Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype

Abstract

Background: The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients.

Methods: RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through June 22, 2022, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included all-cause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Meta-analysis included only studies which compared ivermectin to placebo or SOC. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. The protocol was register in PROSPERO (CRD42021257471).

Results: Twenty-five RCTs fulfilled inclusion criteria (n = 6310). Of those, 14 compared ivermectin with placebo, in night ivermectin associated with SOC was compared to SOC and two studies compared ivermectin to an active comparator. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR = 0.76; 95%CI: 0.52-1.11) or mechanical ventilation (RR = 0.74; 95%CI: 0.48-1.16). This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR = 1.07; 95%CI: 0.84-1.35).

Conclusions: The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.

Keywords: COVID-19; Evidence-based medicine; Ivermectin; Meta-analysis; Mortality; Novel coronavirus; SARS-CoV-2; Systematic review; Therapeutics.

Fig. 1

Flow of information through the different phases of the systematic review. The flowchart was adapted from the Preferred Reporting Items for Systematic Review and Meta-Analyses flow chart model

Fig. 2

Forest plots showing the risk of mortality in patients who took ivermectin compared to controls, stratified by placebo or other drugs. RR relative risk. Asterisk indicates that this study had two control groups, one with placebo and the other with another drug. We included in the pooled analysis only the comparator arm which used placebo

Fig. 3

Forest plots showing the risk of mechanical ventilation requirement in patients who took ivermectin compared to controls, stratified by placebo or other drugs. RR relative risk

Fig. 4

Forest plots showing sensitivity analysis of mortality and mechanical ventilation according to the percentage of confirmed COVID-19 patients and risk of bias. RR relative risk