乌鸦传媒

Hospitalized patients with COVID-19 coronavirus infection treated with high-dose chloroquine diphosphate (CQ) in conjunction with azithromycin or oseltamivir experienced higher rates of death and adverse cardiac events compared with a low-dose group, an unplanned interim analysis of a phase IIb trial found.

Lethality until day 13 was higher in the high-dose group versus the low-dose group (39% vs 15%, respectively), with more patients in the high-dose group experiencing QTc intervals of greater than 500 milliseconds (18.9% vs 11.1%), reported Marcus Vinícius Guimarães Lacerda, MD, of Fundação de Medicina Tropical in Brazil, and colleagues.

A preliminary analysis was performed on 81 patients after 11 patients died in the high-dose group, and four patients died in the low-dose group, the authors .

"Based on these findings, in which a higher dosage of CQ showed the opposite of the study's hypothesis, the [Data and Safety Monitoring Board] recommended the immediate interruption of the high-dosage group for all ages and that all patients be unmasked and reverted to the low-dosage group," the authors wrote.

However, they noted they were not able to assess the "toxic role" of chloroquine independently, because all patients were already receiving azithromycin, according to hospital protocol.

Most patients were also receiving oseltamivir for suspected influenza infection, which could also have impacted QTc interval and caused adverse cardiac effects, the team added.

The had a pre-determined sample size of 440 patients, but had enrolled only 81 -- 41 to the high-dose group (600 mcg CQ twice daily for 10 days) and 40 to the low-dose group (450 mcg CQ twice daily on day 1, and once daily for 4 days).

Enrolled patients were a mean age of 51 and three-quarters were men, although patients in the high-dose group were older and 18% had heart disease versus none in the low-dose group.

The authors noted that after adjustment, high-dose CQ was not associated with increased odds of death when controlled by age (adjusted OR 2.8, 95% CI 0.9-8.5), adding that neither ventricular tachycardia nor torsade de pointes were seen in these patients.

Because there was no placebo group, the authors said they examined "historical data based on very similar patients not receiving CQ."

"The lethality rates observed here were not lower; however, we cannot reliably conclude that CQ was of no benefit," the researchers said.

In addition, they noted, the high-dose group included more older patients with heart disease, who would be more susceptible to cardiac complications, with or without chloroquine treatment. Other limitations included the small sample size, the lack of a placebo group, and the single-center design.

While chloroquine could be used to "decrease the viral load in respiratory secretions," potentially decreasing transmission, "patients using CQ failed to present evidence of substantial viral clearance by day 4," even with azithromycin, Lacerda and co-authors said.

Other notable adverse events included one patient who developed rhabdomyolysis, the breakdown of damaged muscle, which can cause kidney damage. The drug was then stopped. Two patients had suspected myocarditis potentially related to SARS-CoV-2 infection, the virus that causes COVID-19. The authors warned that in these cases "drugs prolonging QTc interval could lead to severe arrhythmias."

An by Stephan Fihn, MD, of the University of Washington in Seattle, and colleagues, argued that weak prior research, "bolstered by anecdotal reports and media attention, have fostered widespread belief in the efficacy" of both hydroxychloroquine and chloroquine.

This trial "should prompt some degree of skepticism toward the enthusiastic claims about chloroquine and perhaps serve to curb the exuberant use," the editorialists wrote. "For the time being, prudent clinicians should discuss with patients and their families, when feasible, the potential risks of this drug and the uncertain benefits before initiating it."

Lacerda and colleagues said they still planned to enroll patients in the low-dosage group to round out the initially planned sample size.

"In view of the results, it is clear that any CQ treatment or protocol design for severe COVID-19 should include previous QTc interval evaluation, close daily monitoring, and dosage modification when needed," the investigators concluded.

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