Huge Study Throws Cold Water on Antimalarials for COVID-19

Editor's Note: The Lancet retracted the Mehra paper cited below on June 4. The authors determined they could not vouch for the data's accuracy after independent peer reviewers said they could not replicate the analyses in the paper, and could not obtain access to the required data.

Chloroquine or hydroxychloroquine (HCQ), with or without an antibiotic, in hospitalized COVID-19 patients were associated with increased risk of death in the hospital and higher rates of arrhythmias, analysis of outcomes in nearly 100,000 patients indicated.

The 15,000 patients who received HCQ or chloroquine were about twice as likely to die compared to controls who did not receive these agents after adjusting for covariates (18.o% for hydroxychloroquine and 16% for chloroquine versus 9.3% for controls), reported Mandeep Mehra, MD, of Brigham and Women's Hospital in Boston, and colleagues.

The drug was also associated with a higher risk of ventricular arrhythmia during hospitalization (6.1% for hydroxychloroquine, 4.3% for chloroquine versus 0.3% for controls), the authors wrote in The Lancet.

Moreover, risks for both in-hospital mortality and ventricular arrhythmia were even higher compared to controls when either drug was combined with a macrolide antibiotic, they noted.

Mehra said in a statement these drugs should not be used as treatments for COVID-19 outside of clinical trials.

"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," he said. "Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death. Randomised clinical trials are essential to confirm any harms or benefits associated with these agents."

Mehra's group analyzed some 96,000 patients from 671 hospitals on six continents with COVID-19 infection, from Dec. 20 to April 14, all of whom had either died or been discharged from the hospital by April 21.

Overall, 14,888 patients were treated with hydroxychloroquine, chloroquine, hydroxychloroquine with a macrolide antibiotic or chloroquine with an antibiotic, and their results were compared to 81,144 controls who did not receive these drugs.

Authors adjusted for demographic factors, as well as cardiovascular disease, diabetes, lung disease, smoking, immunosuppressed conditions and baseline disease severity.

The estimated excess risk attributable to the drug regimen rather than other factors, such as comorbidities, ranged from 34% to 35%.

Arrhythmia's greatest risk was in the group who received hydroxychloroquine and a macrolide antibiotic such as azithromycin (8% versus 0.3% of controls), and this regimen was associated with a more than five-fold risk of developing an arrhythmia while hospitalized, though cause and effect cannot be inferred, the group noted.

"Previous small-scale studies have failed to identify robust evidence of a benefit and larger, randomised controlled trials are not yet completed," said co-author Frank Ruschitzka, MD, Director of the Heart Center at University Hospital Zurich in a statement. "However, we now know from our study that the chance that these medications improve outcomes in COVID-19 is quite low."

An accompanying editorial by Christian Funck-Brentano, MD, PhD, and Joe-Elie Salem, MD, PhD, of Sorbonne Université in Paris, noted limitations of the observational data, but said the authors "should be commended for providing results from a well designed and controlled study ... in a very large sample of hospitalized patients."

They also cautioned against attributing the increased risk of hospital deaths to the higher incidence of arrhythmias, noting that "the relationship between death and ventricular tachycardia was not studied and causes of deaths (i.e., arrhythmic vs non-arrhythmic) were not adjudicated."

The editorialists nevertheless concluded both hydroxychloroquine and chloroquine, with or without azithromycin, "are not useful and could be harmful in hospitalized patients with COVID-19," and stressed the importance of clinical trials for these drugs.

"The global community awaits the results of ongoing, well powered randomized controlled trials showing the effects of chloroquine and hydroxychloroquine on COVID-19 clinical outcomes," they wrote.

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