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

Lewnard et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(23)00118-4

Mar 2023

Retrospective 7,274 outpatients in the USA treated with paxlovid and matched controls, showing lower combined hospitalization/death with treatment.

With a small percentage of eligible patients receiving treatment, confounding by indication, healthcare seeking behavior, knowledge of COVID-19 treatments, etc. is likely significant. Authors partially address this in their matching procedure. Notably, authors do not appear to address confounding by contraindication, and matching is unable to find a match for patients that seek adjuvant treatments (e.g., paxlovid + vitamin D). Confounding may be more significant for patients that seek care earlier.

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.

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.

Important missing comments or errors? Let us know.

death/mechanical ventilation/ICU, 84.1% lower, RR 0.16, p = 0.03.

death/mechanical ventilation/ICU, 89.2% lower, RR 0.11, p = 0.07, within 5 days.

risk of death/hospitalization, 53.6% lower, RR 0.46, p = 0.03.

risk of death/hospitalization, 79.6% lower, RR 0.20, p = 0.008, within 5 days.

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

Lewnard et al., 15 Mar 2023, retrospective, USA, peer-reviewed, 12 authors, study period 31 December, 2021 - 7 April, 2022. Contact: jlewnard@berkeley.edu.

This Paper Paxlovid All

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

Dr Joseph A Lewnard, PhD John M Mclaughlin, Debbie Malden, Vennis Hong, PhD, L Jodar PhD Laura Puzniak, MD Bradley K Ackerson, Bruno J Lewin, PhD Jeniffer S Kim, Sally F Shaw, Harpreet Takhar, Luis Jodar, Sara Y Tartof

The Lancet Infectious Diseases, doi:10.1016/s1473-3099(23)00118-4

Background In the USA, oral nirmatrelvir-ritonavir is authorised for use in patients aged 12 years or older with mildto-moderate COVID-19 who are at risk of progression to severe disease and hospitalisation. We aimed to establish the effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and death in people with COVID-19 in an outpatient prescribing context in the USA. Methods In this matched observational outpatient cohort study in the Kaiser Permanente Southern California (CA, USA) health-care system, data were extracted from electronic health records of non-hospitalised patients aged 12 years or older who received a positive SARS-CoV-2 PCR test result (their index test) between April 8 and Oct 7, 2022, and had not received another positive test result within the preceding 90 days. We compared outcomes between people who received nirmatrelvir-ritonavir and those who did not receive nirmatrelvir-ritonavir by matching cases by date, age, sex, clinical status (including care received, the presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), vaccination history, comorbidities, health-care seeking during the previous year, and BMI. Our primary endpoint was the estimated effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions or death within 30 days of a positive test for SARS-CoV-2. Findings 7274 nirmatrelvir-ritonavir recipients and 126 152 non-recipients with positive SARS-CoV-2 tests were included in our study. 5472 (75•2%) treatment recipients and 84 657 (67•1%) non-recipients were tested within 5 days of symptom onset. Nirmatrelvir-ritonavir had an overall estimated effectiveness of 53•6% (95% CI 6•6-77•0) in preventing hospital admission or death within 30 days of a positive test for SARS-CoV-2, which increased to 79•6% (33•9-93•8) when nirmatrelvir-ritonavir was dispensed within 5 days of symptom onset. Within the subgroup of patients tested within 5 days of symptom onset and whose treatment was dispensed on the day of their test, the estimated effectiveness of nirmatrelvir-ritonavir was 89•6% (50•2-97•8). Interpretation In a setting with high levels of COVID-19 vaccine uptake, nirmatrelvir-ritonavir effectively reduced the risk of hospital admission or death within 30 days of a positive outpatient SARS-CoV-2 test.

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