Carnicelli, Anthony PAnthony PCarnicelliHong, HwanheeHwanheeHongConnolly, Stuart JStuart JConnollyEikelboom, JohnJohnEikelboomGiugliano, Robert PRobert PGiuglianoMorrow, David ADavid AMorrowPatel, Manesh RManesh RPatelWallentin, LarsLarsWallentinAlexander, John HJohn HAlexanderBahit, M CeciliaM CeciliaBahitBenz, Alexander PAlexander PBenzBohula, Erin AErin ABohulaChao, Tze-FanTze-FanChaoDyal, LeanneLeanneDyalEzekowitz, MichaelMichaelEzekowitzFox, Keith AaKeith AaFoxGencer, Baris FarukBaris FarukGencerHalperin, Jonathan LJonathan LHalperinHijazi, ZiadZiadHijaziHohnloser, Stefan HStefan HHohnloserHua, KaiyuanKaiyuanHuaHylek, ElaineElaineHylekKato, Eri TodaEri TodaKatoKuder, JuliaJuliaKuderLopes, Renato DRenato DLopesMahaffey, Kenneth WKenneth WMahaffeyOldgren, JonasJonasOldgrenPiccini, Jonathan PJonathan PPicciniRuff, Christian TChristian TRuffSteffel, JanJanSteffelWojdyla, DanielDanielWojdylaGranger, Christopher BChristopher BGranger2024-10-092024-10-092022-01-25https://boris-portal.unibe.ch/handle/20.500.12422/66681Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation (AF). Meta-analyses using individual patient data offer significant advantages over study-level data. Methods: We used individual patient data from the COMBINE AF database, which includes all patients randomized in the 4 pivotal trials of DOACs vs warfarin in AF (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71,683 patients were included (29,362 on standard-dose DOAC, 13,049 on lower-dose DOAC, 29,272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke/systemic embolism (883/29312 [3.01%] vs 1080/29229 [3.69%]; HR 0.81, 95% CI 0.74-0.89), death (2276/29312 [7.76%] vs 2460/29229 [8.42%]; HR 0.92, 95% CI 0.87-0.97) and intracranial bleeding (184/29270 [0.63%] vs 409/29187 [1.40%]; HR 0.45, 95% CI 0.37-0.56), but no statistically different hazard of major bleeding (1479/29270 [5.05%] vs 1733/29187 [5.94%]; HR 0.86, 95% CI 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke/systemic embolism (531/13049 [3.96%] vs 1080/29229 [3.69%]; HR 1.06, 95% CI 0.95-1.19) but a lower hazard of intracranial bleeding (55/12985 [0.42%] vs 409/29187 [1.40%]; HR 0.28, 95% CI 0.21-0.37), death (1082/13049 [8.29%] vs 2460/29229 [8.42%]; HR 0.90, 95% CI 0.83-0.97), and major bleeding (564/12985 [4.34%] vs 1733/29187 [5.94%]; HR 0.63, 95% CI 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke/systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (p=0.01) and lower creatinine clearance (p=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (p=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction p=0.02) and lower-dose DOACs (interaction p=0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with AF.en600 - Technology::610 - Medicine & health300 - Social sciences, sociology & anthropology::360 - Social problems & social servicesarticle10.48350/1644063498530910.1161/CIRCULATIONAHA.121.056355