Use of Proton Pump Inhibitors and the Risk of Cholangitis

A Nationwide Cohort Study

Yang Won Min; Danbee Kang; Ju-Young Shin; Minwoong Kang; Joo Kyung Park; Kwang Hyuck Lee; Jong Kyun Lee; Kyu Taek Lee; Poong-Lyul Rhee; Jae J. Kim; Eliseo Guallar; Juhee Cho; Hyuk Lee

Disclosures

Aliment Pharmacol Ther. 2019;50(7):760-768. 

In This Article

Methods

Study Population and Design

The NHIS-NSC is a population-based retrospective cohort consisting of a representative sample of 2.2% of Korean citizens enrolled in the NHIS.[18] The NHIS is Korea's universal single-payer national health care system. NHIS covers all regions of Korea and maintains national records of all insurance-covered in-patient and out-patient visits, procedures and prescriptions. NHIS-NSC sampling consisted of a systematic stratified random sample with proportional allocation within each stratum. The sampling procedures and representativeness of the cohort are described in detail elsewhere.[18] In Korea, the NHIS also provides free of charge to all insured subjects, annual or biennial health screening exams assessing cardiovascular and diabetes risk factors, including smoking and alcohol drinking habits. Approximately, 72% of eligible beneficiaries undergo such screening exams.[19]

We used the person-level longitudinal NHIS-NSC registration, claim and health screening exam data recorded between 1 January 2002 and 31 December 2013.[18] Our study population included all men and women ≥20 years of age participating in the NHIS-NSC cohort with at least one health screening during 1 January 2003 and 31 December 2013 (N = 588 326). We then excluded participants who had cholangitis (N = 691) or history of cholangiocarcinoma, gallbladder (GB) cancer or pancreas cancer (N = 568) between 1 January 2002 and the baseline screening exam. In addition, we excluded participants who had taken PPIs within 180 days before the baseline screening exam (N = 2426). The final sample consisted of 584 723 participants (291 604 men and 293 119 women; Figure 1). The Institutional Review Board of the Samsung Medical Center approved this study and waived the requirement for informed consent, as we used only de-identified data.

Figure 1.

Flowchart of study participants

Data Sources

The NHIS-NSC cohort includes four databases covering insurance eligibility, medical treatments, medical care institutions and health screening exams. The insurance eligibility database contains information on age, sex, residential area and income percentile. The medical treatment database includes claims data on all in-patient and out-patient visits, procedures and treatment claims, including details of the disease and prescriptions. The health screening exam database included questionnaire information on smoking status and frequency of alcohol intake and height, weight and blood pressure measurements.[18] Body mass index (BMI) was calculated as weight (in kg) divided by height (in m) squared.

NHIS claims for in-patient and out-patient visits, procedures and prescriptions were coded using the International Classification of Diseases, 10th Revision (ICD-10), adopted in Korea in 1995, and using the Korean Drug and Anatomical Therapeutic Chemical Codes.[14,20] As the NHIS routinely audits the claims, such data are considered reliable and have been used in numerous peer-reviewed publications.[18,21–23] A previous validation study of discharge diagnoses in the NHIS database compared against medical records found an overall positive predictive value of 80.24%.[18]

Definition of PPI Exposure

PPI use was identified in prescriptions with Korean Drug and Anatomical Therapeutic Chemical Codes A02BC01, A02BC02, A02BC03, A02BC04, A02BC05. PPI use was considered as a time-varying variable to control immortal time bias.[24,25] To avoid reverse causation bias due to the possible prescription of PPIs for symptoms caused by cholangitis, we considered that PPI use could not be responsible for cases of cholangitis occurring in the first 7 days after initiating PPI treatment. Also, as the effects of PPI on the microbiome may persist after medication use has ended, for each PPI prescription, we considered that the patient continued to be potentially affected by the effects of PPIs until 30 days after the date of expiration of the prescription (ie, we assumed that the effect of PPIs had a residual effect that persisted for 30 days after using the medication). If a new prescription was redeemed <30 days after the expiration of a prior prescription, the gap was considered as an exposure period (continuing PPI treatment). If a new prescription was redeemed ≥30 days after the expiration of a previous prescription, the gap was coded as a non-exposure period between two different PPI treatments. In sensitivity analysis, we repeated the analyses assuming that the period of residual effect of PPIs after using the medication was 60 or 90 days instead of 30 days.

Outcome Definition

The study outcome was the development of cholangitis, defined as a new ICD-10 code K83.0 or K80.3, which included codes K80.30 and K80.31 added since 2007, in any hospitalisation or out-patient visit claims during follow-up.

