Trial of High-Dose Chloroquine for COVID-19 Halted After Deaths

Brazilian doctors stopped using a high dose of chloroquine to treat COVID-19 patients after an interim analysis showed it was associated with a higher mortality rate than a lower dose, according to results they reported in today’sJAMA Network Open.

After 13 days of treatment, 16 of the 41 (39%) of the COVID-19 patients in the high-dose group had died compared with 6 of the 40 (15%) in the low-dose group. 

After the doctors stopped the trial comparing the high and low doses, they continued to treat patients with the lower dose of chloroquine. In this trial, the high-dose group received 600 milligrams of the antimalarial drug twice a day for 10 days while the low-dose group received 450 milligrams twice daily for one day and then once daily for four days.

Chloroquine diphosphate is one of the antimalarial drugs that is being used to treat COVID-19 on an empirical basis as well as in clinical trials. President Donald Trump has pinned hopes on a closely related drug, hydroxychloroquine.

Cardiac arrhythmias, including ventricular tachycardia and torsades de pointes, are a known side effect of chloroquine. According to the results reported in JAMA Network Open, 18.9% of the high-dose patients had ECGs indicative of an irregular heartbeat compared with 11.1% of the patients in low-dose group.

Lead author Mayla Gabriela Silva Borba and her colleagues at the Hospital e Pronto-Sororro Delphina Rinaldi Abdel Aziz in Manaus noted that all the patients were already being treated with azithromycin and most (89.6%) were also being treated with oseltamivir for suspected flu infection. As a result, they said they couldn’t tease out the toxic side effects of chloroquine independent of it being used with azithromycin. Reports from China had called attention to chloroquine and azithromycin having synergistic effects that might cause heart problems, and arrhythmias are identified side effect of oseltamivir.

Borba and her colleagues noted that age was an important cofounder; patients randomized to the higher dose were older, on average, than those in the low-dose group (54.7 years vs. 47.4). Although it has to be interpreted with caution because of the small sample size, a multivariate analysis showed that chloroquine was not associated with death once patient age was taken into account.