White House trade adviser Peter Navarro has promoted the “astonishing” results of an observational study that found hydroxychloroquine was associated with lower mortality for patients hospitalized for COVID-19. But the study has limitations, and multiple randomized controlled trials have found the drug is not beneficial to hospitalized patients.
In a July 7 press conference, Navarro highlighted the results of a study from the Henry Ford Health System in Michigan, saying it “showed an astonishing 50% reduction in the mortality rate for patients taking hydroxychloroquine,” and that “importantly, the study was based on what’s called early treatment.”
Minutes earlier in a CNN interview, Navarro, who is an assistant to the president and director of the Office of Trade and Manufacturing Policy, also referenced the study, saying of hydroxychloroquine: “It appears to work … in a very significant way,” adding, “It will save lives.”
Outside experts, however, dispute the notion that the Henry Ford study treated its patients much earlier than other studies, and are skeptical of its findings, as they clash with every other rigorously performed study testing the drug against the coronavirus.
“All the evidence points to [hydroxychloroquine] not being effective for improving mortality outcomes in the hospital,” said Eli Rosenberg, an associate professor of epidemiology and biostatistics at the State University of New York’s University at Albany, who has conducted a hydroxychloroquine study. “So this definitely stands quite at odds with where all the science currently is.”
Navarro also announced that based on the new findings, physicians from Henry Ford were petitioning the Food and Drug Administration to issue an emergency use authorization for hydroxychloroquine for early hospitalized COVID-19 patients, outpatients and for prophylaxis, or prevention.
The health system confirmed in a statement to FactCheck.org that it had “formally asked the FDA for reconsideration of their Emergency Use Authorization of the drug for a clearly defined list of clinical uses, including use in clinical trials,” but did not answer additional questions about the request.
Because hydroxychloroquine is approved for other uses, physicians can legally prescribe the drug for any reason, but without the EUA, the drug cannot be obtained from the Strategic National Stockpile.
The FDA previously revoked its hydroxychloroquine EUA for hospitalized patients on June 15, citing the findings of a large randomized controlled trial in the U.K., among other evidence. The agency determined that the drug was unlikely to be effective and the potential benefits of its use no longer outweighed the risks, given the possibility of serious cardiac side effects.
Navarro, notably, did not mention that three randomized controlled trials — considered the highest level of evidence in science — all failed to find that hydroxychloroquine benefits patients hospitalized for COVID-19.
The Henry Ford study, which was published in the International Journal of Infectious Diseases on July 1, looked back at the outcomes of 2,541 patients who were admitted to the hospital system and were given hydroxychloroquine, the antibiotic azithromycin, both drugs or neither. It was observational and did not randomize patients to treatment groups, nor did it blind patients or physicians to the medications that were given.
In touting the new study, Navarro also gave the misleading impression that the bulk of the evidence favors hydroxychloroquine, which is an antimalarial that is also used to treat autoimmune diseases such as lupus and rheumatoid arthritis.
“There’s over 60 studies that we’ve looked at on a spreadsheet. Fifty of them support the therapeutic or prophylactic use of hydroxychloroquine,” he said. “The 11 that don’t, a good number of those are discredited studies.”
We asked the White House for the spreadsheet or its contents, but did not receive a reply. There is one retracted study, published in the Lancet on May 22, that claimed hydroxychloroquine did not benefit hospitalized COVID-19 patients and may have increased mortality. Those conclusions, however, were based on registry data from the company Surgisphere, which other scientists found highly suspicious and did not match up with government reports. Three of the authors retracted the paper about two weeks later when the underlying data could not be verified.
Although the results are not yet published, the RECOVERY trial in the U.K., which included 1,542 patients receiving hydroxychloroquine and 3,132 patients receiving usual care, found no difference in survival nor improvement in hospital stay or other outcomes.
“These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19,” the investigators said in a June 5 press release that also announced the end of the hydroxychloroquine part of the trial.
“Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs,” said Dr. Peter Horby, a professor of emerging infectious diseases and global health at the University of Oxford and the trial’s lead investigator.
The National Institutes of Health announced on June 20 that it, too, was halting its hydroxychloroquine trial in hospitalized patients, known as ORCHID, after a data and safety monitoring board reviewed interim data.
While hydroxychloroquine was not harmful, the board concluded the drug was “very unlikely to be beneficial” to hospitalized patients, according to the agency’s news release. The trial was a blinded, placebo-controlled randomized clinical trial, and at the time of closure, included more than 470 enrollees who were currently hospitalized or expected to be hospitalized for COVID-19.
