‘Urgent confirmation from randomised clinical trials is needed.’

A large observational study has linked hydroxychloroquine and chloroquine use to increased rates of mortality and heart arrhythmias in hospitalised COVID-19 patients

A large observational study published in The Lancet has looked at treatment of COVID-19 patients with the antimalarial drug chloroquine or hydroxychloroquine, taken with or without a macrolide (azithromycin or clarithromycin).

Data was drawn from 671 hospitals in six continents. Over 96,000 patients met the inclusion criteria, having been hospitalised between 20 December 2019 and 14 April 2020 with a positive laboratory finding for SARS-CoV-2.

Of these, 14,888 patients were in the treatment groups—1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide.

The remaining 81,144 patients were in the control group.

After controlling for multiple confounding factors—age, sex, race, BMI, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity)—when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality.

Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were also independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit.

Previous evidence was derived from either small anecdotal studies or inconclusive small randomised trials.

The researchers caution that it is not possible to exclude the possibility that other, unmeasured factors were responsible for the apparent link between treatment with these drugs and the decrease in patient survival because of the nature of observational studies, and randomised trials are urgently needed.

However they warn that their findings suggest not only an absence of therapeutic benefit but also potential harm with the use of these drug regimens.

“This is the first large scale study to find statistically robust evidence that treatment with chloroquine or hydroxychloroquine does not benefit patients with COVID-19,” said lead author Professor Mandeep R. Mehra, a professor of medicine at Harvard Medical School and Executive Director of the Brigham and Women’s Hospital Center for Advanced Heart Disease in Boston, USA.

“Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death,” he warned.

“Randomised clinical trials are essential to confirm any harms or benefits associated with these agents. In the meantime, we suggest these drugs should not be used as treatments for COVID-19 outside of clinical trials.”

In an associated comment in The Lancet, Christian Funck-Brentano and Joe-Elie Salem from Sorbonne Université in France explore why chloroquine or hydroxychloroquine might be hazardous for COVID-19 patients and associated with cardiac toxicity.

One hypothesis to explain the increased risk of death with the drugs is that their antiviral and immunomodulatory properties could worsen COVID-19 severity in some patients, they suggest.

“Nevertheless, the increased incidence of ventricular arrhythmias is intriguing. Chloroquine, hydroxychloroquine, and azithromycin have sodium channel blocking properties that might contribute to proarrhythmia and heart failure in the context of myocardial injury and hypoxia present in COVID-19. This hypothesis remains to be tested,” they say.

See the full study here

See the associated comment here

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