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Meta-Analysis
. 2021 Jun 21;28(4):e434-e460.
doi: 10.1097/MJT.0000000000001402.

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Andrew Bryant  1 , Theresa A Lawrie  2 , Therese Dowswell  2 , Edmund J Fordham  2 , Scott Mitchell  3 , Sarah R Hill  1 , Tony C Tham  4
Affiliations
Meta-Analysis

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Andrew Bryant et al. Am J Ther. .

Abstract

Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

FIGURE 1.
FIGURE 1.
Study flow diagram from search on 25 April 2021.
FIGURE 2.
FIGURE 2.
Risk-of-bias summary: review authors' judgments about each risk of bias item for each included study.
FIGURE 3.
FIGURE 3.
Death due to any cause.
FIGURE 4.
FIGURE 4.
Death due to any cause, excluding an outlier study responsible for the heterogeneity.
FIGURE 5.
FIGURE 5.
Death due to any cause, excluding high risk-of-bias studies.
FIGURE 6.
FIGURE 6.
Death due to any cause, excluding studies with active controls.
FIGURE 7.
FIGURE 7.
Funnel plot of ivermectin versus control for COVID-19 treatment for all-cause death (subgrouped by severity).
FIGURE 8.
FIGURE 8.
Trial sequential analysis using DL random-effects method with parameter estimates of α = 0.05, β = 0.1, control rate = 7.8%, RRR = 62%, and diversity = 49.5%.
FIGURE 9.
FIGURE 9.
Sensitivity analysis excluding an outlier study responsible for the heterogeneity, showing trial sequential analysis using DL random-effects method with parameter estimates of α = 0.05, β = 0.1, control rate = 7.8%, = 62%, and diversity = 0%.
FIGURE 10.
FIGURE 10.
Sensitivity analysis excluding an outlier study responsible for the heterogeneity, showing trial sequential analysis using Biggerstaff–Tweedie random-effects method with parameter estimates of α = 0.05, β = 0.1, control rate = 7.8%, RRR = 62%, and diversity = 14.2%.
FIGURE 11.
FIGURE 11.
Sensitivity analysis excluding an outlier study responsible for the heterogeneity, showing trial sequential analysis using Sidik–Jonkman random-effects method with parameter estimates of α = 0.05, β = 0.1, control rate = 7.8%, RRR = 62%, and diversity = 71.9%.
FIGURE 12.
FIGURE 12.
Need for mechanical ventilation.
FIGURE 13.
FIGURE 13.
Improvement.
FIGURE 14.
FIGURE 14.
Deterioration.
FIGURE 15.
FIGURE 15.
COVID-19 infection (prophylaxis studies).
See this image and copyright information in PMC

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