Nirmatrelvir–Ritonavir Decreased Risk of Death in Patients at Risk of Severe Illness from COVID-19


Relative efficacy of nirmatrelvir–ritonavir appears similar across risk groups, but older adults at risk of severe COVID-19 may benefit more.

Nirmatrelvir–ritonavir is associated with a significant reduction in the risk of hospital admission from COVID-19 and all-cause death, according to new data published in the Canadian Medical Journal. Investigators suggest that under-vaccinated or unvaccinated patients aged 70 years and older would see the most protection against severe illness from COVID-19 with the drug combination.

“In this population-level evaluation of nirmatrelvir–ritonavir we observed a significant reduction in the odds of hospital admission from COVID-19 and all-cause death, which supports the ongoing use of this antiviral drug to treat patients with mild illness who are at risk of severe COVID-19,” the study authors wrote.

By 2022, nirmatrelvir–ritonavir was funded for use by all patients in Ontario, Canada. Only older patients, those with comorbidities, or under vaccinated individuals could access this treatment option. Investigators in Ontario decided to evaluate nirmatrelvir–ritonavir on health outcomes during the time of Omicron and its subvariants in a randomized controlled trial (RCT) called the Evaluation of protease inhibition for COVID-19 in high-risk patients (EPIC-HR).

The investigators conducted the population-based cohort study of patients residing in Ontario between April and August 2022. Among 242,536 patients who tested positive for COVID-19 as determined by a polymerase chain reaction (PCR) test, 8876 received nirmatrelvir–ritonavir, whereas the rest of the cohort did not. Patients who received treatment were older, had 3 or more vaccine doses, more comorbidities, and were more likely to meet high-risk criteria.

The results of the weighted primary analysis showed that patients on nirmatrelvir–ritonavir had a 2.1% risk of hospital admission or death compared to those not given this treatment (3.7%).

“Our findings were similar across strata of age, drug–drug interactions, vaccination status and comorbidities,” the study authors wrote.

The data showed that nirmatrelvir–ritonavir reduced the relative risk or absolute risk of severe COVID-19 by 89% and 6%, respectively. Risk factors associated with severe infection were older age, obesity, comorbidities, and time from previous vaccination.

Absolute risk reduction from this drug was less for younger patients at a lower risk of severe COVID-19. Additionally, previous vaccination or COVID-19 infection were associated with significant protection against severe illness.

Study limitations included that it did not include patients who tested positive using a rapid antigen test. Additionally, it was an observational study and therefore, risks immortal time bias. Finally, investigators excluded outcomes from the index date, or prior to the index date, which can manifest as a smaller number of hospital admissions from COVID-19.

“Ongoing evaluation to monitor effectiveness in the population with new circulating variants is critical to inform optimal use over time,” the study authors wrote in the paper.


Schwartz K, Wang J, Tadrous M, et al. Population-based evaluation of the effectiveness of nirmatrelvir–ritonavir for reducing hospital admissions and mortality from COVID-19. Accessed on February 13, 2023. CMAJ February 13, 2023.

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