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Pharmaceutical manufacturers have ramped up production of chloroquine amid hopes that the antimalarial drug will prove effective against COVID-19.

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Antimalarials widely used against COVID-19 heighten risk of cardiac arrest. How can doctors minimize the danger?

Sciences COVID-19 reporting is supported by the Pulitzer Center.

On 19 March, as much of the United States shut down to contain the new coronavirus, genetic cardiologist Michael Ackerman and his wife drove 7.5 hours to retrieve their son from college. On the radio, they heard medical experts discussing chloroquine and hydroxychloroquine, two antimalarial drugs that President Donald Trump had just touted at a press briefing, despite no conclusive evidence that they can treat COVID-19. A doctor on the show asserted that the drugs have proved to be completely safe because they’ve been used against malaria for decades and are also used to tame overactive immune cells in lupus and rheumatoid arthritis.

“I was kind of going crazy in the car,” Ackerman remembers. “My wife was like, ‘Settle down, settle down.’” At the Mayo Clinic, Ackerman treats patients predisposed to heart arrhythmias because of genetic conditions. Chloroquine and hydroxychloroquine, he knows, have a potentially fatal side effect: They can cause a type of irregular heart rhythm that sometimes leads to cardiac arrest. “The side effect is rare—that’s the great news,” Ackerman says. But doctors can’t say just how risky these drugs are for gravely ill COVID-19 patients based on data from other groups of people who have taken them over the decades. The expert on the radio was comparing, “not apple to oranges, but apples to watermelons,” he says.

Ackerman soon heard another perspective that troubled him: In the battle against COVID-19, the risk of arrhythmia was “friendly fire” that doctors would just have to accept. So he and his colleagues drafted what they called “urgent guidance,” published 25 March in Mayo Clinic Proceedings, explaining that doctors can prevent deaths by identifying and monitoring the people at greatest risk—and if an arrhythmia appears, withdrawing the drugs or taking other measures to stabilize the heart.

Treating COVID-19 patents with hydroxychloroquine, a derivative of chloroquine generally thought to have less severe side effects, has become standard at many hospitals. The drug is often combined with the antibiotic azithromycin, which some studies suggest also has antiviral effects. The U.S. Food and Drug Administration has authorized emergency use of both chloroquine and hydroxychloroquine for COVID-19 patients. But no large, randomized trial has proved these drugs—alone or in combination with azithromycin—are effective against the disease.

“You can never make any risk zero,” says Athena Poppas, a cardiologist at Brown University. “If the benefits were clearly shown to be high, then we might take an x% risk of sudden death,” she says, “but we don’t even have [evidence of] benefit. We have theory.”

Evidence of potential harm from these drugs is beginning to trickle out. A clinical trial in Brazil that gave chloroquine and azithromycin to 81 people hospitalized for COVID-19 was halted after investigators found more deaths in the group getting the higher of two doses, according to a preprint the team published on 16 April on medRxiv. Electrocardiography (EKG) readouts indicating increased arrhythmia risk were also more common in the high-dose group. Researchers conducting the trial received death threats on social media, and conservative media outlets accused them of giving patients excessively high doses to purposely smear the drug.

An analysis of data from 368 U.S. veterans treated for COVID-19, posted in a preprint today, found the risk of death from any cause was greater for those who received hydroxychloroquine than for those who didn’t, even after researchers adjusted for the fact that patients with more severe disease were more likely to receive the drug. And a woman in New York died this month after her general practitioner prescribed hydroxychloroquine and azithromycin for coronaviruslike symptoms, NBC News reported last week. (There’s no proof that drug-induced arrhythmia caused her death, Ackerman says, “but it smells awfully fishy.”) Now, researchers are trying pin down the rates of this side effect in COVID-19 patients and are urging diligent heart monitoring during treatment.

“When the media says this looks to be a safe drug—in certain contexts, that’s true,” says Wesley Self, an emergency physician at Vanderbilt University conducting a clinical trial of hydroxychloroquine. “However, when you’re talking about potentially treating millions of patients, even rare side effects become very important.”

Doctors think chloroquine and hydroxychloroquine might help COVID-19 patients by inhibiting the coronavirus from entering cells and by taming a potentially deadly overreaction of the patient’s immune system. But a small trial in France that lent initial support to hydroxychloroquine as a COVID-19 treatment has been widely criticized for methodological flaws, including a failure to randomize the study groups. And subsequent small trials—including a randomized study of 150 patients in China, posted last week as a preprint—haven’t found evidence of effectiveness.

