A Comparison of the Frequencies of Medical Therapies for Overactive Bladder in Men and Women: Analysis of More Than 7.2 Million Aging Patients

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1 EUROPEAN UROLOGY 57 (2010) available at journal homepage: Platinum Priority Voiding Dysfunction Editorial by Roger Dmochowski on pp of this issue A Comparison of the Frequencies of Medical Therapies for Overactive Bladder in Men and Women: Analysis of More Than 7.2 Million Aging Patients Brian T. Helfand a, R. Mark Evans b, Kevin T. McVary a, * a Northwestern University, Feinberg School of Medicine, Department of Urology, Chicago, IL, USA b Healthcare Education Products and Standards, American Medical Association, Chicago, IL, USA Article info Article history: Accepted December 10, 2009 Published online ahead of print on December 17, 2009 Keywords: Urinary bladder overactive Anticholinergic therapy Men Women Abstract Background: The study of overactive bladder (OAB) symptoms has historically focused on women. However, it is now evident that men, including those with benign prostatic hyperplasia, have OAB symptoms that respond to anticholinergic therapy. The current OAB treatment frequencies by gender are unknown. Objective: The aim of the study was to compare the treatment patterns among men and women diagnosed with OAB. Design, setting, and participants: Patients 45 yr in the IMS Health data set with more than one diagnosis code for OAB during a 12-mo period ending December Intervention: Treated patients filled a prescription for either an anticholinergic or a tricyclic antidepressant medication; untreated patients did not. Measurements: Frequencies of OAB diagnoses and medical therapies by age and gender were compared. Results and limitations: Of the patients 45yr with an OAB diagnosis, 24.4% of these were treated; 75.6% went untreated. Only 25.6% of those treated were men. The diagnosis and treatment frequency increased in both men and women as a function of age. However, in every age group, there was a significantly ( p < 0.001) decreased proportion of men treated compared with women. Conclusions: Despite OAB prevalence, many patients receive no medical treatment. Although the usefulness of OAB medications in men is becoming increasingly recognized, men are significantly less likely to be treated with OAB medications than women. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Northwestern University Feinberg School of Medicine, Department of Urology, 303 E. Chicago Ave., Tarry , Chicago, IL 60611, USA. Tel ; Fax: address: k-mcvary@northwestern.edu (K.T. McVary). 1. Introduction Lower urinary tract symptoms (LUTS) is an umbrella term used to describe a constellation of symptoms that have been grouped into storage, voiding, and postmicturition symptoms [1]. Overactive bladder (OAB) symptoms represent a subset of storage LUTS that specifically includes urgency with or without urge incontinence, frequency, and nocturia [1] /$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 57 (2010) In all patients, storage symptoms can be related to a number of etiologies (eg, infection, neurologic conditions, bladder carcinoma) [2]. The traditional association in men, especially older men with benign prostatic hyperplasia (BPH), is that these symptoms originate with the prostate, the symptoms of prostatism. However, it is well recognized that urinary symptoms poorly correlate with underlying pathophysiology. Similar storage and voiding symptoms can also be produced by other forms of obstruction in men (eg, urethral stricture, impaired detrusor contractility) [2]. In contrast, female LUTS were historically referred to as OAB and were thought to originate almost exclusively from the bladder [3]. However, it is now recognized that many women with these symptoms have bladder outlet obstruction (BOO) and/or detrusor underactivity of the bladder. Therefore, based on historic associations, incorrect terminologies, and overlapping clinical presentations, the true prevalence of OAB in both genders has been unknown. Several recent studies have documented a similar overall prevalence of OAB symptoms (ranging from approximately 8 20%) that increases as a function of age in both men and women [4 9]. Interestingly, the prevalence of associated incontinence appears to be different between genders [7,8]. OAB without urge incontinence is more common in men, whereas associated incontinence has a female predominance. The frequency of associated female incontinence increases with age but significantly increases after approximately 45 yr. In contrast, male-associated incontinence increases with age but rises sharply after approximately 65 yr. Regardless of gender or etiology, OAB symptoms significantly compromise health-related quality of life (QoL) [7,10]. Despite the impact of OAB symptoms, underreporting secondary to a patient s embarrassment stands as an obstacle to successful treatment [11]. Even when diagnosed, OAB is often left untreated [11,12]. As previously mentioned, this lack of treatment has been particularly prevalent in men for a number of reasons, including relatively decreased rates of associated incontinence in men [3]. Furthermore, there has been concern for the use of anticholinergic therapies in men with BPH because of a fear of aggravating urinary retention [13]. In addition, alternative medical and surgical therapies (eg, a-adrenergic antagonists, transurethral resection of the prostate) have traditionally been used to treat BPH, even when OAB symptoms were the primary complaint [14,15]. Anticholinergic therapy has recently been shown to be safe in men with OAB and BPH [16,17]. Although it is still unclear which parameters (eg, optimal postvoid residual volume) delineate an increased risk of urinary retention, using anticholinergics in men with OAB significantly improves symptoms [16,18]. Most of the research conducted on treatment frequencies for LUTS/OAB symptoms has historically been conducted on women. However, recent data suggest that the prevalence of OAB symptoms is similar in both genders [5,7]. Therefore, it was of interest to determine if their treatment frequencies were similar. The aim of the present analysis was to compare the frequency of medical therapies for OAB in a large population of men and women. 