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Impact of double‐blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta‐analysis
Author(s) -
Lega J.C.,
Mismetti P.,
Cucherat M.,
Fassier T.,
Bertoletti L.,
Chapelle C.,
Laporte S.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12294
Subject(s) - medicine , atrial fibrillation , stroke (engine) , warfarin , myocardial infarction , randomized controlled trial , cardiology , mechanical engineering , engineering
Summary 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 ). Objectives 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 ( C ochran's c hi‐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 X a 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.