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From Brief19: New Study Questions The Safety And Efficacy Of Hydroxychloroquine For Covid-19

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April 14, 2020

In a preprint of a randomized clinical trial posted in medRxiv, researchers in Brazil randomized patients to receive either the anti-malarial drug chloroquine (CQ) 600mg twice daily for ten days or 450mg low dose CQ for five days.

Compared to low-dose CQ, patients receiving high dose CQ had more adverse cardiac effects (25 percent of patients’ hearts began to have abnormally long recovery times between beats, known as a “long QTc interval”) and even increased mortality (17 percent). When the researchers compared the patients in this study to those who had not received CQ, fatality rates were similar suggesting that the effects of CQ for covid-19 are negligible. It is important to note that only half of the patients assessed had laboratory-confirmed SARS-Cov-2 infection. The other half had the “covid-19” syndrome, which was not confirmed by labs but, rather, by physicians’ suspicion only.

Analysis: This “preprint publication” has not been peer-reviewed by experts. Other considerations: 1) These patients were also taking azithromycin, an antibiotic which, like CQ, is known to increase the QTc interval of the heart. So, the potentially dangerous cardiac side effect of CQ seen here may be synergistic with azithromycin. 2) It is possible that some of the patients without laboratory confirmed SARS-Cov-2 may have had viruses other than SARS-CoV-2. That said, despite some limitations, this is the first randomized clinical trial of CQ. These “negative results” are not unexpected. Randomized trials frequently deliver disappointing results for medications that have “anecdotal evidence showing promise” for a disease. This study casts serious doubt as to the effectiveness of CQ for treating covid-19.

Worse, the results of this study provide some evidence that CQ (and its cousin hydroxychloroquine) might be harmful while not offering any help to covid-19 patients. Though many hospitals continue to use these medications, there remains no compelling evidence to support the routine use of CQ or hydroxychloroquine for treating covid-19 infection.

Shared with permission from Brief19, a daily review of #covid-19 research and policy.

Read more in today’s Brief19

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\ \ April 22, 2020\ In a preprint study posted to medRxiv, NIH-funded researchers from the Veterans Affair (VA) and University of Virginia looked at outcomes of 368 hospitalized patients in the VA system with confirmed SARS-CoV-2 infection. Patients received hydroxychloroquine (HC) or hydroxychloroquine and azithromycin (AZ), or standard of care (neither of these medications). The study assessed whether death or the need for mechanical ventilation was more frequent in any of the three groups. Patients who received HC were a bit sicker at the start of the study than those who did not receive the drug. Patient given only HC died 27.8 percent of the time. Those who received HC plus AZ died 22.1 percent of the time. Patients who received neither only died 11.4 percent of the time. Thus, the patients who received HC, or HC plus AZ died more often than those who only received "standard" treatment that did not include these medications. This is a large difference. In addition, there was no evidence that the medications reduced the risk for the need of mechanical ventilation.\ Is this another major blow to the use of HC for patients with severe covid-19? Possibly. However, this is an observational study that looked at patient information in medical databases, rather than a randomized trial that collected data in real time and divvied patients into groups that were slated to either receive the drugs of interest or placebos. This means the patients in this study received the drugs that treating physicians deemed appropriate at the time. To overcome some of these limitations, the researchers performed statistical analyses that adjusts for the increased severity of illness found in the patients who received HC. This is called "propensity score matching." Propensity matching, while helpful, doesn't completely negate the limitations of observational studies likes these.\ Analysis: So far, there has been no high-quality evidence to support the use of HC. Other studies that have shown signs of benefit from HC have similar limitations to those found in this study. However, this study is an important reminder that it is unsafe and unwise to assume that giving an unproven drug to sick patients will either do nothing or help. That mindset is dangerous. Giving an unproven drug to patients will either help, not help, or harm patients.\ Shared with permission from Brief19, a daily review of #covid-19 research and policy.](https://app.figure1.com/case-detail/0b31d9c6-64f6-413f-8511-44878808263f)