2. Materials and methods The IMS Health patient claims data set encompassed a 1-yr period ending December This data set included integrated administrative claims from >85 different national private health care plans in the United States and contained information on patients of all ages with a current International Classification of Diseases, 9th revision (ICD-9), diagnostic code for OAB (596.xx, 788.3x). We limited our data set to patients 45 yr. Prescription drug data were linked directly to those patients with an OAB diagnosis. Medication use was recorded for all OAB medical therapies at the generic level as well as the drug-class level. Medications for OAB included the antimuscarinic and tricyclic agents (eg, tolterodine, oxybutinin, solifenacin, darifenacin, hyoscyamine, dicyclomine, trospium, flavoxate, propantheline). We also documented common male comorbidities (eg, BPH, ICD-9 codes 600.xx, 596.0, 788.2x; erectile dysfunction, codes , ), female comorbidities (postmenopausal vaginal atrophy, code 627.3; multiple sclerosis, code 340.xx), and gender-neutral comorbidities (eg, diabetes, code 250.xx and hypertension, codes 401.x 404.xx). For the purposes of the study, patients with a diagnosis of OAB who filled a prescription for an OAB medication (defined as either an anticholinergic and/or tricylic medication) during the study period were categorized as treated; those who did not were classified as untreated. Statistical analyses using SAS v.9.2 (SAS, Cary, NC, USA) were used to compare the frequencies of medical therapies between different groups of patients. Specifically, we performed tests comparing proportions, and the standard normal Z table was used to assess for significance. In addition, x 2 analyses were used to test for trends. 3. Results The IMS Health data set included clinical information on patients. Men represented 47.2% (n = ) of this population. Within the database, we identified a subset of patients (n = ; 5.3% of total population) with a diagnosis of OAB. Specific analysis demonstrated that of the patients 45 yr of age, (7.1%) had a diagnosis of OAB (Fig. 1). The overall prevalence of OAB increased as a function of age: 4.9% of all patients were yr, 6.7% of patients were yr, and 9.6% of patients were >65 yr. Fig. 2 shows that the OAB prevalence also increased as a function of age in both genders ( p trend < 0.001). Interestingly, there was a significantly ( p < 0.001) higher prevalence of OAB in every age group of women compared with men. The OAB prevalence also increased at different rates depending on gender and age group. For example, an additional 2.6% of female patients between 55 and 64 yr of age carried an OAB diagnosis compared with women between 45 and 54 yr. A similar overall increase was observed in the prevalence of OAB women in the >65 yr age group. Men exhibited a similar increase in the prevalence of OAB between the two youngest age groups. Interestingly, the greatest increase in prevalence (3.5%) occurred in men >65 yr compared with men yr. Of the total population of patients 45yr, 24.4% (n = ) were treated pharmacologically for their OAB symptoms. More than 74% (n = ) of this treated group were women (Fig. 1). Specific analysis by gender revealed that only 17.1% (n = ) of men 45 yr with OAB were provided medical therapies during the study

3 588 EUROPEAN UROLOGY 57 (2010) Fig. 1 The frequency of overactive bladder (OAB) medical therapy in >7.2 million patients with a diagnosis of OAB. Of the >187 million patients in the IMS Health data set, were I45 yr and had a diagnosis of OAB. The estimated prevalence of OAB was 5.6% and 8.4% among men and women, respectively. Analysis of treatment rates in male patients revealed that 24.4% of patients were treated and 75.6% were untreated. A significantly higher percentage of women received medications during the study period compared with men. period, which was significantly ( p < 0.001) less than the number of women treated (28.6%; n = ; Fig. 1). Subgroup analyses revealed that the proportion of treated patients significantly increased as a function of age for both men and women ( p trend < 0.001; Fig. 3). However, the percentage of patients that received pharmacologic therapy increased at different rates based on gender. For example, 22% of female patients between the ages of 45 and 54 yr were treated for OAB, in comparison with 28% and 33% of patients ages yr and >65 yr, respectively (Fig. 3). This represented an approximately 5 6% increase in treatment rates based on age group. In comparison, an additional 3% of men between the ages of 55 and 64 yr were treated. Interestingly, the largest increase in treatment frequency (7%) was observed in the male >65 yr age group. This increased frequency was proportionately greater than similar-age female counterparts. Finally, in an attempt to better understand what drives physicians to treat patients with OAB, we analyzed the treatment prevalence in patients based on the presence of Fig. 2 The prevalence of overactive bladder (OAB) diagnosis in >102 million patients as a function of age and gender. Patients from the IMS data set I45 yr of age were identified. The prevalence of a diagnosis of OAB was determined by both age group and gender. The overall prevalence of OAB in the data set was 7.1%. The frequency of OAB diagnoses increased significantly ( p trend <0.001) as a function of increasing age in both genders. In every age group, significantly more women were diagnosed than men ( p < 0.001).

