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There was no difference in risk of intubation or death in hospitalized patients with COVID-19 coronavirus infection treated with hydroxychloroquine, an antimalarial also used in the treatment of certain autoimmune diseases, compared with patients receiving other treatments, an observational study found.

A multivariate analysis found (HR 1.04, 95% CI 0.82-1.32), reported Neil Schluger, MD, of Columbia University Irving Medical Center in New York City, and colleagues in the New England Journal of Medicine.

"Given the observational design and the relatively wide confidence interval, the study should not be taken to rule out either benefit or harm of hydroxychloroquine treatment," the authors wrote, adding that their findings "do not support the use of hydroxychloroquine at present outside randomized clinical trials testing its efficacy."

NEJM Editor-in-Chief Eric J. Rubin, MD, PhD, and several colleagues authored an editorial noting that claims of efficacy for hydroxychloroquine, chloroquine, and azithromycin have been "based largely on anecdotes and case series."

And now, based on these findings, ," they wrote.

"The authors used modern methods to rigorously analyze data that are available now, despite the well-understood limitations of observational studies," the editorialists stated. "We have chosen to publish this report so that clinicians will have some information that is based on rigorous analyses of observational data."

Indeed, Schluger and colleagues emphasized their use of a multivariable regression model with inverse probability weighting according to patients' propensity scores. The analysis adjusted for likely confounders including age, race/ethnicity, body mass index, diabetes, kidney disease, and hypertension, among others.

The researchers examined records for 1,446 consecutive patients hospitalized for COVID-19 from March 7 to April 8 at a large medical center in New York City. Of these, sufficient data from 1,376 patients was available. Follow-up was around 23 days, and about 59% of patients received hydroxychloroquine (600 mg twice on day 1, and 400 mg daily, for a median of 5 days).

Notably, the authors cited medical center guidelines to determine which patients received hydroxychloroquine, which included patients with moderate-to-severe illness, defined as a resting oxygen saturation of less than 94% while breathing ambient air. Another option included hydroxychloroquine combined with 500 mg of azithromycin on day 1 and 250 mg daily for 4 more days.

The azithromycin suggestion was removed on April 12, and the hydroxychloroquine suggestion on April 29, with the decision left to the discretion of the treatment team.

The primary endpoint was time from study baseline to intubation or death. Overall, 25% of patients progressed to a primary endpoint event, with 180 patients intubated and 166 dying without intubation. Schluger and colleagues noted that at the time of data cut-off, 232 patients had died, 1,025 survived to hospital discharge, and 119 were still hospitalized.

Almost half of patients who received hydroxychloroquine received it within 24 hours of presenting to the emergency department and the start of study follow-up, with 86% receiving it within 48 hours.

The authors noted that patients receiving hydroxychloroquine were more severely ill than those who did not, and a crude, unadjusted analysis found that patients in the hydroxychloroquine group were more likely to die or be intubated compared to those who did not receive the drug (HR 2.37, 95% CI 1.84-3.02).

On multivariate analysis, there was also no significant difference in the composite primary endpoint with azithromycin (HR 1.03, 95% CI 0.81-1.31). Sensitivity analyses all yielded similar results.

Schluger's group and the editorialists both emphasized the importance of randomized clinical trials in determining the efficacy of hydroxychloroquine.

"The results leave open the possibility that these agents could have a modest benefit, but do not rule out a detrimental effect, something that will probably be learned only through well-designed and well-conducted randomized, controlled trials," Rubin and colleagues wrote.

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