The potential for arrhythmia, meanwhile, is well-documented. Chloroquine and hydroxychloroquine block channels on heart muscle cells that control the flow of ions, which governs the heart’s electrical recharging between beats. Doctors gauge the heart’s ability to properly recharge with an EKG readout called the QT interval. If this phase of electrical activity goes on too long—more than about one-half of a second—the heart can enter an irregular rhythm that can cause it to stop beating altogether.

Azithromycin raises concerns because it, too, can block ion channels and tinker with the heart’s electrical pattern. The rationale for adding it to hydroxychloroquine is murky, many researchers say. But the French study found that patients cleared the virus faster with the two-drug cocktail than with hydroxychloroquine alone. “That study, however poorly designed and conducted, made a difference,” says Daniel Prieto-Alhambra, a pharmacoepidemiologist at the University of Oxford. “People started using the data to make decisions.”

In a preprint posted on 10 April on medRxiv, Prieto-Alhambra and colleagues looked for clues about the safety of this combination in the medical records of nearly 1 million people in six countries taking hydroxychloroquine for rheumatoid arthritis. More than 300,000 of them also took azithromycin at some point to treat an infection. The researchers found that a person’s risk of heart failure in the month after starting hydroxychloroquine was comparable to the risk from starting another common arthritis drug, sulfasalazine. But in the month after adding azithromycin to hydroxychloroquine, the risk of cardiovascular death more than doubled.

And there’s reason to think heart complications will be more common in people with a coronavirus infection than in those with autoimmune disease, says Lior Jankelson, a cardiac electrophysiologist at New York University (NYU). Hospitalized COVID-19 patients tend to be older, and some are already taking other drugs that can extend their QT interval. Because pre-existing heart conditions seem to increase the severity of COVID-19, many patients may already be at risk of arrhythmia. And the virus itself can attack many organs, including the heart and kidneys, damage that can bump arrhythmia risk higher as a patient deteriorates.

Jankelson and his colleagues recently measured changes in QT interval for 84 COVID-19 patients who received hydroxychloroquine and azithromycin at NYU’s Langone Medical Center. Although none went into cardiac arrest during the study, 11% had QT intervals so prolonged that they were considered at high risk of arrhythmia, the researchers reported on 3 April in a medRxiv preprint. (They are now following up those results in a larger group of COVID-19 patients.) They also found that a normal QT interval before starting the drugs did not indicate that a person would avoid dangerous QT prolongation. In other words, it’s not just the people with an obvious risk of arrythmia who could develop cardiac side effects when they get the drug cocktail.

That finding suggests vigilance will be key, Jankelson says. “I probably would not prescribe the drug if I could not ensure continuous … [daily EKG] monitoring.” Many hospitals, including Jankelson’s, rely on telemetry—continuous heart monitoring at the bedside. And there are several technologies for taking an EKG reading at home and transmitting it to a doctor, he notes, though it’s not clear how commonly they’re used to monitor COVID-19 patients outside the hospital.

The Infectious Diseases Society of America, the American College of Cardiology, and the U.S. National Institutes of Health all recommend that patients only receive chloroquine or hydroxychloroquine in the context of a clinical trial until there is more evidence that the drugs are effective. Careful screening and monitoring are common in such trials. For example, a 510-patient study of hydroxychloroquine known as ORCHID, funded by the U.S. National Heart, Lung, and Blood Institute, excludes COVID-19 patients who have an abnormally long QT interval, have a history of a QT-prolonging condition, or take potentially QT-prolonging drugs.

“We’ve spent innumerable hours thinking about how we safely monitor all of this in the context of clinical research,” says Matthew Semler, a critical care physician at Vanderbilt who, with Self and others, helped design ORCHID’s protocol. “And yet the same benefits and risks are posed … as a part of clinical practice, and that has essentially no regulation, and is widely variable.”

The current situation with hydroxychloroquine “is exactly what we try and avoid in medicine—hundreds of thousands of patients are being administered this medication outside of the context of research in which we can learn about its safety and efficacy,” Semler adds. “That’s a dangerous situation to be in.”

With reporting by Herton Escobar.