en
Scientific article
English

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

Published inCirculation, vol. 145, no. 4, p. 242-255
Errata
  • In Figure 4, the hazard ratios and 95% confidence intervals are incorrect. Figure 4 has been replaced with an updated version to correct this error.
  • DOI : 10.1161/CIR.0000000000001058
  • PMID : 35188800
Publication date2022-01-25
First online date2022-01-05
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.

eng
Keywords
  • Anticoagulants
  • Atrial fibrillation
  • Meta-analysis
  • Stroke
  • Warfarin
  • Administration, Oral
  • Age Factors
  • Aged
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use
  • Female
  • Humans
  • Male
  • Network Meta-Analysis
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Sex Factors
  • Warfarin / pharmacology
  • Warfarin / therapeutic use
Funding
  • Johnson & Johnson and Bayer - ROCKET AF
  • Boehringer Ingelheim - RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy)
  • Bristol Myers Squibb and Pfizer - ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
  • Daiichi-Sankyo - ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48)
Citation (ISO format)
CARNICELLI, Anthony P et al. 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. In: Circulation, 2022, vol. 145, n° 4, p. 242–255. doi: 10.1161/CIRCULATIONAHA.121.056355
Main files (1)
Article (Published version)
accessLevelRestricted
Secondary files (3)
Identifiers
ISSN of the journal0009-7322
148views
27downloads

Technical informations

Creation04/01/2022 12:01:00 PM
First validation04/01/2022 12:01:00 PM
Update time03/16/2023 8:57:05 AM
Status update03/16/2023 8:56:59 AM
Last indexation05/06/2024 2:36:12 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack