Non-vitamin K antagonist oral anticoagulants with amiodarone, P-glycoprotein inhibitors, or polypharmacy in patients with atrial fibrillation: Systematic review and meta-analysis

Background: Amiodarone, which inhibits CYP2C9 and P-glycoprotein, is commonly prescribed with non-vitamin K antagonist oral anticoagulants (NOACs) and polypharmacy in high-risk atrial fibrillation (AF) patients. We studied efficacy and safety of NOACs in AF patients receiving amiodarone, P-glycoprotein inhibitor, or polypharmacy. Methods: After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), four phase-III randomized trials comparing NOACs and warfarin in “with/without amiodarone,” “with/without P-glycoprotein inhibitors,” or “with/without multiple (≥5, polypharmacy) concomitant drugs” subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risks (RRs) for stroke/systemic thromboembolism (SSTE), major bleeding (MB), intracranial hemorrhage (ICH), and all-cause mortality. Results: Among patients taking amiodarone, superiority of NOACs over warfarin in non-amiodarone users disappeared in terms of SSTE (p = 0.11), MB (p = 0.95), ICH (p = 0.26), and mortality (p = 0.32). No safety benefit (MB) of NOACs compared to warfarin was shown in patients taking P-glycoprotein inhibitors (p = 0.47), but SSTE prevention was still superior with NOACs compared to warfarin in the same patient group [RR = 0.78 (0.61–0.99), p = 0.04, I ² = 11%]. In AF patients with polypharmacy, NOACs showed a lower risk of SSTE [RR = 0.82 (0.71–0.96), p = 0.01, I ² = 0%] and mortality [RR = 0.91 (0.83–0.99), p = 0.04, I ² = 0%], but not MB (p = 0.81) compared to warfarin. Conclusions: NOACs were equivalent to warfarin among AF patients with concomitant amiodarone use in terms of efficacy, safety, and mortality. There was no safety benefit of NOACs over warfarin in patients using polypharmacy or P-glycoprotein inhibitors. Systematic review registration: The protocol of this meta-analysis was registered on PROSPERO under CRD42018104808 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018104808).