Nicotine-replacement therapy, as a surrogate of smoking, and the risk of hospitalization with Covid-19 and all-cause mortality: a nationwide, observational cohort study in France
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Abstract
Introduction
Several studies have reported an unexpectedly low prevalence of current smoking among hospitalized patients with Covid-19. However, these studies mostly compared observed to expected rates of smoking without direct comparison with individual controls.
Objective
To examine the association of nicotine-replacement therapy, as a surrogate of smoking, with hospitalization and all-cause mortality during the first wave of SARS-CoV-2 epidemic in France.
Methods
We conducted a nationwide matched “exposed/unexposed” cohort study using information from the French national health data system which covers the entire French population. We conducted two separate analyses, the first in individuals exposed to nicotine-replacement therapy without major smoking-related diseases (cancer, cardiovascular and/or respiratory diseases) and the second in those presenting these conditions. We included all individuals, aged between 18 and 75 years, who had been reimbursed at least one nicotine-replacement therapy between November 15, 2019, and February 15, 2020. For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). The three end points were a hospitalization with Covid-19, a death or an intubation in hospitalized patients with Covid-19, and all-cause mortality. We compared outcomes in individuals who were exposed to nicotine-replacement therapy with those in individuals who were not, using a multivariable Cox model with inverse probability weighting according to the propensity score.
Results
In the first analysis, 297,070 individuals without major smoking-related diseases exposed to nicotine-replacement therapy were matched with 558,228 unexposed individuals without major smoking-related diseases. Individuals were aged on average 45.6 years (standard deviation: 12.7) and 48.8% were male.
From February 15, 2020 to June 7, 2020, hospitalization with Covid-19 occurred in 647 patients (151 patients in the nicotine-replacement therapy group and 496 patients in the unexposed group). In the main multivariable analysis, nicotine-replacement therapy was associated with a decreased risk of hospitalization with Covid-19 compared with unexposed individuals (hazard ratio, 0.50; 95% CI, 0.41 to 0.61). Nicotine-replacement therapy exposure was also associated with a decreased risk of intubation or death in hospitalized individuals with Covid-19 (13 vs. 73 patients, hazard ratio, 0.31; 95% CI, 0.17 to 0.57) but with an increased risk of all-cause mortality (251 vs. 231 deaths, hazard ratio, 1.49; 95% CI, 1.24 to 1.80).
In the second analysis, 128,768 individuals with major smoking-related diseases exposed to nicotine-replacement therapy were matched with 243,793 unexposed individuals. Individuals were aged on average 55.3 years (standard deviation: 11.4) and 53.3% were male. In the main multivariable analysis, nicotine-replacement therapy exposure was neither associated with risk of hospitalization with Covid-19 (240 patients in the nicotine-replacement therapy group and 398 patients in the unexposed group, hazard ratio, 1.13; 95% CI, 0.94 to 1.38) nor with risk of death or an intubation in hospitalized individuals with Covid-19 (48 vs. 61 patients, hazard ratio, 1.00; 95% CI, 0.65 to 1.54). All-cause mortality was higher in the nicotine-replacement therapy group (1040 vs. 366 deaths, hazard ratio, 3.83; 95% CI, 3.41 to 4.31).
Conclusions
This large-scale observational study suggests that smoking, measured by exposure to nicotine-replacement therapy, was associated with an increased risk of overall mortality during the first wave of SARS-CoV-2 epidemic in France, although it was associated with a lower risk of severe Covid-19 in individuals without major related-smoking diseases. Experimental and clinical studies are needed to disentangle the potential mechanisms of nicotine and/or smoking in Covid-19 risk. Whatever the nature of these associations, the global impact of smoking is harmful for health even over a short epidemic period.
Article activity feed
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SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in France Metropolitan), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of … SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in France Metropolitan), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in France Metropolitan), and complementary universal health insurance (CMU-C). Table 2: Resources
Software and Algorithms Sentences Resources Drugs are coded according to the Anatomical Therapeutic Chemical (ATC) classification. ATCsuggested: NoneAll calculations were performed using SAS, version 9.4 software (SAS Institute Inc.). SASsuggested: (SASqPCR, RRID:SCR_003056)SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in … SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in France Metropolitan), and complementary universal health insurance (CMU-C). Table 2: Resources
Software and Algorithms Sentences Resources Drugs are coded according to the Anatomical Therapeutic Chemical (ATC) classification. ATCsuggested: NoneAll calculations were performed using SAS, version 9.4 software (SAS Institute Inc.). SASsuggested: (SASqPCR, RRID:SCR_003056)SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
-
SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of … SciScore for 10.1101/2020.07.28.20160630: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). Blinding not detected. Power Analysis not detected. Sex as a biological variable For each exposed individual, we randomly selected, from the entire French Metropolitan population, up to two non-exposed individuals matched for the following variables: age (same year of birth), sex (male or female), department of residence (n=96 in France Metropolitan), and complementary universal health insurance (CMU-C). Table 2: Resources
Software and Algorithms Sentences Resources Drugs are coded according to the Anatomical Therapeutic Chemical (ATC) classification. ATCsuggested: NoneAll calculations were performed using SAS, version 9.4 software (SAS Institute Inc.). SASsuggested: (SASqPCR, SCR_003056)<div style="margin-bottom:8px"> <div><b>SAS Institute</b></div> <div>suggested: (Statistical Analysis System, <a href="https://scicrunch.org/resources/Any/search?q=SCR_008567">SCR_008567</a>)</div> </div> </td></tr></table>Data from additional tools added to each annotation on a weekly basis.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
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