Note: The Pregistry website includes expert reports on more than 2000 medications, 300 diseases, and 150 common exposures during pregnancy and lactation. For the topic Coronavirus (COVID-19), go here. These expert reports are free of charge and can be saved and shared.
Note: On June 15, 2020, the Food and Drug Administration (FDA) revoked the emergency use authorization for the drugs hydroxychloroquine and chloroquine for the treatment of COVID-19. After reviewing the current research available on the drugs, the FDA determined that the drugs do not meet “the statutory criteria” for emergency use authorization as they are unlikely to be effective in treating COVID-19 based on the latest scientific evidence, the agency noted on its website.
From US history class, you may remember William Henry Harrison for being the first candidate from the Whig Party to be elected to the presidency of the United States, or for dying on April 4, 1841, just 32 days into his term. You may also recall his campaign slogan, “Tippecanoe and Tyler Too”, but did you know that Harrison was also the only US president to go to medical school? Though from Virginia, Harrison was sent to the University of Pennsylvania, the nation’s first medical school, to study under the famed Dr. Benjamin Rush. He didn’t stay long enough to graduate, but this experience made Harrison the closest thing to a medical doctor that has ever held the nation’s highest office. Despite this distinction, though, Harrison is not known to have handed out medical advice at any point during his tragically short presidential term, as he was not a doctor and knew well that prescribing medicines was not part of his job description.
Over the course of 176 years following Harrison’s untimely death, 34 more men held the presidency without doing anything that could possibly be construed as medical advice. Realizing that, by virtue of their high office, they could easily be mistaken for an authority on anything, including medicine, all of these men, from John Tyler to Barack Obama, avoided any suggestions that they were taking any particular drug and that others should follow their example. This year, however, the current US president has moved beyond such boundaries. He did this by announcing that he has been taking the drug hydroxychloroquine and implying that he may also have been taking another drug called azithromycin as a preventive measure against COVID-19. Even worse, during his announcement, he went as far as to suggest that others should also take hydroxychloroquine based on a rationale that they have “nothing to lose”.
Regarding hydroxychloroquine, or any medication, you should take advice only from your doctor, and not take advice from the president of the United States. Although it is unusual to delve directly into a commentary on politically charged events in a medical blog, it is equally unusual for a US president to say or imply that people should take a particular medication. This makes it appropriate to unpack a response on this blog, so let’s move forward on the basis that, whether you like him or not, Donald Trump is called Mr. President in accordance with the office that he holds, but he is not called Dr. President, because he is not a doctor.
With this perspective in mind, we should analyze a few highlights of what the president has said, over the past few months, regarding hydroxychloroquine and its sister drug, chloroquine. In particular, we need to hone in on this idea that a person taking hydroxychloroquine to prevent COVID-19 has “nothing to lose”. I suspect that nearly everyone who is reading this would likely not take medication based on anything that the president says in a press conference. However, to boost your confidence, perhaps helping you explain the issue to anyone you know who might be compelled to take hydroxychloroquine on account of the president’s comments, let’s explore the accuracy of his most notable comments regarding the drug.
One point that the president has made is that many patients have been given hydroxychloroquine to confront COVID-19. This is absolutely true. Because the drug has been available, and because laboratory studies have shown that it can interfere with the ability of SARS-CoV-2 (the virus that causes COVID-19) to attach to lung cells, doctors in hospitals around the world have been prescribing hydroxychloroquine to COVID-19 patients, often together with a medication from a class called macrolide antibiotics. Most commonly, the macrolide given is azithromycin, and the idea is that this macrolide makes hydroxychloroquine work better, as does zinc, a mineral that you are supposed to get in your diet anyway. Meanwhile, the World Health Organization (WHO) has been studying the effectiveness and safety of these drugs in a large prospective trial; that is, a study in which some COVID-19 patients are given the drugs while others are not. Such a trial allows for researchers to compare getting a drug versus not getting the drug in groups of patients with otherwise similar circumstances. This is much better than a retrospective study–a study in which patients are compared based on who received or didn’t receive the drugs for reasons other than to compare the drugs’ usefulness. As an example, if hydroxychloroquine was given more often in sicker patients, then by comparing patients who received the drug with patients who did not receive it, you are actually comparing patients who are more sick with patients who are less sick. This makes it very hard to get useful information from a retrospective study, which is why a prospective study is much better.
On June 15, 2020, the Food and Drug Administration (FDA) revoked the emergency use authorization for the drugs hydroxychloroquine and chloroquine for the treatment of COVID-19. After reviewing the current research available on the drugs, the FDA determined that the drugs do not meet “the statutory criteria” for emergency use authorization as they are unlikely to be effective in treating COVID-19 based on the latest scientific evidence, the agency noted on its website.
