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Reasonable Doubt

Reasonable Doubt

Hydroxychloroquine Studies for COVID-19 Are Methodological Garbage

Runde, Dan MD

doi: 10.1097/01.EEM.0000669320.14561.00
    hydroxychloroquine, coronavirus, COVID-19
    hydroxychloroquine, coronavirus, COVID-19:
    The provenance of this image is unknown despite EMN's extensive efforts to track down its creator. It has become a popular response to questionable COVID-19 social media posts.

    Emergency medicine is not a specialty well-suited to the reticent or passive. As I've said before, every day we are forced to make critical decisions, quickly and in the face of limited or imperfect information. That's never been truer than during this current pandemic.

    Emergency departments are described as front-line health care locations with good reason. On the other hand, our specialty has embraced evidence-based clinical practice with gusto. Perhaps that was born of wanting to be able to push back intelligently against frustrating, unnecessary, and sometimes harmful requests made by consulting services. (Hey, NG lavage! EMN. 2015;37[11]:20; But it's an attribute that has served us well in the past and has never been more important than today. That's why we need to talk about hydroxychloroquine and chloroquine and why we must think hard before giving it to patients.

    I know you have heard about it. It has been touted as a game-changer by some very important but less-than-scientifically-literate people. There have been reports of hoarding and shortages. And haven't we seen headlines everywhere about some French trials that show it's super-effective? These COVID-19 patients are sick, and far too many of them are dying. Doesn't that mean we should try something, anything, while we're in the middle of this crisis?

    Well, no. Despite our desire to act, anyone administering hydroxychloroquine outside of a clinical trial is letting his gut get the better of his brain. That could lead to real harm to real people.

    This is a drug with the potential to cause serious and deadly side effects. The American Heart Association has put out a warning. (April 8, 2020; Anecdotal reports of bad outcomes are increasingly common. Hospitals in Sweden have stopped using chloroquine due to concern over side effects. (Newsweek. April 6, 2020; Same thing in France. (Newsweek. April 8, 2020; A trial in Brazil was just stopped due to an increase in dangerous arrhythmias in patients getting chloroquine. (New York Times. April 12, 2020; Not a good start for the “first, do no harm” crowd, right?

    Weak Studies

    But what about those French trials? I could spend 10 times the space I have for this article going through the reasons that the trials by Didier Raoult, MD, and his colleagues aren't worth the digital paper they are printed on, but for the sake of brevity and to try to avoid giving myself a rage-induced stroke, I will just hit the high points.

    • The first “trial” had only 36 subjects, was open-label and nonrandomized, and it had huge methodological flaws. (Int J Antimicrob Agents. 2020 Mar 20:105949;
    • One of the authors on the paper also happens to be the editor-in-chief of the journal in which it was published (though the publisher said he was not part of the peer review), and the article was accepted for publication in less than 24 hours.
    • Dr. Raoult has a history of being associated with dubious research methodology and of fabricating and altering results. (For Better Science. March 26, 2020;
    • The society that oversees the journal in which the article was published and its publisher, Elsevier, announced an investigation into the “the content, the ethical approval of the trial and the process that this paper underwent to be published within the International Journal of Antimicrobial Agents.” (March 11, 2020; Yikes.
    • The second “study,” by this same crew, is somehow of even lower quality than the first one. For example, there was no control group. Along with a number of other methodological issues, this basically makes it impossible to interpret or apply the results they published. (Travel Med Infect Dis. 2020 Apr 11:101663;


    The headline-making articles on the wonders of hydroxychloroquine have been methodological garbage and are being headed up by someone who has a history of questionable ethics and could be said to have a dubious grasp of things like science. (He said he doesn't believe in control groups for infectious disease studies, for example.) Thank you, next.

    These aren't the only studies out there, but they have received the most attention. If you're interested in a nice analysis of these papers, I recommend checking out the piece by emergency physician Justin Morgenstern, MD, but suffice it to say he wasn't impressed. (April 9, 2020;

    Tagging on to that, we also have the preprint, pre-peer-reviewed results of what appears to be the largest RCT on hydroxychloroquine to date (i.e., April 20, 2020). It was open-label, no placebo group, and even though we know these biases result in favor of treatment, this was still a negative study for its primary and secondary outcomes. As a nice bonus, we got a 21.2 percent in adverse events for the hydroxychloroquine group, which means we get a number needed to harm of 5 in an otherwise negative trial. Not great, Bob! (Yes, that's a dated “Mad Men” reference; you're welcome).

    Things are changing rapidly, and it's entirely possible that by the time this article is in print we'll have definitive results from a few high-quality studies that show patient-oriented benefits for these medications to treat COVID-19. Until we do, however, it's definitely on us to chill out, as the kids say. This isn't a case of anything is better than nothing. Medical history is rife with examples of “therapies” that turned out to be not just worthless but actively harmful. Until we know better, we need to be the adults in the room, even when trying something would be easier than the alternative. No one said this was going to be easy. Please be smart, be patient, and be safe.

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    Dr. Rundeis the assistant residency director and an assistant professor of emergency medicine at the University of Iowa Hospitals and Clinics, where he serves as co-director for the associate fellowship in medical education. He creates content for and is a member of the editorial board, and is a content contributor Follow him onTwitter@Runde_MC, and read his past articles at

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