Chloroquine and hydroxychloroquine increase risk of death in COVID-19

    Treatment with chloroquine or hydroxychloroquine, with or without a macrolide, appears to increase the risk of death in patients with COVID-19, according to findings of a multinational registry analysis published in The Lancet.1

    Registry data from 671 hospitals in six continents were used to evaluate the safety and benefit of chloroquine or hydroxychloroquine, with or without a macrolide, in a total of 96 032 patients hospitalised with COVID-19 between December 2019 and April 2020. Patients received chloroquine (n=1868), hydroxychloroquine (3016), chloroquine plus a macrolide (3783), hydroxychloroquine plus a macrolide (6221), or none of these treatment regimens (81 144; controls).

    Overall, 11.1% of patients died during hospitalisation.

    Chloroquine, hydroxychloroquine, chloroquine plus a macrolide, and hydroxychloroquine plus a macrolide were independently associated with an increased risk of in-hospital mortality. The adjusted rate of in-hospital death and the adjusted hazard ratio (aHR) for death versus the death rate in controls was 16.4% (aHR 1.365; 95% CI 1.218, 1.531) with chloroquine, 18.0% (aHR 1.335; 95% CI 1.223, 1.457) with hydroxychloroquine, 22.2% (aHR 1.368; 95% CI 1.273, 1.469) with chloroquine plus a macrolide, and 23.8% (aHR 1.447; 95% CI 1.368, 1.531) with hydroxychloroquine plus a macrolide.

    All four regimens were also independently associated with an increased risk of new-onset ventricular tachycardia or fibrillation. The incidence of ventricular arrhythmias was 4.3% (aHR 3.561; 95% CI 2.760, 4.596) with chloroquine, 6.1% (aHR 2.369; 95% CI 1.935, 2.900) with hydroxychloroquine, 6.5% (aHR 4.011; 3.344, 4.812) with chloroquine plus a macrolide, and 8.1% (aHR 5.106; 95% CI 4.106, 5.983) with hydroxychloroquine plus a macrolide.

    "In summary, this multinational, observational, real-world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19," said the authors.

    Remarks from the WHO Director-General

    Two months ago, the WHO initiated the Solidarity Trial to evaluate the safety and efficacy of four drugs and drug combinations against COVID-19, said Dr Tedros Adhanom Ghebreyesus, Director-General of WHO, at a media briefing on COVID-19 on 25 May 2020.2 To date, 17 of the 35 countries participating in the Solidarity Trial have enrolled nearly 3500 patients.

    However, after the results of the above observational trial were published in The Lancet, the Executive Group of the Solidarity Trial met and agreed "to review a comprehensive analysis and critical appraisal of all evidence available globally," said the Director-General. The Executive Group has implemented a temporary pause of the hydroxychloroquine arm within the Solidarity Trial while the safety data is reviewed by the Data Safety Monitoring Board, but the other treatment arms are continuing.

    "This concern relates to the use of hydroxychloroquine and chloroquine in COVID-19. I wish to reiterate that these drugs are accepted as generally safe for use in patients with autoimmune diseases or malaria," he said.

    References

    1. Mehra MR, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet : 22 May 2020. Available from: URL: https://doi.org/10.1016/S0140-6736(20)31180-6

    2. WHO Director-General. WHO Director-General's opening remarks at the media briefing on COVID-19 - 25 May 2020. Internet Document : 25 May 2020. Available from: URL: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020

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    Chloroquine and hydroxychloroquine increase risk of death in COVID-19. Reactions Weekly 1806, 1 (2020). https://doi.org/10.1007/s40278-020-79019-x

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