Introduction
Atrial fibrillation (AF) is an age-related cardiac arrhythmia, and the elderly aged between 65-85 have occupied nearly 70% of AF patients[1, 2]. Elderly AF patients are often accompanied by a huge comorbidity burden and polypharmacy use. Polypharmacy refers to the situation in which an individual uses multiple drugs at the same time, but there is no international consensus on the threshold and measurement methods of drug use[3].
In patients with AF, oral anticoagulation is necessary to prevent thrombotic events. Current evidence has indicated that the non–vitamin K antagonist oral anticoagulants (NOACs) served as a safer and more effective alternative to warfarin for nonvalvular AF patients, featured fewer drug-food interactions, and rapid onset of action[4-7]. However, when encountering polypharmacy, a critical treatment issue is presented. In this setting, anticoagulated patients with polypharmacy frequently exhibit an unexpected dose-response relationship to oral anticoagulant (OAC) therapy, in which polypharmacy has been demonstrated to be a risk factor for both anticoagulation-related events such as bleeding and thromboembolism[8-10].
Despite guideline recommendations [ESC, APHRS][11, 12], only approximately 50% of elderly AF patients received OAC therapy[1]. On the one hand, owing to the multiple comorbidities and polypharmacy, these patients take the risks of pill burden, drug-drug interaction, non-adherence, and adverse drug events[13]. On the other hand, the bleeding risk associated with advanced age makes the use of anticoagulants more cautious[14]. In this context, the exploration of safe and effective OAC treatments for AF patients with polypharmacy is necessary.
Several post-hoc analyses of randomized controlled trials (RCTs) in patients with AF polypharmacy have been conducted. For example, Focks et al. conducted a post-hoc analysis of the ARISTOTLE trial and showed that apixaban was more effective than warfarin and was at least just as safe[9]. Numerous real-world studies, such as the ARISTOPHANES study have demonstrated that the effectiveness and safety profiles are more favorable for NOACs vs warfarin[15].
We therefore performed this comprehensive systematic review and meta-analysis via high-quality studies to determine the effectiveness and safety of NOACs versus Vitamin K antagonists (VKAs) in AF patients with polypharmacy. The aims of this meta-analysis were as follows: (1) comparing the risks of stroke, death, and bleeding in AF patients with and without polypharmacy; (2) assessing the efficacy and safety outcomes of NOACs versus VKAs in patients with AF and polypharmacy; (3) assessing the effects of NOACs versus VKAs in AF patients with and without polypharmacy.