Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials

Pathog Glob Health. 2021 Oct-Dec;115(7-8):456-466. doi: 10.1080/20477724.2021.1936818. Epub 2021 Jun 15.


Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is unclear. We reviewed published literature for evidence of an association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients.Methods: Articles were retrieved until April 29th, 2021 by searching in seven databases. Data were combined using the general-variance-based method.Results: A total of 25 cohort studies (N=41,339 patients) and 11 randomized clinical trials (RCTs; N=8,709) were found. The use of HCQ was not associated with mortality in meta-analysis of RCTs (pooled risk ratio (PRR): 1.08, 95%CI: 0.97-1.20; I2=0%), but it was associated with 20% lower mortality risk (PRR=0.80, 95%CI: 0.69-0.93; I2=80%) in pooling of cohort studies. The negative association with mortality was mainly apparent by pooling cohort studies that used lower doses of HCQ (≤400 mg/day; PRR=0.69, 95%CI: 0.57-0.87). Use of HCQ+AZM (11 studies) was associated with 25% non-statistically significant lower mortality risk (PPR=0.75; 0.51-1.10; P=0.15). Use of HCQ was not associated with severe adverse events (PRR=1.12, 95%CI: 0.88-1.44; I2=0%).Conclusions: HCQ use was not associated with mortality in COVID-19 patients in pooling results from RCTs (high level of certainty of evidence), but it was associated with 20% mortality reduction when findings from observational studies were combined (low level of certainty of evidence). The reduction of mortality was mainly apparent in observational studies where lower doses of HCQ were used. These findings might help disentangling the debate on HCQ use in COVID-19.

Keywords: COVID-19; SARS-COV-2; hydroxychloroquine; mortality.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antiviral Agents / therapeutic use
  • COVID-19 Drug Treatment*
  • Chloroquine
  • Humans
  • Hydroxychloroquine* / adverse effects
  • Randomized Controlled Trials as Topic
  • SARS-CoV-2
  • Treatment Outcome


  • Antiviral Agents
  • Hydroxychloroquine
  • Chloroquine

Grant support

The authors have no funding to report.