for publication.

        • Stoddard MF
        • Dawkins PR
        • Prince CR
        • Ammash NM
        Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study.
        J Am Coll Cardiol. 1995; 25: 452-459
        • Brown J
        • Sadler DB
        Left atrial thrombi in nonrheumatic atrial fibrillation: assessment of prevalence by transesophageal echocardiography.
        Int J Card Imaging. 1993; 9: 65-72
        • Vaziri SM
        • Larson MG
        • Lauer MS
        • Benjamin EJ
        • Levy D
        Influence of blood pressure on left atrial size. The Framingham Study.
        Hypertension. 1995; 25: 1155-1160
        • Flegel KM
        • Harley J
        Risk factors for stroke and other embolic events in patients with nonrheumatic atrial fibrillation.
        Stroke. 1989; 20: 1000-1004
        • Moulton AW
        • Singer DE
        • Haas JS
        Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study.
        Am J Med. 1991; 91: 156-161
        • Chan KL
        Transesophageal echocardiographic risk factors for stroke are related to gender and age: observations from the SPAF III Study.
        Circulation. 1995; 92 ([suppl 1, abstr]): I-283
        • Asinger RW
        • Dick CD
        Clinical and transthoracic echo predictors of left atrial spontaneous echo contrast in patients with nonvalvular atrial fibrillation.
        Circulation. 1995; 92 ([suppl 1, abstr]): I-284
        • Man-Son-Hing M
        • Laupacis A
        • O'Connor A
        • Wells G
        Warfarin for atrial fibrillation: the patient's perspective.
        Arch Intern Med. 1996; 156: 1841-1848
        • Flegel KM
        • Hutchinson TA
        • Gromme PA
        • Tousignant P
        Factors relevant to preventing embolic stroke in patients with nonrheumatic atrial fibrillation.
        J Clin Epidemiol. 1991; 44: 551-560
        • Hurlen M
        • Erikssen J
        • Smith P
        • Arnesen H
        • Rollag A
        Comparisons of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3,166 outpatients.
        J Intern Med. 1994; 236: 299-304
        • Goodman SG
        • Langer A
        • Durica SS
        • Raskols GE
        • Comys PC
        • Gray RJ
        • et al.
        Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease.
        Am J Cardiol. 1994; 74: 657-661
        • Meade TW
        • Roderick PJ
        • Brennan PJ
        • Wilkes HC
        • Kelleher CC
        Extracranial bleeding and other symptoms due to low dose aspirin and low intensity oral anticoagulation.
        Thromb Haemostas. 1992; 68: 1-6
        • European Atrial Fibrillation Trial Study Group
        Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia.
        N Engl J Med. 1995; 333: 5-10