title: Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis.
abstract: BACKGROUND
  The prospective, randomized, open, blinded endpoint evaluation (PROBE) design has been proposed as a valid alternative to the double-blind (DB) design for trials comparing new oral anticoagulants (NOAs) with INR-adjusted vitamin K antagonists in patients with non-valvular atrial fibrillation (NVAF).
  
  
  OBJECTIVE
  To determine whether the observed treatment effects of NOAs in patients with NVAF differ between PROBE/open-label trials and DB trials.
  
  
  METHODS
  All phase II or III trials were eligible. The main efficacy and safety outcomes were stroke/systemic embolism (SSE) and major bleeding, respectively. Other outcomes included ischemic SSE, hemorrhagic stroke, intracranial and extracranial bleeding, myocardial infarction, and all-cause and cardiovascular mortality. Interaction (Cochran's chi-squared test) between PROBE and DB designs was tested.
  
  
  RESULTS
  Thirteen studies (61 620 patients) were included. For SSE, a greater treatment effect of NOAs vs. INR-adjusted warfarin was observed in PROBE trials (RR 0.76, CI 0.65-0.89) compared with DB trials (RR 0.88, CI 0.78-0.98), but the interaction test was non-significant (P = 0.16). A significant 67% enhancement of treatment effect was found with PROBE/open-label trials compared with DB trials (interaction test, P = 0.05) for hemorrhagic stroke. No other interaction was significant. A non-significant interaction (P = 0.07) between oral direct thrombin inhibitors (RR 0.33; 0.22-0.51) and factor Xa inhibitors (RR 0.54; 0.40-0.72) was seen. No heterogeneity was found for any outcome.
  
  
  CONCLUSIONS
  Our meta-analysis showed no significant interaction of study design for the main efficacy and safety outcomes. However, the non-significantly exaggerated reduction in SSE suggests interdependence of treatment effect and PROBE design, especially for hemorrhagic stroke.
authors: Service de Médecine Interne et de Médecine Vasculaire, Hôpital Lyon Sud, Centre Hospitalo-Universitaire de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France. jean-christophe.lega@chu-lyon.fr
authors: J-C
authors: JC
authors: Lega
authors: P
authors: P
authors: Mismetti
authors: M
authors: M
authors: Cucherat
authors: T
authors: T
authors: Fassier
authors: L
authors: L
authors: Bertoletti
authors: C
authors: C
authors: Chapelle
authors: S
authors: S
authors: Laporte
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D015982:Bias; D016009:Chi-Square Distribution; D004311:Double-Blind Method; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D016015:Logistic Models; D016017:Odds Ratio; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants
keywords: anticoagulants; atrial fibrillation; bias; meta-analysis; stroke