Bias as a source of inconsistency in ivermectin trials for COVID-19: A systematic review (preprint)

ABSTRACT

Background and purposeThe objective of this systematic review is to summarize the effects of ivermectin for the prevention and treatment of patients with COVID-19 and to assess inconsistencies in results from individual studies with focus on risk of bias due to methodological limitations. Evidence reviewWe searched the L.OVE platform through July 6, 2021 and included randomized trials (RCTs) comparing ivermectin to standard or other active treatments. We conducted random-effects pairwise meta-analysis, assessed the certainty of evidence using the GRADE approach and performed sensitivity analysis excluding trials with risk of bias. ResultsWe included 29 RCTs which enrolled 5592 cases. Overall, the certainty of the evidence was very low to low. Compared to standard of care, ivermectin may reduce mortality, may increase symptom resolution or improvement, may increase viral clearance, may reduce infections in exposed individuals and may decrease hospitalizations (Risk difference (RD) 21 fewer per 1000, 95%CI 35 fewer to 4 more). However, after excluding trials classified as "high risk" or "some concerns" in the risk of bias assessment, most estimates of effect changed substantially Compared to standard of care, low certainty evidence suggests that ivermectin may not significantly reduce mortality (RD 7 fewer per 1000, 95%CI 77 fewer to 108 more) nor mechanical ventilation (RD 6 more per 1000, 95%CI 43 fewer to 86 more), and moderate certainty evidence shows that it probably does not significantly increase symptom resolution or improvement (RD 14 more per 1000, 95%CI 29 fewer to 71 more) nor viral clearance (RD 12 fewer per 1000, 95%CI 84 fewer to 76 more). It is uncertain if ivermectin increases or decreases severe adverse events and symptomatic infections in exposed individuals. Conclusions and RelevanceIvermectin may not improve clinically important outcomes in patients with COVID-19 and its effects as a prophylactic intervention in exposed individuals are uncertain. Previous reports concluding significant benefits associated with ivermectin are based on potentially biased results reported by studies with substantial methodological limitations. Further research is needed.