1. In this trial emulation study, molnupiravir and nirmatrelvir-ritonavir reduced all-cause mortality in vaccinated and unvaccinated hospitalized patients with coronavirus disease 2019 (COVID-19).

2. Molnupiravir and nirmatrelvir-ritonavir did not cause any significant reduction in intensive care unit (ICU) admissions or need for ventilatory support.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Molnupiravir and nirmatrelvir-ritonavir have been authorized by the United States Food and Drug Administration for emergency use in non-hospitalized patients for the treatment of COVID-19. Phase three randomized controlled trials have demonstrated the efficacy and safety of molnupiravir and nirmatrelvir-ritonavir with some inconsistency. Therefore, there remains a gap in knowledge as to the effectiveness of molnupiravir and nirmatrelvir-ritonavir in reducing mortality and severe COVID-19 in the inpatient setting. Overall, this study found that molnupiravir and nirmatrelvir-ritonavir reduced all-cause mortality in vaccinated and unvaccinated hospitalized patients with COVID-19. Though, they did not cause a significant reduction in ICU admission or the need for ventilatory support. This study was limited by not directly comparing the effectiveness of molnupiravir versus nirmatrelvir-ritonavir in vaccinated people. This study excluded patients with prior SARS-CoV-2 infections, as well as not having information on days from symptom onset and site of hospitalization. Nevertheless, the findings are significant, as they demonstrated that molnupiravir and nirmatrelvir-ritonavir were associated with a lower risk of death among hospitalized patients with COVID-19 regardless of vaccination status. However, no significant reduction in ICU admission or need for ventilatory support was observed.

Click to read the study in AIM

Relevant Reading: Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System

In-Depth [trial emulation study]: This trial emulation study used clinical data from hospital records from the Centre for Health Protection of the Government of the Hong Kong Special Administrative Region. Patients aged 18 years or older hospitalized with COVID-19 were eligible for the study. Patients who had a history of COVID-19 before the start of the inclusion period (hospitalized with SARSCoV- 2 reinfections during the inclusion period); receipt of either molnupiravir or nirmatrelvir–ritonavir before the index date (started antiviral treatment in the community setting); or admission to the ICU, receipt of ventilatory support, or death on the index date were excluded from the study. The primary outcome measured was all-cause mortality. Outcomes in the primary analysis were assessed via a per-protocol analysis with the Charlson Comorbidity Index and pooled logistic regression models. Based on the primary analysis, the use of molnupiravir or nirmatrelvir-ritonavir in hospitalized patients with COVID-19 was associated with a lower risk for all-cause mortality (molnupiravir: Hazard Ratio [HR], 0.87; 95% Confidence Interval [CI], 0.81 to 0.93; nirmatrelvir–ritonavir: HR, 0.77; 95% CI, 0.66 to 0.90) but no significant risk reduction in terms of ICU admission (molnupiravir: HR, 1.02; 95% CI, 0.76 to 1.36; nirmatrelvir–ritonavir: HR, 1.08; 95% CI, 0.58 to 2.02) or the need for ventilatory support (molnupiravir: HR, 1.07; 95% CI, 0.89 to 1.30; nirmatrelvir–ritonavir: HR, 1.03; 95% CI, 0.70 to 1.52). No significant differences in outcomes when stratifying drug treatment based on the number of COVID-19 vaccine doses received was observed. In summary, this study demonstrated that molnupiravir and nirmatrelvir-ritonavir effectively reduced all-cause mortality in hospitalized patients with COVID-19.

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