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High vs. Low Doses of Chloroquine Diphosphate for SARS-CoV-2
Quick Takes
- The study findings suggest that higher dosage of chloroquine should not be used for the treatment of severe COVID-19.
- The limited sample size did not allow the study to show any benefit overall regarding treatment efficacy.
- QTc interval prolongation in the high-dose group may have been in part due to almost all patients receiving azithromycin and oseltamivir.
Study Questions:
What is the safety and efficacy of two chloroquine diphosphate (CQ) dosages in patients with severe coronavirus disease 2019 (COVID-19)?
Methods:
This was a parallel, double-blinded, randomized, phase IIb clinical trial with patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were randomized to receive high-dosage chloroquine (600 mg CQ twice daily for 10 days) or low-dosage chloroquine (450 mg twice daily on day 1 and once daily for 4 days). The study was conducted at a tertiary center in Brazil.
Results:
A total of 81 patients (41 to high-dosage group and 40 to low-dosage group) were enrolled before the trial was terminated early by the Data Safety and Monitoring Board (the planned enrollment had been 440 patients). Patients had a mean age of 51 years, and 75% were men. Older age (mean age, 54.7 years vs. 47.4 years) and more heart disease (17.9% vs. 0%) were seen in the high-dose group. Viral RNA was detected in 77.5% and 75.6% of patients in the low-dosage and high-dosage groups, respectively. Mortality at 13 days was 39% in the high-dosage group and 15% in the low-dosage group. The high-dosage group had more instances of QTc interval >500 ms (18.9%) compared with the low-dosage group (11.1%). Two patients in the high-dose group (2.7%) experienced ventricular tachycardia. Respiratory secretion at day 4 was negative in only 22.2% of patients.
Conclusions:
This study suggests that the higher chloroquine dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards and increased mortality.
Perspective:
The authors tested the hypothesis that high-dose chloroquine in COVID-19 patients with severe disease would lead to improved outcomes compared with low-dose chloroquine, but the opposite was found. Prior studies suggested that high drug concentrations were needed for antiviral effect. The intended sample size was 440 individuals, but due to high mortality rates in the high-dose group, the Data Safety and Monitoring Board terminated the trial after only 18% of individuals had been enrolled. There was no association of the QTc interval prolongation and subsequent death, so the higher mortality rate is due to non-arrhythmogenic cause. There were no instances of torsades de pointes. Of note, all patients were also receiving azithromycin, and nearly all were receiving oseltamivir. Unfortunately, because the study was terminated early, the study arms were not well matched; the patients randomized to high-dose chloroquine were older and had more cardiac comorbidities. A great number of randomized trials are being conducted and will provide further clarification on the role of chloroquine in the management of COVID-19 infection in patients with various disease severity.
Clinical Topics: Arrhythmias and Clinical EP, COVID-19 Hub, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Statins
Keywords: Arrhythmias, Cardiac, Azithromycin, Chloroquine, Coronavirus, COVID-19, Critical Illness, Heart Diseases, Oseltamivir, Primary Prevention, RNA, Viral, SARS Virus, severe acute respiratory syndrome coronavirus 2, Tachycardia, Ventricular, Torsades de Pointes
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