Predictions from randomized controlled trials

Estimated rates from randomized controlled trials of thromboembolic and major bleeding events within low, medium, and high risk categories were obtained from publications of the RE-LY trial comparing dabigatran to warfarin and the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin (additional details in the web appendix).⁴

The RE-LY trial published rates of stroke or systemic embolism for participants within three categories of CHADS₂ (0-1, 2, ≥3) for participants randomized to receive either warfarin or a 150 mg dose of dabigatran.¹⁶ We applied these rates to the population treated as part of routine care by calculating the CHADS₂ score in the routine care population, categorizing initiators of dabigatran or warfarin into the three risk categories, and then assigning each patient the rate reported from the trial according to exposure and risk stratum.

Although annual rates of major bleeding in the RE-LY trial were published for the overall study population, estimates were not provided for risk categories of the HAS-BLED score.³ Owing to the lack of published evidence on bleeding event rates stratified by baseline risk from the RE-LY trial, we obtained bleeding event rates within three categories of the HAS-BLED score (0-1, 2, ≥3) in patients randomized to the warfarin arm from publications for a trial comparing a different novel oral anticoagulant agent, apixaban, with warfarin (ARISTOTLE).¹⁷

We applied the annual rates of major bleeding within low, medium, and high risk categories of HAS-BLED from patients receiving warfarin in the ARISTOTLE trial to initiators of warfarin in routine care, using estimates derived from each of the three definitions of major bleeding used in the trial. Major bleeding in the ARISTOTLE trial was defined using three different criteria: ISTH (International Society on Thrombosis and Haemostasis), TIMI (thrombolysis in myocardial infarction), and GUSTO (global use of strategies to open occluded arteries; details in web appendix).^{17 18 19} To obtain the annual risk of major bleeding for patients receiving dabigatran in our routine care cohort, we multiplied the predicted annual rate of major bleeding within each HAS-BLED risk group for warfarin initiators by the hazard ratio from the RE-LY trial comparing dabigatran with warfarin on risk of major bleeding.¹⁷