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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
ABSTRACT
BackgroundReliable information is an essential component for responding to the COVID-19 epidemic, especially regarding the availability of critical care beds (CCBs). We propose three contributions: a) ICUBAM (ICU Bed Availability Monitor), a tool which both collects and visualizes information on CCB availability entered directly by intensivists. b) An analysis of CCB availability and ICU admissions and outcomes using collected by ICUBAM during a 6-week period in the hard-hit Grand Est region of France, and c) Explanatory and predictive models adapted to CCB availability prediction, and fitted to availability information collected by ICUBAM. MethodsWe interact directly with intensivists twice a day, by sending a SMS with a web link to the ICUBAM form where they enter 8 numbers: number of free and occupied CCBs (ventilator-equipped) for both COVID-19 positive and COVID-19- negative patients, the number of COVID-19 related ICU deaths and discharges, the number of ICU refusals, and the number of patients transferred to another region due to bed shortages. The collected data are described using univariate and multivariate methods such as correspondence analysis and then modeled at different scales: a medium and long term prediction using SEIR models, and a short term statistical model to predict the number of CCBs. ResultsICUBAM was brought online March 25, and is currently being used in the Grand Est region by 109 intensivists representing 40 ICUs (95% of ICUs). ICUBAM allows for the calculation of CCB availability, admission and discharge statistics. Our analysis of data describes the evolution and extent of the COVID-19 health crisis in the Grand Est region: on April 6th, at maximum bed capacity, 1056 ventilator-equipped CCBs were present, representing 211% of the nominal regional capacity of 501 beds. From March 19th to March 31st, average daily COVID-19 ICU inflow was 68 patients/day, and 314 critical care patients were transferred out of the Grand Est region. With French lockdown starting on March 17th, a decrease of the daily inflow was found starting on April 1st: 23 patients/day during the first fortnight of April, and 7 patients/day during the last fortnight. However, treatment time for COVID-19 occupied CCBs is long: 15 days after the peak on March 31st, only 20% of ICU beds have been freed (50% after 1 month). Region-wide COVID-19 related in-ICU mortality is evaluated at 31%. Models trained from ICUBAM data are able to describe and predict the evolution of bed usage for the Grand Est region. ConclusionWe observe strong uptake of the ICUBAM tool, amongst both physicians and local healthcare stakeholders (health agencies, first responders etc.). We are able to leverage data collected with ICUBAM to better understand the evolution of the COVID-19 epidemic in the Grand Est region. We also present how data ingested by ICUBAM can be used to anticipate CCB shortages and predict future admissions. Most importantly, we demonstrate the importance of having a cross-functional team involving physicians, statisticians and computer scientists working both with first-line medical responders and local health agencies. This allowed us to quickly implement effective tools to assist in critical decision-making processes.
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BACKGROUND: Fibrinogen concentrate is widely used in traumatic hemorrhagic shock despite weak evidence in the literature. The aim of the study was to evaluate the effect of fibrinogen concentrate administration within the first 6 hours on 24-hour all-cause mortality in traumatic hemorrhagic shock using a causal inference approach. METHODS: Observational study from a French multicenter prospective trauma registry was performed. Hemorrhagic shock was defined as transfusion of four or more red blood cell units within the first 6 hours after admission. The confounding variables for the outcome (24-hour all-cause mortality) and treatment allocation (fibrinogen concentrate administration within the first 6 hours) were chosen by a Delphi method. The propensity score was specified with a data-adaptive algorithm and a doubly-robust approach with inverse proportionality of treatment weighting allowed to compute the average treatment effect. Sensitivity analyses were performed. RESULTS: Of 14,336 patients in the registry during the study period, 1,027 in hemorrhagic shock were analyzed (758 receiving fibrinogen concentrate within 6 hours and 269 not receiving fibrinogen concentrate). The average treatment effect, expressed as a risk difference, was -0.031 (95% confidence interval, -0.084 to 0.021). All sensitivity analysis confirmed the results. CONCLUSIONS: Fibrinogen concentrate administration within the first 6 hours of a traumatic hemorrhagic shock did not decrease 24-hour all-cause mortality. LEVEL OF EVIDENCE: Prognostic, level III.
