Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF): Design and Rationale: From the COMBINE AF (A Collaboration between Multiple institutions to Better Investigate Non-vitamin K antagonist oral anticoagulant use in Atrial Fibrillation) Investigators

Am Heart J. 2021 Mar;233:48-58. doi: 10.1016/j.ahj.2020.12.002. Epub 2020 Dec 6.


Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date.

Design: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771).

Conclusion: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

Keywords: Atrial fibrillation; Factor Xa inhibitor; Meta-Analysis; Stroke; Warfarin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Academic Medical Centers
  • Aged
  • Anticoagulants / therapeutic use*
  • Aspirin / therapeutic use
  • Atrial Fibrillation / complications*
  • Computer Security
  • Databases, Factual*
  • Embolism / prevention & control*
  • Female
  • Humans
  • Information Dissemination
  • Male
  • Multicenter Studies as Topic / statistics & numerical data
  • Network Meta-Analysis
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Stroke / prevention & control*
  • Warfarin / therapeutic use


  • Anticoagulants
  • Warfarin
  • Aspirin