Hazard ratio with 95% confidence interval of efficacy outcomes (NOACs vs warfarin) in patients with and without VHD. A, Stroke or systemic embolism. B, Death. In ARISTOTLE, patients received apixaban 5 mg twice daily. ENGAGE AF used a higher dose, and patients received edoxaban 60 mg once daily. RE‐LY was higher dose, and patients received dabigatran 150 mg twice daily. In ROCKET AF, patients received rivaroxaban 20 or 15 mg once daily. ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CI, confidence interval; ENGAGE AF, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation; IV, instrumental variable; NOAC, non–vitamin K antagonist oral anticoagulant; RE‐LY, Randomized Evaluation of Long‐Term Anticoagulation Therapy; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; VHD indicates valvular heart disease.