Safety and Efficacy of Concomitant Nirmatrelvir/Ritonavir and Direct Oral Anticoagulant Therapies for COVID‐19 Among Patients With Atrial Fibrillation

Background Concomitant use of nirmatrelvir/ritonavir with direct oral anticoagulants (DOACs) for COVID‐19 is challenging due to potential drug–drug interactions. This study assessed the safety and effectiveness of nirmatrelvir/ritonavir compared with RNA‐dependent RNA polymerase inhibitors in patients with COVID‐19 and atrial fibrillation treated with a DOAC. Methods We conducted a territory‐wide retrospective study of patients with COVID‐19 hospitalized in Hong Kong between January and November 2022 for antiviral therapy who had atrial fibrillation managed with a DOAC. Clinical outcomes including 30‐day all‐cause death, ischemic stroke, myocardial infarction, and bleeding events were evaluated. Results Overall, 1297 (91%) patients were prescribed an RNA‐dependent RNA polymerase inhibitor, and 127 (9%), nirmatrelvir/ritonavir. Among patients treated with nirmatrelvir/ritonavir, 77 (60.6%) continued DOAC treatment, 30 (23.6%) switched to low‐molecular‐weight heparin, and 20 (15.7%) withheld anticoagulation therapy. After propensity score matching (n=1270), 1143 and 127 patients were in the RNA‐dependent RNA polymerase inhibitor and nirmatrelvir/ritonavir groups, respectively. On univariate analysis, the 30‐day all‐cause death was lower in the nirmatrelvir/ritonavir group (5.51% versus 12.1%; P =0.033). However, after adjusting for covariates including age and COVID‐19 severity, this difference was no longer statistically significant. The incidence of bleeding events was not significantly different between groups ( P =0.654), and there were no statistically significant differences in ischemic stroke, myocardial infarction, or need for ventilatory support. Conclusions In a territory‐wide cohort of hospitalized patients with COVID‐19 and atrial fibrillation on a DOAC, nirmatrelvir/ritonavir therapy was associated with lower unadjusted 30‐day all‐cause death compared with RNA‐dependent RNA polymerase inhibitors; however, this difference was not significant after adjusting for age and COVID‐19 severity.