Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

November 12, 2007

EDITORIAL OVERVIEW

Sender Herschorn, MD, FRCSC, Professor and Chair, Department of Urology, University of Toronto, Toronto, Ontario

PANEL

Greg Bailly, MD, FRCSC, Department of Urology, Dalhousie University, Halifax, Nova Scotia

Kevin V. Carlson, MD, FRCSC, Diplomate, American Board of Urology, Director of Incontinence and Urodynamics, Clinical Instructor, Division of Urology/Department of Surgery, University of Calgary, Calgary, Alberta

Sender Herschorn, MD, FRCSC, Professor and Chair, Department of Urology, University of Toronto, Toronto, Ontario

Martine Jolivet-Tremblay, MD, FRCSC, Director, External Program, Clinical Assistant Professor of Medicine, Université de Montréal, Montreal, Quebec

Jean-Guy Vézina, MD, FRCSC, Clinical Professor of Surgery, Université Laval, Quebec City, Quebec

Editorial Overview

In men, lower urinary tract symptoms (LUTS) are most commonly attributed to bladder outlet obstruction (BOO) secondary to benign prostate enlargement. The role of urinary urgency or urgency incontinence due to overactive bladder (OAB) is less appreciated. Yet studies have indicated that 30% to 60% of men with BOO also have OAB, a condition that can develop secondary to BOO or from coexisting detrusor overactivity. Men may also develop OAB in the absence of BOO. A growing appreciation of the high prevalence of OAB in men is generating new algorithms in how LUTS is evaluated and treated.

OAB, which is characterized by urinary urgency often with increased frequency of urination and occasionally urgency incontinence, is most commonly associated with involuntary detrusor contractions. It is an age-related complaint in both women and men, but it can be overshadowed in importance in men by benign prostatic hyperplasia (BPH), which is present in half of men by age 50 and nearly 80% of men at age 80. Although it is reasonable to think first of BPH and its complications, particularly BOO, in men with LUTS, OAB in men should not be discounted. In patients with LUTS, treatment of OAB may be critical for relief of symptoms with or without BOO.

Anticholinergic agents, the most effective and most widely studied OAB treatment in women, were once thought to be relatively contraindicated in aging men, due largely to the theoretical risk of acute urinary retention. However, recent data from numerous controlled studies have found acute urinary retention to be a very rare complication of these agents. This is a critical finding and an important basis on which to reconsider diagnostic algorithms and empirical treatment choices. OAB is a treatable condition in both genders. Considering OAB in men with LUTS offers an important opportunity to increase the proportion of individuals with acceptable relief of symptoms. It must be pointed out, however, that most of these studies have been 12 weeks in duration.

In men, appreciation of the multiple etiologies of LUTS is an important starting point for developing and modifying treatment plans to control symptoms. Dominant symptoms often provide guidance for a reasonable first-line therapy, but it is also essential to consider coexisting problems and their interrelationship. For example, while BOO and OAB may be independent processes, they may also interact. In particular, increased pressure at the bladder outlet, associated with causes of BOO, may produce damage to detrusor smooth muscle cells that results in increased excitability and propensity for involuntary contractions.

Objective testing, such as urodynamic studies, can help in the differential diagnosis of OAB and BOO, but empirical treatments are a reasonable approach that can be considered by primary care physicians. Although alpha-adrenergic receptor antagonists, sometimes combined with 5-alpha reductase inhibitors, have been widely considered a standard for first-line therapy in aging men with LUTS, it is also reasonable to consider an anticholinergic agent in individuals whose predominant symptoms are consistent with OAB, such as urgency or urgency incontinence. If symptoms are not controlled with one approach, the other treatment can be added. Many men may benefit from concomitant therapies for BOO and OAB.

Study Findings

The evidence of benefit from anticholinergic therapies in patients with LUTS is derived from a series of studies published over the past several years. The most common design has been to test the addition of an anticholinergic agent to an alpha-adrenergic antagonist alone. One example is a randomized trial of the anticholinergic agent tolterodine with the alpha-adrenergic blocker tamsulosin that was published in the Journal of the American Medical Association (Kaplan et al. JAMA 2006; 296:2319-28). Another is a comparison of the alpha-adrenergic blocker doxazosin with or without tolterodine that was published in the British Journal of Urology (Lee et al. BJU 2004;94:817-20).

