Statistical Analysis Plan for a Randomized Controlled Trial of Intensive Blood Pressure Control on Cardiovascular risk Reduction in Patients with Atrial Fibrillation.

Introduction: Elevated blood pressure (BP) is a key modifiable risk factor for cardiovascular (CV) complications in patients with atrial fibrillation (AF). While current guidelines recommend modest BP targets, the optimal target in AF patients remains uncertain. The Cardiovascular Risk Reduction in Atrial Fibrillation Trial (CRAFT) is a multicenter, prospective, randomized, open-label, blinded-endpoint trial that evaluates whether intensive home systolic BP control (<120 mmHg) is superior to standard BP control (<135 mmHg) in reducing major CV events. The primary outcome is a hierarchical composite of time to CV death, stroke, myocardial infarction, and heart failure hospitalization. A total sample of 1,675 participants provides 80% power to detect a win ratio of 1.50 between groups after a mean of 3 years of follow-up.

Methods: This statistical analysis plan (SAP) was developed by the trial statistician and principal investigators, in collaboration with the steering committee and international experts. The SAP specifies the planned analyses of baseline characteristics, patients' intervention, primary and secondary outcomes, subgroup effects, and safety outcomes. Analyses will be conducted on an intention-to-treat (ITT) analysis using the win-ratio method for the primary endpoint, and Cox proportional hazards and Poisson regression for secondary analyses. Sensitivity analyses and strategies for handling missing data are also described.

Discussion: A pre-defined SAP was established for the CRAFT trial to ensure a transparent and verifiable analysis. The SAP was finalized prospectively, independent of treatment assignment, with the goal of preserving internal validity and minimizing analytical bias.