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Hydroxycloroquine increased risk of death in coronavirus patients - Lancet


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Antimalarial drug touted by President Trump is linked to increased risk of death in coronavirus patients, study says

An analysis of 96,000 patients shows those treated with hydroxychloroquine were also more likely to suffer irregular heart rhythms


President Trump spoke about taking an antimalarial drug earlier this week. (Jim Lo Scalzo/EPA-EFE/Shutterstock)
President Trump spoke about taking an antimalarial drug earlier this week. (Jim Lo Scalzo/EPA-EFE/Shutterstock)
May 22, 2020 at 8:28 a.m. EDT
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A study of 96,000 hospitalized coronavirus patients on six continents found that those who received an antimalarial drug promoted by President Trump as a “game changer” in the fight against the virus had a significantly higher risk of death compared with those who did not.

People treated with hydroxychloroquine, or the closely related drug chloroquine, were also more likely to develop a type of irregular heart rhythm, or arrhythmia, that can lead to sudden cardiac death, it concluded.

The study, published Friday in the medical journal the Lancet, is the largest analysis to date of the risks and benefits of treating covid-19 patients with antimalarial drugs. It is based on a retrospective analysis of medical records, not a controlled study in which patients are divided randomly into treatment groups — a method considered the gold standard of medicine. But the sheer size of the study was convincing to some scientists.

“It’s one thing not to have benefit, but this shows distinct harm,” said Eric Topol, a cardiologist and director of the Scripps Research Translational Institute. “If there was ever was hope for this drug, this is the death of it.”

David Maron, director of preventive cardiology at the Stanford University School of Medicine, said that “these findings provide absolutely no reason for optimism that these drugs might be useful in the prevention or treatment of covid-19.”

Past studies also found scant or no evidence of hydroxychloroquine’s benefit in treating sick patients, while reports mounted of dangerous heart problems associated with its use. As a result, the Food and Drug Administration last month warned against the use of the drug outside hospital settings or clinical trials.

The new analysis — by Mandeep Mehra, a Harvard Medical School professor and physician at Brigham and Women’s Hospital, and colleagues at other institutions — included patients with a positive laboratory test for covid-19 who were hospitalized between Dec. 20, 2019, and April 14, 2020, at 671 medical centers worldwide. The mean age was 54 years, and 53 percent were men. Those who were on mechanical ventilators or who received remdesivir, an antiviral drug made by Gilead Sciences that has shown promise in decreasing recovery times, were excluded.

 

Nearly 15,000 of the 96,000 patients in the analysis were treated with hydroxychloroquine or chloroquine alone or in combination with a type of antibiotics known as a macrolide, such as azithromycin, within 48 hours of their diagnosis.

The difference between patients who received the antimalarials and those who did not was striking.

 

For those given hydroxychloroquine, there was a 34 percent increase in risk of mortality and a 137 percent increased risk of a serious heart arrhythmias. For those receiving hydroxychloroquine and an antibiotic — the cocktail endorsed by Trump — there was a 45 percent increased risk of death and a 411 percent increased risk of serious heart arrhythmias.

Those given chloroquine had a 37 percent increased risk of death and a 256 percent increased risk of serious heart arrhythmias. For those taking chloroquine and an antibiotic, there was a 37 percent increased risk of death and a 301 percent increased risk of serious heart arrhythmias.

Cardiologist Steven Nissen of the Cleveland Clinic said the new data, combined with data from smaller previous studies, suggests that the drug “is maybe harmful and that no one should be taking it outside of a clinical trial.”

 

Jesse Goodman, a former FDA chief scientist who is now a Georgetown University professor, called the report “very concerning.” He noted, however, that it is an observational study, rather than a randomized controlled trial, so it shows correlation between the drugs and certain outcomes, rather than a clear cause and effect.

Peter Lurie, a former top FDA official who now heads the Center for Science in the Public Interest, called the report “another nail in the coffin for hydroxychloroquine — this time from the largest study ever.”

He said it was time to revoke the emergency use authorization issued by the FDA, which approved the drug for seriously ill patients who were hospitalized or for whom a clinical trial was not available.

The new study’s findings cannot necessarily be extrapolated to people with mild illness at home or those, like Trump, who are taking the antimalarials as a prophylactic. The president stunned many doctors earlier this week when he said he was taking a pill “every day” — despite FDA warnings that the use of the drug should be limited to those in a hospital setting or in clinical trials. (He has since said he is close to finishing his course of treatment and would stop taking the medication in “a day or two.”)

A large study of health-care workers that examines the use of hydroxychloroquine as a preventive measure against covid-19 is in the works, but no results have been released.

There have been at least 13 studies in recent months on hydroxychloroquine or chloroquine as a treatment for covid-19 patients. They have included randomized controlled studies and observational analyses encompassing patients on the continuum from mild illness to those near death. Evidence of any benefit, such as viral clearance or improved symptoms, has been almost nonexistent. But many found an increased risk in adverse cardiac reactions — especially when combined with the antibiotic azithromycin.

Earlier this month, some proponents of hydroxychloroquine seized on a study out of New York University’s Langone Health center that threw zinc into the mix with hydroxychloroquine and azithromycin, and showed the treated group had a higher rate of survival. But researchers emphasized that it only showed that the combination had some promise. They said the results also could have been due to other factors, such as the zinc being added to patients’ regimens later in the pandemic when hospital treatments and procedures had been refined.

Last week, the National Institutes of Health announced a clinical trial of 2,000 adults to determine if hydroxychloroquine and azithromycin could be used to treat coronavirus patients.

Topol, of the Scripps Research Translational Institute, suggested that the researchers should reconsider the ethics of those trials, given the increasing evidence of potential harm. “It’s very hard to ignore that signal, and it’s worrisome to continue giving it,” he said.

Geoffrey Barnes, a cardiovascular specialist at the University of Michigan, said the study’s approach and its findings were “striking” in making the case that “the risk with these drugs is real.” However, he said that due to the enthusiasm some Americans have for the drug and the Lancet study’s findings, randomized trials are even more important.

“There has been so much discussion about this drug that I think the scientific and medical community has an obligation to define what the potential benefit or risk is in the best way possible,” Barnes said.

When the first large wave of sick patients began showing up at hospitals in March, doctors had very little to offer them. As a result, many took a gamble on hydroxychloroquine. The drug had been shown to have strong antiviral properties in cell cultures, was widely available and was thought to be rather benign in terms of side effects. For years, hydroxychloroquine has been considered a generally safe and effective treatment for malaria, lupus and rheumatoid arthritis.

But those findings of safety were at lower doses than were being used at hospitals during the early days of the surge in patients in the United States and mostly in patients who were healthy. The population infected with covid-19 in hospitals, it turned out, was already at higher risk of cardiovascular complications because many suffer from high blood pressure or other heart issues. Doctors also discovered that, to their surprise, the novel coronavirus appeared to directly or indirectly attack the heart, including by reducing its ability to pump, creating an imbalance in its electrical rhythms, and attacking blood vessels.

Peter Whoriskey contributed to this report.

The letter from White House physician Sean P. Conley about President Trump taking hydroxychloroquine. (Jon Elswick/AP)
The letter from White House physician Sean P. Conley about President Trump taking hydroxychloroquine. (Jon Elswick/AP)
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Summary

Background

Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

Findings

96032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Interpretation

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

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