Pharmacoepidemiology study of association between domperidone and cardiovascular adverse event : a nested case-control and case-time-control study

다국어 초록 (Multilingual Abstract)

Background

Recent epidemiological studies have suggested that domperidone may increase the risk of severe cardiac arrhythmias, and new safety concerns regarding other cardiovascular (CV) disease also exists.


Objective

The aim of this study is to investigate whether the use of domperidone increases the risk of cardiovascular adverse events, including arrhythmias, hypertension, myocardial infarction, ischemic stroke and heart failure.

Methods

A nested case-control study was conducted using the Sample Cohort data from the National Health Insurance Service in South Korea from 2002 to 2015. From the study cohort of subjects with a prescription for domperidone or metoclopramide, patients diagnosed with arrhythmias, hypertension, myocardial infarction, ischemic stroke and heart failure were defined as cases. Controls were matched on sex, age, province, insurance type, income level, cohort entry date and follow-up duration. The risk of cardiovascular events in domperidone users versus risk in no-users and the risk in domperidone users versus risk in metoclopramide users were evaluated with multivariable conditional logistic regression. Also, the risk was estimated for each category of sex, age group, average daily domperidone dose (≤30mg and >30mg) and whether co-medication of CYP3A4 inhibitors or QT prolonging drugs with domperidone. Using the same cases and controls, I conducted a case-time-control analysis in consideration of possible residual confounding and time-varying exposure.

Results

From patients with a new, first-time prescription for domperidone or metoclopramide (N=652,569), 26,939 event cases were matched to 43,813 controls. The adjusted odds ratio for all 5 cardiovascular adverse events was 1.24 (95% CI 1.06-1.46) versus non-use. Among the cardiovascular outcomes, the risk of hypertension was statistically significant higher in domperidone users (OR 1.26, 95% CI 1.06-1.49) versus non-use. A higher cardiovascular risk was observed in patients who were co-exposed with QT prolonging drugs (OR 3.67, CI 0.58-23.34). In the case-time-control analysis, the odds ratio for overall cardiovascular adverse events was 0.93 (95% CI 0.74-1.16) versus non-use. The association between domperidone and any cardiovascular outcome was not observed in the within-subject comparison. All sensitivity analyses were consistent with the main findings in this study. Also, no increased risk was observed for all cardiovascular adverse events when compared to metoclopramide in nested case-control (aOR, 0.85; 95% CI, 0.73-0.99) and in case-time-control analysis (aOR, 0.80; 95% CI 0.54-1.17). Majority of domperidone prescriptions were low doses (30mg or less) and short period (7 days or less).

Conclusion

The results suggested that low dose and transient domperidone use was not associated with arrhythmias, hypertension, myocardial infarction, ischemic stroke and heart failure. However, co-medication with interacting drugs could be a potential factor for the cardiovascular risk.

목차 (Table of Contents)

• Chapter 1. Introduction 1
• 1.1 Background 1
• 1.2 Objective 6
• Chapter 2. Literature Review 7
• 2.1 Previous Studies on cardiovascular risk of domperidone 7
• 2.2 Previous studies on cardiovascular risk other than arrhythmia of domperidone. 13
• 2.3 Biological mechanism of domperidone 16
• Chapter 3. Material and Methods 18
• 3.1 Data Sources 18
• 3.2 Study Design 21
• 3.3 Active comparator – metoclopramide 22
• 3.4 Study subjects for a nested case-control study 24
• 3.5 Exposure Assessment for a nested case-control study 28
• 3.6 Potential confounders 30
• 3.7 Statistical Analysis for the nested case-control study 39
• 3.8 Study subjects for a case-time-control study 41
• 3.9 Exposure Assessment for a case-time-control study 42
• 3.10 Statistical analysis for the case-time-control study 43
• 3.11 Ethical Approval 45
• Chapter 4. Results 46
• 4.1 Study Population Characteristics 46
• 4.2 Odds Ratio of the nested case-control study 54
• 4.3 Stratified analysis of the nested case-control study: patient characteristics 58
• 4.4 Stratified analysis of the nested case-control study: daily dose of domperidone 73
• 4.5 Sensitivity analysis of the nested case-control study 76
• 4.6 Odds Ratio of the case-time-control study 79
• Chapter 5. Discussion 85
• 5.1 Comparison with previous studies; domperidone use and cardiovascular risk 85
• 5.2 Comparison with previous studies; cardiovascular risk of domperidone compared to metoclopramide 87
• 5.3 Biological mechanism of domperidone and metoclopramide regarding to cardiovascular risk 88
• 5.4 Strength 90
• 5.5 Limitation 91
• 5.6 Implications 93
• Chapter 6. Conclusion 95
• Reference 96
• Appendix 104
• Korean Abstract 136