DOACs Versus Warfarin Outcomes Across Human Development Index Levels in Atrial Fibrillation

BACKGROUND: Atrial fibrillation is common and often undertreated in low- and middle-income countries, which are underrepresented in clinical trials. Differences in healthcare systems, medication access, and anticoagulation monitoring may affect oral anticoagulant use and outcomes. The Human Development Index (HDI) is a United Nations measure of overall level of human development incorporating health, education, and standard of living. PURPOSE: To evaluate whether the efficacy and safety of DOACs versus warfarin vary by HDI in patients with AF and high risk for stroke. MethodS: Fifty-two countries across 6 continents from COMBINE-AF (an individual patient-level meta-analysis of 4 global RCTs) were stratified into very-high, high, and medium HDI groups based on standard cutpoints. Outcomes were analyzed using adjusted Cox Proportional Hazards models comparing standard-dose (SD) DOACs with warfarin stratified across the 3 HDI categories, for the primary efficacy (stroke or systemic embolic events [SSE]), safety (major bleeding) endpoints, and net clinical outcome (NCO: SSE, major bleeding, or death). Models were adjusted for baseline characteristics and time-in-therapeutic range (TTR) in the warfarin arm. HDI was also analyzed as a continuous variable. RESULTS: Among 58,015 patients, 29,055 (50.1%) received SD DOACs and 28,960 (49.9%) received warfarin. Overall, 30,660 patients (52.9%) were from very-high HDI countries, 18,997 (32.7%) from high HDI countries, and 8,358 (14.4%) from medium HDI countries. Compared to patients from very-high HDI countries, those from high and medium HDI countries were significantly younger (median ages 74, 70 and 67, respectively), had lower DOAC bleeding risk scores (median 6, 5, and 5), and lower TTR with warfarin (median 70%, 61%, and 56%; P<0.001). While HDI and TTR were weakly correlated (Pearson correlation coefficient 0.30), both were significant independent predictors of outcomes. After adjustment, SD DOACs reduced stroke/SSE consistently across HDI strata compared to warfarin (p-trend 0.29) ( Fig 1A ). The relative risk reduction in major bleeding with SD DOACs versus warfarin was greatest in lower HDI countries (p-trend <0.001) ( Fig 1B ). For the net clinical outcome, SD DOACs were associated with progressively greater benefit with decreasing HDI (p-trend 0.004) ( Fig 1C ). For every 0.10 unit increase in HDI, adjusted hazard ratios for SD DOACs vs warfarin increased by 9.5% for stroke/systemic embolism, 16.8% for major bleeding and 8.3% for net clinical outcomes (p-interactions 0.068, <0.001, 0.001, respectively) ( Fig 2 ). Conclusion: The benefits of SD DOACs over warfarin in reducing stroke or systemic embolism were consistent across HDI strata, with significantly greater reductions in major bleeding and more favorable net clinical outcomes with SD DOACs in lower HDI countries, where the potential for clinical benefit appears greatest.