An External Control Arm for the Oral Factor XIa Inhibitor Asundexian Phase 2 Trial in Atrial Fibrillation (PACIFIC-AF) Using Electronic Health Records.

Introduction: The aim of this study was to assess the applicability of an external control arm (ECA) approach in the clinical development of the oral factor XIa inhibitor asundexian for stroke prevention in patients with atrial fibrillation (AF), using prospectively collected data from the phase 2 PACIFIC-AF trial (NCT04218266) and real-world individual-level data from patients with AF treated with apixaban in the Optum de-identified Electronic Health Record data set (Optum EHR) 2013-2019.

Methods: To build ECAs, real-world patients meeting trial eligibility criteria were matched to patients enrolled in PACIFIC-AF. The primary outcome was the composite of International Society on Thrombosis and Haemostasis-defined major bleeding or clinically relevant non-major bleeding. Event rates were compared between PACIFIC-AF and ECAs at 85 days of trial duration and projected up to 2 years.

Results: Overall, 160,153 real-world patients met PACIFIC-AF eligibility criteria and were matched to patients from the PACIFIC-AF apixaban arm on 101 variables, with matching ratios of 1:10, 1:5, and 1:1. At day 85, the number of events for the primary outcome was 92 (3.68%) in the 1:10 ECA (2500 patients) and 6 (2.40%) in the PACIFIC-AF apixaban arm (250 patients), with incidence rates of 16.67 (90% confidence interval [CI] 13.92-19.63) and 11.10 (90% CI 4.83-19.45) per 100 person-years, respectively.

Conclusions: ECAs matching the PACIFIC-AF apixaban arm could be built from EHRs with concordant event rates for key trial endpoints. The ECA approach enabled the determination of event rates for treatment duration up to 2 years, thereby informing the asundexian pivotal phase 3 trial in AF.