In the JAMA study, 172 men at 95 urology clinics in the United States were randomized to placebo, extended-release (ER) tolterodine 4 mg, tamsulosin 0.4 mg, or both. For entry, patients were required to have a total International Prostatic Symptom Score (IPSS) of 12 or higher and urinary symptoms that included at least eight micturitions per 24 hours of which at least three episodes involved urgency. Urinary incontinence was not a required inclusion criterion. Symptom scores, patient perception of benefit and medication tolerability were included among outcome measures.

For essentially all measures of benefit, the combination of the two active treatments was superior to either agent alone or to placebo. The mean reduction in urinary frequency was 2.54 episodes per 24 hours vs. 1.41 episodes for placebo (P<0.001). The mean reduction in urgency episodes with incontinence was reduced 0.88 episodes per 24 hours vs. 0.31 on placebo (P=0.005). There were also significant reductions in urgency episodes without incontinence and number of micturitions per night. These improvements were reflected in a greater improvement in mean IPSS (-8.02 vs. -6.19; P=0.003) and patient-perceived benefit (80% vs. 62%; P<0.001).

Importantly, the improvements in symptoms were achieved with a low risk of adverse events, including acute urinary retention. The incidence of this latter side effect was 0% with the placebo and 0.4% with the combination. Dry mouth was reported by 21% of patients on the combination vs. 2% on placebo, but other adverse events commonly associated with anticholinergic agents, such as constipation or somnolence, were comparable in active treatment groups vs. placebo. The incidence of all of these side effects was less than 5% on either active therapy or placebo.

The BJU study used a very different design, testing the addition of tolterodine to an alpha-adrenergic receptor blocker. In this prospective study of 144 men at a tertiary-care urology centre in Korea, urodynamic studies were conducted prior to treatment in subgroup patients with BOO or BOO plus OAB. OAB was defined as the presence of involuntary detrusor contractions. All patients were initiated on doxazosin 4 mg/day for three months. If symptoms were not controlled, tolterodine 2 mg b.i.d. was added. Symptoms were then reassessed at the end of another three months on both therapies.

Consistent with population-based estimates, 47% of the men with symptomatic BOO in this study also had OAB according to the urodynamic evaluation. It is notable that those with both conditions were significantly older (mean age of 68.5 vs. 63.1 years; P=0.001), had a higher mean IPSS (25.5 vs. 21.5; P=0.001) than those with BOO alone.

Of the 76 men with BOO only, 79% had a symptomatic improvement on the alpha-adrenergic blocker. In contrast, only 35% of the 68 men with both BOO and OAB reported a symptomatic improvement after taking doxazosin for three months. However, 73% of these non-responders did have a symptomatic improvement when tolterodine was added. The investigators also observed that 38% of the BOO patients who did not respond to the alpha-adrenergic blocker, all of whom went on to receive tolterodine, also responded with the addition of the anticholinergic agent.

Again, tolerability to the combination was reassuring. Acute urinary retention was observed in 3.3% of those receiving both drugs, but it resolved within 24 hours of discontinuing therapy. Dry mouth was again common, reported by 27% of patients, but other side effects, such as dizziness and postural hypotension, occurred in 2% of patients or less with little difference between the incidences on the combination vs. doxazosin alone.

These data are consistent with a growing number of studies that suggest the need for a re-evaluation of LUTS management in men. The common perception that the risk of urinary retention provides a relative contraindication for anticholinergic drugs in aging men has been shown to be unwarranted. Rather, these compounds may play an important role in controlling symptoms or improving the symptom control achieved with alpha-adrenergic blockers. Although better methodologies to distinguish OAB from BOO on clinical evaluation would be helpful, an empirical approach to management is reasonable. The essential step is to consider OAB in men with LUTS who do not achieve acceptable storage symptom control on BPH treatment.

Conclusion

The high prevalence of prostate enlargement in older men is well recognized, but up to 60% of men who present with LUTS, such as frequent awakenings due to urinary urgency, have OAB either as an independent or coexisting condition. Although concern about the risk of urinary retention has produced reluctance to employ anticholinergic agents in aging men, controlled studies, most of which are up to 12 weeks in duration, indicate that the risk of this complication is low and that these agents are generally well tolerated. Anticholinergic agents can play an important role alone in selected patients or in addition to alphaadrenergic blockers and 5-alpha reductase inhibitors in LUTS control. Clinicians should remain alert to the contribution of OAB in aging men.

