Editor’s note: The study that was the subject of this story has been retracted.

A new study underlines safety concerns about using the malaria drugs hydroxychloroquine and chloroquine to treat Covid-19, and heightens questions about whether or not the drugs are effective at all.

The study, which was published in the Lancet, cannot answer the question of whether or not hydroxychloroquine and chloroquine can help patients fight off Covid-19 or whether the drugs increase or decrease the death rates in those patients. Those answers can only come from large studies in which patients are randomly assigned to either receive the drugs or a placebo. Dozens of such studies are ongoing.

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The results, however, are a reminder of the risks of deciding to use medicines without clear evidence of their benefits and risks.

One of the findings of the current study seems hard to ignore: that the drugs increase the risk of dangerous disturbances in heart rhythms. These are known side effects of both medicines, but the increases in the study are striking. After adjustment for other risk factors, it appears that patients on hydroxychloroquine had double the risk of ventricular arrhythmias, and those on chloroquine had triple. When an antibiotic such as azithromycin was added, as some proponents have advocated, the risk jumped to fivefold.

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“It’s a very striking finding and it’s convincing to me,” said Steven Nissen, a cardiologist at the Cleveland Clinic. “Based upon these findings and others, no one should take hydroxychloroquine with or without an antibiotic unless they are in a randomized controlled trial. It should not be used in the general population to prevent or to treat Covid-19 infection.”

Eric Topol, director and founder of the Scripps Research Translational Institute and a cardiologist, noted the risk in a series of tweets. “It’s no longer that hydroxychloroquine has no sign of efficacy,” he wrote, “it  is associated with an increase in mortality.”

The study is the largest observational study so far on the use of chloroquine and hydroxychloroquine to treat Covid-19; it combined data from 15,000 Covid-19 patients at  671 hospitals on six continents who were treated with the drugs. Those patients were compared to 81,000 patients who had Covid-19 but did not receive the drugs.

Other observational studies have made comparisons in smaller populations. A study of 368 U.S. veterans also showed that the drugs might be potentially harmful. But two different studies each including 1,400 patients treated in New York during the Covid-19 pandemic showed no impact on mortality at all.

The difficulty with observational (sometimes called “real-world”) studies is that, often, the patients whom doctors choose to treat with a drug are different — in this case, probably sicker — than those who go untreated. 

The study in veterans “basically was a paper that showed that sick patients were more likely to get prescribed hydroxychloroquine, and the sick patients die. Now is it that it’s hydroxychloroquine that’s causing the death, or is it the fact that sick patients are the ones that more frequently die of Covid-19?” Amy Abernethy, the principal deputy commissioner at the Food and Drug Administration, told STAT this earlier this week. 

Adding more patients helps. But the problem is that, while researchers can control for risk factors that they know about, they can’t rule out that patients getting chloroquine and hydroxychloroquine are dying for reasons they don’t understand that have nothing to do with the drugs.

Still, the results don’t bode well for the malaria drugs as Covid-19 treatments. After controlling for risks such as weight, heart disease, and lung disease, the mortality rate in the control group was 9%. For those who received hydroxychloroquine, it was 18%; when an antibiotic was added, it was more than 20%. That’s not what would be expected if the drugs were highly effective treatments.

The results about heart rhythm issues are harder to discount, because they are known side effects of the drugs. Observational studies are generally seen as useful for picking up side effects.

Trying hydroxychloroquine as a Covid-19 treatment was sensible. Just as early laboratory studies showed that remdesivir, the drug developed by Gilead Sciences that the National Institute of Allergy and Infectious Disease found might shorten the time it took patients to recover from Covid-19 in a randomized clinical trial, so too did hydroxychloroquine. And results are conflicting. A 62-patient randomized study in China even seemed to show some benefit from the drug.

Even if the results from the new study, led by researchers at the Brigham and Women’s Hospital Center for Advanced Heart Disease/Cardiomyopathy in Boston, hold up, it’s still possible the drug could have some benefit. Researchers are testing it for preventing people who are exposed to the virus from being infected. Again, that can only come from randomized controlled studies.

Hydroxychloroquine use spiked dramatically after the drug was embraced by President Trump, who on Monday said that he himself was taking the drug, and commentators on Fox News. Sean Hannity read a letter from a doctor recounting his own experience using the drugs as a treatment on air.

Results from some of the first large, randomized studies of hydroxychloroquine are expected soon, including a study being conducted by the French government and one at the University of Minnesota. If they show that the drugs were actually harmful, it will be another giant misstep in the response to the virus. If they show it works, we’ll have another tool — probably a small one — in combating the pandemic. 

