Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines
American Journal of Therapeutics: July/August 2021 - Volume 28 - Issue 4
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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Main findings
Twenty-four RCTs (including 3 quasi-RCTs) involving 3406 participants were included, with sample sizes ranging from 24 to 476 participants. Twenty-two trials in treatment and 3 trials in prophylaxis met review inclusion, including the trial of Elgazzar et al, which reported both components. For trials of COVID-19 treatment, 16 evaluated ivermectin among participants with mild to moderate COVID-19 only; 6 trials included patients with severe COVID-19. Most compared ivermectin with placebo or no ivermectin; 3 trials included an active comparator (Table 1). Three RCTs involving 738 participants were included in the prophylaxis trials. Most trials were registered, self-funded, and undertaken by clinicians working in the field. There were no obvious conflicts of interest noted, with the exception of two trials.85,139
Ivermectin treatment versus no ivermectin treatment
Twenty-two trials (2668 participants) contributed data to the comparison ivermectin treatment versus no ivermectin treatment for COVID-19 treatment.
All-cause mortality
Meta-analysis of 15 trials, assessing 2438 participants, found that ivermectin reduced the risk of death by an average of 62% (95% CI 27%–81%) compared with no ivermectin treatment [average RR (aRR) 0.38, 95% CI 0.19 to 0.73; I2 = 49%]; risk of death 2.3% versus 7.8% among hospitalized patients in this analysis, respectively (SoF Table 2 and Figure 3). Much of the heterogeneity was explained by the exclusion of one trial44 in a sensitivity analysis (average RR 0.31, 95% CI 0.17–0.58, n = 2196, I2 = 22%), but because this trial was at low risk of bias, it was retained in the main analysis. The source of heterogeneity may be due to the use of active comparators in the trial design. The results were also robust to sensitivity analyses excluding 2 other studies with an active treatment comparator (average RR 0.41, 95% CI 0.23–0.74, n = 1809, I2 = 8%). The results were also not sensitive to the exclusion of studies that were potentially at higher risk of bias (average RR 0.29, 95% CI 0.10–0.80, 12 studies, n = 2095, I2 = 61%), but in subgroup analysis, it was unclear as to whether a single dose would be sufficient. The effect on reducing deaths was consistent across mild to moderate and severe disease subgroups. Subgrouping data according to inpatient and outpatient trials was not informative because few outpatient studies reported this serious outcome. The conclusions of the primary outcome were also robust to a series of alternative post hoc analyses that explored the impact of numerous trials that reported no deaths in either arm. Extreme sensitivity analyses using a treatment arm continuity correction of between 0.01 and 0.5 did not change the certainty of the evidence judgments (Table 3).
Trial sequential analysis
TSA, using the DL random-effects method, showed that there may have been sufficient evidence accrued before the end of 2020 to show significant benefit of ivermectin over control for all-cause mortality. The cumulative z-curve in Figure 8 crossed the trial sequential monitoring boundaries after reaching the required IS, implying that there is firm evidence for a beneficial effect of ivermectin use over no ivermectin use in mainly hospitalized participants with mild to moderate COVID-19 infection.
Ivermectin prophylaxis versus no ivermectin prophylaxis
Three studies involving 738 participants evaluated ivermectin for COVID-19 prophylaxis among health care workers and COVID-19 contacts. Meta-analysis of these 3 trials, assessing 738 participants, found that ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86% (79%–91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09–0.21; 5.0% vs. 29.6% contracted COVID-19, respectively; low-certainty evidence; downgraded due to study design limitations and few included trials) (Figure 15). In 2 trials involving 538 participants, no severe adverse events were recorded (SoF Table 4).
More:
https://journals.lww.com/americantherapeutics/fulltext/2021/08000/ivermectin_for_prevention_and_treatment_of.7.aspx
