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Early Termination of the Stroke Prevention in Atrial Fibrillation I Trial: Protecting Participant Interests in the Face of Scientific Uncertainties and the Cruel Play of Chance

  • Robert G. Hart
  • Lesly A. Pearce
  • Ruth McBride
  • Richard A. Kronmal
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Abstract

The Stroke Prevention in Atrial Fibrillation (SPAF) I trial evaluated aspirin and warfarin for prevention of stroke and nonCNS emboli in elderly patients with nonvalvular atrial fibrillation. Participants were categorized as either warfarin-eligible or warfarin-ineligible based on contraindications to or refusal of anticoagulation, and interim efficacy monitoring examined treatment effects separately by warfarin eligibility. The planned primary analyses compared aspirin to placebo among all participants and warfarin to placebo among warfarin-eligible patients. The study was terminated early following the second interim analysis due to a large reduction in thromboembolic events by aspirin versus placebo among the subgroup of warfarin-eligible participants (1 vs. 18, respectively, relative risk reduction = 94%, p < 0.001). This reduction was not evident among warfarin-ineligible patients (25 vs. 28, respectively, relative risk reduction = 8%, p = 0.8). The reduction by aspirin vs. placebo for all aspirin-assigned patients (the planned primary analysis) was significant (26 vs. 46, respectively, relative risk reduction = 42%, p = 0.02), but this resulted from pooling of subgroups with dissimilar responses. While the extreme effect of aspirin in anticoagulation-eligible participants was suspected to be due to the play of chance, termination of the SPAF I trial was justified to protect the interests of warfarin-eligible participants assigned placebo. The potential implications of interim efficacy monitoring of multiple subgroups should be carefully considered when planning interim monitoring.

Keywords

Atrial Fibrillation Interim Analysis Stroke Prevention Relative Risk Reduction Case Study Approach 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Hart RG, Halperin JL, Pearce LA, Anderson DC, Kronmal RA, McBride R, et al. 2003. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med 138:831–838.Google Scholar
  2. 2.
    Stroke Prevention in Atrial Fibrillation Investigators. 1990. Design of a multicenter randomized trial for the Stroke Prevention in Atrial Fibrillation Study. Stroke 21:538–545.CrossRefGoogle Scholar
  3. 3.
    Stroke Prevention in Atrial Fibrillation Investigators. 1993. A differential effect of aspirin in the Stroke Prevention in Atrial Fibrillation Study. J Stroke Cerebrovasc Dis 3:181–188.CrossRefGoogle Scholar
  4. 4.
    Stroke Prevention in Atrial Fibrillation Investigators. 1991. The Stroke Prevention in Atrial Fibrillation Study: Final results. Circulation 84:527–539.Google Scholar
  5. 5.
    Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. 1989. 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.CrossRefGoogle Scholar
  6. 6.
    Antiplatelet Trialists’ Collaboration. 1988. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists’ Collaboration. BMJ 296:320–331.CrossRefGoogle Scholar
  7. 7.
    Stroke Prevention in Atrial Fibrillation Investigators. 1994. Warfarin vs. aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 343:687–691.Google Scholar
  8. 8.
    Stroke Prevention in Atrial Fibrillation Investigators. 1990. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med 322:863–868.Google Scholar
  9. 9.
    Hart RG, Benavente O, McBride R, Pearce LA. 1999. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A Meta-analysis. Ann Intern Med 131:492–501.Google Scholar
  10. 10.
    Atrial Fibrillation Investigators. 1997. The efficacy of aspirin in patients with atrial fibrillation: Analysis of pooled data from three randomized trials. Arch Intern Med 157:1237–1240.CrossRefGoogle Scholar
  11. 11.
    Antithrombotic Trialists’ Collaboration. 2002. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86.CrossRefGoogle Scholar
  12. 12.
    van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, Petersen P, et al. 2002. Oral anticoagulants vs. aspirin in nonvalvular atrial fibrillation: An individual patient metanalysis. JAMA 288:2441–2448.CrossRefGoogle Scholar
  13. 13.
    Pocock SJ. The role of external evidence in data monitoring of a clinical trial. 1996. Stat Med 15:1285–1293.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Robert G. Hart
    • 1
  • Lesly A. Pearce
    • 2
  • Ruth McBride
    • 3
  • Richard A. Kronmal
    • 4
  1. 1.Department of Medicine (Neurology)University of Texas Health Science CenterSan Antonio
  2. 2.Minot
  3. 3.Axio Research CorporationSeattle
  4. 4.Department of BiostatisticsUniversity of WashingtonSeattle

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