Risk of Out-of-Hospital Sudden Cardiac Death in Users of Domperidone, Proton Pump Inhibitors, or Metoclopramide: A Population-Based Nested Case-Control Study

INTRODUCTION Epidemiological studies have linked domperidone use with serious cardiac arrhythmias, including sudden cardiac death, but data on age, dose, and duration of use are limited. OBJECTIVES The aim of this study was to assess the risk of out-of-hospital sudden cardiac death associated with domperidone use versus proton pump inhibitors (PPIs), metoclopramide, or non-use of all three medications, and to evaluate the risk of sudden cardiac death in relation to age and domperidone dose. METHODS This was a population-based case-control study nested in a cohort of subjects aged ≥2 years in the Clinical Practice Research Datalink with one or more prescriptions for domperidone, any PPI, or metoclopramide from 2005 to 2011. Out-of-hospital sudden cardiac death was assessed by linkage with Hospital Episode Statistics and death certificates. Controls were matched on age, sex, and medical practice. The risk of sudden cardiac death in domperidone users versus risk in users of PPIs or metoclopramide was evaluated with multivariable conditional logistic regression; case-crossover analysis addressed possible residual confounding. RESULTS From the study cohort (n = 681,104), 3239 sudden cardiac death cases were matched to 12,572 controls. The adjusted odds ratio (95 % confidence interval) for sudden cardiac death with current use of domperidone alone was 1.71 (0.92-3.18) versus non-use of study medications, 1.26 (0.68-2.34) versus current PPI use, and 0.40 (0.17-0.94) current metoclopramide use. The adjusted odds ratio (95 % confidence interval) relative to exposure to no study drug for domperidone >30 mg/day (eight cases, five controls) was 3.20 (0.59-17.3) and 1.65 (0.89-3.07) for age ≥61 years (27 cases, 49 controls). The odds ratio (95 % confidence interval) was 3.17 (1.72-5.83) for within-person periods of domperidone use versus non-use in the case-crossover analysis. CONCLUSIONS Compared with non-use of any study drug, current domperidone use was associated with sudden cardiac death in nested case-control and case-crossover analyses, with a suggestion of higher risk in older persons and users of higher daily doses.