The largest study to date on the use of the antimalaria drugs hydroxychloroquine and chloroquine in COVID-19 patients found that the drugs had no benefit, and were instead associated with a higher risk of death in the hospital and serious heart rhythm complications.
The observational study, published today in The Lancet, found that a drug regimen of hydroxychloroquine or chloroquine, either alone or with a macrolide antibiotic, was associated with an increased mortality risk of 34% to 45% compared with COVID patients who didn't receive drugs. Patients who received these drug regimens were between two and five times more likely to experience ventricular arrythmia during hospitalization compared with the control group.
The implications of the findings are limited by the fact that they are from an observational study and not a randomized controlled trial, which is the gold standard for evaluating whether a drug is truly safe and effective against a disease. Still, the authors of the study say they present another case against continued use of the drugs in COVID-19 patients outside of a clinical trial.
No benefit—but potential harms
In the study, US and Swiss researchers analyzed 96,032 patients hospitalized for COVID-19 at 671 hospitals on six continents from Dec 20, 2019, through Apr 14, 2020, all of whom had been either discharged from the hospital or died by Apr 21. The analysis looked at patients who received one of four treatments within 48 hours of hospitalization—hydroxychloroquine alone, hydroxychloroquine with a macrolide antibiotic (either azithromycin or clarithromycin), chloroquine alone, and chloroquine with a macrolide—and compared them to patients who received none of those drugs.
Overall, 14,888 of the patients received one of the treatments: 1,868 received chloroquine, 3,783 received chloroquine with a macrolide, 3,016 received hydroxychloroquine, and 6,221 received hydroxychloroquine with a macrolide. The control group consisted of 81,114 patients. Most of the patients were in North America.
The main outcomes of interest were in-hospital mortality and the occurrence of new ventricular arrythmias. The analysis controlled for various confounding factors, including demographic variables (age, sex, ethnicity), body mass index, comorbidities, disease severity at presentation, and use of other medications.
A total of 10,698 patients (11.1%) died. Compared with the control group, 9.3% of whom died, treatment with hydroxychloroquine alone (18%, hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.2 to 1.5), hydroxychloroquine with a macrolide (23.8%; HR, 1.4; 95% CI, 1.4 to 1.5), chloroquine alone (16.4%; HR, 1.4; 95% CI, 1.2 to 1.5), and chloroquine with a macrolide (22.2%; HR, 1.4; 95% CI, 1.3 to 1.5) were independently associated with an increased risk of dying in the hospital.
Incidence of heart rhythm complications ranged from 0.3% in the control group to 8.1% in the treatment groups. After adjusting for confounding factors, the analysis found that, compared with the control group, hydroxychloroquine alone (6.1%; HR 2.4; 95% CI, 1.9 to 2.9), hydroxychloroquine with a macrolide (8.1%; HR, 5.1; 95% CI, 4.1 to 6.0), chloroquine alone (4.3%; HR, 3.6; 95% CI, 2.8to 4.6), and chloroquine with a macrolide (6.5%; HR, 4.0; 95% CI, 3.3 to 4.8) were all independently associated with an increased risk of new ventricular arrhythmia during hospitalization. The researchers did not look at whether in-hospital mortality was linked to patients' cardiovascular risk.
The findings from a propensity score analysis—which balances the study groups to make them comparable by accounting for the likelihood that patients with more severe illness would be treated with the drugs—were consistent with the primary analysis.
"Our large-scale, international, real-world analysis supports the absence of a clinical benefit of chloroquine and hydroxychloroquine and points to potential harm in hospitalised patients with COVID-19," the authors wrote. "These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed."
The authors were careful to note, however, that the results should be interpreted with caution because of the observational design, which cannot fully account for unmeasured confounding factors, and that a cause-and-effect relationship between treatment with the drugs and survival should not be inferred.
Results highlight need for clinical trial data
The analysis is the latest of several observational studies to suggest that hydroxychloroquine and chloroquine have little benefit for COVID-19 patients and may cause harm. The drugs have been widely used since the US Food and Drug Administration (FDA) issued an Emergency Use Authorization in late March, following the results of a small French study that indicated hydroxychloroquine combined with azithromycin significantly reduced the viral load in a handful of patients.
The previous observational studies, conducted in a variety of patient populations, have found that hydroxychloroquine or chloroquine, either with or without azithromycin, have not reduced death or severe outcomes, the need for mechanical ventilation, or admissions to intensive care compared with patients who didn't receive the drugs. Others have linked use of the drugs in COVID-19 patients with prolonged QT interval, which can cause an irregular heartbeat and increase the risk of sudden cardiac arrest. QT prolongation is a known side effect of hydroxychloroquine.
Concerns about heart rhythm problems in some COVID-19 patients treated with hydroxychloroquine or chloroquine prompted the FDA to issue a safety warning on April 24. The National Institutes of Health and medical professional organizations have also recommended against using the drugs in COVID-19 patients outside of clinical trials.
But in most of the observational trials, the patients receiving hydroxychloroquine or chloroquine have been sicker. Walid Gellad, MD, MPH, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said this is why the results of the current study should be taken with a grain of salt, and why randomized trial results are desperately needed "to get us much closer to the truth."
"All observational studies comparing those who use hydroxychloroquine to those who don't suffer from confounding by indication—hydroxychloroquine patients are sicker," said Gellad, who was not involved in the study. "One can try to do statistical adjustment to deal with that confounding, but it is often not enough, and my informed guess is that is the case for this study."
There are several clinical trials under way. Among them is a trial evaluating whether prophylactic use of hydroxychloroquine can help prevent COVID-19. That issue was highlighted this week when President Trump announced that he was taking the drug as a preventive measure.