Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

Abstract

Objective To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. Design Retrospective cohort study. Setting An 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. Participants All 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. Intervention Patients 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 measures The 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. Results A 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). Conclusions 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 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.

The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients

“…In our study, the addition of azithromycin to HCQ does not seem to add any clear benefit. A large multicentre observational study reported no association between HCQ, or HCQ with azithromycin, and lower mortality but significantly higher rates of discharge home were observed for patients treated by HCQ [29].…”

Hydroxychloroquine in COVID-19: An updated systematic review with meta-analysis

“…Hospital mortality was reported by nine studies [16,20,21,24,26,28,[31][32][33]. Two studies evaluated 28-day mortality [18,27]. Ip et al [22] reported the 30-day and Mahevas et al [25], the 21-day mortality.…”

“…Clinical worsening was reported in six RCTs [12][13][14][15][16][17] and three observational studies. [27,29,32]. Clinical worsening was variously described as development of "severe" illness [12], resolution of fever and improvement in oxygen saturation [14], requirement for hospitalization [17,29] requirement for ICU transfer [27], requirement for mechanical ventilation [32], symptom severity on a 10-point visual analog scale [15], clinical status on a 7-point ordinal scale [16], and alleviation of cough with fever resolution [12].…”

“…Neither study revealed a significant change in clinical status at 2 weeks with hydroxychloroquine administration. A large retrospective observational study from France suggested reduced requirement for ICU transfer and higher rates of 28-day discharge with hydroxychloroquine; however, this study was limited by lack of information on respiratory parameters including the requirement for oxygen therapy, invasive, or non-invasive ventilation [27].…”

“…The risk of bias among the included RCTs, assessed by the Cochrane risk of bias tool, is presented in Figures 2 and 3. Among the observational studies, one was considered to be at low risk, [19] eight at moderate risk, [20][21][22][23][24][25][26][27] seven at serious risk [12,[28][29][30][31][32][33] and one at a critical risk of bias [5].…”