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
Key result
Standard-dose DOACs cut stroke or systemic embolism ~19% vs. warfarin in AF.
- HR 0.81
- 95% CI 0.74-0.89
- n=71,683
Why the study?
DOACs are preferred over warfarin in AF, and individual patient data meta-analyses offer substantial advantages over study-level data.
Does standard-dose or lower-dose DOAC reduce stroke or systemic embolism compared to warfarin in patients with atrial fibrillation?
Population
71 683 patients with AF across 4 pivotal trials
Comparison
Standard-dose DOAC vs lower-dose DOAC vs warfarin
Design
Individual patient data network meta-analysis of randomized clinical trials
Authors
Discussion
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Member takes
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We felt we had a public service obligation here. We didn't want the wider community to just be leaving elderly patients on a vitamin K antagonist when we think we have a better alternative. At a minimum, doctors should be having the discussion with elderly patients who are frail and say, 'Look, there is a new class of drugs available. Here are the advantages. Here are the disadvantages. They are more costly. And so let's think about what's best for you.'”
Implication
Confirms standard-dose DOACs as preferred over warfarin for stroke prevention in atrial fibrillation; strengthens pooled evidence from four pivotal trials.
Key Points
- To assess the comparative efficacy and safety of standard-dose and lower-dose direct oral anticoagulants versus warfarin in patients with atrial fibrillation, including interaction testing by age and sex.
- Analyzed individual patient data from 71 683 patients randomized across 4 pivotal trials (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48) in the COMBINE AF database.
- Assigned 29 362 patients to standard-dose DOACs, 13 049 to lower-dose DOACs, and 29 272 to warfarin, with a median follow-up of 26.6 months after censoring at 32 months.
- Applied network meta-analyses using a stratified Cox model with random effects and evaluated covariate-by-treatment interactions across age, sex, and clinical subgroups.
- Standard-dose DOACs significantly reduced stroke or systemic embolism (883/29 312 [3.01%] vs 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74–0.89]), death (2276/29 312 [7.76%] vs 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87–0.97]), and intracranial bleeding (184/29 270 [0.63%] vs 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37–0.56]) compared with warfarin, without a statistically significant difference in major bleeding (1479/29 270 [5.05%] vs 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74–1.01]).
- Lower-dose DOACs showed no statistically significant difference in stroke or systemic embolism versus warfarin (531/13 049 [3.96%] vs 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95–1.19]), while significantly reducing death (1082/13 049 [8.29%] vs 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83–0.97]), intracranial bleeding (55/12 985 [0.42%] vs 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21–0.37]), and major bleeding (564/12 985 [4.34%] vs 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45–0.88]).
- Treatment effects were consistent across age and sex for stroke, systemic embolism, and death, though younger patients derived significantly greater major bleeding benefits versus warfarin from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01).
Study Design
Type
Meta-Analysis (n=71,683)
Multicenter
Yes
Structured PICO
Does standard-dose or lower-dose DOAC reduce stroke or systemic embolism compared to warfarin in patients with atrial fibrillation?
P
Population
71,683 patients with atrial fibrillation from 4 pivotal randomized trials, median age 72 and 37.3% female, followed for a median of 26.6 months.
I
Intervention
Standard-dose DOACs (dabigatran 150mg BID, rivaroxaban 20mg QD, apixaban 5mg BID, or edoxaban 60mg QD) and lower-dose DOACs
C
Comparator
Warfarin
O
Outcome
Composite of any stroke (ischemic, hemorrhagic, or other) or systemic embolismcomposite
Main Result
Hazard Ratio: 0.81 (95% CI 0.74–0.89)
Absolute Event Rate: 3.01% vs 3.69%
Patient-level network meta-analysis confirms DOACs provide superior efficacy and safety compared to warfarin across age groups, with standard-dose DOACs particularly favored in patients without prior VKA use.
Limitations
- Univariable analyses for individual outcomes separately may introduce type I error inflation due to multiplicity
- Potential multivariable collinearity between covariates not accounted for
- Patients from randomized trials do not represent an unselected group in general practice
- Few patient-reported outcomes were collected
- Data describing temporary discontinuation of study drug and study drug adherence were not included
- Aggregating trials with different study drugs and doses may obscure subtle differences
Cite This Study
Carnicelli et al. (2022) conducted a meta-analysis in Atrial Fibrillation (n=71,683). Standard-dose DOAC vs. Warfarin was evaluated on Composite of any stroke (ischemic, hemorrhagic, or other) or systemic embolism (HR 0.81, 95% CI 0.74-0.89). Standard-dose DOACs significantly reduced the hazard of stroke or systemic embolism by 19% (HR 0.81) compared with warfarin in patients with atrial fibrillation.