Reference: JAMA Intern Med. 2022 Feb 18 early online
Two years after the emergence of COVID-19, researchers have explored the efficacy of a wide variety of repurposed medications, including antivirals, anti-inflammatories, and anti-parasitic therapies. Corticosteroids took an early lead after publication of the RECOVERY trial, but hydroxychloroquine and ivermectin each brought some controversy. A meta-analysis of 10 prior trials of patients with mild or moderate COVID-19 found that ivermectin did not reduce all-cause mortality or length of hospital stay.
Investigators in Malaysia conducted an unblinded randomized trial comparing five days of ivermectin plus standard care compared to standard care alone for adults ≥ 50 years of age with mild to moderate COVID-19. Participants had at least one risk factor for severe disease. Exclusion criteria included asymptomatic disease, > 7 days since symptom onset, hypoxemia, pregnancy, or recent use of antivirals. All were admitted to a COVID-19 quarantine center for closer monitoring. The investigators recruited 500 participants, of which 241 from the ivermectin group and 249 from the standard care group were included in a modified intention-to-treat analysis. Participants had a mean age of 62.5 years, and most had hypertension (75.3%) and/or diabetes (53.5%). Over half had completed two COVID-19 vaccine doses. Concomitant therapies administered included corticosteroids (27%), antibiotics (22%), and systemic anticoagulation (28.6% with ivermectin vs. 22.9% with standard care). The primary outcome was the proportion of participants requiring oxygen therapy to maintain an oxygen saturation ≥ 95%.
The primary outcome was similar between the two groups, with 21.6% (52/241) in the ivermectin group requiring oxygen compared to 17.3% (43/249) in the standard care group (relative risk [RR] 1.25, 95% CI 0.87-1.80). There was no difference in the rate of oxygen requirements in subgroup analysis, including vaccine status. Both groups had similar rates of intensive care unit admission (2.5% vs. 3.2%, RR 0.78, 95% CI 0.27-2.20), mean length of stay (7.7 vs. 7.3 days), and in-hospital all-cause mortality at 28 days (1.2% vs. 4.0%, RR 0.31, 95% CI 0.09-1.11). Complete resolution of symptoms by day 5 was also similar in both groups. The ivermectin group had higher rates of adverse events (13.7% vs. 4.4%), mostly driven by diarrhea.
This trial sought to answer whether ivermectin has efficacy for mild-to-moderate COVID-19, but it may actually raise more questions. Despite the lack of statistical significance, the wide confidence interval for mortality doesn’t exclude the possibility of benefit if the trial were repeated. The choice to use 95% as the threshold for supplemental oxygen is interesting, and may overestimate benefit, as a lower threshold is more often used in the US. The healthcare system in Malaysia is unique in other ways, and many of the individuals admitted for quarantined supervision in this study would have been managed at home in other countries. If treated at home, mild hypoxemia (the minimal threshold for the primary outcome) may not have been detected in many participants, potentially altering the conclusion. Also potentially confounding the results is the fact that Malaysia has an estimated prevalence of Strongyloides stercoralis of upwards of 30%, an infection exacerbated by systemic steroids. It has been hypothesized that the benefits of ivermectin in a population with COVID-19 and high rates of Strongyloides are really from treating the unintentional harms of corticosteroid therapy as opposed to a benefit of treating COVID-19 itself. The lack of blinding additionally clouds the outcomes of interest. In light of these results and those from the other 10 trials before it, the magnitude of benefit of ivermectin for COVID-19, if any, is probably small.
For more information, see the topic Management of COVID-19 in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, family physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.