To our knowledge, this is the most comprehensive systematic review and meta-analysis of the efficacy of ivermectin among COVID-19 patients in peer-reviewed randomized clinical trials. Our aim was to appraise potential efficacy of ivermectin compared to placebo or SOC. Although our preliminary results suggest that ivermectin may reduce mortality, it is crucial to highlight that when trials with a high risk of bias are excluded, ivermectin results in a non-significant decrease in mortality. We found that in comparison with placebo or SOC, using ivermectin did not significantly change our outcomes, including progression to severe disease, negative RT-PCR, recovery, duration of hospitalization, time to negative RT-PCR, and viral load. Although no risk of publication bias was observed in primary outcomes, it is noteworthy that, based on the Cochrane handbook's suggestions, the power of these tests is too low for less than 10 studies to be included. We also identified that some registered RCTs finished without reporting results and so there may be publication bias. The overall certainty of evidence suggest that more research is needed and final conclusions should not be drawn based on the current findings and there is insufficient evidence to recommend it for therapeutic purposes in the context of health care at this time. To determine the impact of individual studies on the pooled estimate, a leave-one-out analysis was performed on primary outcomes. It was observed that omitting one study (Lim et al. [19]) considerably changed the pooled estimate of progression to severe disease. Therefore, further investigation into the results of this recently published study is necessary. Among 19 randomized trials included; 10 studies concluded that ivermectin may have a possible effect in treating COVID-19. To address the conflicts and clear up the gray area; we precisely assessed the risk of bias of studies using the Cochrane risk-of-bias tool for randomized trials. Of all included studies in our review, 9 had a high risk of bias, and 2 had moderate risk of bias. This level of bias raises concerns regarding the accuracy of the results and quality of the studies and should be noted to prevent wrong conclusions. Any decision made upon the findings of these studies should be carefully appraised before taking it into action to avoid possible complications. A study by Shakhsi-Niaee et al. [39] declared a significant reduction in mortality rate among ivermectin groups. Howerever, we do not consider it as a valid source of information due to the low quality of evidence and unclear or high risk of bias in multiple domains [15, 48, 49]. In addition, major sources of concern have been raised about this study [39], which may lead to retraction of this study in the future [15, 50].
The first systematic review published on this topic by Padhy et al.[51] claimed a significant reduction in all-cause mortality and significant clinical improvement although stating a high risk of bias for all studies and very-low quality of evidence. Cruciani et al.[52] published a systematic review with the primary outcome of overall mortality and progression to severe disease including 11 RCTs with 2436 participants. They concluded that when the analysis was limited to patients with baseline severe disease, ivermectin significantly decreased mortality compared to mild to moderate disease. However, they stated that the quality of evidence was very low due to the risk of bias. Kow et al. [53] concluded a preliminary positive effect on reduction of all-cause mortality by reviewing 6 studies, although they declared a high risk of bias for 4 out 6 studies. Roman et al. [54] published a systematic review and meta-analysis with primary outcomes such as all-cause mortality, length of hospital stay, and AEs and secondary outcomes of SARS-CoV-2 clearance on respiratory samples, clinical improvement, need for mechanical ventilation, and severe AEs. Their quality assessment demonstrated a high risk of bias among 8 out of 10 studies, and they reported a low or very low quality of evidence for all outcomes. They found that ivermectin did not reduce primary or secondary outcomes in patients with mostly mild disease and claimed that ivermectin is not a viable option for treating COVID-19 and should be used only in the context of clinical trials. Deng et al. [55] published a systematic review which excluded retracted studies and articles withdrawn from preprint servers. They concluded that based on available evidence, ivermectin does not significantly alter the outcomes of the disease including viral clearance, duration of hospitalization, mortality and incidence of mechanical ventilation. Except for mortality, their findings were consistent with our study in terms of the efficaciousness of ivermectin in the setting of COVID-19. The authors of a retracted meta-analysis [23] recently provided an update on their prior conclusions, which were based on separating the included studies regarding the quality of the trials as determined by the Cochrane Risk of Bias tool. The authors included 12 trials (including Elgazzar et al.'s retracted study) to investigate the possible role of study quality in pooled results. Their findings are in line with our study, which demonstrates that studies with a high risk of bias or probable medical fraud were necessary to find a substantial positive effect of ivermectin on survival [56].