Now, in lauding hydroxychloroquine during his press conference, the president actually alluded to the retrospective nature of studies published up to that point that had suggested that hydroxychloroquine was not effective against COVID-19. He didn’t use the word “retrospective”; he merely referred to patients receiving hydroxychloroquine while on the brink of death. But, then, something dramatic happened. A big study was published in the journal The Lancet (a very prestigious medical journal based in the UK), suggesting that hydroxychloroquine, chloroquine, and azithromycin not only did not help COVID-19 patients, but actually increased their mortality–made them die more easily–for the exact reason that we would expect, namely the triggering of dangerous heart arrhythmias. Largely on account of the Lancet paper, the WHO stopped the ongoing prospective study of these drugs in COVID-19 patients, because it meant that the drugs were even more dangerous than the disease.
Soon after the Lancet had published the paper, more than 140 scientists and physicians questioned the study results. Then, within a few weeks, the authors of the study learned of a problem with their data – data that were collected and analyzed by a company, called Surgisphere, operated by one of the authors on the study, so they asked Surgisphere to release details on the data analysis. When Surgisphere refused, the authors asked the Lancet to retract the paper, and so the Lancet retracted it. This had expanding effects, because Surgisphere also had been involved in another big paper in another major medical journal, the New England Journal of Medicine. That paper had concluded that two important groups of blood pressure medications (ARBs and ACE inhibitors) did not increase the chances that people with COVID-19 would develop severe disease, as we discussed here on The Pulse, not long after that paper came out. So, that paper too was retracted, and, more relevant to hydroxychloroquine, the WHO has since checked its safety data and concluded that the drugs are safe enough for the trial to resume.
Putting all of this together, you may be thinking that the president was correct to downplay concerns about the safety of hydroxychloroquine. However, his schpiel about taking the drug himself could easily distract people from this fact: no doctor who is up to speed with clinical guidelines and with the science of COVID-19 would prescribe hydroxychloroquine to people who do not have COVID-19 as a preventive treatment against the virus. Regardless of the how the WHO trial and other clinical studies of hydroxychloroquine, chloroquine, and azithromycin turn out, if the president has actually received hydroxychloroqine as a preventive treatment, this would fall within the realm of health quackery.
The president has also said, numerous times, that hydroxychloroquine is a well-known drug that has been used for many decades against malaria and for many years to treat rheumatological diseases, such as systemic lupus erythematosus (“lupus”). This also is accurate. The very reason why hydroxychloroquine entered the scene in COVID-19 therapy is that it was already on the shelf, ready to be tested for its clinical effectiveness, without the need to test it for toxic effects, as would be needed for a brand new medication. But the fact that many people are taking a drug for other diseases does not mean that the drug is harmless. In evidence-based medicine, treatments are given if the benefits outweigh the risks.
This brings us to our central point of discussion concerning whether one has “nothing to lose” by taking hydroxychloroquine, since the main risk of the drug is a complication involving the rhythm of the heart that we mentioned earlier, so let’s analyze that. Specifically, the problem with hydroxychloroquine is that it can lengthen what cardiologists call the QT interval on an electrocardiogram. This is the time that passes from the moment that the electrical activity of the heart’s two ventricles changes in a way that causes the ventricles to contract to the moment when the electrical situation of the ventricles has returned to the state that existed before the first change. Normally, the QT takes place within a certain amount of time, but extension of that time can lead to an extremely dangerous change in the heart’s rhythm that can spiral out of control, leading to the fatal arrhythmias that seemed to be the problem when the now retracted Lancet study came out. The risk for a prolonged QT interval increases further when azithromycin or another macrolide is combined with hydroychloroquine. Thus, the use of one or both drugs is justified only when the serious risks to the heart are exceeded by demonstrated benefits of taking the drug, and only when the person is in a situation in which her heart can be monitored, such as in a hospital.
In terms of its safety during pregnancy, based on studies of women taking hydroxychloroquine for rheumatological diseases, such as lupus, hydroxychloroquine is generally considered safe during pregnancy. However, there are also some concerns about possible birth defects. Thus, it is not something that you should be taking, unless you absolutely need it and have discussed it with your doctor. Additionally, whether you need it for rheumatological conditions or not, the risk of lengthening the QT interval, putting the person at risk of dangerous arrhythmias, is still there, and hydroxychloroquine is not something that you can just take on a whim. It’s a serious medication that may or may not prove useful in people who have COVID-19, but as a preventive measure, it is not really in the running, given the risks that it poses and the difficulty in monitoring for the risks in people who are not in the hospital.