4 EUROPEAN UROLOGY 57 (2010) Fig. 3 The frequency of treated and untreated patients for overactive bladder (OAB) symptoms as a function of both age and gender. The frequency of medical therapy use was determined in male and female patients included in this study. Subgroup analysis based on patient age demonstrated there was an increase in the frequency of medical therapy by age group. However, a significant increased percentage of women were treated in comparison with similar-age male counterparts. Interestingly, the largest increase in the rate of treatment occurred in men >65 yr (21%) compared with men between the ages of 55 and 64 yr (14%). comorbidities associated with OAB (eg, BPH, erectile dysfunction, postmenopausal vaginal atrophy, multiple sclerosis, hypertension, dyslipidemia, diabetes) [13,19 21]. Obesity as a comorbidity was not evaluated because of the known unreliability of these codes rather than lack of association or low prevalence in this population. In general, the presence of any one of these comorbidities was associated with an increased frequency of medical treatment for OAB. For example, 18.6% and 19.0% of men with BPH and erectile dysfunction were treated with pharmacologic therapy, respectively. In contrast, a significantly greater proportion of women with codiagnoses of either postmenopausal vaginal atrophy (31.7%) or multiple sclerosis (38.6%) were treated with OAB medications. Patients with codiagnoses such as hypertension, dyslipidemia, and diabetes were associated with a 25.9%, 24.1%, and 26.5% frequency of treatment for OAB symptoms, respectively. Taken together, although men with either BPH or erectile dysfunction tend to be treated more frequently than men without these comorbidities, the prevalence of treatment is still relatively decreased compared with patients with other comorbidities. 4. Discussion Many studies have documented the prevalence of OAB symptoms [5 8]. However, to our knowledge, no study has reported the associated frequency of medical therapies. The present study confirms that the diagnosis of OAB increases linearly as a function of age in both genders. In addition, we report that the frequency of medical therapy mirrors this trend. However, although the percentage of patients in the treated groups increases in both men and women, women are significantly more likely to receive medical therapies in any age group. Approximately 7.1% of patients 45 yr within the IMS Health data set have a diagnosis of OAB. Subgroup analysis by gender demonstrated that the prevalence among aging men and women is approximately 5.6% and 8.4%, respectively. These rates are similar to prior reports of prevalence estimates of OAB using a claims database [9]. However, our results are lower than recent OAB prevalence estimates in adults 40 yr ranging between approximately 11% and 16% for men and approximately 13% and 17% for women [5 7]. The differences in prevalence estimates are likely based on differences in estimating OAB prevalence. This study used ICD-9 diagnostic codes to determine the prevalence of OAB, whereas many prior studies used questionnaires to survey patients. Thus a higher prevalence would be expected in studies that actively investigate a diagnosis. Numerous studies demonstrated that OAB has a profoundly negative effect on both subjective and objective measures of QoL [7,10]. In fact, it has been shown that OAB symptoms can lead to depression and low self-esteem and have an impact on many social situations [22]. However, the present study shows that only a minority of all patients, particularly men, with a diagnosis of OAB (approximately 24%) are provided medical therapy. One potential reason for the relative low frequency of treatment in both men and women may be the associated cost. Several studies recently estimated the economic burden of OAB disease (including direct medical costs, direct nonmedical costs, and indirect costs) at more than $12 billion annually [23]. Therefore many patients may not elect to start medical therapies secondary to cost alone. In addition, many patients may have opted for lifestyle/behavioral alterations (eg, decreased fluid intake, smoking cessation) before initiating pharmacologic therapy. Other reasons for lower rates of treatment include insufficient relief of symptoms and side effects of the medication. Physician or patient preference for nondrug approaches may also be a factor. However, although all these factors may contribute to the lack of administered medical therapies, they certainly do not explain the entire phenomenon or gender differences. Perhaps the observed discrepancies and gender bias in treatment trends are related to the presence of incontinence or other comorbidities. The National Overactive Bladder