Questions and Answers With:

Greg Bailly, MD, FRCSC • Sender Herschorn, MD, FRCSC • Kevin V. Carlson, MD, FRCSC • Martine Jolivet-Tremblay, MD, FRCSC

Q. Is OAB defined differently in men than it is in women?

Dr. Carlson: The International Continence Society (ICS) characterizes OAB as “urgency, with or without urge incontinence, usually with frequency and nocturia.” The definition is not gender-specific.

Dr. Bailly: The definition of OAB is the same in men and women. However, one potential source of confusion is that the predominant etiologies for OAB may differ.

Dr. Herschorn: Whether it is a male or a female presenting with OAB, the primary symptom is urgency, and this is critical for distinguishing OAB from other conditions. I think one weakness with the current ICS definition is that it requires other causes to be ruled out. Although this caveat reminds physicians to exclude urinary tract infection (UTI) as a source of symptoms, OAB may be seen alone or in association with various lower urinary tract problems such as BPH in men and pelvic floor dysfunction in women.

Dr. Vézina: Although the definition of OAB is the same for men and women, I think physicians should not ignore the fact that men with OAB often have obstruction as well.

Q. What is the proper use of the term LUTS—lower urinary tract symptoms—in relation to OAB?

Dr. Jolivet-Tremblay: LUTS encompasses all voiding and filling problems encountered in patients regardless of gender, not just OAB. With regard to filling symptoms, the most significant in terms of bladder overactivity are frequency, nocturia, urgency and urgency incontinence. With regard to voiding symptoms, the most significant are weak stream, impression of incomplete emptying, postmicturition dribble, dysuria, hesitancy and intermittency.

Dr. Vézina: LUTS is often a more appropriate term to describe symptoms because it refers to the presence of any urinary tract complaint rather than a specific pathology. OAB is just one of the symptom complexes within LUTS.

Dr. Bailly: LUTS is an umbrella term for any lower urinary tract symptom, including symptoms of impaired storage or voiding. OAB refers to the storage component of LUTS, such as the urgency and frequency.

Q. The definition of OAB may be the same in men and women, but are there differences in the way men and women present with this complaint?

Dr. Vézina: When referring strictly to OAB in the absence of obstructive symptoms, the presentation is no different in men than it is in women, except men tend to report fewer episodes of incontinence in the context of urgency.

Dr. Jolivet-Tremblay: In general, voiding symptoms are more frequent in men than in women. However, I find that the symptoms of OAB are less well tolerated in men than in women. In particular, episodes of incontinence appear to be a much bigger problem for men than women.

Dr. Herschorn: Of referrals at our centre that turn out to have OAB, we find that most females were initially sent to resolve bladder problems while most males were initially sent for prostate problems. This demonstrates the prevailing prejudice that most urinary complaints in men are due to the prostate even if their chief complaint is urgency. Men do seem to be more bothered by OAB symptoms, particularly those that occur at night, than women, but I think the preconceptions about the symptoms are more different than the actual presentation.

Q. In men who present with symptoms involving urinary urgency, with or without obstruction, what is the first step in diagnosis? How often does prostate enlargement and OAB coexist?

Dr. Jolivet-Tremblay: If urgency is the main symptom, OAB should be considered, but a careful history is essential, because about two-thirds of men with OAB also have prostate enlargement. This means that it is important to ask about hesitancy, flow, and other issues that will provide insight about voiding. It is also important to ask about lifestyle. For example, if someone is drinking eight cups of coffee per day, this may in part explain symptoms.

Dr. Bailly: It is important to recognize that OAB can be present in the presence or absence of bladder outlet obstruction. Patient history and symptoms are an important guide. If a patient reports a good strong flow and no voiding problems in the context of obstruction, I think it is reasonable to address OAB first. More often, men with urgency also present with some degree of voiding symptoms as well. In these patients, it is critical to address all of the problems that may be contributing to symptoms.

Dr. Vézina: I think that both conditions often coexist, but I still think it is useful to consider prostate issues first, particularly if there are any voiding symptoms. In such patients, a first-line treatment for the prostate, such as alpha-blockers, may solve the problems due to voiding in order to more clearly reveal those problems due to OAB.