Other Variables

For each participant, the study baseline was considered the time of the first health screening exam during the study period. Information on age, sex, residential area and income level was obtained from the NHIS insurance eligibility database for the year of the baseline health screening exam. The number of out-patient clinic visits for each calendar year was obtained from the medical treatments database. Information on smoking and drinking habits and BMI was obtained from the baseline health screening exam.

Information on hepatobiliary comorbidities and the use of immune-suppressants, antibiotics and systemic corticosteroids throughout follow-up was obtained the from the medical treatments database. We considered the following hepatobiliary and upper gastrointestinal diseases that could influence the risk of cholangitis: GB stones (K80.2), common bile duct/intrahepatic bile duct (CBD/IHD) stones (K80.5), biliary stricture/atresia (K83.1, Q44.3, Q44.2), biliary cysts (K83.5, Q44.4), liver cirrhosis (K70.30, K70.31, K74.60-K74.62, K74.69, K74.1, K74.10-K74.12, K74.19), gastro-oesophageal reflux disease (K21), gastric ulcer (K25), duodenal ulcer (K26) and IBD (K50,1-K50.9, K51.0-K51.9).[20] Use of immune-suppressants, antibiotics and systemic corticosteroids throughout follow-up was identified by Korean Drug and Anatomical Therapeutic Chemical codes (Table S1 and Table S2).

Statistical Analysis

The study endpoint was the development of cholangitis. Participants contributed person-time of follow-up from the date of the baseline health screening exam until the development of cholangitis, death or the end of the study period (31 December 2013), whichever first occurs. The study exposure was PPI use, considered as a time-varying variable. For each PPI treatment course, participants who took PPIs contributed person-time to the exposed group starting 7 days after the date of the initial prescription until 30 days after date of expiration of the last prescription (see Definition of PPI exposure above). In sensitivity analysis, we repeated the analysis assuming that PPI exposure could not be responsible for cases of cholangitis occurring in the first 14 days after treatment initiation. Unexposed person-time was contributed by participants who did not take PPIs and participants who took PPI contributed unexposed person-time while they were not taking them (Figure S1). Data regarding PPI prescriptions dispended after the patient had developed cholangitis were not included in the study, as study follow-up ended with the first episode of cholangitis during the study period.

We used a proportional hazards regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident cholangitis comparing PPI use vs non-use. We used three models with increasing degrees of adjustment to account for potential confounding factors. Model 1 was adjusted for age (5-year categories), sex, residential area (metropolitan and rural) and income percentile (≤30th, >30th-≤70th, >70th percentiles) for the year of the baseline health screening exam as time-fixed variables. Model 2 was further adjusted for BMI (<18.5, ≥18.5-<23, ≥23-<25, ≥25 kg/m2 and unknown), smoking status (never, former, current and unknown) and frequency of alcohol intake (<1, 1-2, 3-4 times per week, almost every day and unknown) at the baseline health screening exam as time-fixed variables. Model 3 was further adjusted for the number of out-patient clinic visits during the year prior to baseline health screening exam as a time-fixed variable, and for the development of hepatobiliary diseases (GB stones, CBD/IHD stones, biliary stricture/atresia, biliary cysts, liver cirrhosis), upper gastrointestinal diseases (gastro-oesophageal reflux disease, gastric ulcer, duodenal ulcer) and for the use of immune-suppressants, antibiotics and systemic corticosteroids over follow-up as time-varying variables. We examined the proportional hazards assumption using plots of the log(-log) survival function and Schoenfeld residuals.

In addition, we performed stratified analyses to evaluate the association of PPI use with the incidence of cholangitis in pre-specified subgroups defined by age (<65 and ≥65 years), sex, income percentiles (≤30th, >30th-≤70th, >70th percentiles), residential area (metropolitan and rural), obesity (no and yes), smoking status (never and ever), alcohol intake (<1 time per week and ≥1 times per week), development of hepatobiliary disease during follow-up (no and yes), upper gastrointestinal disease during follow-up (no and yes), use of immune-suppressants during follow-up (no and yes), use of antibiotics during follow-up (no and yes), use of systemic corticosteroids during follow-up (no and yes) and number of out-patient clinic visits during the year prior to baseline health screening exam (<5 and ≥5).

Finally, to evaluate the long-term effects of PPI on the risk of cholangitis among PPI users, we calculated HRs by time since PPI use, categorised as within PPI treatment (on PPI), and <30 days, 30-90 days and >90 days after PPI discontinuation. All analyses were performed using STATA version 14 (StataCorp LP).

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