Patients treated with high doses of the malaria drug also had more evidence of new arrhythmia

Treatment with a high-doses of the malaria drug chloroquine appeared to be associated with increased heart arrhythmia and death in patients presumed to have Covid-19 in a study from Brazil, which was terminated during patient accrual due to the adverse events.

Preliminary findings from the CloroCovid-19 trial showed a 3.6-fold higher death rate at day 13 among patients treated with 600 mg twice daily for 10 days (high-dose group), compared to patients receiving 450 mg twice daily on day 1 and once daily for 4 days (low-dose group).

Patients in the higher-dose arm also developed heart arrhythmia at a higher rate, leading researchers to conclude that high doses of the drug should not be recommended for the treatment of severe Covid-19 “especially among patients also receiving azithromycin and oseltamivir, because of safety concerns regarding QTc interval prolongation and increased lethality.”

The peer-reviewed findings, published April 24 in JAMA Network Open, heighten concerns about the safety and efficacy of the chemically similar malaria drugs chloroquine and hydroxychloroquine, which have been widely promoted by the Trump administration and conservative media outlets for the treatment of Covid-19.

But news of the Brazil study findings, first published prior to peer-review last week, and negative early findings from a study of U.S. veterans with coronavirus, have muted much of the public cheerleading for the drugs in recent days.

In the veterans’ study, posted April 23 prior to peer review on the server medRxiv, use of hydroxychloroquine, either with or without azithromycin, was not associated with reductions in the need for mechanical ventilation in patients hospitalized for coronavirus, and there was a suggestion of increased mortality in patients receiving the malaria drug.

The CloroCovid-19 trial was designed to enroll 440 patients with suspected severe Covid-19 from a single tertiary care facility in Manaus, Brazil, but recruitment was stopped after 81 patients entered the study. The mean age of the patients was 51 (13.9) years, three-fourths (75.1%) were men, and 41 were randomized to the high-dosage group and 40 to the lower-dosage group.

Among the main study findings:

  • Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and established heart disease (5 of 28 [17.9%] vs 0) were more common in the high-dose group.
  • Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively.
  • Death at day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40).
  • The high-dosage group had more instances of QTc interval greater than 500 milliseconds (7 of 37 patients[18.9%]) compared with the low-dosage group (4 of 36 [11.1%]).

The researchers noted that during the planning phase of the study, Brazilian health officials authorized the compassionate use of chloroquine and hydroxychloroquine, “with pressure on physicians to prescribe the drug for patients with severe Covid-19,” which impacted the study design.

“Although this is not an imperative against running placebo-controlled trials, it triggered an ethical dilemma regarding the conduct of randomized clinical trials offering placebo treatment for patients strongly influenced by the media favoring chloroquine use,” wrote researcher Mayla Gabriela Sliva Borba, MD, and colleagues.

The study group plans to continue enrolling patients to receive the low-dose treatment to further monitor the safety profile of the drug in the setting of Covid-19.

In an accompanying editorial, Stephan Fihn, MD, of the University of Washington, Seattle, and colleagues, wrote that despite the discouraging findings, “several observations prevent concluding categorically that high-dose chloroquine was toxic and that the likely mechanism was arrhythmogenesis.”

Fihn and colleagues noted the lack of an apparent association of the appearance of QTc interval prolongation and subsequent death in the study cohort. In addition, nearly all patients in the study were also being treated with azithromycin and oseltamivir, which may also prolong the QTc interval.

“Thus, one can only conclude from this trial that high-dose chloroquine (and by close association, hydroxychloroquine) in combination with azithromycin and possibly oseltamiver, is potentially associated with increased mortality among patients with severe, suspected Covid-19,” they wrote.

Early this week, the National Institutes of Health issued new Covid-19 treatment guidelines, which concluded that there is not enough evidence to recommend for or against chloroquine or hydroxychloroquine for Covid-19. The expert NIH panel did, however, recommend against using hydroxychloroquine with azithromycin due to potential toxic effects.

Fihn and colleagues wrote that the CloroCovid-19 study highlighted the challenges and also the successes of rapidly designing, approving, funding and executing coronavirus treatment trials.

“In the current torrent of data, the half-life of information is short. A novel observation from a week earlier rapidly becomes common knowledge or is superseded by more definitive studies,” they wrote.

“That so much research is being conducted and published underscores the robustness of the scientific publishing enterprise and should be heartening to the world population as we all wait anxiously for information and signs of progress.”

  1. Early findings from the CloroCovid-19 trial suggest that higher doses of chloroquine may be harmful and should not be used in the treatment of Covid-19, especially among patients also receiving treatment with azithromycin and oseltamivir.

  2. Covid-19 patients who received high-dosage chloroquine diphosphate (600 mg twice daily for 10 days) had more than twice the death rate at day 13 as patients receiving a lower-dosage regimen (450 mg twice daily on day 1 and once daily for 4 days) – 39% versus 15%.

Salynn Boyles, Contributing Writer, BreakingMED™

This research was funded by the Government of the Amazonas State, Farmanguinhos, Superintendencia da Zona Franca de Manaus, and others. The study funders had no role in the design and conduct of the study, nor the analysis and interpretation of the data.

Cat ID: 125

Topic ID: 79,125,287,503,728,932,730,933,125,190,469,926,192,927,151,928,925,934