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A warning to those considering combination therapy with hydroxychloroquine (HCQ) for COVID-19: individually, some medications being considered have been known to put users at risk of sudden cardiac death, major U.S. medical societies said.

The antimalarial drug HCQ (Plaquenil) and the antibiotic azithromycin have both been known to prolong the QT interval and provoke torsade de pointes in some cases, according to joint guidance from the American Heart Association (AHA), the American College of Cardiology (ACC), and the Heart Rhythm Society (HRS).

Based on post-marketing adverse event reports, serious arrhythmias and cardiac arrest are known risks for chloroquine, hydroxychloroquine, and azithromycin, whereas the HIV drug combination lopinavir/ritonavir (Kaletra) carries "potential risk," the authors noted in the document in Circulation, the Journal of the American College of Cardiology, and Heart Rhythm Journal.

"Given the potential for increased risks related to combinations of medications that prolong the QT interval, we urge careful consideration to ensure patients with cardiovascular disease or others at increased risk can be monitored appropriately," said HRS President and co-author Andrea Russo, MD, of Cooper Medical School of Rowan University in Camden, New Jersey, in a statement.

Regardless of the medications taken in COVID-19, seriously ill patients may already be at risk of serious arrhythmias by virtue of hypokalemia, hypomagnesemia, fever, and an inflammatory state, the societies warned.

Ways to minimize arrhythmia risk include electrocardiographic/QT interval monitoring, correction of hypokalemia (to >4 mEq/L) and hypomagnesemia (to >2 mg/dL), and avoiding QTc-prolonging agents whenever feasible, according to the guidance.

"In patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible," the authors acknowledged.

Since March, President Trump and others have touted the benefits of hydroxychloroquine and azithromycin in COVID-19.

Recently, a small randomized study of hydroxychloroquine alone indeed showed that the antimalarial drug conferred shorter time to clinical recovery and improved pneumonia among hospitalized COVID-19 patients in China.

"The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease," said AHA President Robert Harrington, MD, of Stanford University in California, in a press release.

"There are very limited data evaluating the safety of combination therapy. Multiple randomized trials are currently being initiated," according to the AHA/ACC/HRS guidance.

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