The absence of an effective treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led clinicians to redirect drugs that are known to be effective for other medical conditions to the treatment of COVID-19. Key among these repurposed therapeutic agents are the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for the treatment of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.1, 2 These drugs have been shown in laboratory conditions to have antiviral properties as well as immunomodulatory effects.3, 4 However, the use of this class of drugs for COVID-19 is based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses, and small, open-label, randomised trials that have largely been inconclusive.5, 6 The combination of hydroxychloroquine with a second-generation macrolide, such as azithromycin (or clarithromycin), has also been advocated, despite limited evidence for its effectiveness.7 Previous studies have shown that treatment with chloroquine, hydroxychloroquine, or either drug combined with a macrolide can have the cardiovascular adverse effect of prolongation of the QT interval, which could be a mechanism that predisposes to ventricular arrhythmias.8, 9
Research in context
Evidence before this study
We searched MEDLINE (via PubMed) for articles published up to April 21, 2020, using the key words “novel coronavirus”, “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “therapy”, “hydroxychloroquine”, “chloroquine”, and “macrolide”. Moreover, we screened preprint servers, such as Medrxiv, for relevant articles and consulted the web pages of organisations such as the US National Institutes of Health and WHO. Hydroxychloroquine and chloroquine (used with or without a macrolide) are widely advocated for treatment of COVID-19 based on in-vitro evidence of an antiviral effect against severe acute respiratory syndrome coronavirus 2. Their use is based on small uncontrolled studies and in the absence of evidence from randomised controlled trials. Concerns have been raised that these drugs or their combination with macrolides could result in electrical instability and predispose patients to ventricular arrhythmias. Whether these drugs improve outcomes or are associated with harm in COVID-19 remains unknown.
Added value of this study
In the absence of reported randomised trials, there is an urgent need to evaluate real-world evidence related to outcomes with the use of hydroxychloroquine or chloroquine (used with or without macrolides) in COVID-19. Using an international, observational registry across six continents, we assessed 96 032 patients with COVID-19, of whom 14 888 were treated with hydroxychloroquine, chloroquine, or their combination with a macrolide. After controlling for age, sex, race or ethnicity, underlying comorbidities, and disease severity at baseline, the use of all four regimens was associated with an increased hazard for de-novo ventricular arrythmia and death in hospital. This study provides real-world evidence on the use of these therapeutic regimens by including a large number of patients from across the world. Thus, to our knowledge, these findings provide the most comprehensive evidence of the use of hydroxychloroquine and chloroquine (with or without a macrolide) for treatment of COVID-19.
Implications of all the available evidence
We found no evidence of benefit of hydroxychloroquine or chloroquine when used either alone or with a macrolide. Previous evidence was derived from either small anecdotal studies or inconclusive small randomised trials. Our study included a large number of patients across multiple geographic regions and provides the most robust real-world evidence to date on the usefulness of these treatment regimens. Although observational studies cannot fully account for unmeasured confounding factors, our findings suggest not only an absence of therapeutic benefit but also potential harm with the use of hydroxychloroquine or chloroquine drug regimens (with or without a macrolide) in hospitalised patients with COVID-19.
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