High-cited favorable studies for COVID-19 treatments ineffective in large trials

OBJECTIVES: To evaluate for coronavirus disease 2019 treatments without benefits in subsequent large randomized controlled trials (RCTs) how many of their most-cited clinical studies had declared favorable results. STUDY DESIGN AND SETTING: Scopus searches (December 23, 2021) identified articles on lopinavir-ritonavir, hydroxychloroquine, azithromycin, remdesivir, convalescent plasma, colchicine, or interferon (index interventions) that represented clinical trials and had >150 citations. Their conclusions were correlated with study design features. The 10 most recent citations for the most-cited article on each index intervention were examined on whether they were critical to the highly cited study. Altmetric scores were also obtained. RESULTS: Forty eligible articles of clinical studies had received >150 citations. Twenty of forty (50%) had favorable conclusions and four were equivocal. Highly cited articles with favorable conclusions were rarely RCTs (3/20), although those without favorable conclusions were mostly RCTs (15/20, P = 0.0003). Only one RCT with favorable conclusions had >160 patients. Citation counts correlated strongly with Altmetric scores, especially news items. Only nine (15%) of 60 recent citations to the most highly cited studies with favorable or equivocal conclusions were critical. CONCLUSION: Many clinical studies with favorable conclusions for largely ineffective coronavirus disease 2019 treatments are uncritically heavily cited and disseminated. Early observational studies and small randomized trials may cause spurious claims of effectiveness that get perpetuated.