This review has strengths in several aspects. Our systematic search protocol was designed for obtaining comprehensive and up-to-date results from 6 databases. That helps to achieve a more accurate estimation of the effect of ivermectin. All of the studies included in our review are peer-reviewed RCTs meaning that we reviewed the highest level of evidence available to avoid deviation from the mainstream of evidence. We observed any supplementary data of the studies to maximize the amount of analyzed data and minimize errors. By excluding studies with questionable methodologies and inadequate follow-up periods, we avoided potential partiality. The evaluation of each outcome was based on the information obtained from at least 2 studies, and the certainty of the evidence was assessed for all reported outcomes. We also faced some limitations. Most of the studies included a small number of participants and presented low to moderate symptoms. Therefore, the assessment of patients with moderate to severe disease has remained a question. Risk of bias was assessed high for several studies, and the quality of evidence for most of the outcomes is low, hence our concern about the applicability of results approving ivermectin efficiency and safety. The majority of the research available did not elaborately elucidate their methodologies. In addition, number of studies had the standard of care or other co-interventions plus ivermectin as intervention and different type of comparators as control. This may affect the accuracy of findings of studies as a proper comparison may not be possible under these circumstances. According to the limitations mentioned above, further research involving large-scale RCTs with a broad spectrum of disease severity and longer follow-up periods is warranted in order to provide adequate evidence regarding the safety and efficacy of ivermectin use for treatment of COVID-19.
Recurrent surges in the mortality rates and economic consequences of the COVID-19 pandemic led to a distressing situation for societies. Accompanied by skepticism towards new drugs and vaccines and misinformation spread by media, this situation resulted in people making efforts in order to seek any accessible treatment regardless of whether health authorities approved it as a safe and efficacious treatment against the disease. One of these drugs was ivermectin, a well-known drug which has been widely used as an anti-parasitic drug for a long time. The idea of overcoming a pandemic with a previously used, widely available and low-cost drug made it challenging for scientists to prevent its public use. Cases were reported of individuals taking highly concentrated forms of this drug formulated for animals such as horses or prescriptions from physicians for treatment or prevention of COVID-19, resulting in hospitalization or ICU admission [57]. The lack of sufficient and concrete scientific evidence regarding the safety and efficacy of ivermectin was also a key factor in throwing the usage of this drug into question. Recent articles were arguing that studies evaluating the effect of ivermectin are biased and that there is a possibility of fraudulent manipulations in the methodology of RCTs [58, 59]. To overcome this predicament, it is of crucial importance to gather the already-existing evidence from relevant studies and meticulously evaluate the outcomes of this drug. Our study was designed to impartially address this issue to provide a clear perspective on the subject of ivermectin for clinicians and researchers. In the concept of COVID-19, useful lessons were learned from ivermectin for researching future potential therapeutic targets during a pandemic, which are critical for both researchers and clinicians. In addition, we identified four possible domains that must be evaluated by researchers whenever a new medication is proposed (Fig. 7).
Fig. 7Recommendations for researchers and meta-analysis authors for assessing the efficacy of future proposed medications during a pandemic in light of what we've learnt from ivermectin
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The quality of included studies in meta-analyses affects the accuracy of the results. As there are controversies regarding ivermectin, we assessed the quality of studies to minimize the misconceptions. Many meta-analyses were conducted based on results obtained from retracted RCTs or those with high ROB without addressing their impact sufficiently. This leads to the spread of misinformation and the formation of low-quality evidence. The exclusion of studies with high or moderate risk of bias from our analyses on primary outcomes resulted in a significant difference in pooled effect results, suggesting that studies with high ROB play a major role in the current confusing state regarding the efficacy of this drug. To avoid this situation, the quality of included trials should be carefully evaluated before concluding that the drug is effective in pandemic situations.
