Negative findings from largest study to date prompted the move

The World Health Organization has temporarily halted a large, international study of hydroxychloroquine for the treatment of Covid-19 due to new evidence linking the drug to an increased risk of death in hospitalized patients.

The largest international study published to date examining hydroxychloroquine and chloroquine in patients hospitalized with Covid-19 showed use of both drugs to be associated with decreased in-hospital survival and increased frequency or ventricular arrhythmias.

Trial findings, published recently in The Lancet, also failed to confirm a benefit for hydroxychloroquine or chloroquine, when used alone or with a macrolide, on other in-hospital outcomes.

On May 25, WHO officials announced that the hydroxychloroquine arm of the global Solidarity Trial would be paused while early safety data from the trial and others examining the drug as a Covid-19 treatment are reviewed.

The WHO-led trial has so far recruited 3,500 patients from 17 countries, with the goal of including patients from 35 countries, to examine the safety and efficacy of various therapies being used for the treatment of patients with Covid-19.

The Solidarity Trial will continue to follow patients treated with the experimental drug remdesivir, the combination antiviral treatments lopinavir/ritonavir, and the cytokine IFN-β-1a.

The anti-malarial and auto-immune drug hydroxychloroquine has been widely promoted by conservative media and others as a potential game changer treatment for patients with Covid-19, and President Trump made headlines earlier this month by announcing that he was taking it in an effort to prevent infection with SARS-CoV-2, despite warnings from the FDA that the drug may cause potentially life-threatening heart rhythm problems.

The observational study is the latest and the largest trial to date to raise safety concerns and suggest little therapeutic benefit for hydroxychloroquine, or the similar drug chloroquine, as a treatment for Covid-19.

Researcher Mandeep Mehra of Brigham and Women’s Hospital, Boston, and colleagues, conducted a multinational registry analysis of the use of the drugs, with and without a macrolide antibiotic, for the treatment of patients hospitalized with the novel coronavirus.

The registry included 671 hospitals on six continents, with data on 96,032 patients hospitalized between Dec. 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2.

Patients who received chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide within 48 hours of receiving their diagnosis were included in the treatment arm, and those not treated with any of the drugs made up the control group. Patients were excluded if they initiated one of the treatments more than 48 hours after diagnosis or while on mechanical ventilation, or if they were treated with remdesivir.

Among the 96,032 patients (mean age 53.8 years, 46.3% women) with Covid-19 included in the analysis, 14,888 were in the treatment groups and 81,144 patients were in the control group. A total of 10,698 (11.1%) patients died while still hospitalized.

After controlling for multiple confounding factors, the patients treated with hydroxychloroquine or chloroquine had significantly higher in-hospital mortality compared to the control group:

  • Hydroxychloroquine (18.0% versus 9.3%, hazard ratio, 1,335; 95% CI, 1.223-1.457).
  • Hydroxychloroquine with a macrolide (23.8% versus 9.3%, HR, 1.447; 95% CI, 1.368-1.531).
  • Chloroquine (16.4% versus 9.3%, HR, 1.365; 95% CI, 1.218–1.531).
  • Chloroquine with a macrolide (22.2% versus 9.3%, HR, 1.368; 95% CI, 1.273-1.469).

Patients in the treatment groups also had significantly higher risk of de novo ventricular arrhythmias during hospitalization:

  • Hydroxychloroquine (6.1% versus 0.3%, HR 2.369; 95% CI, 1.935-2.900).
  • Hydroxychloroquine with a macrolide (8.1% versus 0.3%, HR, 5.106; 95% CI, 4.106-5.983).
  • Chloroquine (4.3% versus 0.3%, HR, 3.561; 95% CI, 2.760-4.596).
  • Chloroquine with a macrolide (6.5% versus 0.3%, HR, 4.011; 95% CI, 3.344–4.812).

In an editorial published with the study, Christian Funch-Brentano and Joe-Elie Salem of the Sorbonne University, Pitie-Salpetriere Hospital, Paris, wrote that despite the limitations inherent in observational data, the study results “indicate an absence of benefit of 4-aminoquinoline-based treatments in this population and suggest that they could even be harmful.”

“It is tempting to attribute the increased risk of in-hospital deaths to the higher observed incidence of drug-induced ventricular arrhythmias, given that these drugs are known to prolong QTc and provoke torsade de pointes,” they wrote. “However, the relationship between death and ventricular tachycardia was not studied and causes of death (i.e., arrhythmic versus non-arrhythmic) were not adjudicated.”

They noted that the number of deaths in the treatment group was significantly greater than the number of patients identified with ventricular arrhythmias.

“The risk of death associated with 4-aminoquinolines alone or combined with a macrolide was similar, whereas it would be expected that the combination of two QTc-prolonging drugs would increase their proarrhythmic potential,” they wrote.

They added that the hazard ratio for death was similar in men and women in the study, even though women have a higher sensitivity to drug-induced QTc prolongation and a higher risk of drug-induced torsade de pointes than men.

“The study therefore does not suggest that the increased risk of death with 4-aminoquinolines was due to a proarrhythmic mechanism,” they wrote. “Another hypothesis to explain the increased risk of death with 4-aminoquinolines is that their antiviral and immunomodulatory properties could worsen Covid-19 severity in some patients. Nevertheless, the increased incidence of ventricular arrhythmias is intriguing.”

They noted that chloroquine, hydroxychloroquine, and azithromycin all have sodium channel blocking properties that might contribute to proarrhythmia and heart failure in the context of myocardial injury and hypoxia present in Covid-19.

“This hypothesis remains to be tested,” they concluded.

  1. The largest international study published to date examining hydroxychloroquine and chloroquine in patients hospitalized with Covid-19 showed that both drugs were associated with decreased in-hospital survival and increased frequency of ventricular arrhythmias.

  2. On May 25, WHO officials announced that the hydroxychloroquine arm of the global Solidarity Trial would be paused while early safety data from the trial and others examining the drug as a Covid-19 treatment are reviewed.

Salynn Boyles, Contributing Writer, BreakingMED™

Funding for this research was provided by Brigham and Women’s Hospital.

Researcher Mandeep Mehra reported receiving personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NupulseCV, FineHeart, Leviticus, Roivant, and Tripple Gene. Researcher Sapan Desai is the founder of Surgisphere Corporation.

Editorial writers’ Christian Funck-Brentano and Joe-Elie Salem declared no competing interests.

Cat ID: 190

Topic ID: 79,190,254,930,500,791,932,570,190,520,926,192,927,151,928,925,934