Positive Association of Male Overactive Bladder Symptoms and Androgen Deprivation: A Nationwide Population-based Cohort Study

Materials and Methods

Data sources. All data in this study were obtained from the Taiwan National Health Insurance Research Database (NHIRD), which is managed by the Taiwan National Health Research Institute (NHRI). The Taiwan National Health Insurance (NHI) program covers at least 99% of the population of the island since 1995. In this study, a systemic sampling from the Taiwan NHIRD between 2001 and 2007 with a total of 1,000,000 individuals was used. These random subjects have been approved by the NHRI to be representative of the general population in Taiwan. The study protocols were approved by the institutional review board (IRB) of Taichung Veterans General Hospital (CE13151-1) and were in accordance with the guidelines of the IRB. There were no statistically significant differences in age and general healthcare between the sample group and all enrollees (data not shown). The database contains medical information regarding ambulatory care, inpatient care, and prescription drugs. Diagnoses were coded according to the International Classification of Disease, 9th revision (ICD-9) which was incorporated into the database since 2000. The database used in this study can be interlinked by the scrambled unique individual's personal identification number (PIN). The NHRI safeguards the privacy and confidentiality of all beneficiaries and transfers the health insurance data to health researchers after ethical approval has been obtained. In this analysis, access to the NHIRD has been approved by the NHRI Ethics Review Committee.

Study population and end-point. Four groups of patients were included in our analysis: prostate cancer with ADT only, BPH with alpha-blockers only, BPH with 5-alpha reductase inhibitors (5ARIs), and healthy controls. The patient selection, sampling and exclusion criteria are shown in Figure 1. Inclusion criteria in the prostate cancer study group met two conditions: (i) newly diagnosed prostate cancer between 2001 and 2007; and (ii) ADT treatment. The exclusion criteria in the study group were: (i) any interventional prostate surgeries or radiation therapy prior to inclusion or after inclusion; (ii) chemotherapy or targeted therapy; (iii) medications for OAB for more than 1 month or OAB diagnosis before prostate cancer diagnosis; (iv) existence of neurological diseases requiring 3 or more visits to outpatient clinics or 1 or more inpatient visits and (v) other types of cancer. The diagnosis of prostate cancer was defined as code ICD-9-CM 185.0. Neurologic diseases were coded ICD-9-CM from 320 to 359 including the majority of central or peripheral neurological diseases. ADT was defined as luteinizing hormone release hormone (LH-RH) agonists or antagonists and other types of anti-androgens. Chemotherapy or targeted therapies were identified by drug scientific names. Medications for OAB were trospium, imipramine, flavoxate, propiverine, oxybutynin, tolterodine and solifenacin. In the BPH group, subjects who met the following criteria were also excluded: (i) receiving interventional prostate surgeries; (ii) previous OAB history; (iii) any kinds of neurologic diseases coded ICD-9-CM from 320 to 359; Incident cases of lower urinary tract symptoms were identified from the NHIRD after the upstream patient selection. The ratio of the number of subjects in the healthy control group to the number of prostate cancer patients was 2:1.

In all four groups, comorbidities, including myocardial infarction (MI, ICD-9-CM 410), heart failure (ICD-9-CM 428), peripheral vascular disease (PVD, ICD-9-CM 443), cerebrovascular accident (CVA, ICD-9-CM 434), dementia (ICD-9-CM 290-294), chronic obstructive pulmonary disease (COPD, ICD-9-CM 490-496), mild chronic liver disease except cirrhosis (CLD, ICD-9-CM 571, except 571.2, 571.5, 571.6), chronic kidney disease (CKD; ICD-9-CM 582–583), diabetes mellitus (DM, ICD-9-CM 250), hyperthyroidism (ICD-9-CM 410–414) were recorded.

Statistical analysis. The data are presented as the mean values and standard deviations (SD) for continuous variables, and proportions for categorical variables. The differences between continuous values were analyzed by using t test for continuous variables, and chi-square test for categorical variables. Multivariate Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between the prevalence of OAB and the four divided groups. Propensity analysis was used for further confirming this association. The cumulative incidence curves were plotted via the Kaplan–Meier method with statistical significance examined by the log-rank test. All statistical analyses were carried out by SAS software version 9.2 (SAS Institute, Inc., Cary, NC, USA). A p-value of <0.05 indicated statistically significant differences.