Effectiveness of Nirmatrelvir–Ritonavir Against the Development of Post–COVID-19 Conditions Among U.S. Veterans

Ioannou et al., Annals of Internal Medicine, doi:10.7326/M23-1394

Oct 2023

Retrospective 9,593 veterans in the USA treated with paxlovid, matched to 9,593 untreated controls, showing no significant difference in post-COVID conditions across 31 different conditions. There was lower risk for the combination of 2 specific conditions (venous thromboembolism and pulmonary embolism) however this was not significant after adjustment for baseline medications which constitute drug-drug interactions or contraindications to nirmatrelvir-ritonavir.

This analysis should be more accurate than many paxlovid retrospective studies. Many studies are biased due to inclusion of patients with contraindications to paxlovid, and due to confounding by treatment propensity, as below. Authors account for contraindications (though not all would be identified) and partially account for treatment propensity by including the frequency of health care encounters in matching.

Confounding by treatment propensity. This study analyzes a population where only a fraction of eligible patients received the treatment. Patients receiving treatment may be more likely to follow other recommendations, more likely to receive additional care, and more likely to use additional treatments that are not tracked in the data (e.g., nasal/oral hygiene c19early.org, c19early.org (B), vitamin D c19early.org (C), etc.) — either because the physician recommending paxlovid also recommended them, or because the patient seeking out paxlovid is more likely to be familiar with the efficacy of additional treatments and more likely to take the time to use them. Malden et al. confirm significant bias in the use of paxlovid, showing that treated patients are more likely to be from affluent neighborhoods, be more health-conscious, and have better access to care. Therefore, these kind of studies may overestimate the efficacy of treatments.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid Hoertel. 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" FDA.

Important missing comments or errors? Let us know.

risk of PASC, 0.7% lower, HR 0.99, p = 0.75, treatment 9,593, control 9,593, adjusted per study, all 31 conditions combined, propensity score matching.

risk of PASC, 5.0% lower, HR 0.95, p = 0.29, treatment 9,593, control 9,593, adjusted per study, cardiac, propensity score matching, supplemental table 11.

risk of PASC, 3.0% higher, HR 1.03, p = 0.67, treatment 9,593, control 9,593, adjusted per study, pulmonary, propensity score matching, supplemental table 11.

risk of PASC, 11.0% lower, HR 0.89, p = 0.21, treatment 9,593, control 9,593, renal, propensity score matching, supplemental table 11.

risk of PASC, 30.0% lower, HR 0.70, p = 0.09, treatment 9,593, control 9,593, adjusted per study, thromboembolic, propensity score matching, supplemental table 11.

risk of PASC, 6.0% lower, HR 0.94, p = 0.26, treatment 9,593, control 9,593, gastrointestinal, propensity score matching, supplemental table 11.

risk of PASC, 4.0% higher, HR 1.04, p = 0.63, treatment 9,593, control 9,593, adjusted per study, neurologic, propensity score matching, supplemental table 11.

risk of PASC, 3.0% higher, HR 1.03, p = 0.65, treatment 9,593, control 9,593, mental health, propensity score matching, supplemental table 11.

risk of PASC, 5.0% higher, HR 1.05, p = 0.45, treatment 9,593, control 9,593, musculoskeletal, propensity score matching, supplemental table 11.

risk of PASC, 6.0% lower, HR 0.94, p = 0.65, treatment 9,593, control 9,593, adjusted per study, endocrine, propensity score matching, supplemental table 11.

risk of PASC, 4.0% higher, HR 1.04, p = 0.69, treatment 9,593, control 9,593, general - malaise, propensity score matching, supplemental table 11.

risk of PASC, 60.0% higher, HR 1.60, p = 0.47, treatment 9,593, control 9,593, general - post-viral fatigue, propensity score matching, supplemental table 11.

risk of PASC, 12.0% higher, HR 1.12, p = 0.41, treatment 9,593, control 9,593, general - ED, propensity score matching, supplemental table 11.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Ioannou et al., 31 Oct 2023, retrospective, propensity score matching, USA, peer-reviewed, 19 authors.

This Paper Paxlovid All

Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans A Target Trial Emulation

BMBCh, MS George N Ioannou, PhD Kristin Berry, PhD Nallakkandi Rajeevan, MS Yuli Li, MD Pradeep Mutalik, PhD Lei Yan, PhD David Bui, PharmD Francesca Cunningham, MPH Denise M Hynes, PhD, RN; Mazhgan Rowneki, MPH Amy Bohnert, PhD, MHS Edward J Boyko, MD, MPH Theodore J Iwashyna, PhD Matthew L Maciejewski, PhD Thomas F Osborne, MD Elizabeth M Viglianti, MD, MPH, MSc Mihaela Aslan, PhD Grant D Huang, PhD Kristina L Bajema

doi:10.7326/M23-1394

Background: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs. Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. Setting: Veterans Health Administration (VHA). Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. Intervention: Nirmatrelvir-ritonavir treatment for acute COVID-19. Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n ¼ 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, À0.29 percentage points [CI, À0.52 to À0.05 percentage points]). Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir.

Author contributions are available at Annals.org.

