Anthony P Carnicelli1,2, Hwanhee Hong2,3, Stuart J Connolly4,5, John Eikelboom4,5, Robert P Giugliano6,7, David A Morrow7, Manesh R Patel1,2, Lars Wallentin1,8,9, John H Alexander1,2, M Cecilia Bahit1,10, Alexander P Benz5, Erin A Bohula6,7, Tze-Fan Chao11, Leanne Dyal5, Michael Ezekowitz1,12, Keith A A Fox13, Baris Gencer14,15, Jonathan L Halperin1,16, Ziad Hijazi8,9, Stefan H Hohnloser17, Kaiyuan Hua2,3, Elaine Hylek1,18, Eri Toda Kato19, Julia Kuder6,7, Renato D Lopes1,2, Kenneth W Mahaffey20, Jonas Oldgren8,9, Jonathan P Piccini1,2, Christian T Ruff6,7, Jan Steffel21, Daniel Wojdyla2, Christopher B Granger1,2. 1. Division of Cardiology (A.P.C., M.R.P., J.H.A., R.D.L., J.P.P., C.B.G.), Duke University, Durham, NC. 2. Duke Clinical Research Institute (A.P.C., H.H., M.R.P., J.H.A., K.H., R.D.L., J.P.P., D.W., C.B.G.), Duke University, Durham, NC. 3. Department of Biostatistics and Bioinformatics (H.H., K.H.), Duke University, Durham, NC. 4. Department of Medicine, McMaster University, Ontario, Canada (S.J.C., J.E.). 5. Population Health Research Institute, Hamilton Health Sciences, Ontario, Canada (S.J.C., J.E., A.P.B., L.D.). 6. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.P.G., D.A.M., E.A.B., J.K., C.T.R.). 7. Thrombolysis in Myocardial Infarction Study Group, Boston, MA (R.P.G., D.A.M., E.A.B., C.T.R.). 8. Uppsala Clinical Research Center and Department of Medical Sciences (L.W., Z.H., J.O.), Uppsala University, Sweden. 9. Department of Medical Sciences (L.W., Z.H., J.O.), Uppsala University, Sweden. 10. Department of Cardiology, INECO Neurociencias Oroño, Santa Fe, Argentina (M.C.B.). 11. Division of Cardiology, Taipei Veterans General Hospital, Taiwan (T.-F.C.). 12. Lankenau Institute for Medical Research, Wynnewood, PA (M.E.). 13. Center for Cardiovascular Science, University of Edinburgh, Scotland (K.A.A.F.). 14. Division of Cardiology, Geneva University Hospitals, Geneva, Switzerland (B.G.). 15. Institute of Primary Health Care (BIHAM), University of Bern, Switzerland (B.G.). 16. The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.). 17. Department of Cardiology, JW Goethe University, Frankfurt, Germany (S.H.H.). 18. Department of Medicine, Boston University School of Medicine, MA (E.H.). 19. Department of Cardiology, Kyoto University, Japan (E.T.K.). 20. Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, CA (K.W.M.). 21. Department of Cardiology, University of Zurich, Switzerland (J.S.).
Abstract
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.
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.
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