  • Everything I’ve heard, Hydroxychloroquine and Zinc in the early stages within the 1st 5 -7 days does wonders against the coronavirus. Studies like the one you were refering to, seems they are in a hospital setting and were already very sick. How can one of the safest drugs in the world (HCQ) be so dangerous now that Covid has appeared. You think Big Pharma is influencing these anti HCQ studies?

    • Not ‘big pharma’ – TDS. Trump uses it so the people with TDS claim that it is dangerous and useless.

  • Look at the incidence of COVID on patients with Lupus and Arthritis being treated with hydroxychloroquine.
    I’ve already read reports of some of these patients being infected with COVID.

  • In addition to above mentioned possible (likely) treatment bias, testing an antiviral in late stage disease, and “potential serious conflict of interest, there is the question of dosage of the chloroquine and hydroxychloroquine used. My actual experience with chloroquine in Africa tells me that this is a very safe drug. I suspect that high doses of CQ or HCQ were used as a ‘Hail Mary’ in some of the sickest patients. “The dose makes the poison.”

    “Designed to fail?” is a good question in our age of “replication crisis.”

    • I thought my comment would go at the bottom of the page. The “above mentioned” things are actually below!

  • The big problem here is the difficulty of separating the actual science from the political agendas. How much of this stuff can we actually trust?

  • In this study, patients treated with chloroquine or hydroxychloroquine were approximately three times more likely to be on ventilators than patients who weren’t treated.

    Why was this? Did treatment with these drugs, not only lack any therapeutic effect, but actually cause a much higher rate of respiratory failure? Could these drugs exacerbate development of ARDS, despite their anti-inflammatory effects and use in lupus and rheumatoid arthritis?

    While that’s certainly possible, perhaps a more plausible explanation is treatment bias related to disease severity, which was not adjusted for in the analysis. This could also explain the higher mortality rate among treated patients.

    The study raises appropriate questions as to whether these drugs are safe and effective, at least in hospitalized COVID-19 patients. However, randomized, controlled clinical trials are necessary to fully answer these questions.

  • Trying it as a treatment made sense. Perhaps even using it more if it showed promise. Touting it as some sort of Lazarus cure because it provides an out from actually doing any of the hard work in managing a pandemic like Trump and Fox News did is criminal.

    • when did the
      Media become medical experts?Im not a Democrat or Republican but don’t leave the public hanging because your in s battle now
      It sounds like there are only to pills red and blue,and we all have to suffer financially and mentally until you achieve your goal

  • Matthew, thank you for writing a more nuanced story about this drug that goes beyond the simpleton “news” reporting of CNN and Fox.

    • Matthew Herper wrote an evenly balanced article. All journalism should be like this.

  • This is similar to an actual malaria study done during my post graduation days which somehow managed to show that artemesenin compounds were superior than quinine sulphate in plasmodium falciparum and cerebral malaria patients.
    This was treatment bias as we invariably chose to use quinine sulphate in patients who were more sick and were in greater risk of death.
    So, such studies has to be done on double blind protocol, because we humans tend to treat our patients emotionally.

  • The chemical structure of hydroxychloroquine prevents it from having any possibility of preventing infection of a cell by SARS -CoV2

  • Some say these drugs in combination with zinc are effective. Were these patients given zinc as well? If they were then this is a dry hole. However, I didn’t think the response to Remdisivir was anything to write home about either.

    • 1. Zinc not even mentioned.
      2. All late stage patients – hello!
      3. “Our study has several limitations. The association of
      decreased survival with hydroxychloroquine or chloroquine
      treatment regimens should be interpreted
      cautiously. Due to the observational study design, we
      cannot exclude the possibility of unmeasured confounding
      factors,” – limited or no assessment of comorbidities; and

      4. Potential serious conflict of interest:

      “Declaration of interests
      MRM reports personal fees from Abbott, Medtronic, Janssen, Mesoblast,
      Portola, Bayer, Baim Institute for Clinical Research, NupulseCV,
      FineHeart, Leviticus, Roivant, and Triple Gene. SSD is the founder of
      Surgisphere Corporation. FR has been paid for time spent as a
      committee member for clinical trials, advisory boards, other forms of
      consulting, and lectures or presentations; these payments were made
      directly to the University of Zurich and no personal payments were
      received in relation to these trials or other activities. ANP declares no
      competing interests.”

      Designed to fail? Again.

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