To date, a number of systematic reviews have been published on this subject. However, most of them include studies by Elgazzar et al. [], or Samaha et al. [60] which now have been retracted from the databases or preprint studies with no peer-review process. Through our manual MEDLINE search, we identified several systematic reviews and meta-analyses based on the results of these fraught studies, reporting an independently significant effect of this drug in their analyses which results in confusion in both clinicians and patients [16,17,18, 61,62,63,64]. We highly advise systematic review and meta-analyses authors to keep themselves informed even after their work has been published in order to keep their findings updated and avoid producing misleading information. This is particularly noticeable in the context of an outbreak such as COVID-19, where there is a pressing need for demonstrating whether novel therapy options are clinically beneficial, and a plethora of low-quality and dubious research are widely available due to the pressing demand.
There have been several websites providing real time meta-analyses of ivermectin studies (https://ivmmeta.com/#top, https://c19ivermectin.com/) reporting its significant beneficial effect based on non-peer-reviewed low quality trials. They also lack protocol registration including methodologies, search strategies, inclusion criteria, quality assessment of the included studies, and the certainty of the evidence of the pooled estimates [14]. This is significant since the majority of individuals can find these websites by searching "ivermectin meta-analysis," which might cause misunderstandings.
Funding source of the studies and its association with the reported results raises concerns regarding the validity of results of the studies since conflicts of interest may affect the outcome of the trials. There are some studies suggesting significant association between the source of funding and outcome of the studies [65, 66]. In these cases, researches may be subject to methodological bias in favor of effectiveness of the intervention, reporting positive effects more frequently. Therefore, it is of great importance to ensure that the results of the study are not influenced by the funding source, and the objectivity of the study is preserved. [67] We performed a subgroup analysis comparing studies that provided information regarding their funding source with studies that did not mention theirs. For most of the outcomes, there was a non-significant difference between subgroups in terms of reporting the efficacy of ivermectin, however, a slight difference was observed in mortality rates. In such controversial state with possible conflicts of interest, it is crucial to carefully consider the funding source of the studies so as to reduce the probability of the study results to be affected by such confounding factors. This assurance could be achieved by journals and editors emphasizing the importance of this issue and demanding authors to provide sufficient information about their funding.
There are some concerns regarding the misprescription of this drug that should be addressed [9, 10, 68]. Ivermectin is a currently used antiparasitic drug with proven efficacy against several diseases such as scabies and filariasis, thus shifting its use towards the treatment of COVID-19 will result in the diversion of limited health-care sources, leaving us deprived of supplies necessary for combating burden of tropical diseases including the two mentioned above [58]. Furthermore, the minimum concentration needed to obtain the anti-SARS-CoV-2 effect of ivermectin is 5 μM, considerably higher than 0.28 μM, the maximum plasma concentration achieved in vivo with a dose of approximately 1700 μg/kg (about nine times the dosificaition approved by FDA) [14]. In January 2022, a study by Buonfrate et al. investigated the efficacy and safety of high-dose ivermectin in the early treatment of COVID-19 patients [20]. The authors claimed that in all RCTs to date, they have utilized the highest dose of ivermectin in the concept of a clinical trial. Their treatment arm included ivermectin single dose 600 μg/kg, and 1200 μg/kg. However, they reported a non-significant difference between ivermectin and placebo in their primary outcome, which was viral reduction. It is noteworthy that they have also seen some adverse events in both the 600 g/kg and 1200 g/kg groups, such as photophobia, visual impairment, abdominal pain, nausea, and fatigue. This could suggest that the medicine is unsafe at higher doses.
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