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- Page navigation anchor for RE: Lack of benefit in preventing COVID-19-related hospitalization in the population based study of nirmatrelvir/ritonavir by Schwartz et al.RE: Lack of benefit in preventing COVID-19-related hospitalization in the population based study of nirmatrelvir/ritonavir by Schwartz et al.
Thank you for the opportunity to respond to Piszczek and Huang’s comment on the rates of death in our study. In the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial by Hammond et al. there were 12 deaths in the placebo arm and 0 in the treatment arm suggesting a potentially important reduction in mortality in patients with COVID-19 treated with nirmatrelvir/ritonavir, however that study was not powered for this outcome.(1) There are a number of limitations in observational research including confounding, but one advantage is potentially greater power to detect significant differences in rare outcomes. In this respect, our study had approximately 80 times the sample size compared to EPIC-HR.(2) Further, we incorporated age, sex, vaccination status, prior infection, risk group, and comorbidities using Inverse Probability of Treatment Weighting to address measured confounding in our data; however we recognize that residual confounding is still possible. Importantly, we want to note that the authors’ derivation of a 0.5% and 0.4% hospitalization rate is incorrect. Technically, this is the proportion of patients with COVID-19 that were hospitalized but did not die, which is a less clinically relevant outcome compared to the composite outcome of hospitalization or death as presented in our study and used in the clinical trials of nirmatrelvir/ritonavir.(1)
Due to the potential for immortal time bias, we applied a number of exclusion cri...
Show MoreCompeting Interests: None declared.References
- Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Apr 14;386(15):1397–408.
- Schwartz KL, Wang J, Tadrous M, Langford BJ, Daneman N, Leung V, et al. Population-based evaluation of the effectiveness of nirmatrelvir–ritonavir for reducing hospital admissions and mortality from COVID-19. CMAJ. 2023 Feb 13;195(6):E220–6.
- Page navigation anchor for RE: Lack of benefit in preventing COVID-19-related hospitalization in the population based study of nirmatrelvir/ritonavir by Schwartz et al.RE: Lack of benefit in preventing COVID-19-related hospitalization in the population based study of nirmatrelvir/ritonavir by Schwartz et al.
Dear Editor,
In their analysis of the primary endpoint, Schwartz et al. found hospital admissions due to COVID-19 or all-cause death to be lower in those exposed to nirmatrelvir-ritonavir than in those who did not receive the drug (2.1% vs. 3.7%; weighted OR 0.56, 95% CI 0.47-0.67).(1) However, in Appendix 1 Table S5, the authors reported the secondary endpoint of death to be 1.6% vs. 3.3% in the nirmatrelvir-ritonavir recipients and non-recipients, respectively (weighted OR 0.49, 95% CI 0.40-0.60). Therefore, the composite endpoint was entirely driven by death, where COVID-19-related hospitalizations, calculated as 0.5% vs. 0.4%, were higher in the nirmatrelvir-ritonavir recipients. While this study uses inverse probability of treatment weighting and therefore the rates of the primary and secondary endpoints are "pseudo-rates", the approximate ratio of death to hospitalization of 3:1 would still be expected despite the adjustment.
Nirmatrelvir-ritonavir has never been shown to reduce mortality. In the EPIC-HR trial, where the primary endpoint of COVID-related hospitalization and all-cause mortality in untreated patients was 6.3%, the mortality in this composite endpoint was 1.15%.(2) This means that for every death, there were 4.5 COVID-related hospitalizations. Furthermore, in a large population-based study of nirmatrelvir-ritonavir use in the Omicron wave in the US, COVID-19 hospitalizations outweighed deaths 40 to 1 in nirmatrelvir-ritonavir rec...
Show MoreCompeting Interests: None declared.References
- 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. CMAJ February 13, 2023 195 (6) E220-E226
- Hammond J, Leister-Tebbe H, Gardner A et. al. Oral nirmatrelvir for high-risk, non-hospitalized adults with COVID-19. NEJM April 14, 2022; 386(15)
- Shah M, Joyce B, Plumb I, et. al. Paxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022. MMWR December 2, 2022; 71(48)