Ivermectin: Cochrane’s most talked about review so far, ever. Why?

Ivermectin: Cochrane’s most talked about review so far, ever. Why?

In this author interview with Stephanie Weibel and Maria Popp, we find out more about their Cochrane review, Ivermectin for treating and preventing COVID-19. The review currently has an Altmetric Attention Score of more than 7000, which makes it the most talked-about review in the history of the Cochrane Library.

Briefly, what is Ivermectin?
Ivermectin is a medicine used to kill parasites, such as intestinal worms (helminths) in animals or scabies in humans. It is inexpensive and it is widely used in regions of the world where parasitic infestations are common, such as in parts of Asia and South America. Ivermectin has few unwanted effects at low doses.

Before the COVID-19 pandemic, some laboratory studies had shown that ivermectin could slow down the reproduction of some viruses, such as the dengue fever virus. In April 2020, similar laboratory tests suggested a weak effect on slowing reproduction of the virus that causes COVID-19, SARS-CoV-2. During 2020, more than 30 clinical studies were started to test ivermectin as a treatment for COVID-19 in humans. Several of the small, early studies have since completed. Some of these studies suggested higher survival rates with ivermectin. This led some advocacy groups to lobby for the widespread introduction of ivermectin in the fight against COVID-19 across the world. However, the true effect of ivermectin on COVID-19 is a matter of ongoing debate.

Tell us briefly what did your Cochrane review find?
We searched for randomized studies that investigated ivermectin to prevent or treat COVID-19 in humans. The studies had to compare ivermectin to placebo, no treatment, usual care or a treatment that was known to work to some extent for COVID-19. In studies that looked at treatment with ivermectin, people had to have laboratory-test confirmed COVID-19 and receive treatment in hospital or as outpatients. We excluded studies that compared ivermectin to medicines that we know do not work, such as hydroxychloroquine, or medicines that we don’t know to be effective against COVID-19.

We found one study for the prevention of COVID-19 that had recruited 156 people in Egypt. We found 13 studies for treatment of COVID-19 that included approximately 1500 people who had moderate COVID-19 and were being treated in hospital or mild COVID-19 and were being treated as outpatients. The studies used different doses of ivermectin and different durations of treatment. We also found 31 ongoing studies, and another 18 that are complete but not yet published or where we have asked the study authors for more information before we can decide whether to include them.

Our main finding is that there is no evidence to support the use of ivermectin either for preventing or treating COVID-19. Because of a lack of good-quality evidence, we do not know whether ivermectin administered in hospital or in an outpatient setting leads to more or fewer deaths after one month when compared with a placebo or usual care.

Further, we do not know whether it improves or worsens patients’ condition, increases or decreases unwanted side effects, or leads to more or fewer negative COVID-19 tests 7 days after treatment. Likewise, we do not know whether ivermectin prevents COVID-19 infection or reduces the number of deaths after high-risk exposure to the SARS-CoV-2 virus.

The current lack of good-quality evidence on the effects of ivermectin is because the studies that we found are mainly small, with limitations in their design, conduct and reporting. The current evidence does not support using ivermectin for treating or preventing COVID-19 outside of well-designed randomized clinical studies.

The review has an Altmetric Attention Score of more than 7000 and is currently the top scoring Cochrane review of all time by this measure.  Why do you think it has provoked so much interest?
The interest in this review presumably reflects the ongoing controversy around the benefit of ivermectin for COVID-19. Some advocacy groups have drawn premature conclusions from small, early trials that suggested large reductions in death. They continuously lobby for the widespread introduction of ivermectin across the world for COVID-19. Based on their advice, health officials and governments of several countries have recommended the use of ivermectin for COVID-19 treatment and prevention.

Other institutions, such as the World Health Organization and the European Medicines Agency, currently state that the evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized studies. Since the work of Cochrane is internationally accepted and considered as independent and of the highest trustworthiness, many people have awaited the Cochrane review on ivermectin to get a clearer, unbiased picture of the current evidence.

We understand that some people are desperate for an inexpensive and widely available solution to the pandemic. This is especially true for health systems struggling to cope with low  vaccination rates and severely affected by third or fourth waves of infection. However, even in a health crisis it remains unethical to recommend the widespread use of a drug that has not been proven to be effective under controlled conditions.

Even with the best of intentions, the idea of prescribing a drug simply because it has not been shown to be ineffective goes against medicine’s guiding principle to ‘do no harm’. This principle should not be ignored, especially when so much ongoing research to address the question of benefit and harm for ivermectin is being carried out in this pandemic. The results from the available clinical studies carried out so far cannot confirm ivermectin’s widely advertised benefits. In other words, we don't know whether ivermectin is helpful or not in the fight against COVID-19. Every drug has harms. Without proven benefit, the weight of harm is even greater. Therefore, ivermectin should currently only be used and examined in randomized controlled studies.

Even with the best of intentions, the idea of prescribing a drug simply because it has not been shown to be ineffective goes against medicine’s guiding principle to ‘do no harm’.

There is strong regional interest in this review, why?
We can only suspect that the interest in any promising treatments or preventive measures will be stronger in regions where there is a new peak of infections. This interest may be stronger in countries with low vaccination rates or a large number of opponents to vaccination.

How has the review informed/helped with the debate about ivermectin as a treatment?
There is a lot of incorrect and misleading information available online about ivermectin. There are many meta-analyses and systematic reviews, some of which have shown extreme mortality benefits. However, unlike our Cochrane review, they have been more inclusive with regard to the studies that are available, and not been conducted using rigorous standards.

We set out to provide a reliable and unbiased summary of evidence for the work of clinical guideline committees and health officials. Before conducting this Cochrane review, we had no prior belief about whether ivermectin was effective , we simply wanted to ensure that clinicians, politicians, and the overall population could base decisions on the most current and trustworthy evidence available. By thoroughly examining and analysing the published studies, we showed that not all studies on which the ivermectin hype is based are actually suitable for investigating the effects of this medicine. Most of the eligible studies had flawed study designs and produced low-quality evidence. Based on this very small pool of limited-quality studies, we can only conclude that ivermectin cannot be considered a ‘miracle drug’ at this point. We hope that the information our review provides reaches clinical, scientific, policy and lay audiences so that they are aware of the uncertainty around the effects of ivermectin in COVID 19.

And what next?
We are continually following the progress of ongoing studies and searching for new study publications of ivermectin. We expect that the 31 ongoing studies and 18 awaiting classification will feature in future versions of this review. Currently, there is an urgent need for good-quality evidence based on randomized controlled studies with appropriate randomization procedures, comparability of study arms and, preferably, a double-blind design.

We are waiting until the accumulating evidence leads to a change in our conclusions before republishing the review. This could involve a change in the results or certainty (for example, the GRADE rating) of one or more prioritized outcomes, or new settings, populations, interventions, comparisons, or outcomes studied.

However, if we consider that there is a strong case for an updated review without an anticipated change to the strength of the evidence (for example, due to heightened interest in this from a policy-maker) we may consider updating the review. We are reviewing the review scope and methods monthly, or more frequently if appropriate, in light of potential changes in COVID-19 research, such as when additional comparisons, interventions, subgroups, outcomes, or new review methods become available.

Tuesday, September 14, 2021