Manuscript handled by: F. R. Rosendaal
Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis
Article first published online: 15 JUL 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 7, pages 1240–1250, July 2013
How to Cite
Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis. J Thromb Haemost 2013; 11: 1240–50., , , , , , .
Final decision: F. R. Rosendaal, 28 April 2013
- Issue published online: 15 JUL 2013
- Article first published online: 15 JUL 2013
- Accepted manuscript online: 9 MAY 2013 10:36AM EST
- Manuscript Received: 31 JAN 2013
- META EMBOL
- Programme Hospitalier de Recherche Clinique
- Ministère de la Santé
- atrial fibrillation;
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).
To determine whether the observed treatment effects of NOAs in patients with NVAF differ between PROBE/open-label trials and DB trials.
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.
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.
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.