Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: the devil is in the details.

Several trials of different designs were conducted to investigate the efficacy and safety of hydroxychloroquine (HCQ) for the prevention and/or the treatment of COVID-19 patients. Recently, it has been reported that HCQ might have been associated with an excess of 16,990 deaths during the first wave of the COVID-19 pandemic in 6 countries. Such attributable risk analysis is associated with many limitations. These previous findings did not adequately address dose-subgroup and sensitivity analyses which precludes any overall firm conclusions on in-hospital mortality attributable to HCQ. We performed a meta-analysis and proposed a stratification by doses of HCQ. By pooling studies employing HCQ doses < or = 2400mg/5 days (i.e., k=12, n patients treated with HCQ=947, n controls=745), an OR of 0.94 (95%CI 0.56; 1.59) was found, indicating no increase in the mortality rate anymore. Importantly, there was no significant reduction in mortality rate with HCQ at < or = 2400mg/5 days neither. The same observation held true when pooling studies employing HCQ doses < or = 4800mg/5 days (i.e., k=25, n patients treated with HCQ=1672, n controls=1479) with an OR of 0.97 (95% CI 0.73; 1.29). Only high dose regimens of HCQ are associated with a significant increase in mortality. Applying an excess of mortality in the population treated with doses where no increase of mortality is found creates a misleading overestimation of deaths associated with the use of HCQ in hospitalized patients with COVID-19. On the other hand, even at low doses HCQ regimen, no reduction in mortality with HCQ was observed suggesting that, when it comes to mortality as the outcome, HCQ did not show a benefit in hospitalized patients suffering from COVID-19. This mainly justifies the past and still up-to-date recommendations and guidelines to not use HCQ in this indication. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Material related to this analysis is freely available on Open Science Framework (https://osf.io/ewudy/).