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ObjectiveTo examine the association between dexamethasone use and mortality among hospitalized patients for COVID-19. DesignMulticenter observational retrospective cohort study. SettingGreater Paris University hospitals, France. Participants12,217 adults hospitalized with COVID-19 between 24 January and 20 May 2020, including 171 patients (1.4%) who received dexamethasone orally or by intravenous perfusion during the visit. Data sourceAssistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measuresThe primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time-to-event analyses adjusting for sex, age, obesity, current smoking status, any medical condition associated with increased COVID-19-related mortality, and clinical and biological severity of COVID-19 at admission, while stratifying by the need of respiratory support (i.e., oxygen or intubation). The primary analysis was a multivariable Cox model and the secondary analysis used a univariate Cox regression in a matched analytic sample. ResultsAmong patients who required respiratory support, the end-point event of death occurred in 10 patients (15.9%) who received dexamethasone and 298 patients (26.4%) who did not. In this group of patients, there was a significant association between dexamethasone use and reduced mortality in both the crude, unadjusted analysis (hazard ratio (HR), 0.40; 95% CI, 0.18 to 0.87, p=0.021) and the adjusted multivariable analysis (HR, 0.46; 95% CI, 0.22 to 0.96, p=0.039). In the sensitivity analysis, the univariate Cox regression model in the matched analytic sample yielded a same tendency, albeit non-significant (HR, 0.31; 95% CI, 0.08 to 1.14, p=0.077). Among patients without respiratory support, the end-point event of death occurred in 14 patients (13.0%) who received dexamethasone and 1,086 patients (10.0%) who did not. In this group of patients, there was no significant association between dexamethasone use and the endpoint. When examining the association between the cumulative dose of dexamethasone received during the visit and the endpoint, we found that the administration of a cumulative dose between 60 mg to 150 mg among patients who required respiratory support was significantly associated with a lower risk of death in the crude, unadjusted analysis (HR, 0.28; SE, 0.58, p=0.028), the adjusted multivariable analysis (HR, 0.24; SE, 0.65, p=0.030), and in the univariate Cox regression model in the matched analytic sample (HR, 0.32; SE, 0.58, p=0.048), whereas no significant association was observed with a different dose. Among patients without respiratory support, there was no significant association between the cumulative dose of dexamethasone and the endpoint in the crude and in the adjusted multivariable analyses. ConclusionsIn this observational study involving patients with Covid-19 who had been admitted to the hospital, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with decreased mortality among those requiring respiratory support.
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ObjectiveTo examine the association between hydroxyzine use and mortality in patients hospitalized for COVID-19, based on its anti-inflammatory and antiviral properties. DesignMulticenter observational retrospective cohort study. SettingGreater Paris University hospitals, France. Participants7,345 adults hospitalized for COVID-19 between 24 January and 1 April 2020, including 138 patients (1.9%) who received hydroxyzine during the visit at a mean dose of 49.8 mg (SD=51.5) for an average of 22.4 days (SD=25.9). Data sourceAssistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measuresThe study endpoint was death. We compared this endpoint between patients who received hydroxyzine and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), clinical and biological markers of diseases severity, and use of other medications. The primary analysis was a multivariable Cox model with inverse probability weighting. Sensitivity analyses included a multivariable Cox model and a univariate Cox regression model in a matched analytic sample in a 1:1 ratio. ResultsOver a mean follow-up of 20.3 days (SD=27.5), 994 patients (13.5%) had a primary end-point event. The primary multivariable analysis with inverse probability weighting showed a significant association between hydroxyzine use and reduced mortality (HR, 0.42; 95% CI, 0.25 to 0.71; p=0.001) with a significant dose-effect relationship (HR, 0.10; 95% CI, 0.02 to 0.45; p=0.003). This association was similar in sensitivity analyses. In secondary analyses conducted among subsamples of patients, we found a significant association between hydroxyzine use and a faster decrease in biological inflammatory markers associated with COVID-19-related mortality, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCRP), and circulating interleukin 6 levels (IL-6) (all p<0.016), with a significant dose-effect relationship for NLR and LCRP (both p<0.037). ConclusionsIn this retrospective observational study, hydroxyzine use was associated with reduced mortality in patients hospitalized for COVID-19. This association may be partially mediated by specific anti-inflammatory properties of H1 antihistamines. Double-blind controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results.
