Himmelreich JCL, Virdone S, Camm J, Pieper K, Harskamp RE, Oto A, Jacobson BF, Sawhney JPS, Lim TW, Gibbs H, Goto S, Haas S, Fox KAA, Jansky P, Verheugt F, and Kakkar AK
Background: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry., Methods: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA., Results: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs., Conclusion: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials., Competing Interests: Competing interests: JC reports institutional grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/BMS and Daiichi Sankyo and personal fees from Portola. KP has consultancies with Johnson & Johnson, Element Science, Artivion and Novartis. AO received a research grant from Pfizer and is Steering Committee Member and National Coordinator of the ENGAGE-AF (TIMI 48) study. BFJ received speaker honoraria from Boehringer, Sanofi, Aspen, Pfizer, Takeda and Astra Zeneca Jitendra Pal Singh Sawhney reports professional/advisory fees outside the submitted work from Pfizer, Astra Zeneca, Novartis, Sanofi, Torrent and Lupin. TWL has received research support from Bayer, Boehringer Ingelheim and Pfizer. HG received honoraria from Bayer Australia, Eli Lilly Australia, Pfizer Australia and BMS Australia Shinya Goto was a recipient of quality personal fees from Jansen and Antos, and Phillips, fees from the American Heart Association as an Associate Editor for Circulation, and Steering Committee fees from Duke University. SH received personal fees from Bayer, BMS, Daiichi Sankyo, Pfizer, Sanofi. KAAF reports grants and personal fees from Bayer/Janssen and Astra Zeneca. PJ has served as a consultant or on an advisory board for Bayer, Boehringer Ingelheim, and Novartis. FV has received grants from Bayer Healthcare, and personal fees from Bayer Healthcare, BMS/Pfizer, Daiichi-Sankyo, and Boehringer-Ingelheim. AKK received personal fees and grants from Bayer AG, Sanofi S.A. and Anthos Therapeutics. JCLH, SV and REH report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)