Dr. Herschorn: The symptoms based on history should provide the guidance for which issue to address first. Some men, particularly younger men, may have OAB without any prostate enlargement. In 2007, I think most physicians will still think of prostate problems first in men, but physicians should not overlook OAB as the primary or contributing factor for symptoms.

Dr. Carlson: Many men with prostate enlargement often have a combination of storage, micturition and postmicturition symptoms. This makes it difficult to develop one protocol for diagnosis in all patients. In one of the better studies looking at this issue, just under half of 144 men identified with urodynamically confirmed BOO had detrusor overactivity (DO). While we do not know how many of these patients had primary idiopathic OAB not directly related to their BOO, it is interesting to observe that 73% of those men with both BOO and DO who did not originally respond to alpha-blocker therapy alone did respond to an anticholinergic.

Q. Are objective tests needed to diagnose OAB or differentiate OAB from prostate enlargement, or is it sufficient to treat symptoms empirically?

Dr. Bailly: When the history does not suggest a predominant obstructive complaint, I consider an empirical trial of an anticholinergic agent to be appropriate to treat the OAB symptoms. However, it is the minority of patients who have pure OAB symptoms. In patients with symptoms of OAB and BOO symptoms, I would consider first empiric treatment with an alpha-blocker. A simple uroflowmetry test might aid in the diagnosis, and rarely, more complex urodynamic evaluations or other objective studies are necessary to differentiate OAB from BOO. Symptom questionnaires and voiding diaries are also helpful.

Dr. Carlson: It is reasonable to initially treat symptoms empirically, after first ruling out significant retention and prostate cancer by the usual methods. Initial work-up should include a focused history, physical examination and urinalysis. I typically administer an IPSS questionnaire to all patients. Although not required, voiding diaries are often helpful. It is reasonable to get a prostate-specific antigen (PSA) as indicated. Flow and post-void residual measurements are done when voiding symptoms are prominent, but these are not needed in all patients. Pressure-flow studies and cystoscopy are reserved for refractory or complex cases.

Dr. Jolivet-Tremblay: Questionnaires, which have now been validated in several languages, can be considered objective tests. More sophisticated tools may not be needed. For example, urinary flowmetry can be helpful for monitoring patients but it is not helpful for diagnosis because it has poor specificity. Urodynamics is useful to confirm uninhibited bladder contractions which are characteristic of OAB, but there is probably only about a 50% chance that contractions will occur when the test is being conducted.

Dr. Vézina: A urodynamic evaluation with pressureflow measurement can be helpful. These can reveal a low flow in obstructive conditions, while the flow will be normal in non-obstructive conditions. However, a questionnaire is often sufficient to confirm that the patient has a normal stream and that he does not have an obstruction. The OAB can then be treated empirically.

Q. Is treatment for OAB in men evidence-based? Are there controlled studies?

Dr. Carlson: Three small independent studies deserve credit for opening our eyes to the clinical efficacy and safety of anticholinergic agents in men with OAB. These are a study by Athanasopoulos et al. published in the Journal of Urology in 2003, a study by Lee et al. published in the British Journal of Urology in 2004, and a study by Kaplan et al. published in the Journal of the American Medical Association in 2006. Each was conducted with the anticholinergic agent tolterodine with or without an alpha-blocker. All showed significant improvement in symptoms in a substantial proportion of patients. There have been at least four subsequent studies, not all of which have been published, corroborating benefit from an anticholinergic agent vs. an alpha-blocker alone in men with OAB. Most studies have been conducted with tolterodine, but one study evaluated oxybutinin.

Dr. Vézina: The majority of studies so far have been conducted with tolterodine. Typically, this anticholinergic has been studied as an adjunct or as an alternative to alpha-blockers. However, the IMPACT study by Roberts et al. in the International Journal of Clinical Practice in 2006 evaluated tolterodine alone in men with persistent OAB. Again, tolterodine demonstrated a highly significant benefit relative to placebo.

Dr. Bailly: Most of these data supporting anticholinergic therapy for the treatment of OAB in men have become available in the last few years, the majority evaluating the use of tolterodine. Although there are a number of controlled studies which have shown that anticholinergic therapy is safe and effective for OAB in men, longer-term studies are needed.

