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0 0.5 1 1.5 2+ PASC, all 31 conditions 1% Improvement Relative Risk PASC, cardiac 5% PASC, pulmonary -3% PASC, renal 11% PASC, thromboembolic 30% PASC, gastrointestinal 6% PASC, neurologic -4% PASC, mental health -3% PASC, musculoskeletal -5% PASC, endocrine 6% PASC, general - malaise -4% PASC, general - post-viral.. -60% PASC, general - ED -12% Paxlovid  Ioannou et al.  EARLY TREATMENT  LONG COVID Does paxlovid reduce the risk of Long COVID (PASC)? PSM retrospective 19,186 patients in the USA No significant difference in PASC Ioannou et al., Annals of Internal Med.., Oct 2023 Favors paxlovid Favors control

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  
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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, (B), vitamin D (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. 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.
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.
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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
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
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