A complex risk schema using a variety of such data that could accurately place more patients in the low risk stratum not requiring anticoagulants than current simple clinically based scores (personalized medicine) should be the goal of future research, but it will be very dif cult to nd non-anticoagulated patient cohorts for prospective validation. Bleeding Risk in AF Observational Studies The rates of major bleeding on vitamin K antagonists (VKAs) among observational cohorts are shown in e-Table 8 and demonstrate highly variable rates, ranging Nevertheless, there is signi cant heterogeneity between the study population characteristics, the inclusion of inception vs experienced OAC cohorts, signi cant disparity in the exposure period (follow-up) and differences in the de nitions of major bleeding employed. In addition, information on the speci c risks of bleeding of the individual cohorts, using a validated bleeding risk score, are lacking, the de nitions of major bleeding were often not provided, and the quality of anticoagulation, such as time in therapeutic range (TTR), is generally lacking. Therefore, direct comparison of the rates of major bleeding on VKA between observational cohorts and with RCTs is problematic. Clinical Trials The de nitions of major bleeding are available in most clinical trials, especially in the non-vitamin K antagonist oral anticoagulant drug (NOAC) trials where International Society on Thrombosis and Haemostasis de nitions were used.71 Before the NOAC era, the rates of major bleeding due to VKA were generally in the range of 1% to 3% per year (e-Table 9). In the 5 NOAC the annual rates of major bleeding of warfarin were between 3% and 4% (Table 3). Data from NOACs trials are more reliable, because patients were randomized to treatment, the majority were double- blinded, and the quality of anticoagulation (such as TTR) was generally better than observational studies. 