Safety cannot justify the use of ivermectin for the management of COVID-19 Free

The coronavirus disease 2019 (COVID-19) pandemic represents an unprecedented public health challenge for countries around the world. The substantial severity and transmissivity of SARS-CoV-2 have led to a global race in the search for a cure to the infectious disease. Within the past 2 years, a considerable amount of research has been published on the prophylaxis, diagnosis and management of COVID-19. However, most of these reports have been anecdotal, observational or non-peer-reviewed.¹ Many COVID-related randomized controlled trials (RCTs) are also rushed, small and/or limited in their validity and reliability.^2,3 These problematic studies, combined with the rapid pace of the pandemic, greatly threaten the principles of evidence-based medicine (EBM) which have become ingrained in our modern healthcare. This is especially evident in the assessment of recent controversial treatments, namely ivermectin.

Following the publication of our recent systematic review on the use of ivermectin in COVID-19 patients,⁴ we have received several inquiries regarding our findings which showed that ivermectin did not significantly increase the number of adverse events in trial settings. Many readers have suggested that the good safety profile identified in our study supports the use of high-dose ivermectin (such as the ∼1700 μg/kg dose used in the previous studies⁵), which they hypothesized may yield a significant treatment effect compared to the low doses included in our review. Readers also expressed a general sentiment similar to that of ‘if ivermectin is safe, then there is no harm in trying it in patients’.

While well-intentioned, these propositions do not align with the foundational principles of EBM, which emphasizes the ‘conscientious, explicit, judicious and reasonable use of modern, best evidence in making decisions about the care of individual patients’.⁶ As discussed in our review, there is a paucity of valid evidence supporting the efficacy of ivermectin. The in vitro study by Caly et al.,⁷ which lent credibility to proponents of ivermectin, used a high concentration of ivermectin that cannot be achieved in vivo with even the highest dose of ivermectin ever prescribed.⁸ The first large-scale RCT supporting the clinical use of ivermectin by Elgazzar et al.⁹ was disseminated as a pre-print and subsequently retracted. Published meta-analyses that demonstrated efficacious outcomes associated with ivermectin have also relied heavily on trial data from non-peer-reviewed sources and did not employ rigorous methodologies.^10,11 Additionally, a recent letter has stated that current reviews and RCTs are not adequately powered to identify any meaningful improvements in patient outcomes. Specifically, the authors noted that trials with over 2000 patients per arm would be needed to confidently establish the efficacy of ivermectin in reducing mortality,¹² which is considerably greater than the hundreds of patients included in recent reviews and RCTs. Thus, optimistic results from small trials and reviews should be viewed with skepticism until their findings can be confirmed in adequately powered studies.

Notwithstanding a lack of clear evidence on the efficacy of ivermectin, it is apparent that many clinicians are still prescribing ivermectin for the treatment or prophylaxis of COVID-19. A study published in December of 2021 found that the number of prescriptions for human-use ivermectin is 24 times as high as the number before the pandemic, with the number of prescriptions quadrupling in a span of 1 month from July to August of 2021.¹³ These findings are alarming, as off-label prescriptions of ivermectin can place patients at an unnecessary risk for toxicities relating to the drug despite results from our review demonstrating that ivermectin is safe in controlled settings. Although rare, ivermectin has been previously associated with serious side effects such as neurological adverse events and toxidermia.^14–16 The number of ivermectin-related calls to poison control centers around the USA has also increased in 2021 with reports of varied toxic effects from ivermectin use.¹³ While we have a good understanding of ivermectin’s safety profile from early clinical trials and small pharmacosurveillance studies, it is unclear whether this profile will carry through to real-world settings with hundreds of thousands of COVID-19 patients, or at dosages higher than those approved by the U.S. Food and Drug Administration (FDA).

Apart from drug toxicities, the widespread clinical use of ivermectin can result in other unintended consequences. For example, normalization of ivermectin use and misleading public statements may sway public opinions to view ivermectin trials as obsolete, which can dissuade patients from participating in these trials and make it more difficult to produce high-quality evidence assessing the efficacy of ivermectin.¹⁷ A sudden increase in the demands of ivermectin may also cause a supply shortage (as was the case with hydroxychloroquine).¹⁸ This may force the public to turn to veterinary ivermectin products, which are often made with higher concentrations (considering they are often made for larger animals) and inactive ingredients that may not be approved for human consumption.¹⁹ Lastly, clinicians’ reliance on ivermectin may distract them from investigating and prescribing more efficacious, evidence-based treatment regimens. This can result in the patients missing the optimal period to prevent disease progression during the early stages of symptomatic infection, resulting in worse outcomes.

During this time of great uncertainty, it is understandable for clinicians to feel like ‘we must do something for our patients.’ The rapid pace of the pandemic, in contrast with the slow progression of clinical trials, makes it appealing for healthcare workers and policymakers to adopt untested treatments based on anecdotal or flawed evidence. However, these actions deviate from the principles of EBM, thereby potentially jeopardizing patients’ safety and fostering the practice of more opinion-based, non-evidence-based care.

In our original review, we specified that ivermectin’s safety profile permits its continued use in controlled, clinical trial settings to further elucidate its role in COVID-19 management. Our conclusion reflects our belief that further RCTs are needed to assess the potential efficacy of this drug; however, until adequately powered and well-designed RCTs can demonstrate significant benefits associated with the use of ivermectin, there is no justification for its use in clinical care settings for COVID-19 treatment.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest. None declared.

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