Dr. Herschorn: One noteworthy observation from the controlled trials is that the incidence of urinary retention has been no higher when the anticholinergic drug is added to the alpha-blocker relative to the alpha-blocker alone. This refutes one of the major concerns about using these agents in men. While most of the studies have only been conducted over a 12-week period, which means we do not know much about the long-term safety of anticholinergics in this population, the data do suggest they are safe for treatment over several months, at least.

Q. The classic training is that anticholinergic agents should not be used in patients with prostate problems because of the risk of urinary retention. Is this still an issue now that several studies have failed to confirm this risk?

Dr. Jolivet-Tremblay: No. I feel that studies to date have clearly established that the risk of retention is low. The risk is the same as that in the general population.

Dr. Bailly: Certainly the dogma has been to use anticholinergic agents cautiously in men with prostate enlargement because of the risk for urinary retention, but this notion has been challenged by the controlled studies, and I find these data convincing. No study has supported this risk.

Dr. Herschorn: The data are clearly reassuring even in men who have BPH in addition to their OAB. Again, I think longer studies are needed, but the acute risk of this complication has not been demonstrated.

Dr. Vézina: In my opinion, I do not think the potential for urinary retention has been entirely discounted. However, the studies do demonstrate that these agents can be used safely when there are no obstructive symptoms. The risk of acute retention appears to be low, but I still think the residual urine should be checked after a few weeks of treatment.

Dr. Carlson: No study has associated anticholinergic agents with urinary retention, even in men with proven obstruction. Basically, retention rates after this therapy has not been significantly greater than the background rate of urinary retention or the rates associated with placebo. However, all of the studies conducted so far have been of short duration. Longer follow-up is needed. As a result, I still think these agents should be used with caution long-term.

Q. In patients suspected of both OAB and enlarged prostate, is there an order in which they should be treated?

Dr. Herschorn: Symptoms should be an important guide. In an older man presenting with urinary symptoms, I think clinicians cannot help but consider the contribution of an enlarged prostate, but if urgency is an important part of the clinical picture with no history of voiding problems, then it is reasonable to switch focus to OAB as the root of the problem.

Dr. Bailly: It is important not to develop preconceptions about men with urinary complaints. Each patient is different. More than half the time, particularly in older men, urgency symptoms suggesting OAB are accompanied with symptoms of bladder outlet obstruction. If urgency and frequency are the predominant complaints and my suspicion of obstruction is low, I will initiate treatment for OAB with an anticholinergic. In patients with both storage and voiding symptoms, I usually start with an alpha-blocker in an attempt to relieve the obstructive component first; then I may add or substitute an anticholinergic drug when I have a better idea of the contribution of OAB. This could be done the other way around, but I am hesitant to start two medications simultaneously, particularly in an elderly population.

Dr. Jolivet-Tremblay: I think it depends completely on symptoms. Even though we have traditionally initiated treatment in males with alpha-blockers, the data do not necessarily support this as the best approach.

Dr. Vézina: I still believe we should start with an alpha-blocker. An alpha-blocker often relieves some of the OAB symptoms, and then the anticholinergic can be added later if needed.

Dr. Carlson: There are no clear guidelines at this time but anecdotally, I think many clinicians now approach the obstructive component first with an alpha-blocker, a 5-alpha reductase inhibitor (5ARI) or both, and then add or switch to an anticholinergic agent if OAB symptoms persist. I think this is a reasonable approach, although better guidelines are needed.

Q. In relatively young patients, would you be more willing to consider a therapy for OAB rather than a therapy for prostate enlargement, such as an alphablocker, as first-line because of the higher probability that OAB is the problem? Is there any group for whom you would consider OAB treatment as first-line?

Dr. Vézina: I really have no problem to start with an anticholinergic in men under age 55 with OAB symptoms.

Dr. Jolivet-Tremblay: I treat OAB first-line, regardless of age, if LUTS are mostly filling-related.

Dr. Bailly: The fact that the patient is relatively young does not rule out obstruction as a contributing factor. This is true not least of all because an enlarged prostate is not the only cause of obstruction. For example, even young men may have a functional obstruction of the bladder neck. I am probably more willing to consider OAB as an isolated diagnosis in younger men, but I think a careful history should direct therapy at any age.

