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

Dryden-Peterson et al., Annals of Internal Medicine, doi:10.7326/M22-2141 (date from preprint)
Dec 2022  
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Mortality 71% Improvement Relative Risk Death/hospitalization 44% Hospitalization 40% Paxlovid  Dryden-Peterson et al.  EARLY TREATMENT Is early treatment with paxlovid beneficial for COVID-19? Retrospective 44,045 patients in the USA (January - July 2022) Lower mortality (p=0.0064) and death/hosp. (p=0.0001) Confounding by health-seeking and additional untracked treatments and measures may substantially overestimate efficacy Dryden-Peterson et al., Annals of Inte.., Dec 2022 Favorspaxlovid Favorscontrol 0 0.5 1 1.5 2+
IPW retrospective 44,551 outpatients age 50+ in the USA, showing lower mortality and hospitalization with paxlovid treatment.
Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid1. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy.
Black box warning. The FDA notes that "severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid"2.
Kamo et al. show significantly increased risk of acute kidney injury. Resistant variants are likely4,5.
This study is excluded in the after exclusion results of meta analysis: only a fraction of eligible patients received treatment and these patients may be more likely to follow other recommendations, receive additional care, and more more likely to use additional untracked treatments such as vitamin D and nasal/oral hygiene.
risk of death, 71.0% lower, RR 0.29, p = 0.006, treatment 11,797, control 32,248, propensity score weighting.
risk of death/hospitalization, 44.0% lower, RR 0.56, p < 0.001, treatment 69 of 11,797 (0.6%), control 310 of 32,248 (1.0%), NNT 266, propensity score weighting.
risk of hospitalization, 40.0% lower, RR 0.60, p = 0.001, treatment 11,797, control 32,248, propensity score weighting.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Dryden-Peterson et al., 13 Dec 2022, retrospective, USA, peer-reviewed, 12 authors, study period 1 January, 2022 - 17 July, 2022. Contact:
This PaperPaxlovidAll
Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System
MD, MSc Scott Dryden-Peterson, BS Andy Kim, MD Arthur Y Kim, ScD Ellen C Caniglia, MD, MPH, MBA Inga T Lennes, MD, MPH Rajesh Patel, RN Lindsay Gainer, RN Lisa Dutton, RN, MSN, NP-C Elizabeth Donahue, MD Rajesh T Gandhi, MD Lindsey R Baden, MD, MPH Ann E Woolley
Annals of Internal Medicine, doi:10.7326/m22-2141
Background: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. Objective: To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages. Design: Population-based cohort study analyzed to emulate a clinical trial using inverse probability-weighted models to account for anticipated bias in treatment. Setting: A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022). Patients: 44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir. Measurements: The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis. Results: During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]). Limitation: Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment. Conclusion: The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further.
Author contributions are available at Previous Posting: This manuscript was posted as a preprint on medRxiv on 17 June 2022. doi:10.1101/2022.06. 14.22276393
Administrative, Kim, Lennes, Patel, Gainer et al., logistic support
Arbel, Sagy, Hoshen, Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge, N Engl J Med, doi:10.1056/NEJMoa2204919
Bar-On, Goldberg, Mandel, Protection of BNT162b2 vaccine booster against Covid-19 in Israel, N Engl J Med, doi:10.1056/NEJMoa2114255
Cole, Hernán, Constructing inverse probability weights for marginal structural models, Am J Epidemiol, doi:10.1093/aje/kwn164
Denz, Klaaßen-Mielke, Timmesfeld, Boucau, Uddin et al., Virologic characterization of symptom rebound following nirmatrelvir-ritonavir treatment for COVID-19. medRxiv, doi:10.1101/2022.05.24.22275326
Dryden-Peterson, Kim, Caniglia, Patel, Dutton et al., ORIGINAL RESEARCH Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System Author Contributions: Conception and design
Ganatra, Dani, Ahmad, Oral nirmatrelvir and ritonavir in non-hospitalized vaccinated patients with Covid-19, Clin Infect Dis, doi:10.1093/cid/ciac673
Ganesh, Philpot, Bierle, Real-world clinical outcomes of bamlanivimab and casirivimab-imdevimab among high-risk patients with mild to moderate coronavirus disease 2019, J Infect Dis, doi:10.1093/infdis/jiab377
Hammond, Leister-Tebbe, Gardner, EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2118542
House, National COVID-19 Preparedness Plan
House, National COVID-19 Preparedness Plan
Højsgaard, Halekoh, Yan, The R package geepack for generalized estimating equations, J Stat Softw, doi:10.18637/jss.v015.i02
Kind, Jencks, Brock, Neighborhood socioeconomic disadvantage and 30-day rehospitalization: a retrospective cohort study, Ann Intern Med, doi:10.7326/M13-2946
Lambrou, Shirk, Steele, Genomic surveillance for SARS-CoV-2 variants: predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) variants-United States, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7106a4
Liang, Zeger, Cole, Hernán, Longitudinal data analysis using generalized linear models, Comput Methods Programs Biomed, doi:10.1093/biomet/73.1.13
O'horo, Challener, Speicher, Effectiveness of monoclonal antibodies in preventing severe COVID-19 with emergence of the Delta variant, Mayo Clin Proc, doi:10.1056/NEJMp1802313
Zou, A modified Poisson regression approach to prospective studies with binary data, Am J Epidemiol
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