Findings also suggest increased risk of mortality and new arrhythmia; authors stress need for randomized trials
A large, multinational, observational registry analysis “found no evidence of benefit” on in-hospital outcomes for the use of hydroxychloroquine or chloroquine, either alone or with a macrolide, in treating COVID-19, according to paper published online Friday in The Lancet.
Mandeep R. Mehra, MD, executive director of the Brigham and Women’s Hospital Center for Advanced Heart Disease, and colleagues analyzed data from the Surgical Outcomes Collaborative (Surgisphere Corp., Chicago).
The authors noted that treatment of COVID-19 with chloroquine or hydroxychloroquine, either alone or with a macrolide, has been advocated despite limited evidence for its effectiveness. They also noted previous reports showing that either chloroquine or hydroxychloroquine combined with a macrolide can cause prolonged QT intervals.
Mehra and colleagues said they conducted their study because “there is a pressing need to provide accurate clinical guidance” amid the widespread use of chloroquine and hydroxychloroquine along with macrolides “often with little regard for potential risk.”
The U.S. Food and Drug Administration cautioned last month that chloroquine or hydroxychloroquine should only be used to treat patients in hospitals or clinical trials, noting reports of serious heart rhythm problems associated with these drugs in COVID-19 patients.
A retrospective analysis released last month on a preprint server reported the possibility of increased mortality in association with this treatment regimen in COVID-19 patients at U.S. Veterans Health Administrations hospitals.
The analysis by Mehra and colleagues released Friday included data from 96,032 patients from 671 hospitals worldwide between Dec. 20 and April 14 with a positive laboratory finding for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They divided the patients into the “treatment” groups (14,888 patients: 1,868 received chloroquine, 3,783 received chloroquine with a macrolide, 3,016 received hydroxychloroquine, and 6,221 received hydroxychloroquine with a macrolide), and the “control” group (81,144 patients).
The patient cohort had mean age of 53.8 years, and 46.3% were women. Most of the patients (63,315) were from North America.
After controlling for confounding factors, including age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors and diabetes, and baseline COVID-19 severity, each treatment was independently associated with an increased risk of both in-hospital mortality and de novo ventricular arrhythmia in comparison with the control group.
The control group’s in-hospital mortality rate was 9.3%. The mortality rates for the treatment subgroups were as follows: hydroxychloroquine (18.0%; hazard ratio [HR], 1.34; 95% confidence interval [CI] 1.22–1.46), hydroxychloroquine with a macrolide (23.8%; HR, 1.45; 95% CI, 1.37–1.53), chloroquine (16.4%; HR, 1.37; 95% CI, 1.22–1.53), and chloroquine with a macrolide (22.2%; HR, 1.37; 95% CI, 1.27–1.47).
The control group’s in-hospital de novo ventricular arrhythmia rate was 0.3%. The corresponding rates for the treatment subgroups were as follows: hydroxychloroquine (6.1%; HR, 2.37; 95% CI, 1.94–2.90), hydroxychloroquine with a macrolide (8.1%; HR, 5.11; 95% CI, 4.11–5.98), chloroquine (4.3%; HR, 3.56; 95% CI, 2.76–4.60), and chloroquine with a macrolide (6.5%; HR, 4.01; 95% CI, 3.34–4.81)
The authors noted several limitations to their study. Because of the observational nature of the study, the authors cannot rule out the possibility of unmeasured confounding factors contributing to increased in-hospital mortality in the treatment groups. Also, the findings do not apply to patients treated in the ambulatory, out-of-hospital setting. The authors finally point out that they did not measure QT intervals nor stratify arrhythmia pattern, and they did not establish whether the association of increased in-hospital mortality with the use of drug regimens is directly linked to the patients’ cardiovascular risk.
“In summary, this multinational, observational, real-world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19,” the authors conclude. “These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed.”
Christian Funck-Brentano, MD, PhD, and Joe-Elie Salem, MD, PhD, both of Sorbonne University, Paris, who were not involved in the study, praised the work of Mehra and colleagues in an accompanying editorial comment. Funck-Brentano and Salem noted that an alternative hypothesis to explain the increased risk of death in the treatment groups is the drugs’ “antiviral and immunomodulatory properties could worsen COVID-19 severity in some patients. Nevertheless, the increased incidence of ventricular arrhythmias is intriguing.”
“The findings from Mehra and colleagues’ study add to preliminary reports suggesting that regimens of chloroquine or hydroxychloroquine, alone or with azithromycin, are not useful and could be harmful in hospitalised patients with COVID-19,” Funck-Brentano and Salem conclude.
The study was funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.
Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020 May 22. https://www.thelancet.com/lancet/article/s0140673620311806
Funck-Brentano C, Salem J-E. Chloroquine or hydroxychloroquine for COVID-19: why might they be hazardous? Lancet 2020 May 22. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31174-0/fulltext