References

Aggarwal, Molina, Beaty, Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of Omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study, Lancet Infect Dis, doi:10.1016/S1473-3099(23)00011-7

Al-Aly, Xie, Bowe, High-dimensional characterization of post-acute sequelae of COVID-19, Nature, doi:10.1038/s41586-021-03553-9

Altman, Andersen, Calculating the number needed to treat for trials where the outcome is time to an event, BMJ, doi:10.1136/bmj.319.7223.1492

Arbel, Sagy, Hoshen, Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge, N Engl J Med, doi:10.1056/NEJMoa2204919

Austin, Cafri, Variance estimation when using propensity-score matching with replacement with survival or time-to-event outcomes, Stat Med, doi:10.1002/sim.8502

Ayoubkhani, Khunti, Nafilyan, Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study, BMJ, doi:10.1136/bmj.n693

Bajema, Berry, Streja, Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. veterans: target trial emulation studies with one-month and six-month outcomes, Ann Intern Med, doi:10.7326/M22-3565

Bernal, Da Silva, Musungaie, Study Group. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Engl J Med, doi:10.1056/NEJMoa2116044

Bull-Otterson, Baca, Saydah, Post-COVID conditions among adult COVID-19 survivors aged 18-64 and ≥65 years-United States, March 2020-November 2021, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7121e1

Butler, Hobbs, Gbinigie, Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial, Lancet, doi:10.1016/S0140-6736(22)02597-1

Carfi, Bernabei, Landi, Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19, JAMA, doi:10.1001/jama.2020.12603

Cohen, Ren, Heath, Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study, BMJ, doi:10.1136/bmj-2021-068414

Crook, Raza, Nowell, Long covid-mechanisms, risk factors, and management, BMJ, doi:10.1136/bmj.n1648

Daugherty, Guo, Heath, Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study, BMJ, doi:10.1136/bmj.n1098

Davis, Mccorkell, Vogel, Long COVID: major findings, mechanisms and recommendations, Nat Rev Microbiol, doi:10.1038/s41579-022-00846-2

Dickerman, Gerlovin, Madenci, Comparative effectiveness of BNT162b2 and mRNA-1273 vaccines in U.S. veterans, N Engl J Med, doi:10.1056/NEJMoa2115463

Dryden-Peterson, Kim, Kim, Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system: a populationbased cohort study, Ann Intern Med, doi:10.7326/M22-2141

Food, Administration, Paxlovid Patient Eligibility Screening Checklist Tool for Prescribers

Gupta, Madhavan, Sehgal, Extrapulmonary manifestations of COVID-19, Nat Med, doi:10.1038/s41591-020-0968-3

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

Hernán, Robins, Using big data to emulate a target trial when a randomized trial is not available, Am J Epidemiol, doi:10.1093/aje/kwv254

Huang, Huang, Wang, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Lancet, doi:10.1016/S0140-6736(20)32656-8

Ioannou, Locke, Green, Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: a target trial emulation study in the U.S. Veterans Affairs healthcare system, EClinicalMedicine, doi:10.1016/j.eclinm.2022.101326

Ioannou, Locke, Hare, COVID-19 vaccination effectiveness against infection or death in a national U.S. health care system: a target trial emulation study, Ann Intern Med, doi:10.7326/M21-3256

Katsoularis, Fonseca-Rodríguez, Farrington, Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study, Lancet, doi:10.1016/S0140-6736(21)00896-5

Labrecque, Swanson, Target trial emulation: teaching epidemiology and beyond, Eur J Epidemiol, doi:10.1007/s10654-017-0293-4

Lewnard, Mclaughlin, Malden, Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system, Lancet Infect Dis, doi:10.1016/S1473-3099(23)00118-4

Najjar-Debbiny, Gronich, Weber, Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients, Clin Infect Dis, doi:10.1093/cid/ciac443

Nalbandian, Sehgal, Gupta, Post-acute COVID-19 syndrome, Nat Med, doi:10.1038/s41591-021-01283-z

Robins, Hernán, Brumback, Marginal structural models and causal inference in epidemiology, Epidemiology, doi:10.1097/00001648-200009000-00011

Rosenbaum, Db, Reducing bias in observational studies using subclassification on the propensity score, J Am Stat Assoc, doi:10.2307/2288398

Statacorp, Chapter 11: Language syntax, Stata Manual

Wang, Porter, Maynard, Predicting risk of hospitalization or death among patients receiving primary care in the Veterans Health Administration, Med Care, doi:10.1097/MLR.0b013e31827da95a

Wong, Au, Lau, Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the Omicron wave in Hong Kong: an observational study, Lancet, doi:10.1016/S0140-6736(22)01586-0

Xie, Bowe, Al-Aly, Berry, Aslan et al., Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records, BMJ, doi:10.1136/bmj-2022-072705

Xie, Bowe, Al-Aly, Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status, Nat Commun, doi:10.1038/s41467-021-26513-3

Xie, Choi, Al-Aly, Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition, JAMA Intern Med, doi:10.1001/jamainternmed.2023.0743

Xie, Choi, Al-Aly, Molnupiravir and risk of post-acute sequelae of covid-19: cohort study, BMJ, doi:10.1136/bmj-2022-074572

Xie, Xu, Al-Aly, Risks of mental health outcomes in people with covid-19: cohort study, BMJ, doi:10.1136/bmj-2021-068993

Xie, Xu, Bowe, Long-term cardiovascular outcomes of COVID-19, Nat Med, doi:10.1038/s41591-022-01689-3

Yan, Streja, Li, Anti-SARS-CoV-2 pharmacotherapies among nonhospitalized US veterans, January 2022 to January 2023, JAMA Netw Open, doi:10.1001/jamanetworkopen.2023.31249

Yip, Lui, Lai, Impact of the use of oral antiviral agents on the risk of hospitalization in community coronavirus disease 2019 patients (COVID-19), Clin Infect Dis, doi:10.1093/cid/ciac687

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