Dr. Carlson: In a young man with predominant OAB symptoms, I am still in the habit of ruling out neurologic disease or bladder pathology first, but I think I am more prepared to consider treatment with anticholinergic agents earlier. However, I think this area may be evolving, and my thoughts on this may change as I continue to evaluate and reflect on the data and on my practice.

Q. Do you feel treatment guidelines for OAB in men would be helpful?

Dr. Herschorn: I think the studies conducted over the last several years have generated enough data to formulate guidelines, and this is something that should be undertaken by one of the large urology societies, such as the American Urological Association. I think such guidelines could be very useful for rational patient management.

Dr. Vézina: Many or most urologists are already making the types of clinical decisions that would be advocated in guidelines, but I think diagnosis and treatment recommendations for LUTS could be very helpful to the general practitioner.

Dr. Bailly: The recent data have really changed the way we approach LUTS in men. The concept that anticholinergic agents can be used in men with OAB is a new way of thinking that will take some time to trickle down to the non-specialists. Guidelines could be very useful in changing practice habits.

Dr. Jolivet-Tremblay: We are lacking formal recommendations for the management of OAB in men, but many experts have been providing recommendations informally at national and international medical meetings that are based on the growing amount of published data that have become available over the last several years. Better management of OAB has important implications for improving quality of life. I think it is important to develop recommendations based on the published data as well as continue to conduct clinical research, particularly into the long-term safety of current treatments.

Q. Can family practitioners adequately manage male OAB if given appropriate guidance about diagnosis and therapy?

Dr. Carlson: Absolutely. They simply need to know that men can have OAB just as women do, and that anticholinergics are safe for the treatment of OAB in men, at least in the short term.

Dr. Bailly: The concepts are fairly straightforward. At least for first-line therapies, such as alpha-blockers and anticholinergic agents, there is no reason why a family physician cannot manage this problem adequately, referring complicated patients or non-responders to a specialist.

Dr. Vézina: Of course they can. They only need adequate information about symptoms, the efficacy of current treatment strategies, and when to refer in the event of a complicated patient.

Q. In patients with OAB and enlarged prostate, what would you recommend for follow-up? Would you routinely monitor for urinary retention?

Dr. Bailly: I ask patients to return in two or three months to review their symptoms. For those in which there is some doubt, I may perform uroflowmetry and measure residual urine. I also often ask patients to keep a voiding diary and to complete symptom questionnaires to ensure that voiding symptoms remain controlled.

Dr. Carlson: My typical follow-up is an office visit at three months in which I take a history and administer an IPSS questionnaire. While I want to confirm the response to and the tolerability of treatment, I would only monitor for retention if there were increasing micturition symptoms.

Dr. Vézina: In my mind, it is mandatory to look for urinary retention even though the risk is low. If it occurs, I think urinary retention is most likely to occur within the first two months, so I would request that the patient return at the end of this period. I use a bladder scan to check for urinary retention, although a bladder catheterization could be considered if a scan is not available.

Dr. Jolivet-Tremblay: I think patients should be closely followed. I ask the patient to schedule a return visit within two months. If symptoms are well controlled, follow-up visits are scheduled every six months. Follow-up is quite simple. In my patients, I administer a questionnaire about symptoms and perform a physical examination. If in doubt, a bladder scan may be reassuring, but I do not perform this routinely. In general, clear advice to patients about the likely benefit of treatment can help manage expectations.

Q. What do you feel is the biggest misconception about OAB in men?

Dr. Herschorn: The perception that OAB is not a common disorder in men and that anticholinergics should not be used in this population.

Dr. Vézina: That general practitioners are not suited to monitoring and treatment of these conditions.

Dr. Jolivet-Tremblay: That all urinary symptoms are the result of prostate obstruction and that if patients are prescribed anticholinergics, they will end up in the ER in the middle of the night with urinary retention!

Dr. Carlson: That LUTS in men is almost always secondary to prostate conditions and that anticholinergic agents are not safe to use in male patients.

Dr. Bailly: That the enlarged prostate is the probable cause of all urinary symptoms in men. The data indicate that we have probably “missed the boat” on this for many years. However, with evidence that anticholinergics are effective the treatment of OAB in men, I think we now have an opportunity to improve quality of life in a large proportion of men who have OAB alone or OAB on top of symptoms driven by an enlarged prostate. -