An Updated Systematic Review and Meta-Analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation, Adverse effects and other Clinical Outcomes of Ivermectin Treatment in COVID-19 Patients

Abstract

Importance/BackgroundDespite the global healthcare’s exhaustive efforts to treat COVID-19, we still do not have an effective cure for it. Repurposing Ivermectin, a known antiparasitic agent, for treating COVID-19 has demonstrated positive results in several studies. We aim to evaluate the benefit and risk of Ivermectin in COVID-19.MethodsWe conducted a systematic search for full-text manuscripts published from February 1, 2020 to March 27, 2021 that focused on efficacy and safety of Ivermectin therapy against COVID-19. The primary outcomes were overall mortality, need for intensive care unit (ICU) admission; secondary outcomes were - adverse effects, need for mechanical ventilation. Random-effects models were used for all analysis.ResultsWe included a total of 38 studies (n=15,002) in the qualitative analysis (Mortality N=28, ICU admission= 8, Mechanical Ventilation= 10, Adverse events=28) and out of these, 30 studies (n=11,291) were included in the quantitative analysis (Mortality N=22, ICU admission= 5, Mechanical Ventilation= 9, Adverse events=17). In the mortality meta-analysis, odds of death were lower in the Ivermectin-arm compared to the non-Ivermectin arm. (OR 0.39, 95% CI 0.22-0.70; I2=81%). Subgroup analysis of 12 randomized controlled trials with severity-based data showed mortality benefit overall (OR 0.33, 95% CI 0.15-0.72; I2=53%) and in the mild/moderate sub-group (OR 0.10, 95% CI 0.03-0.33; I2=0%). Benefit of Ivermectin in decreasing; the need for ICU admission (OR 0.48, 95% CI 0.17-1.37; I2=59%) and mechanical ventilation (OR 0.64, 95% CI 0.40-1.04; I2=17%) was not significant. The quantitative analysis of adverse effects with Ivermectin use was inconclusive (OR 0.92, 95% CI 0.64-1.33; I2=14%).ConclusionOur meta-analysis suggests that Ivermectin could be an effective adjuvant therapy in reducing mortality, particularly in patients with mild-moderate clinical presentation of COVID-19. Trends of decreased need for ICU admissions and mechanical ventilation were observed but were not significant. The analysis for adverse effects was inconclusive.HighlightsWhat We Already Know about This TopicCOVID-19 is an ongoing global pandemic, for which Ivermectin has been tried on a therapeutic and prophylactic basis.Results from several clinical trials and observational studies suggest that Ivermectin may improve survival and clinical outcomes with a good safety profile when compared with other treatments; however, the current evidence is limited.What This Article Tells Us That Is NewThis systematic review and meta-analysis provide a summary of the latest literature on the efficacy and safety of Ivermectin use for COVID-19.Based on our quantitative and qualitative analysis, we found that Ivermectin may be a potentially useful adjuvant therapy in reducing mortality, the need for ICU admissions and mechanical ventilation in COVID-19 patients.

Ivermectin for COVID-19 in Peru: 14-fold reduction in nationwide excess deaths, p<0.002 for effect by state, then 13-fold increase after ivermectin use restricted

“…54 Among the most recent and comprehensive of the eight meta-analyses noted above reported a pooled total of 31 deaths among 1,101 subjects in IVM treatment groups and 91 deaths among 1,064 controls from 11 RCTs, amounting to a 67% reduction in mortality, with a statistical significance for overall effect of p=0.005. 46 Two animal studies of IVM treatment at low human-equivalent doses, one for SARS-CoV-2 in golden hamsters 55 and another for a related betacoronavirus (MHV-A59) in mice, 56 found major, highly statistically significant treatment benefits, consistent with those found in the RCTs noted above. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, as reviewed, 57,58 is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.…”

“…controls achieved in RCT's for IVM treatment of COVID-19. 46 The system of large randomized clinical trials as a requirement for new drug approvals has served public health well. These allow screening for dangerous side effects and can determine if important therapeutic gains obtained in relatively small percentages of subjects persist under more rigorous scrutiny.…”

“…3 with more than 20 randomized clinical trials (RCTs) conducted for such IVM treatments. 3,43,44 Seven of eight meta-analyses of these IVM treatment RCTs reporting in 2021, all done using Cochrane analysis methodology, found significant [44][45][46][47][48] or possible 49,50 indications of IVM efficacy, with a mean 0.33 relative risk (RR) of mortality vs. controls. The eighth meta-analyses reported no efficacy for IVM, specifying a value of RR=1.1 for mortality, 51 but corrected that to RR=0.37 (a 63% mortality reduction) in a revised version after fixing switched treatment and control values for one key RCT.…”

Vaccine Development Throughout History

“…Fever, myalgia, cough, dyspnea, and flulike symptoms are the most frequent symptoms of COVID-19, which predominantly affects the respiratory system. From asymptomatic infection to respiratory failure, multi-organ dysfunction, and death, the COVID-19 has a wide spectrum of clinical presentations [33]. COVID-19 has been linked to harmful effects on other body systems in addition to the respiratory system [34][35][36][37][38].…”

Identification and Development of Therapeutics for COVID-19

“…Hope for the potential of ivermectin peaked with the release of a preprint reporting results of a multicenter, double-blind RCT where a 4-day course of ivermectin was associated with clinical improvement and earlier viral clearance in 400 symptomatic patients and 200 close contacts ( 124 ); however, concerns were raised about both the integrity of the data and the paper itself ( 125 , 126 ), and this study was removed by the preprint server Research Square ( 127 ). A similarly sized RCT suggested no effect on the duration of symptoms among 400 patients split evenly across the intervention and control arms ( 128 ), and although meta-analyses have reported both null ( 129 , 130 ) and beneficial ( 131 – 138 ) effects of ivermectin on COVID-19 outcomes, the certainty is likely to be low ( 132 ). These findings are potentially biased by a small number of low-quality studies, including the preprint that has been taken down ( 139 ), and the authors of one ( 140 ) have issued a notice ( 131 ) that they will revise their study with the withdrawn study removed.…”