The role of prescription drugs in female overactive bladder syndrome—A population‐wide cohort study

Abstract Purpose Overactive bladder (OAB) syndrome has severe effects on quality of life. Certain drugs are known risk factors for OAB but have not been investigated in a population‐wide cohort. The objective of this study was to investigate the role of prescription drugs in the etiology of the OAB. Methods Retrospective cohort study using a population‐wide database of 4 185 098 OAB‐naïve women followed Strengthening the Reporting of Observational Studies in Epidemiology guidelines. We investigated the subscription use of anticholinergic medication and 188 chemical substances, which are suspected triggers for OAB (trigger medications [TMs]). We hypothesized a relationship between the prescription for one or more TM and the prescription for anticholinergic medication against OAB (marker medication [MM]). Results The use of MM in Austria increased from 2009 to 2012 on average by 0.025 percentage points per year (95% confidence interval [CI]: 0.015‐0.036). In December 2012, 1 in 123 women filled a prescription for any MM, equaling an average utilization of 0.84%. The relative risk of filling a prescription for a MM 6 months after filling a prescription for a TM was 2.70 (95% CI: 2.64‐2.77). All investigated medication classes showed a higher risk for the prescription for MM. Medication from classes “genitourinary system and sex hormones” and “systemic anti‐infectives” caused the highest increase in risk (109% and 89%, respectively). Prescriptions for class “cardiovascular system” caused the lowest increase in the risk (15%). Conclusion Certain prescription medications are a significant risk factor for the need to take anticholinergic medication as a consequence.

For example, polyuria is a common side effect of loop diuretics, possibly leading to elevated urinary frequency and urgency. 6 Nonsteroidal anti-inflammatory drugs may lead to exacerbation of nocturia by redistributing body fluids. 7 Acetylcholinesterase inhibitors have cholinergic activity, leading to OAB symptoms. 8 Calcium channel blockers are associated with a malfunction of adequate relaxation and emptying of the bladder. The daily use of oral estrogens is considered to worsen urinary incontinence; however, its pathophysiology remains unknown. 9 Antidepressants, antipsychotics, and benzodiazepines drugs, which impact on the central nervous system, have also been shown to trigger the development of OAB. 10,11 Their effects might result from relaxing the pelvic floor muscles, interference with afferent nerve pathways from the bladder, or from indirectly leading to an inability to toilet.
OAB and its impact on quality of life are probably more pronounced in the elderly, a population already impaired by other medical comorbidities and vulnerable to the side effects of medications. 12 Previous studies, including those of our own research group for patient cohorts not restricted by age, have shown that patients are often overtreated with prescription drugs. Heinze et al reported a prevalence of 13%-15% of double medication with antihypertensive, lipid-lowering, or hypoglycemic drugs in a populationwide study. 13 The role of prescription drug utilization in the etiology of the OAB has not yet been investigated using a rigorous scientific approach applied to a population-wide cohort. In order to reduce medication risks in OAB patients, a greater understanding of the prevalence and use of these prescription medications is necessary.
The objective of this study was firstly to describe the prevalence of filling a prescription for anticholinergic medication (marker medication [MM] for OAB over a 4-year period), and secondly to investigate the role of specific prescription drugs in the etiology of the OAB by means of a population-wide cohort study.

| Study design
We conducted a retrospective cohort study using a large populationwide database. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines in analyzing and reporting our data (File S1).

| Database
A large, comprehensive data set, provided by 13 Austrian social security institutions, covering over 9 million insured persons in Austria had already served for studying double medication. 13 As social insurance is mandatory in Austria, this database holds population-wide pseudonymized records of all drug prescriptions filled over several years. This database was used to evaluate a possible correlation of utilization of specific drug classes with the incidence of OAB syndrome.

| Study population
The study population consisted of 4 185 098 insured and OAB-naïve women without age limit in Austria who, during the time period of January 2009 to December 2012, had a contract with one of the nine provincial sickness funds or one of the four nationwide social security institutions for independent entrepreneurs, farmers, federal employees, and railway or mining employees.

| Primary hypothesis
We hypothesized that in Austrian women of any age, there could be a relationship between the prescription for one or more trigger medications (TMs) and the prescription for MM for OAB syndrome.
A basic assumption of the study was that the prescription filling for any of the following four anticholinergic drugs indicated OAB syndrome in a woman: trospium chloride • Prescriptions for medication from class "genitourinary system and sex hormones" and "anti-infectives for systemic use" cause the highest increase in risk for the prescription for medication against OAB (by 109% and 89%, respectively).
licensed. We defined the four aforementioned drugs as MM for the presence of OAB.

| Data base
We devised a list of 188 chemical substances according to ATC Classification System level 5, in 13 anatomical main groups (ATC level 1), which are suspected to trigger the development or deterioration of OAB. ATC is a World Health Organization (WHO) controlled pharmacologic coding system, which lists all active ingredients of drugs according to the organ system which they act on. 14 The inclusion of a chemical substance into the list was based on a review of the scientific literature [6][7][8][9][10][11][15][16][17][18][19][20][21][22][23][24][25] and a cross-check with Clinical Pharmacology, an online pharmacologic database. 26 We defined these substances as "TM." The substances that were tested for their role as TM are shown in their respective drug class according to ATC in Table 1  The same way of analysis was repeated for women of at least 65 years of age, as the subgroup of elderly patients is discussed in the literature.

| Statistical analysis
All computations were carried out using SAS software Version 9.4 (SAS Institute Inc., Cary, NC, 2012).

| RESULTS
In 2011, the Government of Austria reported 4 296 293 women living in Austria. 27 Our data set for this study comprised a total of 4 185 098 OAB-naïve women, that is, women who had filled any pre-  Table 2. Of 901 924 women filling prescriptions for "TM," that is, medication suspected to cause OAB syndrome during the first half of 2012, Filling prescriptions for class "G" (genitourinary system and sex hormones) and "J" (anti-infectives for systemic use) caused the highest increase in risk for filling prescriptions for MM (by 109% and 89%, respectively). Filling prescriptions for medication class "C" (cardiovascular system) caused the lowest, but still significant increase in the risk for a MM (by 15%).
In addition to the analysis presented for the full age range of our cohort, we performed the same way of analysis restricted to the 977 886 women ≥65 years old (Table S1). In women ≥65 years old, filling a prescription for TM still held a significantly higher risk for the intake of MM but the adjusted RRs were generally smaller than in the general population. For 6 of 11 medication classes, the RRs were approximately equal to those in the general population. In the older female population, the RRs for filling a prescription for MM were smaller for 5 of 11 medication classes. This effect was possibly owed to the higher prevalence of MM intake in this age group, which was almost twice as high as in the general population (1.20% compared to 0.66%).
When we extended the analysis for the full age range to the more specific medication classes of ATC level 2, the overall result was similar (see results Table 4). Six medication classes on ATC level 2 showed an adjusted RR of >2 with CIs excluding parity. These six classes were "antipruritics including antihistamines, anesthetics, and so on" (D04), "sex hormones and modulators of the genital system" (G03), "antimycotics for systemic use" (J02), "immunostimulants" (L03), "anesthetics" (N01), and "other nervous system drugs" (N07). In other words, filling prescriptions for medication from these classes increased the risk for the need of medication against OAB the most.

| DISCUSSION
This study found firstly that the use of prescribed anticholinergic drugs to treat OAB syndrome increased significantly over a recent 5-year period in the study population. Secondly, the results confirmed that the initiation of certain TM, most importantly sex hormones and anti-infectives, carries an increased risk to develop OAB syndrome in women who previously had not used either group of medication.
These results validate suspected substances as "TM" for OAB in a large population-wide data set.
In Austria, the filling of prescriptions for anticholinergic drugs to and "other nervous system drugs" (N07). These results corroborate the demand to investigate patients' medication use as part of the diagnostic work up for women with OAB syndrome. 29 We computed the list of 188 substances that we defined as TM based on a thorough review of the existing literature and a search of "Clinical Pharmacology," an online pharmacologic database. We acknowledge the fact that this list might not be complete and that more substances, especially from the same class, for example, imipenem in addition to meropenem, rivastigmine or galantamine in addition to donepezil might be TMs. We have only analyzed substances that to date have been suspected to cause or worsen OAB.
This study did not set out to detect new substances which might act as TM for OAB syndrome. This study set out to confirm in a large, population-based cohort that suspected substances indeed have to be considered as increasing the risk for OAB syndrome.
Polymedication is recognized as a major health problem and our study adds to the importance of taking analyzing medication intake in patients. In this way, our study has the potential to raise the awareness of pharmacovigilance in caregivers concerned with urinary incontinence.
We statistically tested 44 out of 94 of all classes of medication on ATC level 2. We did not "screen" our database for new TM. To test or "screen" the more than 1400 known medical substances for yet unknown TM would require a database with even more than the 4+ million data sets which were available for this study.
One strength of this study is the fact that with 4 185 098 subjects, it is the largest study on this topic to date. Previous studies were based on smaller cohorts or populations. 4,5 Another strength of this study is the fact that by controlling for hospital discharge diagnoses we were able to reduce the risk of confounding bias in our analysis. We corrected for 43 ICD codes including medical conditions like mood disorders, diabetes mellitus, and dementia, which are all known to be a risk factor for urinary incontinence.
We had to make general assumptions for the period of intake of MMs regarding our prevalence estimate, as no individual intake and compliance data were available. Our approach to investigate the influ-  There are limitations to our study. First, we based the diagnosis "OAB syndrome" on the fact that women filled a prescription for anticholinergic medication rather than on a clinical examination.
Thus, our conclusions refer to the consequences of filling prescriptions for TM on the filling of prescriptions for anticholinergic medication rather than on the influence of true medication intake on the incidence of OAB. However, the substances trospium, oxybutynin, tolterodine, and solifenacin are almost exclusively prescribed to treat OAB, and it seems fair to assume that filling a prescription for anticholinergic medication is a reliable proxy for the presence of OAB syndrome.
On the other hand, women who suffer from OAB but do not take anticholinergic drugs against it could not be detected in this study. Anticholinergics that were not available in Austria during the study period were darifenacin, desfesoterodine, emepronium, fesoterodine, flavoxate, meladrazine, mirabegron, propiverine, and terodiline. Also, we do not know the proportion of women who fill a prescription for medication but then do not take it or do not take the prescribed medication appropriately.
However, a significant proportion of noncompliance would only increase the observed effect of TM necessitating the prescription for anticholinergic medication and would thus not change our conclusion.
Our assessment of OAB was solely based on the utilization of medication to treat OAB. There are other ways to treat OAB than taking medication, and our approach may have missed OAB cases in which women chose to be treated by physical therapy or onabotulinum toxin A injections only.
However, this restriction is unlikely to exaggerate the effects of TM on the occurrence of OAB, on the contrary; we rather assume that the effects are underestimated.

| CONCLUSION
In women, the utilization of certain prescription medication is a significant risk factor for the development of OAB syndrome and the need to take anticholinergic medication, thereby contributing to anticholinergic burden.