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
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 71683 patients were included (29362 on standard-dose DOAC, 13049 on lower-dose DOAC, and 29272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard stroke or systemic embolism (883/29312 [3.01%] versus 1080/29229 [3.69%]; HR, 0.81 [95% CI, 0.74–0.89]), death (2276/29312 [7.76%] versus 2460/29229 [8.42%]; HR, 0.92 [95% CI, 0.87–0.97]), and intracranial bleeding (184/29270 [0.63%] versus 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%] versus 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 or systemic embolism (531/13049 [3.96%] versus 1080/29229 [3.69%]; HR, 1.06 [95% CI, 0.95–1.19]) but a lower hazard of intracranial bleeding (55/12985 [0.42%] versus 409/29187[1.40%]; HR, 0.28 [95% CI, 0.21–0.37]), death (1082/13049 [8.29%] versus 2460/29229 [8.42%]; HR, 0.90 [95% CI, 0.83–0.97]), and major bleeding (564/12985 [4.34%] versus 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 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.
Fazit:
Nach dieser pharmagesponserten Studie ist es bei jüngeren Patienten eher nützlich, ein DOAC zu geben (in normaler Dosis). Bei älteren Patienten (ab 80 Jahren) ist die Gabe von VKA wahrscheinlich sicherer. Eine nicht begründete Dosisreduktion von DOAC (Nierenwerte o.ä.) schadet und sollte nicht „aus dem Bauch heraus“ eingesetzt werden. Bei Jüngeren mit GI-Blutungen in der Vorgeschichte empfehlen sich allerdings VKA.