ABSTRACT
IntroductionSeveral 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. ObjectiveTo 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. MethodsWe 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. ResultsIn 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). ConclusionsThis 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.
ABSTRACT
ObjectiveTo assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. DesignRetrospective cohort study. SettingAn analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. ParticipantsAll adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. InterventionPatients were further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measuresThe primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. ResultsA total of 4,642 patients (mean age: 66.1 {+/-} 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving HCQ alone or HCQ plus AZI were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the HCQ and Neither drug groups for 28-day mortality: AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the HCQ group: AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the HCQ+AZI vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). ConclusionsUsing a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials. WHAT THIS PAPER ADDS?O_ST_ABSWhat is already known on this subjectC_ST_ABS- The use of Hydroxychloroquine (HCQ) or HCQ with azithromycin (AZI) has been associated with viral load reduction at 6 days in COVID-19 infected patients - No difference between HCQ and no-HCQ groups in terms of risk of death or need for mechanical ventilation was found in two large cohorts of hospitalized COVID-19 infected patients What this study adds- Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ on 28-day mortality - Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and AZI, but not with HCQ alone - Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies
