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Background

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. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

Findings

96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. 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) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, 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 independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Interpretation

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

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Antimalarial drug touted by President Trump is linked to increased risk of death in coronavirus patients, study says

A study of 96,000 hospitalized coronavirus patients on six continents found that those who received an antimalarial drug promoted by President Trump as a “game changer” in the fight against the virus had a significantly higher risk of death compared with those who did not.

People treated with hydroxychloroquine, or the closely related drug chloroquine, were also more likely to develop a type of irregular heart rhythm, or arrhythmia, that can lead to sudden cardiac death, it concluded.

The study, published Friday in the medical journal the Lancet, is the largest analysis to date of the risks and benefits of treating covid-19 patients with antimalarial drugs. It is based on a retrospective analysis of medical records, not a controlled study in which patients are divided randomly into treatment groups — a method considered the gold standard of medicine. But the sheer size of the study was convincing to some scientists.

“It’s one thing not to have benefit, but this shows distinct harm,” said Eric Topol, a cardiologist and director of the Scripps Research Translational Institute. “If there was ever hope for this drug, this is the death of it.”

David Maron, director of preventive cardiology at the Stanford University School of Medicine, said that “these findings provide absolutely no reason for optimism that these drugs might be useful in the prevention or treatment of covid-19.”

Past studies also found scant or no evidence of hydroxychloroquine’s benefit in treating sick patients, while reports mounted of dangerous heart problems associated with its use. As a result, the Food and Drug Administration last month warned against the use of the drug outside hospital settings or clinical trials.

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The new analysis — by Mandeep Mehra, a Harvard Medical School professor and physician at Brigham and Women’s Hospital, and colleagues at other institutions — included patients with a positive laboratory test for covid-19 who were hospitalized between Dec. 20, 2019, and April 14, 2020, at 671 medical centers worldwide. The mean age was 54 years, and 53 percent were men. Those who were on mechanical ventilators or who received remdesivir, an antiviral drug made by Gilead Sciences that has shown promise in decreasing recovery times, were excluded.

Mehra said in an interview that the widespread use of antimalarials for covid-19 patients was based on the idea of “a desperate disease demands desperate measures," but that we have learned a hard lesson from the experience about the importance of first doing no harm.

In retrospect, Mehra said, using the drugs without systematic testing was “unwise.”

“I wish we had had this information at the outset,” he said, “as there has potentially been harm to patients.”

Nearly 15,000 of the 96,000 patients in the analysis were treated with hydroxychloroquine or chloroquine alone or in combination with a type of antibiotics known as a macrolide, such as azithromycin or clarithromycin, within 48 hours of their diagnosis.

The difference between patients who received the antimalarials and those who did not was striking.

For those given hydroxychloroquine, there was a 34 percent increase in risk of mortality and a 137 percent increased risk of a serious heart arrhythmias. For those receiving hydroxychloroquine and an antibiotic — the cocktail endorsed by Trump — there was a 45 percent increased risk of death and a 411 percent increased risk of serious heart arrhythmias.

Those given chloroquine had a 37 percent increased risk of death and a 256 percent increased risk of serious heart arrhythmias. For those taking chloroquine and an antibiotic, there was a 37 percent increased risk of death and a 301 percent increased risk of serious heart arrhythmias.