Reference: Ann Intern Med. 2020 Jul 16
There are few potential treatments for COVID-19 that have received more attention than hydroxychloroquine (HCQ). Early in the pandemic, uncontrolled studies suggested benefit in hospitalized patients, but subsequent observational data have found no evidence of benefit. A recent randomized placebo-controlled trial examined potential benefits of HCQ in symptomatic outpatients treated early in their illness asking if HCQ could either decrease symptoms or reduce hospitalizations.
The trial occurred when testing for COVID-19 was limited and results were often delayed, and therefore enrolled persons with either laboratory-confirmed COVID-19 or COVID-19-compatible symptoms and an epidemiologic link to a contact with laboratory-confirmed COVID-19. A total of 491 patients from the United States or Canada were randomized to either placebo or HCQ 800 mg orally, followed by 600 mg 6-8 hours after the first dose and then 600 mg daily for 4 more days. Symptoms were assessed at baseline and on days 3, 5, 10, and 14 using a 10-point visual analog scale. The primary endpoints were originally designated as reduction of hospitalization and reduction of intensive care unit admission, but due to an event rate that was much lower than expected, the primary outcome was changed to reduction of symptoms over 14 days. Of the 491 patients, 465 had outcome data regarding hospitalization or death, and 423 had at least one survey response regarding symptoms. While the authors stated that the analysis was done using the intention-to-treat principle, patients who did not have outcomes reported for symptoms or for hospitalization or death were not included in the analysis. Also, of the patients enrolled, only 341 (81%) had either a positive PCR result or a high-risk exposure to a PCR-positive contact. The remaining patients had COVID-19 symptoms, but no confirmed PCR-positive contact.
Symptoms were not significantly different at any time point between those treated or not treated with HCQ. On day 5, 54% of the HCQ group had symptoms compared with 56% of the placebo group, and on day 14, the symptom rates were 24% with HCQ and 30% with placebo (p = 0.21). The rate of hospitalization or death was 3.2% with 1 death in each group, and 10 hospitalizations in the placebo group and 4 in the HCQ group (p = 0.29). In post hoc analysis, the use of supplemental zinc or vitamin C did not improve the effect of HCQ compared with HCQ alone.
These results argue against a significant benefit of using HCQ for patients with COVID-19. While this trial has numerous methodologic problems (including the difference between self-reported symptoms and objective findings such as hypoxemia), the evidence is the highest quality to date. The good news is that the rate of the most concerning outcome, hospitalization or death, was much lower than the 10% rate expected when the trial was planned. Unfortunately, to get a definitive answer to whether there might be benefit for that outcome would require a much larger trial than the researchers were able to conduct, and it seems at this point that we would need better evidence than currently exists to justify such a trial. So at this point, the best available evidence still indicates that hydroxychloroquine for early symptomatic COVID-19 is of unproven benefit.
For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School. Edited by Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed, and Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed.