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21st Annual Congress of the European Association of Urology

Paris, France / April 5-8, 2006

Overactive bladder (OAB) affects an estimated 15 to 20% of adults in North America and has a clinically significant impact on quality of life, quality of sleep and mental health (Stewart WF. World J Urol 2003;20(6):327-36). Nonetheless, it remains underdiagnosed in primary care, as patients are often reluctant to discuss symptoms and clinicians do not ask about bladder problems (Smith DA. Adv Nurse Pract 2004;12(3):26-33). With this high prevalence and with few patients being treated, there is room for improvement in proper diagnosis and treatment (Milson et al. BJU Int 2001;87(9):760-6). Men, in particular, infrequently receive antimuscarinics despite evidence that they experience OAB-like symptoms similar to those seen in women and bothered by those symptoms at least as much as women are (Peter TJ. J Urol 1997; 157:885-8).

Investigating Possible Gender-driven Diagnosis

As clinical management of OAB has evolved, a gender-driven paradox may have left male patients at a disadvantage with respect to therapeutic outcomes. Primary care physicians and gynecologists traditionally have cared for female OAB patients, whereas urologists have assumed much of the responsibility for treating bladder symptoms in men, commented Dr. Steven A. Kaplan, New York-Presbyterian Hospital, and Professor of Urology, Weill Cornell Medical College, New York. This has led to different approaches to treatment of similar types of symptoms leading clinicians to more or less reflexively attribute lower urinary tract symptoms (LUTS) in men to the prostate. In fact, LUTS can arise from problems related to the bladder, the prostate, or both (Abrams P. Urology 2003;61:37-49).

“I’ve always been fascinated by how we look at men and women differently,” remarked Dr. Kaplan. “When a woman has urinary frequency, we say she has a bladder problem and give her an antimuscarinic agent. When a man has frequency, we say he has a prostate problem and give him a prostate medication. At the end of the day, a bladder is a bladder, yet we look at them differently. I think we should be rethinking this.”

Redefining Treatment Algorithms in Men

Although men have predominantly OAB-type bladder symptoms, they are treated with benign prostatic hyperplasia (BPH) agents such as a-blockers, with less-than-sterling results. Lee et al., for example, found that only 35% of men with bladder outlet obstruction and detrusor overactivity improved with a-blocker monotherapy (BJU Int 2004;94(6):817-20). However, among men with only bladder outlet obstruction, a-blocker monotherapy was effective about 75% of the time. Patients with bladder outlet obstruction and detrusor overactivity who did not respond to the a-blocker then received add-on antimuscarinic therapy and 73% of them experienced symptomatic improvement. “We have to change our mindset as to where these agents may play a role, ”Dr. Kaplan told delegates. He added, “a-blockers should remain the mainstay of therapy [yet] the question is whether patients with persistent symptoms will benefit from the addition of an antimuscarinic. I think the data suggest they will.”

Dr. Kaplan and colleagues recently reported findings from a clinical trial of monotherapy with tolterodine extended-release (ER) formulation in men with OAB symptoms who discontinued a-blocker therapy because of a lack of efficacy or adverse events (J Urol 2005;174(6):2273-5). After six months of treatment, the mean daily micturition frequency had decreased from 9.8 to 6.3. Nocturnal frequency declined from 4.1 to 2.9, and the American Urological Association Symptom Score decreased by an average 6.1 points. These findings suggest that the ER formulation may be a reasonable therapeutic option as initial therapy or after failed treatment with a-blockers.

“Most of the symptoms that bother patients and maybe don’t resolve with traditional therapies are OAB-type symptoms,” explained Dr. Kaplan. “That would suggest that we might need to redefine the type of therapy algorithms we use.” Specifically, the therapeutic algorithms may encourage increased use of antimuscarinics to treat urinary symptoms in men.

OAB in Primary Care

Assessing OAB symptoms through patient-reported outcomes (PROs) was the main focus of the 12-week, multicentre, open-label, non-randomized IMPACT (Improvement in Patients: Assessing Symptomatic Control with Tolterodine ER) clinical trial. Speaking on behalf of investigators, Dr. Walter Artibani, University of Verona, Italy, reported on the study involving 898 patients (863 of whom had complete data: 155 men, 708 women) with OAB treated in 98 primary care practices throughout the US. Patients received 4 mg q.d. of the ER formulation for 12 weeks and the primary end point was the change from baseline in patients’ most bothersome OAB symptom.

At study entry, 87.3% of the patients rated the bothersomeness of OAB symptoms as either moderate or severe. They cited night-time and daytime frequency as the most bothersome symptoms. “The results of the IMPACT trial showed that daytime and nocturnal frequency were at least as bothersome as incontinence, which came as a surprise to us,” commented Dr. Artibani.

IMPACT on Quality of Life

When the study ended, treatment had reduced night-time frequency by 40% and daytime frequency by 30%. At week 12, among patients who rated their most bothersome symptom at baseline as urge urinary incontinence (UUI) and urgency, treatment resulted in an 80% and 78% reduction in the symptom, respectively. The magnitude of improvement was similar in men and women, noted Dr. Artibani.

Overall, treated patients had a 63% reduction in symptom bother score, and the health-related quality-of-life (HRQOL) score improved by 53%. Patients reported substantial improvement in the QOL domains of coping, concern and sleep. Active treatment was associated with a low incidence of adverse events. Dry mouth was the most common adverse event, cited by 10% of patients.

Another analysis demonstrated that symptomatic improvement correlated with improvement in Patient Perception of Bladder Condition (PPBC) questionnaire and HRQOL scores. As well, comparison of pre- and post-treatment assessment by means of the Bother Rating Scale showed that treatment significantly reduced each of the most bothersome symptoms reported by patients (P<0.0001). PPBC data showed that almost 80% of patients experienced some degree of improvement after 12 weeks of tolterodine therapy, including major improvement in 50% (Figure 1). The OAB questionnaire (OAB-q) symptom bother scale, HRQOL scale, and HRQOL subscales all improved significantly from baseline to 12 weeks (P<0.0001).

Figure 1. Patient perception of bladder condition at Week 12 by most bothersome OAB symptom

The magnitude of improvement was clinically meaningful as well as statistically significant. Dr. Artibani stated that the agent “significantly reduced these symptoms to a similar degree in men and women. In general, we can say that OAB symptoms can be effectively treated in the primary care setting with tolterodine ER.”

Validity of Patient-reported Outcomes

For OAB, validated measures of PROs have been developed and include the OAB-q and the PPBC. The instruments provide important insights into understanding symptom bother, changes in HRQOL associated with OAB, and effects of OAB treatment (Siami P. Clin Ther 2002;24(4):616-28, Coyne KS. Qual Life Res 2005;14(3):849-55).

IMPACT data were analyzed with respect to relationships between objective improvement in OAB symptoms recorded in three-day bladder diaries and changes in the OAB-q and PPBC. Variables assessed in the three-day bladder diary included daily micturition rate, nocturnal micturitions, UUI episodes and urgency episodes.

By week 12, all bladder diary variables had improved significantly (P<0.0001). The improvement was observed in the intent-to-treat population and when patients were stratified according to their most bothersome OAB symptom. Also by week 12, statistically significant improvement (P<0.0001) had occurred in all OAB-q domains, regardless of whether the data were analyzed by the intent-to-treat population or by the most bothersome symptom (Table 1).

Table 1. Median change
k 12 in OAB-q domains

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Improvement in PPBC scores correlated most strongly with reduction in urgency score recorded in the bladder diary, followed by correlations with reduction in UUI, nocturnal frequency and daytime frequency. A similar pattern of correlations was observed for the OAB-q domains and bladder diary variables.

Additional evidence of the correlation between PROs and objective measures of OAB symptoms emerged from a post hoc analysis of data from a randomized, placebo-controlled clinical trial involving 987 OAB patients (813 women, 174 men) led by Dr. Philip van Kerrebroeck, University Hospital Maastricht, The Netherlands. Patients were randomized to tolterodine ER 4 mg q.d. or placebo and followed for 12 weeks. Seven-day bladder diaries and PPBC were completed at baseline and week 12. Relationships between change in PPBC scores and median percentage change in UUI episodes were evaluated using Spearman’s coefficients.

“Objective symptoms can sometimes be difficult to score,” remarked Dr. van Kerrebroeck. “The perception of bladder condition could perhaps be an even more important item to predict the chances to relieve the patient of symptoms and perhaps improve QOL.”

At the end of the trial, actively treated patients had a significantly greater reduction in UUI episodes (71%) than did patients given placebo (33%, P<0.0001). Additionally, more actively treated patients experienced improvement in PPBC scores than did placebo-treated patients (58% vs. 45%, P<0.0001).

The results confirm the relevance of disease-specific PRO measures in the assessment of OAB treatment effects.

Dr. van Kerrebroeck told delegates, “We now realize that QOL-related aspects of OAB are perhaps even more important than objective findings, because there can be a disconnect between objective findings, HRQOL aspects and patient perception. That has to do with the fact that we now know from the pathophysiologic background that urgency is a driving force for the other abnormalities, including abnormal frequency and incontinence. That means that urgency, by definition, is a subjective perception. If this is a driving force, then we should aim to ameliorate it.”

Examining OAB Impact on Family Members

Although OAB adversely affects patients’ HRQOL, the impact of OAB on patients’ family members is unknown. An initial assessment of an instrument to evaluate OAB’s impact on family members indicated the instrument is reliable and valid and can demonstrate that family members are affected by another’s disease, even when the family member does not live with the patient.

A 32-item draft version of the OAB Family Impact Measure (OAB-FIM) was administered to 193 patient/ family member dyads (163 patients with OAB and 30 controls). After an initial assessment of the draft OAB-FIM, investigators eliminated 13 items because of limited variability, redundancy, or inadequate factor loadings. The revised 19-item, six-subscale OAB-FIM instrument was administered to the same 193 patient/family member groups.

Family members’ scores on all OAB-FIM subscales correlated significantly with their respective patients’ scores on all OAB-q domains and the PPBC, reported Dr. Louis Matza, United BioSource Corporation, Bethesda, Maryland. Additionally, all OAB-FIM subscales differentiated between family members of OAB patients and family members of control patients. Family members’ scores on all OAB-FIM subscales were linearly related to clinician ratings of patients’ OAB severity.

“The questionnaire appears to have very good reliability and validity,” reported Dr. Matza. “Our results suggest that OAB does have a negative impact on patients’ family members, even those family members who do not live with the patient.”

Summary

Antimuscarinics are well established as first-line therapy for the treatment of OAB. However, as Dr. Kaplan remarked, “As we sort of redefine the role of antimuscarinics, we see that the prevalence of OAB is similar between men and women, yet men are four times less likely to receive an antimuscarinic.” Looking at the male and female bladder differently is something we should be rethinking, he explained. Data presented here demonstrated the safety and efficacy of tolterodine ER as monotherapy in both men and women as well as in combination with an a-blockers in men with both bladder outlet obstruction and detrusor overactivity. Finally, objective symptom improvement statistically and clinically correlates with the patients’ perception of change in bladder condition and in HRQOL improvement.