Relationship between International Normalized Ratio and Outcomes in Modern Trials with Warfarin Controls

INTRODUCTION: A target international normalized ratio (INR) of 2-3 has been recommended for patients with atrial fibrillation (AF) and risk factors for thromboembolism. This recommendation is largely based on evidence from observational studies a decade ago. This study utilized collective data from modern trials with warfarin controls to examine the relationship of warfarin anticoagulation, as assessed by INR, on the clinical outcome events of interest. METHODS: Data on warfarin-treated patients from three clinical studies supporting the approval of dabigatran (Pradaxa), apixaban (Eliquis), and edoxaban (Savaysa) were pooled. Ischemic stroke, intracranial hemorrhage (ICH), and all-cause death were selected as the outcome events of interest. Multivariate Cox regression modeling was performed to examine the association between time-dependent INR and each outcome event. Benefit-risk assessment was evaluated by summing the estimated annual event rate for ischemic stroke and ICH. RESULTS: A total of 21,883 patients representing 322 ischemic strokes, 288 ICHs, and 657 all-cause deaths were included in the analysis. The models used suggest that the risk of ischemic stroke is greatly reduced when INR exceeds 2; in contrast, the risk of ICH increases monotonically as INR increases. When combining ischemic stroke and ICH events, the lowest estimated annual event rate was observed between INR of 2 and 2.5; the risk only slightly increased between INR of 1.8 and 3.0. Similarly, a U-shaped relationship between INR and the risk of all-cause death was found. CONCLUSIONS: This study using collective warfarin data from recent large prospective trials indicates that INR between 2 and 2.5 provides the best balance between ischemic stroke and ICH, as well as optimal protection against death in patients with AF.