Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex
Authors: Carnicelli Anthony P. , Hong Hwanhee , Connolly Stuart J. , Eikelboom John , Giugliano Robert P. , Morrow David A. , Patel Manesh R. , Wallentin Lars , Alexander John H. , Cecilia Bahit M. , Benz Alexander P. , Bohula Erin A. , Chao Tze-Fan , Dyal Leanne , Ezekowitz Michael , A.A. Fox Keith , Gencer Baris , Halperin Jonathan L. , Hijazi Ziad , Hohnloser Stefan H. , Hua Kaiyuan , Hylek Elaine , Toda Kato Eri , Kuder Julia , Lopes Renato D. , Mahaffey Kenneth W. , Oldgren Jonas , Piccini Jonathan P. , Ruff Christian T. , Steffel Jan , Wojdyla Daniel , Granger Christopher B. ,   on behalf of the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) Investigators
Published: January 2022

Background:
Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data.

Methods:
We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (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], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 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 (HRs [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, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74–0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87–0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37–0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74–1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95–1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21–0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83–0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [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 or 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 atrial fibrillation.