Efficacy and Safety of Non–Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation

Abstract

BACKGROUND: The efficacy and safety of non–vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m 2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m 2 . RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2–32.2) kg/m 2 , and the median BW was 81.0 (interquartile range, 70.0–94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across a BMI with an NOAC. NOACs reduced stroke/SEE overall (HR adj , 0.80 [95% CI, 0.73–0.88]; P <0.001), with a generally consistent effect across BMI ( P trend across HRs, 0.48). NOACs also reduced major bleeding overall (HR adj , 0.88 [95% CI, 0.82–0.94]; P <0.001), but with attenuation of the benefit at a higher BMI ( P trend , 0.003). The overall treatment effects of an NOAC versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death, which, although was reduced overall with an NOAC (net clinical outcome, HR adj , 0.91 [95% CI, 0.87–0.95]; P <0.001; death, HR adj , 0.91 [95% CI, 0.86–0.97]; P =0.003), tended to favor warfarin at a higher BMI ( P trend , 0.001 and 0.08, respectively). This finding was not explained by differences in ischemic or fatal bleeding events. All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOAC versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated at a higher BMI and BW. Death and the net clinical outcome are reduced with NOACs versus warfarin overall, although there remain uncertainties for these outcomes at a very high BMI and BW.