ABSTRACT
BackgroundHaloperidol, a widely used antipsychotic, has been suggested as potential effective treatment for Covid-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2. MethodsWe examined the association between haloperidol use and respiratory failure at AP-HP Greater Paris University hospitals. Data were obtained regarding all adult patients hospitalized with Covid-19 since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. We compared outcomes between patients who were exposed to haloperidol and those who were not, using a multivariable Cox regression model with inverse probability weighting according to the propensity score. ResultsOf the 13,279 hospitalized adult patients with positive Covid-19 RT-PCR test, 667 patients (5.0%) were excluded because of missing data. Of the remaining 12,612 patients, 104 (0.8%) were exposed to haloperidol. Over a mean follow-up of 20.8 days, the primary endpoint of respiratory failure respectively occurred in 27 patients (26.0%) exposed to haloperidol and 1,700 patients (13.6%) who were not. Among survivors, the secondary endpoint of discharge home occurred in 26 patients (32.1%) who received haloperidol and 6,110 patients (55.3%) who did not. In the main analysis, there were no significant associations between haloperidol use and the primary (HR, 1.09; 95% CI, 0.60 to 1.97, p=0.772) and secondary (HR, 0.88; 95% CI, 0.50 to 1.53, p=0.643) endpoints. Results were similar in multiple sensitivity analyses. ConclusionIn this observational study involving patients with Covid-19 who had been admitted to the hospital, haloperidol use was not associated with risk of intubation or death, or with time to hospital discharge home. These results suggest that haloperidol is unlikely to have a clinical efficacy for Covid-19.
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On the grounds of its anti-inflammatory and potential antiviral effects, chlorpromazine has been suggested to be effective treatment for Covid-19. We examined the association between chlorpromazine use and respiratory failure among all hospitalized adults with Covid-19 at the 39 Greater Paris University hospitals since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death in a time-to-event analysis adjusting for numerous potential confounders. We used a multivariable Cox model with inverse probability weighting according to the propensity score. Of the 12,217 adult inpatients with a positive Covid-19 RT-PCR test included in the analyses, 57 (0.47%) received chlorpromazine. Over a mean follow-up of 20.8 days, the primary endpoint occurred in 29 patients (50.9%) exposed to chlorpromazine and 1,899 patients (15.6%) who were not. In the main analysis, there was a positive significant association between chlorpromazine use and the outcome (HR, 1.67; 95% CI, 1.09 to 2.56, p=0.019), while a Cox regression in a matched analytic sample yielded non-significant association (1.38; 95% CI, 0.91 to 2.09, p=0.123). These findings suggest that chlorpromazine is unlikely to have a clinical efficacy for Covid-19.
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ObjectiveTo examine the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19. DesignMulticenter observational retrospective cohort study. SettingGreater Paris University hospitals, France. Participants7,345 adults hospitalized with COVID-19 between 24 January and 1 April 2020, including 460 patients (6.3%) who received an antidepressant during the visit. Data sourceAssistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measuresThe primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), disease severity and other psychotropic medications. The primary analyses were multivariable Cox models with inverse probability weighting. ResultsOver a mean follow-up of 18.5 days (SD=27.1), 1,331 patients (18.1%) had a primary end-point event. Unadjusted hazard ratio estimates of the association between antidepressant use and the primary outcome stratified by age (i.e., 18-50, 51-70, 71-80, and 81+) were non-significant (all p>0.072), except in the group of patients aged 71-80 years (HR, 0.66; 95% CI, 0.45 to 0.98; p=0.041). Following adjustments, the primary analyses showed a significant association between use of any antidepressant (HR, 0.64; 95% CI, 0.51 to 0.80; p<0.001), SSRI (HR, 0.56; 95% CI, 0.42 to 0.75; p<0.001), and SNRI (HR, 0.57; 95% CI, 0.34 to 0.96; p=0.034), and reduced risk of intubation or death. Specifically, exposures to escitalopram, fluoxetine, and venlafaxine were significantly associated with lower risk of intubation or death (all p<0.05). These associations remain significant in multiple sensitivity analyses, except for the association between SNRI use and the outcome. ConclusionsSSRI use could be associated with lower risk of death or intubation in hospitalized patients with COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed. What is already known on this topicO_LIA prior meta-analysis, mainly including studies on selective serotonin reuptake inhibitors (SSRIs), showed that antidepressant use in major depressive disorder was associated with reduced levels of several pro-inflammatory cytokines, including IL-6, TNF-, and CCL-2, which have been suggested to be associated with severe COVID-19. C_LIO_LIA recent in-vitro study supports antiviral effects of the SSRI fluoxetine on SARS-CoV-2. C_LIO_LITo our knowledge, no study has examined the efficacy of antidepressants in patients with COVID-19. C_LI What this study addsO_LIIn a multicenter observational retrospective study, we examined the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19, adjusting for patient characteristics, disease severity and other psychotropic medications. C_LIO_LIAntidepressant use was significantly and substantially associated with reduced risk of intubation or death. C_LIO_LIAt the level of antidepressant classes, SSRI use was significantly and substantially associated with reduced risk of intubation or death, but not other antidepressant classes. C_LIO_LIAt the level of antidepressant medications, exposures to the SSRIs fluoxetine and escitalopram, and the SNRI venlafaxine were significantly associated with lower risk of intubation or death. C_LIO_LIDouble-blind controlled randomized clinical trials of these medications for COVID-19 are needed. C_LI
ABSTRACT
We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across 5 countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on comorbidities and temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.