Title Page
Contents
Abstract 12
Chapter 1. INTRODUCTION 14
1. Background 14
2. Study Objectives 19
Chapter 2. LITERATURE REVIEW 20
1. Previous Studies 20
1.1. The efficacy of PPI treatment on asthma: a meta-analysis 20
1.2. Association between PPI use and risk of developing asthma: observational studies 25
1.3. Association between PPI use and risk of asthma: randomized controlled trials and post hoc analysis 32
2. The needs for the present study 36
Chapter 3. MATERIALS AND METHODS 39
1. Data Source 39
2. Study Design 41
3. Study Population 44
4. Exposure Assessment 46
5. Outcome Definition 49
6. Potential Confounders 51
7. Statistical Analysis 56
8. Subgroup Analysis 58
9. Sensitivity Analysis 59
10. Ethical Approval 63
Chapter 4. RESULTS 64
1. Selection of study population 64
2. Characteristics of Study Cohort 67
1) Baseline demographics 67
2) Comorbidities 68
3) Concomitant medications 68
4) Incident users vs. prevalent users 68
3. Main Analysis 74
1) Association between PPI use and risk of developing asthma 74
2) Analyses for duration-response and dose-response relationship 77
3) Individual PPI 78
4. Subgroup Analysis 89
5. Sensitivity Analysis 100
Chapter 5. DISCUSSION 111
1. Principal Findings 111
2. Potential mechanisms of PPIs on asthma 113
3. Comparison with other studies 115
4. Strengths and Limitations 122
1) Strengths 122
2) Limitations 123
Chapter 6. CONCLUSIONS 125
References 126
논문요약 134
Table 1. Summary of meta-analyses on the efficacy of PPI treatment on asthma 23
Table 2. Summary of literature review of observational study on the risk of developing asthma 28
Table 3. Summary of literature review of randomized controlled trial on PPI use and the risk of asthma 34
Table 4. The significance of this study compared to the previous studies 38
Table 5. Codes to identify PPI prescriptions 47
Table 6. Codes to identify H2RA prescriptions 47
Table 7. Codes used to define the outcome 49
Table 8. Definitions of the covariates measured in the present study 53
Table 9. Summary of addressing confounder in the present study 55
Table 10. Summary of sensitivity analyses in the present study 61
Table 11. Baseline characteristics of patients with PPI prescription and H2RA prescription 69
Table 12. Baseline characteristics of incident new-users and prevalent new-users after propensity score matching 72
Table 13. Incidence rate and hazard ratios of risk of asthma treated with PPIs versus H2RAs 75
Table 14. Incidence rate of risk of asthma treated with PPIs versus H2RAs according to duration of medication use, cumulative dose and average dose per duration 79
Table 15. Hazard ratios of risk of asthma treated with PPIs versus H2RAs according to duration of medication use, cumulative dose and average dose per duration 80
Table 16. Incidence rate of of risk of asthma treated with PPIs versus H2RAs according to duration of medication use observed during 6 months, 1 year, 3 years, and 5 years follow-up periods 81
Table 17. Hazard ratios of of risk of asthma treated with PPIs versus H2RAs according to duration of medication use observed during 6 months, 1 year, 3 years, and 5 years follow-up periods 83
Table 18. Baseline characteristics of patients according to average dose per duration 85
Table 19. Incidence rate and hazard ratios for asthma according to individual drugs 88
Table 20. Incidence rate for the risk of asthma treated with PPIs and H2RAs in the stratified analysis 91
Table 21. Unadjusted and adjusted hazard ratio for the risk of asthma treated with PPIs and H2RAs in the stratified analysis 95
Table 22. Sensitivity analysis with additional prescription within 30, 60, or 90 days 101
Table 23. Sensitivity analysis with alternative definition of outcome 102
Table 24. Sensitivity analysis by new user status 104
Table 25. Sensitivity analysis with exposure set including less than 35 days of interval between H2RA prescription and PPI prescription 105
Table 26. Sensitivity analysis with lag time periods 107
Table 27. Sensitivity analysis with additional adjustment for calendar time 108
Table 28. Sensitivity analysis that assessed the effects from unmeasured confounders 110
Figure 1. Nationwide trends of PPI utilization in South Korea, 2016-2020 15
Figure 2. Prevalent new-user comparative cohort with prescription-based exposure set.... 42
Figure 3. Study diagram 43
Figure 4. Flow chart for the selection of the study population in the study 66
Figure 5. Kaplan-Meier curves comparing cumulative incidence of asthma in patients treated with PPI and H2RA in overall study cohort 76
Figure 6. Forest plot of subgroup analysis for the risk of asthma treated with PPIs and H2RAs 99
Figure 7. Forest plot of sensitivity analysis for the risk of asthma treated with PPIs and H2RAs 109