An evaluation of co-use of chloroquine or hydroxychloroquine plus azithromycin on cardiac outcomes: A pharmacoepidemiological study to inform use during the COVID19 pandemic

Res Social Adm Pharm. 2021 Jan;17(1):2012-2017. doi: 10.1016/j.sapharm.2020.04.031. Epub 2020 Apr 30.


Background: Chloroquine or hydroxychloroquine (chloroquine) plus azithromycin is considered as therapy for COVID-19. With benefit evaluations underway, safety concerns due to potential additive effects on QTc prolongation should be addressed.

Objective: We compared risk of cardiac adverse events between combinations of chloroquine and azithromycin and chloroquine and amoxicillin.

Methods: We conducted a retrospective cohort study using the IBM MarketScan Commercial Claims and Medicare Supplemental Databases, 2005-2018. We included autoimmune disease patients aged ≥18 years initiating azithromycin or amoxicillin for ≥5 days during chloroquine treatment. Patients had continuous insurance coverage ≥6 months before combination use until 5 days thereafter or inpatient death. Two outcomes were sudden cardiac arrest/ventricular arrhythmias (SCA/VA) and cardiac symptoms. We followed patients for up to 5 days to estimate hazard ratios (HR). Covariates were adjusted using stabilized inverse probability treatment weighting.

Results: We identified two SVC/VA events among >145,000 combination users. The adjusted incidence of cardiac symptoms among azithromycin and amoxicillin users was 276 vs 254 per 10,000 person-years with an adjusted HR of 1.10 (95%CI, 0.62-1.95).

Conclusion: Combination use of chloroquine and azithromycin at routine doses did not show pronounced increases in arrhythmias in this real-world population, though small sample size and outcome rates limit conclusions.

Keywords: CI, confidence interval; COPD, Chronic obstructive pulmonary disease; COVID19; Cardiac events; Chloroquine; FDA, U.S. Food & Drug Administration; HR, hazard ratio; Hydroxychloroquine; QTc prolongation; SCA/VA, sudden cardiac arrest and ventricular arrhythmias; SIPTW, Standardized inverse probability treatment weighting.

Publication types

  • Evaluation Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Azithromycin / administration & dosage*
  • Azithromycin / adverse effects
  • COVID-19 / drug therapy
  • COVID-19 / epidemiology*
  • Chloroquine / administration & dosage*
  • Chloroquine / adverse effects
  • Cohort Studies
  • Drug Therapy, Combination / adverse effects
  • Female
  • Heart Diseases / chemically induced
  • Heart Diseases / epidemiology*
  • Humans
  • Hydroxychloroquine / administration & dosage*
  • Hydroxychloroquine / adverse effects
  • Male
  • Middle Aged
  • Pharmacoepidemiology / methods*
  • Retrospective Studies
  • Risk Factors
  • Young Adult


  • Hydroxychloroquine
  • Azithromycin
  • Chloroquine