Ivermectin Treatment for Covid-19 | NEJM – nejm.org

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Reis et al. (May 5 issue)1 present the results of the TOGETHER platform trial, a large trial of ivermectin in outpatients with Covid-19. The relative risk of hospitalization or prolonged observation in the emergency department owing to Covid-19 (the primary outcome) in the ivermectin group as compared with the placebo group was 0.90 (95% Bayesian credible interval, 0.70 to 1.16), and the relative risk of death (a secondary outcome) was 0.88 (95% Bayesian credible interval, 0.49 to 1.55).1 The prespecified threshold for the clinical utility of ivermectin was a 37.5% difference, as compared with placebo, in the relative risk of a primary-outcome event, a threshold that is probably too conservative for a drug such as ivermectin. The relative risk estimates in the trial were compatible with reductions of up to 30% in the risk of hospitalization or prolonged observation and 51% in the risk of death with ivermectin.
Given the wide availability and low cost of ivermectin and that the dosage used in the trial appeared to be safe, such treatment effects could be an important benefit for high-risk patients who do not have access to approved Covid-19 vaccines and costly therapies. The results of the TOGETHER trial were eagerly awaited because of their potential to inform the debate over ivermectin as treatment,2 but they were arguably nondefinitive3 regarding the two most relevant outcomes for outpatients with Covid-19.4
Leonardo Furlan, Ph.D.
University of São Paulo Medical School, São Paulo, Brazil

No potential conflict of interest relevant to this letter was reported.
1. Reis G, Silva EASM, Silva DCM, et al. Effect of early treatment with ivermectin among patients with Covid-19. N Engl J Med 2022;386:17211731.
2. Furlan L, Caramelli B. The regrettable story of the “Covid Kit” and the “Early Treatment of Covid-19” in Brazil. Lancet Reg Health Am 2021;4:100089100089.
3. Montori VM, Kleinbart J, Newman TB, et al. Tips for learners of evidence-based medicine: 2. Measures of precision (confidence intervals). CMAJ 2004;171:611615.
4. World Health Organization. Therapeutics and COVID-19: living guideline. July 14, 2022 (https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.4).
In the article by Reis and associates, we noticed a discrepancy regarding vaccinated participants. In the Methods section of their article, the authors stated that patients who had been vaccinated against SARS-CoV-2 were eligible for participation. However, the protocol, available with the full text of the article at NEJM.org, listed vaccination against SARS-CoV-2 as the fourth exclusion criterion. Furthermore, the previously published master protocol did not mention vaccination status in the selection process.1 We assumed that vaccinated persons were allowed to participate in the trial. However, the authors did not indicate the number of vaccinated patients in each trial group.
Public information shows that during the trial period (March 23, 2021, through August 6, 2021), the proportion of persons in the Brazilian population who were fully vaccinated increased from 2.03% to 21.07%.2 Thus, vaccination status could have been a confounder, and this information is needed to properly interpret the results of the trial. In addition, an ad hoc subgroup analysis according to vaccination status would be of interest.
Jorge H. Mejía, M.D.
Junta Regional de Calificación e Invalidez de Bogotá y Cundinamarca, Bogota, Colombia
Carlos A. Jimenez, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX
No potential conflict of interest relevant to this letter was reported.
1. Reis G, Silva EASM, Silva DCM, et al. A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol. August 5, 2021 (https://gatesopenresearch.org/articles/5-117). preprint.
2. Our World in Data. Share of people who completed the initial Covid-19 vaccination protocol (https://ourworldindata.org/grapher/share-people-fully-vaccinated-covid).
Reis et al. conclude that ivermectin is ineffective for the treatment of Covid-19. However, they found the treatment to be safe, with no significant differences in the incidence of adverse events between the patients who received ivermectin and those who received placebo. Those results are confusing and must be balanced with real-world data. It is well known that uncontrolled or inappropriate use of ivermectin can lead to severe or fatal adverse drug reactions such as hypotension, ataxia, or seizures.1 Since the first mention of ivermectin as a potential treatment for Covid-19 in May 2020, a surge in adverse drug reactions to ivermectin has been reported to pharmacovigilance centers. Between 2019 and 2020, there was a 166% increase in spontaneous notifications in VigiBase, the pharmacovigilance database of the World Health Organization.2 Between May 1, 2020, and April 1, 2022, a total of 2944 adverse drug reactions associated with ivermectin were reported: 167 (5.7%) were severe, and there were 46 deaths or life-threatening conditions (1.6%) and 67 hospitalizations (2.3%). In addition to being ineffective, the off-label use of ivermectin may be harmful.
Romain Barus, Ph.D.
Sophie Gautier, Ph.D.
Guillaume Wabont, Pharm.D.
Lille University Hospital, Lille, France

No potential conflict of interest relevant to this letter was reported.
1. Temple C, Hoang R, Hendrickson RG. Toxic effects from ivermectin use associated with prevention and treatment of Covid-19. N Engl J Med 2021;385:21972198.
2. Lindquist M. VigiBase, the WHO Global ICSR Database System: basic facts. Drug Inf J 2008;42:409419.
The authors reply: Furlan suggests that a 37.5% difference in the relative risk of a primary-outcome event was too optimistic. Adaptive trials using interim analyses are not influenced by a priori sample-size estimates. Two new large trials have also shown a lack of treatment benefit of ivermectin.1,2
Mejía and Jimenez inquire about vaccination status. It would be unethical to withhold access to vaccines from participants during a pandemic. By the time our trial was completed, 6% of the patients had received at least one dose of vaccine.
Barus et al. raise safety concerns. We agree that these concerns should be considered.
Gilmar Reis, M.D., Ph.D.
Cardresearch–Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
Edward J. Mills, Ph.D., F.R.C.P.
McMaster University, Hamilton, ON, Canada

Since publication of their article, the authors report no further potential conflict of interest.
1. Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med 2022;387:599610.
2. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group, Naggie S. Ivermectin for treatment of mild-to-moderate COVID-19 in the outpatient setting: a decentralized, placebo-controlled, randomized, platform clinical trial. June 12, 2022 (https://www.medrxiv.org/content/10.1101/2022.06.10.22276252v1). preprint.
December 15, 2022
N Engl J Med 2022; 387:e66
DOI: 10.1056/NEJMc2207995

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