The Food and Drug Administration (FDA) today issued a warning on the use of the antimalaria drugs hydroxychloroquine and chloroquine for treating COVID-19.

The warning is related to the potential for the drugs to prolong the QT interval—a cardiogram measurement used to assess some of the electrical properties of the heart—and cause abnormal heart rhythms, particularly in patients with cardiac conditions. Those risks may increase when the drugs are combined with the antibiotic azithromycin, which can further increase the risk for sudden cardiac arrest.

Hydroxychloroquine and chloroquine, either alone or in combination with azithromycin, are being studied for COVID-19 but are also increasingly being prescribed to COVID-19 patients outside the hospital setting. The FDA says use of the drugs should be limited to clinical trials or for treating certain hospitalized patients under the agency's Emergency Use Authorization (EUA), which was issued in late March.

"The FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT prolonging medicines," the FDA said in its drug safety communication.

"Therefore, we would like to remind health care professionals and patients of the known risks associated with both hydroxychloroquine and chloroquine. We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information."

Because of the potential for these adverse side effects, treatment guidelines issued by the National Institutes of Health earlier this week also recommended against the use of hydroxychloroquine or chloroquine in COVID-19 patients, either alone or in combination with azithromycin, outside of clinical trials.

Study raises red flags

The heart issues associated with use of hydroxychloroquine and chloroquine in COVID-19 patients are highlighted in a study published today in JAMA Network Open. The findings are from one of the many clinical trials being conducted to determine the safety and efficacy of the drugs in treating COVID-19.

In the study, researchers from Brazil and Spain report that a high dosage of chloroquine given to COVID-19 patients at a Brazilian hospital was associated with more patient deaths than a low dose of the drug, and that a higher percentage of high-dose patients experienced prolongation of the corrected QT (QTc) interval. The patients were taking part in the phase 2b randomized CloroCovid-19 trial, which had a target of 440 patients but was terminated after only 81 patients were enrolled, based on the occurrence of adverse events.

Of the 81 patients enrolled in the double-blind, randomized trial, 41 were allocated to a high-dosage group that received 600 milligrams (mg) of chloroquine (CQ) twice daily for 10 days, and 40 were in a low-dosage group that received 450 mg of CQ twice daily for 1 day and once daily for 4 days. All patients also received azithromycin, and 92.5% of the high-dosage group and 86.8% of the low-dosage group received the flu antiviral drug oseltamivir (Tamiflu).

All patients in both groups had severe illness, and post-enrollment testing confirmed COVID-19 in 75.6% of the high-dose patients (31 of 41) and 77.5% of the low-dose group (31 of 40). The patients in the high-dosage group were older than those in the low-dosage group (mean age 54.7 years vs 47.4 years) and had more heart disease (17.9% vs 0%).

The primary outcome of the trial was death by day 28, with the working hypothesis that the lethality rate in the high-dosage chloroquine group would be half that of the low-dosage group.

Preliminary analysis on day 13, however, found that 39% of the high-dosage patients (16 of 41) had died, compared with 15% of the low-dosage patients (6 of 40). In addition, a QTc interval of greater than 500 milliseconds was observed in 18.9% of high-dosage patients (7 of 37), compared with 11.1% of the low-dosage patients (4 of 36). But the researchers said they found no clear association between the appearance of QTc interval prolongation and death.

Based on these results, an independent data and safety monitoring board recommended ending the enrollment of patients in the high-dosage group, and all patients were moved to the low-dosage group.

"In the context of patients with severe COVID-19, our study raises enough red flags to stop the use of a high-dose regimen (ie, 12 g of CQ during 10 days), because the risks of toxic effects overcame the benefits," the authors wrote.

They note, however, that since all patients were also receiving azithromycin and most were on oseltamivir (which also increases the QTc interval), they could not independently assess the toxic role of chloroquine. Another limitation is that the high-dosage group had more patients who were susceptible to cardiac complications.

"In any case, use of CQ in older patients, especially those with heart disease, should be conducted with caution," they said.

Skepticism needed, experts say

In an editorial that accompanies the study, a trio of experts from the University of Washington, University of Iowa, and the Minneapolis Heart Institute say that, because of the noted limitations, the only conclusion that can be made is that high doses of chloroquine, in combination with azithromycin and potentially oseltamivir, are potentially associated with increased mortality in patients with severe COVID-19.

But they argue that the results should dampen some of the hype about hydroxychloroquine and chloroquine, both of which have been touted by the Trump administration and some media outlets as an effective treatment for COVID-19 since the results of an uncontrolled French study published in March suggested the drugs had a potential antiviral effect. Despite warnings from several health experts about the need for more evidence of efficacy, including National Institute of Allergy and Infectious Diseases Director Anthony Fauci, MD, thousands of patients are now taking the drugs as part of their treatment, according to the Wall Street Journal.

The authors say they hope the ongoing clinical trials will provide more information about the efficacy and safety of the drugs.

"In the interim, the results of this trial…should prompt some degree of skepticism toward the enthusiastic claims about chloroquine and perhaps serve to curb the exuberant use," they wrote. "For the time being, prudent clinicians should discuss with patients and their families, when feasible, the potential risks of this drug and the uncertain benefits before initiating it."