RR:C19 Evidence Scale rating by reviewer:
Although repurposing of drugs for the Coronavirus Disease 2019 (COVID-19) has been an important target of clinical research over this pandemic, many of the assessed compounds do not have benefits or these are marginal, including chloroquine, azithromycin, as well as ivermectin. Even more, in the case of asymptomatic infections due to the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the assessment of prophylaxis have been complexed, and so far, up to July 29, 2021, no available drugs are useful for that purpose, including ivermectin.
The study of Morgenstern et al, from Dominican Republic, failed to correctly assess any potential benefit of ivermectin, as prophylaxis in healthcare workers. In the first place, this is an observation study. The efficacy and real impact of drug intervention should be assessed in controlled-randomized clinical trials, to reduce the bias and to obtain a close magnitude of the benefits, control or adjust confounding factors and especially to also assess the safety of interventions. In this case, the study is an observational one, retrospective, and not an experimental study, nor a clinical trial. The study is limited in terms of their sample size, only 326 healthcare workers, not randomly selected, then suffering from selection bias, and additionally mixing different type of healthcare workers, that may have impact on the outcome, as having physicians, nurses, assistants and even administrative workers.
The statistical analyses are some confusing and at the same, although authors indicated that performed a multivariate analysis, there is no clear detail on the confounding variables that may bias the final result.
The figure 4, clearly evidenced that the benefit of using ivermectin, is really marginal. During most of the time up to beyond day 21, intervals overlap, then no showing significant differences. Only at day 28, a significant difference is observed. By the way, for how long would a healthcare worker would be taking ivermectin as prophylaxis? One month? In practical terms, the use prophylaxis, even been effective, is not useful. But, again, a retrospective study cannot confirm it is useful. And despite that, most good quality systematic reviews, including a Cochrane systematic review, published on July 28, 2021 (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015017.pub2/full?highlightAbstract= ivermectin), clearly conclude: “Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.” Additionally, the European Medicines Agency advises against the use of ivermectin for prophylaxis outside RCTs (http://ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19- outside-randomised-clinical-trials).
Authors recognized the limitations of the design, including “Since this is not a randomized study, it does not allow us to clear certain confounding factors, such as the fact that the Ivermectin group could be made up of healthcare personnel more concerned with prevention in general, including greater personal protection measures and more careful use of the PPE, reducing the risks of contracting SARS-CoV-2.” And indeed, the use of PPE should be assessed in such context. Additionally, as author stated “there was no RT-PCR test at the exit of this study, neither in the Ivermectin group nor in the control group. There is the possibility that asymptomatic cases were not detected.”
Authors recommend the “compassionate use of PrEP with Ivermectin 0.2 mg/kg PO per dose weekly, in countries where vaccination has not yet been possible should be considered, for the healthcare personnel, highly exposed to the SARS-CoV-2 infection”, but even in Latin America, most of the healthcare workers, have been vaccinated, then, this recommendation is no longer valid, and instead of recommending prophylaxis, which is clearly needed, widely support not by observational studies, as this one, but instead by good quality phase 3 randomized clinical trials, showing efficacy, and even effectiveness studies, are vaccines. Healthcare workers are a priority for national COVID-19 vaccination plans, and would be extremely rare, in July 29, 2021, even in Latin America, where this study was developed, to found physicians and other healthcare workers not vaccinated, at least by opportunity. Certainly, there is a low, but existing, hesitancy in physicians and healthcare workers for the COVID-19 vaccines.
Controlled randomized studies are not only “desirable” as Morgenstern et al, suggested, but mandatory to assess efficacy, and to have reliable evidence to make any related recommendation. But again, after massive vaccination programs, prioritizing healthcare workers, the use of ivermectin, and in general any other drug, would be not efficacious, nor effective, but even less cost-effective. Vaccines are key for protection of healthcare workers against COVID-19, not drugs with marginal or controversial benefits, as the case of ivermectin.
The manuscript has poor 3-lines and 4-word Introduction, without any reference. With Methods poorly described, and a Discussion barely citing only 6 references. Then, this study has a poor review of literature, and omits relevant systematic reviews, especially those published in the BMJ by the World Health Organization, that also advice against the use of ivermectin.
Since our solicitation of reviews, this preprint has been published in Cureus journal and the link to the published manuscript can be found here.