On its face, it was a major finding: Antimalarial drugs touted by the White House as possible COVID-19 treatments looked to be not just ineffective, but downright deadly. A study published on 22 May in The Lancet used hospital records procured by a little-known data analytics company called Surgisphere to conclude that coronavirus patients taking chloroquine or hydroxychloroquine were more likely to show an irregular heart rhythm—a known side effect thought to be rare—and were more likely to die in the hospital.
Within days, some large randomized trials of the drugs—the type that might prove or disprove the retrospective study’s analysis—screeched to a halt. Solidarity, the World Health Organization’s (WHO’s) megatrial of potential COVID-19 treatments, paused recruitment into its hydroxychloroquine arm, for example. (Update: At a briefing on 3 June WHO announced it would resume that arm of the study.)
Hours earlier, The New England Journal of Medicine (NEJM) issued its own EOC about a second study using Surgisphere data, published on 1 May. The paper reported that taking certain blood pressure drugs including angiotensin-converting enzyme (ACE) inhibitors didn’t appear to increase the risk of death among COVID-19 patients, as some researchers had suggested. (Several studies analyzing other groups of COVID-19 patients support the NEJM results.) “Recently, substantive concerns have been raised about the quality of the information in that database,” an NEJM statement noted. “We have asked the authors to provide evidence that the data are reliable.”
A third COVID-19 study using Surgisphere data has also drawn fire. In a preprint first posted in early April, Surgisphere founder and CEO Sapan Desai and co-authors conclude that ivermectin, an antiparasitic drug, dramatically reduced mortality in COVID-19 patients. In Latin America, where ivermectin is widely available, that study has led government officials to authorize the drug—although with precautions—creating a surge in demand in several countries.
Chicago-based Surgisphere has not publicly released the data underlying the studies, but today Desai told Science through a spokesperson that he was “arranging a nondisclosure agreement that will provide the authors of the NEJM paper with the data access requested by NEJM.”
Meanwhile, the questions swirling around the Lancet paper have left leaders of the halted chloroquine trials weighing whether to restart. “The problem is, we are left with all the damage that has been done,” says White, a co-investigator on a trial of hydroxychloroquine for COVID-19 prevention that was halted at the request of U.K. regulators last week. Headlines proclaiming deadly effects will make it hard to recruit patients to key studies, he says. “The whole world thinks now that these drugs are poisonous.”
A striking observation
Desai’s co-authors on the Lancet paper were cardiologist Mandeep Mehra of Harvard University’s Brigham and Women’s Hospital (BWH), cardiologist Frank Ruschitzka of the University Hospital Zürich, and cardiac surgeon Amit Patel, who listed affiliations with the University of Utah and HCA Research Institute in Nashville, Tennessee. Their study described an analysis of Surgisphere-provided electronic health record data from patients already treated for COVID-19 at 671 hospitals on six continents.
According to the paper, the analysis included nearly 15,000 patients prescribed chloroquine or hydroxychloroquine, alone or in combination with a class of antibiotics that has been suggested to boost its effects. A control group consisted of more than 81,000 patients who hadn’t gotten the experimental drugs. After controlling for potentially confounding factors such as age, race, pre-existing disease, and COVID-19 severity, the researchers found that the risk of dying in the hospital was 9.3% for the control group versus 23.8% for those getting hydroxychloroquine alongside an antibiotic—apparently the riskiest of the treatment combinations. The results echoed a preprint published last month, based on a much smaller group of patients in U.S. Veterans Health Administration medical centers, which suggested an increased risk of death for patients who were prescribed hydroxychloroquine alone (though not in combination with an antibiotic).
In 25 May media briefing, WHO Director-General Tedros Adhanom Ghebreyesus cited the Lancet results in announcing a “temporary pause” in Solidarity’s hydroxychloroquine arm. Regulators in France and the United Kingdom also instructed investigators, including White’s team, to halt enrollment in trials of the malaria drug. And Sanofi, which manufactures the branded hydroxychloroquine drug Plaquenil, said it would temporarily stop recruiting patients to its two clinical trials of the drug.
The potential of hydroxychloroquine for treating COVID-19 has become a political flashpoint, and the questions around the Lancet paper have provided new fodder to the drug’s supporters. French microbiologist Didier Raoult, whose own widely criticized studies suggested a benefit from the drug, derided the new study in a video posted today, calling the authors “incompetent.” On social media, some speculated that the paper was part of a conspiracy against hydroxychloroquine.
For scientists running randomized trials of hydroxychloroquine, an urgent question has been how to respond to the paper and the many questions raised about it. Some studies were not halted at all. A hydroxychloroquine trial known as ORCHID, funded by the U.S. National Heart, Lung, and Blood Institute, opted to keep running after its data and safety monitoring board (DSMB) reviewed safety data from already enrolled participants, says Semler, a co-investigator on the study.
WHO’s paused Solidarity trial is awaiting a similar review from its DSMB, says Soumya Swaminathan, the organization’s chief scientist. The pause will allow time for a review of published studies and interim data from Solidarity itself, she says. WHO paused the trial to show investigators and potential study participants that the agency takes safety issues seriously, she says. “We want to reassure people that the WHO didn’t make any kind of value judgment on the use of hydroxychloroquine.”
credited to AAAS SCIENCE