Publication date: Dec 21, 2025
While treatment with nirmatrelvir/ritonavir or molnupiravir is effective in lowering the rate of severe COVID-19, the effectiveness of these antivirals in reducing the risk of cardiovascular outcomes, especially among the hospitalized population, remains largely unknown. In this study, we assessed the real-world effectiveness of nirmatrelvir/ritonavir and molnupiravir on short- and long-term cardiovascular complications of COVID-19 using a target trial emulation design. Two target trials of COVID-19 antivirals were emulated by using a territory-wide, population-based, retrospective cohort of hospitalized patients in Hong Kong. Nine cardiovascular outcomes were evaluated in both short-term (day 0-21) and long-term (day 22-365) post-SARS-CoV-2 infection. Compared with the control group, the use of nirmatrelvir/ritonavir was associated with a significantly lower one-year risk of cardiovascular mortality, composite cardiovascular complications, major adverse cardiac events, cerebrovascular disorders, dysrhythmia, ischemic heart disease, and other cardiac disorders following infection. Molnupiravir use was associated with a short-term risk reduction in cardiovascular complications, but only a marginal risk reduction in long-term cardiovascular mortality among other complications. This study demonstrated the effectiveness of nirmatrelvir/ritonavir in reducing the risks of short- and long-term cardiovascular complications following a SARS-CoV-2 infection among the hospitalized population. Our findings suggested health-related benefits of prescribing nirmatrelvir/ritonavir over molnupiravir against severe cardiovascular post-acute sequelae of COVID-19 in the long term.
