title: Monitoring the ACTIVE-W trial: some issues in monitoring a noninferiority trial.
abstract: Noninferiority comparisons of new to current therapies and the use of composite outcomes represent significant advances in the design of clinical trials. They increasingly characterize trials of new cardiovascular agents, posing new challenges to Data Safety Monitoring Boards (DSMB) and principal investigators. The ACTIVE-W study was a noninferiority comparison of the combination of clopidogrel and acetylsalicylic acid versus oral anticoagulant among patients with atrial fibrillation. When unexpectedly high rates of stroke and then of the composite outcome of stroke, non-central nervous system systemic embolism, myocardial infarction, and vascular death emerged, the DSMB modified its monitoring plan and conducted its first formal interim analysis much earlier than had been planned in the DSMB charter. The study was terminated when only 27% of the anticipated outcomes had occurred. This paper discusses issues of appropriate stopping guidelines for noninferiority trials and the early emergence of significant harm in relation to one component (stroke) of a composite outcome. Conditional power was not determined concurrently with the HRs during the monitoring of ACTIVE-W; however, the members of the DSMB now believe that such calculations should be considered as useful adjuncts to the calculation of HRs and could lead to earlier termination of noninferiority trials whose interim results suggest futility, without the need for convincing proof of harm.
authors: University of British Columbia, Vancouver, British Columbia, Canada. jacairns@medd.med.ubc.ca
authors: John A
authors: JA
authors: Cairns
authors: Janet
authors: J
authors: Wittes
authors: D George
authors: DG
authors: Wyse
authors: Janet
authors: J
authors: Pogue
authors: Michael
authors: M
authors: Gent
authors: Jack
authors: J
authors: Hirsh
authors: John
authors: J
authors: Marler
authors: Edward L C
authors: EL
authors: Pritchett
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage; D001241:Aspirin / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D001713:Biphenyl Compounds / Q000008:administration & dosage; D026661:Clinical Trials Data Monitoring Committees; D000077144:Clopidogrel; D003657:Decision Making; D005260:Female; D006801:Humans; D000077405:Irbesartan; D008297:Male; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D013777:Tetrazoles / Q000008:administration & dosage; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077144:Clopidogrel; D000077405:Irbesartan; D013988:Ticlopidine; D001241:Aspirin