Low dose hydroxychloroquine is associated with lower mortality in COVID-19: a meta-analysis of 26 studies and 44,521 patients

Di Castelnuovo, A.; Costanzo, S.; Cassone, A.; Cauda, R.; de Gaetano, G.; Iacoviello, L.

Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is not well characterized. We conducted two meta-analyses to evaluate the association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients. Methods: Articles were retrieved until October 20th, 2020 by searching in seven databases. Data were combined using the general variance-based method on relative risk estimates. Results: A total of 26 articles were found (N=44,521 COVID-19 patients, including N=7,324 from 4 randomized clinical trials (RCTs)); 10 studies were valuable for analysing the association of HCQ+AZM. Overall, the use of HCQ was associated with 21% lower mortality risk (pooled risk ratio: 0.79, 95%CI: 0.67 to 0.93; high level of heterogeneity: I2=82%, random effects). This association vanished (1.10, 95%CI: 0.99 to 1.23 and 1.10, 95%CI: 0.99 to 1.23) when daily dose >400 mg or total dose >4,400 mg were used, respectively). HCQ+AZM was also associated with 25% lower mortality risk, but uncertainty was large (95%CI: 0.50 to 1.13; P=0.17). No association was apparent when only pooling the 4 RCTs (13.8% of the overall weight; pooled risk ratio: 1.11, 95%CI: 0.99 to 1.24). Conclusions: HCQ use was not associated with either increased or decreased mortality in COVID-19 patients when 4 RCTs only were evaluated, while a 7% to 33% reduced mortality was observed when observational studies were also included. The association was mainly apparent when pooling studies using lower doses of HCQ. These findings can help disentangling the debate on HCQ use in COVID-19.