Executive members of coronavirus therapy candidate global assessment came to decision after new data showed the therapy was linked to increased mortality and cardiovascular event risk.
The World Health Organization (WHO) has announced intentions to temporarily suspend the hydroxychloroquine arm of its Solidarity Trial while the trial’s executive group reviews available, robust randomized data assessing the polarizing therapy in treatment of patients with confirmed coronavirus 2019 (COVID-19).
In an announcement made by WHO Director-General Dr. Tedros Adhanom Ghebreyesus on Monday afternoon, the global organization cited data published by The Lancet on Friday, May 22, which showed autoimmune therapies hydroxychloroquine or chloroquine—with or without a macrolide—did not conclusively show in-hospital outcome benefits.
A team of investigators from the US and Switzerland, led by Mandeep R. Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, conducted the international registry analysis of the considered therapies among 96,032 SARS-CoV-2 confirmed patients hospitalized in 671 hospitals across 6 continents.
The patient population was split among 14,888 (15.5%) patients receiving treatment—1868 on chloroquine, 3783 on chloroquine plus macrolide, 3016 on hydroxychloroquine, and 6221 on hydroxychloroquine plus macrolide—and 81,144 serving as control, meaning they received none of these treatments.
Mehra and colleagues excluded data from patients for whom one of the observed therapies was initiated >48 hours post-coronavirus diagnosis or while they were on mechanical ventilation, as well as those who received remdesivir. They sought an outcome of in-hospital mortality and de-novo ventricular arrhythmias.
Combination hydroxychloroquine and second-generation macrolides including azithromycin have been advocated for COVID-19 care by public officials, investigators noted, despite their limited evidence for efficacy—and even previous research showing any combination of the therapies can increase cardiovascular event risk, including ventricular tachycardia or ventricular fibrillation.
Despite this conflict between public advocacy and clinical concern, countries have opted to stockpile the drugs in question over the past few months.
“Although several multicenter randomized controlled trials are underway, there is a pressing need to provide accurate clinical guidance because the use of chloroquine or hydroxychloroquine along with macrolides is widespread, often with little regard for potential risk,” investigators wrote.
Mean patient age was 53.8 years, with 46.3% of observed patients being women. With control for confounding factors including age, sex, race/ethnicity, body mass index (BMI), cardiometabolic disease history, immunosuppressed condition, lung disease, and smoking status, every combination of chloroquine, hydroxychloroquine, and a macrolide therapy was associated with an increased risk of in-hospital mortality versus other COVID-19 therapies:
Risk of patient de-novo ventricular arrhythmia during hospitalization was, again, significantly increased with every combination of observed therapy versus control:
The findings, which were comprised of 63,315 (65.9%) COVID-19 patients in North America, also indicated that greater patient BMI is associated with worse in-hospital survival rates. They also implied that drugs designed to stabilize cardiovascular function, including and improve endothelial cell dysfunction, including ACE inhibitors, might improve COVID-19 patient prognosis.
But overall, the associated risk of in-hospital mortality and cardiovascular events in patients treated with chloroquine, hydroxychloroquine, and/or a macrolide led to a severe recommendation from Mehra and colleagues.
“These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomized clinical trials is needed,” they concluded.
According to the WHO’s website, the Solidarity Trial is an ongoing, actively-recruiting assessment which currently includes 3500 patients from 17 countries. However, recruitment is being pursued in twice that many countries (35), including 400 hospitals.
The international clinical trial is assisting clinicians in finding effective treatments for COVID-19, comparing 4 therapy options to standard of care for their relative effectiveness against the virus.
Executive investigators are aiming to uncover slowed disease progression or improved survival associated with any of the currently observed drugs—or any new candidates added based on emerging evidence.
“The pressure COVID-19 puts on health systems means that WHO considered the need for speed and scale in the trial,” the WHO’s site reads. “While randomized clinical trials normally take years to design and conduct, the Solidarity Trial will reduce the time taken by 80%.”
In Adhoman’s media briefing on May 25, he shared that the Solidarity Trial executive group met on the day following the published Lancet findings.
This group, which represents 10 of the countries participating in the global COVID-19 therapy trial, agreed that a comprehensive analysis and critical appraisal of this hydroxychloroquine evidence, and other data, was necessary.
“The review will consider data collected so far in the Solidarity Trial and in particular robust randomized available data, to adequately evaluate the potential benefits and harms from this drug,” Adhoman stated.
The director-general reiterated that this concern relates directly to the use of hydroxychloroquine and chloroquine in COVID-19 treatment, and that other arms of the Solidarity Trial are continuing.
Use of the therapies in question for autoimmune disease or malaria care, Adhoman continued, is still accepted as generally safe by the WHO. Further updates on the organization’s assessment of hydroxychloroquine and chloroquine can be expected at a later date.