5 590 EUROPEAN UROLOGY 57 (2010) Evaluation Program provided data on the prevalence and burden of OAB symptoms [7]. The results of the study suggested that although the prevalence of OAB symptoms was similar among men and women, the frequency of women with OAB symptoms and incontinence increased at a faster rate with age compared with men. Similar results can be extrapolated from our study because there was a steady but significant increase in treatment by age in women. Therefore, if incontinence is the driving factor for medical intervention, then it is not surprising we see a higher but steady proportion of women being treated in each age group, including women >65 yr. In addition, it is of note that women with comorbidities that may predispose to incontinence (eg, postmenopausal vaginal atrophy, multiple sclerosis) were significantly more likely to be treated than men with any other comorbidity. Interestingly, the presence of dyslipidemia, a seemingly unrelated disease, increased treatment frequency. The following possible reasons account for this finding: (1) Dyslipidemia directly increases OAB symptoms, a prospect that should evoke further investigation; (2) dyslipidemia may be associated with other comorbidities that increase OAB symptoms; and (3) other biases unrelated to dyslipidemia may be present. Although this association does not imply causality, further investigation into the mechanisms underlying this relationship is warranted. Taken together, our data suggest that the presence of OAB and associated incontinence may contribute to some of the gender discrepancies of treatment. The etiology of male OAB symptoms is thought to arise from BPH-related BOO, leading to ischemia, cholinergic denervation, and detrusor overactivity [24,25]. Thus, although they are not codependent, men with BPH often have OAB. Interestingly, the present results indicate that < 20% of these patients are treated with OAB medications, despite growing evidence that anticholinergic agents can safely and effectively treat male OAB symptoms, even in patients with urodynamically confirmed BOO [16,26,27]. Reasons for withholding treatment in this population may be related to a historic misclassification of these symptoms as prostatism [28]. Therefore many of these men may have been treated with other forms of medical therapy for BPH. In fact, a recent study demonstrated that most men with OAB symptoms and no BPH diagnosis were prescribed these medications [14,15]. In addition, men in this study may not have received treatment due to mild symptom severity, a lack of associated incontinence or bother, side effects of the medications, and intervention with other BPH therapies (medication and surgery). Taken together, men may have been proportionally undertreated in this study due to the presence and concern of LUTS secondary to BPH. Further education in the use of OAB medications in this group of patients is needed. Several limitations of this study deserve mention. First, the IMS Health data set documents the diagnoses and treatment patterns of a large insured population. Therefore the treatment patterns in other populations (ie, uninsured or Medicare enrollees) should be examined. In addition, because this database contains limited information on patients 75 yr of age, other studies specifically addressing OAB treatment in this population should be performed. Also, ICD-9 coding does not provide information about the continuation and/or effectiveness of treatment. Because OAB has a poorly understood natural history with spontaneous annual remission rates of approximately 30% and rather high discontinuation rates for medical therapies [29,30], it is currently unknown how many patients continue to receive medical therapies and/or experience OAB symptoms in this data set. In addition, OAB diagnoses were determined by ICD-9 coding, and thus the types of symptoms were not able to be obtained. Thus the definition of OAB used and the severity of symptoms are subject to debate. In addition, it would have also been useful to evaluate the frequency of therapies in relation to the prevalence of incontinence, data that were not readily available. Finally, because OAB symptoms in men have historically been related to BPH, other medical (eg, a-adrenergic antagonists) or surgical therapies may have been prescribed. It would be interesting to note the frequencies of these therapies in comparison with OAB medications. 5. Conclusions The current study demonstrates that the diagnosis and treatment of OAB increases with age in both genders. However, although physicians are becoming increasingly aware of OAB symptoms in men, the frequency of treatment is still significantly decreased in comparison with women. Further education regarding the availability and efficacy of pharmacologic therapy in both men and women is needed for patients and physicians. Author contributions: Kevin T. McVary had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Helfand, Evans, McVary. Acquisition of data: Helfand, Evans. Analysis and interpretation of data: Helfand, Evans, McVary. Drafting of the manuscript: Helfand. Critical revision of the manuscript for important intellectual content: Helfand, Evans, McVary. Statistical analysis: Helfand. Obtaining funding: None. Administrative, technical, or material support: Helfand, Evans. Supervision: McVary. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: Report from the standardisation

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