\ \ April 7, 2020\ A paper published in JAMA on April 6th describes the outcomes of patients with confirmed SARS-CoV-2 infection who were admitted to Intensive Care Units in Lombardy, Italy. Of the 1,591 patients admitted to the ICUs, most were men (82 percent) and the average age was 63 years old. Almost all patients—99 percent—required at least some help with breathing, including 88 percent who required a mechanical ventilation (a breathing machine). At the time of the study, 26 percent of the patients followed in this study had already died, while another 58 percent remain in the ICU.\ This study is notable for several reasons. First, this study represents the largest group of ICU patient outcomes described since the start of the covid-19 pandemic. Second, the authors shared intricate details in this publication, providing important insights into the needs of covid-19 patients ICUs. Finally, the results provide further evidence that older patients with chronic disease (high blood pressure, lung disease, etc) tend to fare poorly when they become sick with covid-19. While this study may not immediately provide “practice-changing” information for emergency physicians and other hospital providers, it is a stark reminder that older patients with multiple medical problems may require higher levels of medical care.\ Shared with permission from Brief19, a daily review of #covid-19 research and policy.](https://app.figure1.com/case-detail/14d88df0-3db6-43b2-bb27-60cb5d296e85)

\ \ April 6, 2020\ In a paper published in the preprint journal medRxiv, researchers in Wuhan, China analyzed medical records of patients hospitalized with confirmed SARS-CoV-2 infection. They separated patients with both covid-19 and high blood pressure (hypertension) into two groups: patients who had been prescribed the antihypertensives “ACE inhibitors” and “ARBs,” and patients who had not been prescribed either of these medications. The question: do ACE inhibitors or ARBs have any effect, good or bad, on covid-19 infection? As previously covered in Brief19, experts have debated the use of these medications.\ In this new study, researchers found that patients taking ACE inhibitors and ARBs were much less likely to develop “very severe” covid-19, and also had lower death rates. Does this mean that patients who have their elevated blood pressure under control have a better chance at good outcomes? It’s possible. High blood pressure appears to be a risk factor for poorer outcomes. Alternatively, might these medications even actively interrupt the virus’ attempt to enter cells, as we have covered? Too soon to say. However, these data do provide some preliminary evidence that patients already taking either an ACE inhibitor or an ARB for high blood pressure may not need to stop taking these medications if they become infected with SARS-CoV-2, as some experts have suggested might be necessary.\ Shared with permission from Brief19, a daily review of #covid-19 research and policy.](https://app.figure1.com/case-detail/53f2dc7d-ec1f-480f-9059-f925f2fdc11d)

\ \ May 12, 2020\ A new study published in JAMA assessed 1,438 hospitalized patients with covid-19 who received hydroxychloroquine and azithromycin (HCQ+AZ), hydroxychloroquine (HCQ) alone, azithromycin (AZ) alone, or neither drug. These 1,438 patients represent 88.2 percent of all covid-19 patients admitted across 25 hospitals in the New York metropolitan region between March 15 and 28, 2020 with a final follow-up date of April 24, 2020. The authors compared in-hospital mortality, cardiac arrest, and abnormal ECG findings (irregular heartbeat or elongation of the "QT interval," which indicates whether the heart is resetting normally after every beat). During the study period, 20.3 percent of all admitted patients died. The probability of dying from covid-19 after receiving HCQ+AZT was 25.7 percent; after receiving HCQ alone, 19.9 percent; after receiving AZ alone, 10 percent, and after receiving neither drug, 12.7 percent. After statistical correction for patient differences among the groups, there were no significant differences in mortality among any of the groups. Many side effects were reported in this study. Patients receiving HCQ+AZ were more likely to suffer from cardiac arrest compared with those in the other groups. However, some caveats are worth noting. This study was an observational study and not a randomized clinical trial, so which patients received various treatments were non-random events. The patients who received HCQ+AZ were notably sicker than the other groups and, therefore, more likely to die regardless of the intervention. Of note, 13 percent of HCQ+AZ patients were mechanically ventilated in less than a day compared to 5 percent of patients who did not receive any drug.\ Meanwhile, in the face of increasingly negative evidence regarding HCQ, some optimists have advanced the theory that HCQ fare better if zinc were included in protocols. While we are aware of no evidence to support this claim, a study preprint published in the journal medRxiv looked at this question. Hospitalized covid-19 patients in New York City who received HCQ+AZ plus zinc were compared with those who received HCQ+AZ alone. The researchers observed no difference in the number of days patients spent in the hospital, in intensive care units or on mechanical ventilators.\ While the paper states that patients who received zinc had half the odds of dying or transitioning to hospice when patients in the ICU were excluded, the methods of the paper are incomplete as currently published; the methods for how the data were pulled from electronic medical records are not adequately described.)\ There has been a steady stream recently of negative studies on HCQ. However, the largest ones have been observational studies, not true trials. An important randomized clinical trial performed in Europe that included patients receiving HCQ is expected to be published this week.\ Shared with permission from Brief19, a daily review of #covid-19 research and policy.](https://app.figure1.com/case-detail/60091b21-13e0-44c5-aa0a-4fdb83409499)

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