The NIH told us by email that investigators were continuing to follow participants and were working toward publication, although given follow-up and time to analyze data, this might take a couple months.
On June 17, the World Health Organization also suspended the hydroxychloroquine arm of its randomized controlled trial, known as Solidarity, given lack of efficacy in hospitalized patients.
On July 4, the WHO officially accepted the trial’s steering committee’s decision to discontinue the hydroxychloroquine arm based on the interim results and other trials, noting that the interim findings show that hydroxychloroquine produces “little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care.”
The agency said the findings were being “readied” for peer-reviewed publication and that its decision does not apply to hydroxychloroquine trials in non-hospitalized patients or those testing the drug for pre- and post-exposure prophylaxis.
Indeed, other trials are still in the works regarding outpatient treatment and prevention, including a very large prevention trial among front-line workers at Henry Ford. The first two randomized controlled trials to announce results on hydroxychloroquine as a preventive, however, have not shown any benefit, including one trial from the University of Minnesota and another in Barcelona, Spain.
In addition to Navarro, President Donald Trump, who has long backed hydroxychloroquine for COVID-19 despite a lack of evidence — and even claimed to take the drug — cheered the Henry Ford findings. On July 6, he shared snippets of the study’s press release in tweets, and later suggested that he had been vindicated.
“The highly respected Henry Ford Health System just reported, based on a large sampling, that HYDROXYCHLOROQUINE cut the death rate in certain sick patients very significantly,” he said in a tweet. “The Dems disparaged it for political reasons (me!). Disgraceful. Act now,” he added, tagging the FDA.
We’ll review the Henry Ford findings and put them in context with the other results to give a more complete picture of where hydroxychloroquine really stands.
Observational Study With Some Oddities
In the Henry Ford study, 18.1% of all patients died in the hospital, compared with 13.5% who received hydroxychloroquine, 22.4% who received azithromycin, 20.1% who received both drugs and 26.4% who received neither.
After controlling for demographics, various risk factors and some markers of disease severity, the authors found that getting hydroxychloroquine was associated with a reduced risk of death.
In another similar analysis, in which the authors matched 190 patients who received hydroxychloroquine with 190 corresponding patients who did not get the drug, hydroxychloroquine was associated with a 51% reduction in the risk of death.
Experts, however, said that because the study was not a randomized trial, it’s difficult to know whether the effect the study’s authors identified is real.
“The concern with any retrospective observational cohort,” explained Dr. David Boulware, a professor of medicine and infectious disease specialist at the University of Minnesota Medical School, “is selection bias.”
“The question is, the people who got the medicine, are they the same as the people who didn’t get the medicine,” he said. “They try to control for that, they do multivariable adjustments and things like that, but there’s still things you can’t totally control statistically to try to compensate for how physicians act.”
In particular, several scientists suspect that the patients who didn’t get hydroxychloroquine may have been more likely to be sicker or more frail and less likely to get as much treatment.
The first clue comes from the fact that while the hospital system seemed to give most patients hydroxychloroquine according to its standardized protocol, a sizable chunk did not receive it.
“When you have a protocol in your hospital and many patients aren’t following the protocol, it makes you think that there’s something different about those patients,” said Dr. Neil Schluger, chair of the department of medicine at New York Medical College, and senior author of another observational study of hydroxychloroquine. “So the comparison right away becomes a little bit problematic.”
Some patients with cardiac issues were excluded from receiving hydroxychloroquine, given safety concerns of the drug. While that’s a reasonable clinical decision, University at Albany’s Rosenberg said, it’s unclear if that meant those patients ended up in the no treatment group in the study.
“They took those people out who have these elevated risks of mortality,” he said. “That will alter the analysis in a fundamental way.”
Another hint: Hydroxychloroquine patients were more likely to be ventilated and enter the ICU, but were less likely to die than those who didn’t get the drug — even though being ventilated and admitted to the ICU are risk factors for worse COVID-19 outcomes.
“That’s very curious,” Rosenberg said, adding that it suggests that many patients who didn’t get hydroxychloroquine might have been in a “low medical intervention situation,” such as having end-of-life orders.
“Why did more patients who got hydroxychloroquine go to the ICU?” Schluger asked. “It makes you think those patients were treated more aggressively than patients who didn’t get hydroxychloroquine.”
