Acute Cardiovascular, Neurological and Metabolic Adverse Events Associated With The Use of Nirmatrelvir/ritonavir or Molnupiravir for COVID-19 Infection: a Nationwide Cohort Study in South Korea

Background: Nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL) are oral antivirals approved for treatment of coronavirus disease 2019 (COVID-19). Their increasing use has unveiled potential safety concerns such as acute cardiovascular, neurological and metabolic adverse events (AEs), yet these have not been explored in a large, population-based study.

Objectives: To compare the risks of acute cardiovascular, neurological and metabolic AEs in patients treated with or without the oral antivirals for COVID-19

Methods: This study was conducted using the COVID-19 oral treatment safety assessment data, constructed through linkage of three nationwide databases: (1) National Health Insurance data to procure medical claims, (2) Real-time Prescription Surveillance data to identify NMVr and MOL users, and (3) National COVID-19 Registry data to capture the date of COVID-19 diagnosis. We identified all adults diagnosed with COVID-19 between 2022 and 2023, and then constructed NMVr and MOL user cohorts by matching up to 4 COVID-19 patients without antiviral treatment record to each NMVr or MOL user using propensity score matching. Index date was defined as the date of treatment initiation for NMVr and MOL users, and date of COVID-19 diagnosis for matched comparators. The outcomes were cardiovascular (i.e., atrial fibrillation, other arrhythmia, bradycardia), neurological (i.e., seizure, neuropathy, encephalomyelitis), metabolic (i.e., acute pancreatitis, acute liver injury) AEs and dysgeusia. Patients were followed from index date to outcome occurrence, censored at Day 14 for cardiovascular, metabolic AEs and dysgeusia, and Day 28 for neurological AEs, or end of study period. For each outcome category, patients with a history of the AEs within 1 year prior to index date was excluded. We estimated hazard ratio (HR) with 95% confidence interval (CI) of each AE for NMVr and MOL users, compared with the matched comparators.

Results: A total of 739,935 NMVr users (mean age [SD] 70.2 years [11.2], 58.5% female) were matched with 2,951,690 comparators, and 150,431 MOL users (71.0 years [11.7], 58.5% female) with 759,521 comparators. NMVr users were at lower risk for developing the cardiovascular AEs (HR 0.74 [95% CI 0.65-0.87] for atrial fibrillation, 0.81 [0.65-0.99] for other arrhythmia, and 0.82 [0.70-0.96] for bradycardia) and dysgeusia (0.58 [0.45-0.74]). For MOL users, the risk was lower only for atrial fibrillation (0.72 [0.53-0.96]) and dysgeusia (0.34 [0.18-0.65]). In both cohorts, null association was observed for neurological and metabolic AEs.

Conclusions: This study reassures the safe use of NMVr and MOL by showing no increased risk of potential safety concerns during and shortly after completing the 5-day treatment course.