With thousands of articles published weekly on COVID-19, navigating the literature on this emerging infectious disease can be daunting. As emergency physicians, important research questions of interest include performance characteristics of various diagnostic tests, risk stratifying patients for discharge versus admission, and, above all, effective treatments. In an era in which preprints (ie, non peer-reviewed drafts of papers being submitted for publication) go viral, and even responsible mainstream media does not always get it right, it’s hard to know what to believe. To help health care professionals and the general public keep up and to fight medical misinformation, a group of emergency physicians started the website Brief19.com. We publish analysis of COVID-19 research and policy five days a week, all for free. (Note: ACEP Now’s medical Editor in Chief, Jeremy Samuel Faust, MD, MS, MA, FACEP, is also Editor in Chief of Brief19.)
Let’s focus on therapeutics. With regard to treatments of potential benefit in the emergency department, there are three big-ticket medicines to consider: dexamethasone, remdesivir, and hydroxychloroquine. The analysis of these three so far is, in order: promising, somewhat promising, and useless.
The main thing to remember is that a thousand retrospective observational studies provide less reliable information than a single well-done randomized controlled prospective clinical trial.
Let’s discuss three important, large, multicenter, randomized clinical trials (RCT). One of the RCTs comes from our own National Institutes of Health (NIH), one from the United Kingdom, and one from Brazil, and all published in the New England Journal of Medicine (NEJM).
Has there ever been a week of shift work where you did not prescribe IV or oral steroids? Unlikely. Dexamethasone, an inexpensive steroid that is commonly used and widely available appears to be the first medication shown in a high-quality study to reduce the rate of death in any subset of COVID-19 patients.
The results come from a larger conglomerate of trials being conducted in the United Kingdom, known as the Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial. Published July 17 in NEJM, patients enrolled in RECOVERY received 6 mg of either oral or IV dexamethasone once daily for 10 days plus standard of care, or standard of care alone.1 The primary outcome was death rate at 28 days after enrollment.
The proportion of patients meeting the primary outcome was 21.6 percent for patients receiving dexamethasone and 24.6 percent standard of care alone. The number needed to treat to prevent one death for a hospitalized patient diagnosed with COVID-19 was 20. Those most likely to benefit were patients who had a new oxygen requirement or were on mechanical ventilation. The results for patients on mechanical ventilation were staggering: 40.7 percent of patients who did not receive dexamethasone had died by day 28 compared with 29 percent among those who did receive dexamethasone. A reduction in deaths of more than 11 percent is an unusually large effect for an ICU study of any kind. Patients who needed oxygen only (but not intubation) also fared better, dying 21.5 percent of the time versus 25 percent among controls.
However, among patients who did not require any oxygen, dexamethasone did not help. In fact, more patients in that group who received the drug died, though the increase was not statistically significant. This is important, because giving dexamethasone to all patients with COVID-19 could be harmful.
The lingering question is whether the extra 11 percent of patients who survived to day 28 among patients on ventilators had improved enough to be awake. That was not reported. Given the relatively low side-effect profile of dexamethasone for patients who are already moribund, it is reasonable to start this medication in the emergency department for patients diagnosed with COVID-19 admitted to the hospital either with a new oxygen requirement or need for intubation.
The Adaptive Covid-19 Treatment Trial (ACTT-1) RCT was published May 22 in NEJM.2 ACTT-1 was a double-blind, randomized, placebo-controlled trial of remdesivir, an antiviral, given to patients within 72 hours of diagnosis of laboratory-confirmed SARS-CoV-2 infection in the in-patient hospital setting. The primary outcome of interest was time to recovery, which was defined as either being well enough to have been released from the hospital or remaining in the hospital for infection-control purposes only (ie, to protect families of the patients, not due to the severity of their illness).
The average recovery time was 11 days in the remdesivir group compared to 15 days in the placebo group. While the study was not assessed to directly and properly measure mortality per se, 7.1 percent of patients receiving remdesivir died by day 14 compared to 11.9 percent in the placebo group (hazard ratio 0.7, 95 percent confidence interval 0.47 to 1.04). Of note, remdesivir did not seem to improve time to recovery in patients who were already receiving high-flow oxygen, non-invasive mechanical ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at time of enrollment. Put another way, critically ill patients remained sick whether or not they received remdesivir, though the reduced length of stay for less severe patients could be an important outcome during any future surges that occur during the pandemic when resources may become limited.
Two big caveats to consider: one-third of patients had not reached day 29 of their course by the time of publication. Interestingly, this data has yet to be published as of August 1, including patient-level mortality analyses. We are left to wonder why. Also, the investigators changed the primary outcome of the study in April, after recruitment began. The initial plan had been to assess overall clinical improvement, including mortality rates. That was changed to an assessment of time to discharge among patients well enough to be sent home.
Several randomized controlled trials have studied hydroxychloroquine’s efficacy in preventing or treating COVID-19. None have shown that it works. The most substantial of these trials was also performed in the United Kingdom by the RECOVERY group (still in preprint) and an RCT from Brazil of patients with mild to moderate COVID-19.3 The study from Brazil was published in NEJM July 23.
In this study, patients were randomized to receive either hydroxychloroquine, hydroxychloroquine and azithromycin, or usual care. At day 15, there were no differences in clinical status, as adjudicated by a seven-point scale (from complete recovery to death). There were also no signals of benefit in secondary outcomes, including fraction of patients requiring intubation. While believers in hydroxychloroquine have advanced excuses explaining why none of the trials assessing this drug have detected a benefit—ranging from time from onset to randomization to whether or not random ingredients from the periodic table of elements were also included (the most common hail-Mary being zinc)—the fact remains that this treatment has failed to even hint at a benefit in any rigorous analysis.
Dexamethasone and remdesivir appear to help patients with severe or critical COVID-19, while hydroxychloroquine does not help those with mild to moderate illnesses—and preprint data suggest no benefit in more severe cases, as well. However, dexamethasone should not be given to all COVID-19 patients, as there may be harm among patients with less severe illness.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19—preliminary report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020. doi:10.1056/NEJMoa2021436.
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19—preliminary report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020. doi:10.1056/NEJMoa2007764.
- Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19 [published online ahead of print, 2020 Jul 23]. N Engl J Med. 2020. doi:10.1056/NEJMoa2019014.