A commentary published with the Henry Ford article also hit upon this counterintuitive result. “Were the decision to withhold treatment related to poor prognosis (e.g. palliative intent), it stands to reason that patients receiving neither hydroxychloroquine nor azithromycin would have the highest mortality,” the authors wrote. “Indeed, the non-treated group had an overall mortality that was higher than the rate of admission to the ICU (26.4% vs. 15.2%), suggesting that many patients were not considered appropriate for critical care.”
Along similar lines, the commentary authors, who were physicians and researchers in Canada and Australia, noted that patients receiving hydroxychloroquine were more than twice as likely to be prescribed steroid medications.
“This is relevant considering the recent RECOVERY trial that showed a mortality benefit with [the steroid] dexamethasone among individuals requiring supplemental oxygen or mechanical ventilation,” the authors wrote, “potentially biasing this study’s results in favor of hydroxychloroquine.”
The study also did not provide information about how patients fared at different time points, which could have influenced outcomes.
“As the Henry Ford Health System became more experienced in treating patients with COVID-19, survival may have improved, regardless of the use of specific therapies,” the commentary said.
Schluger also noticed that when the Henry Ford authors matched the hydroxychloroquine patients to those who did not receive the drug, the analysis included only a small fraction — 190 — of the more than 2,500 patients.
“That to me seems quite unusual and really indicates that the patients just weren’t the same,” Schluger said. When he used the technique in his observational study, he included 1,085 patients out of a total of 1,446.
But rather than comparing the observational studies, Schluger said the larger point is that there are randomized controlled trials now.
“The vast majority of evidence by now — I mean, really, an overwhelming amount of evidence — suggests that hydroxychloroquine has no effect,” he said. “And now we have randomized controlled trials, so in a sense the whole issue of observational studies is a little bit moot.”
Unsubstantiated Claim About Earlier Treatment
A central claim, both by Navarro, and the authors of the study, is that early treatment is a key reason why the results were positive for hydroxychloroquine this time, whereas in the past they have been negative.
“We attribute our findings that differ from other studies to early treatment, and part of a combination of interventions that were done in supportive care of patients, including careful cardiac monitoring,” said Dr. Marcus Zervos, the division head of infectious disease for Henry Ford Health System, and a co-author of the study.
But other experts say there’s little to back that claim.
“I don’t believe that at all,” said Boulware, “because they don’t have data to support that.” The Henry Ford study, he said, specifically said that it did not catalog when patients’ symptoms began, making it impossible to know whether the hospital treated patients any sooner or not.
The health system did treat patients soon upon admission — 82% within a day, and 91% within two. But, as Boulware said, “in the other studies they were also being treated early, so it wasn’t like that was unique.”
In Rosenberg’s observational study, which the Henry Ford paper explicitly cited in its discussion as having included patients who received hydroxychloroquine at any time during hospitalization, the median time to the first hydroxychloroquine dose was one day. (The Henry Ford authors also claimed mortality was “significantly higher” in this study, but the overall mortality was 20.3% — just a few percentage points above its own.)
“This idea that somehow these folks were treated earlier in Michigan,” Rosenberg said, “that’s not consistent with the data.”
In Schluger’s observational study, 46% were treated within 24 hours after arriving at the emergency room, and 86% were treated within 48 hours.
How the Henry Ford study compares with the large clinical trials is unknown, since those details have not yet been published. The NIH, however, told us that in its trial, patients needed to test positive for the coronavirus within the past 10 days to be eligible, and that patients were excluded if it had been more than 10 days from the beginning of any acute respiratory symptoms.
It’s possible that hydroxychloroquine does need to be given early to show any effect, Boulware said, even if the Henry Ford study cannot make that claim.
But that answer best comes from a randomized controlled trial. Boulware said he was aware of nine randomized controlled trials testing hydroxychloroquine in COVID-19 outpatients; two have results but are not yet published, while the others are struggling with enrollment. One from the NIH closed on June 20 when it had enrolled only 20 people.
Giving hydroxychloroquine very early — before or after exposure to the coronavirus, for prevention — is also still a possibility, although Boulware’s post-exposure study did not find the drug to be effective, and another unpublished trial also turned up negative.
Navarro can say hydroxychloroquine is still worth studying, but it’s misleading to classify the vast majority of evidence as positive, and to fail to mention several randomized controlled trials that found no benefit in hospitalized patients when playing up a study that was also conducted in hospitalized patients.
“It’s very interesting that of all the administration people, the only person that they can get to come out and promote hydroxychloroquine is not a physician,” said Boulware. “That should probably be a big red flag.”
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