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.

102nd Annual Meeting of the American Urological Association

Anaheim, California / May 19-24, 2007

As stated here at the AUA meeting by Dr. Alexis E. Te, Director, Brady Prostate Center and Co-Director, Urodynamics, New York Presbyterian Hospital, and Associate Professor of Urology, Weill Medical College, Cornell University, New York, the pathophysiologies of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) are inextricably intertwined.

Pathophysiology

Changes in prostate size and muscle tone affect urine flow through the prostatic urethra, narrowing the flow and creating bladder outflow obstruction. This functional urodynamic obstruction produces compensatory changes in the bladder that result in increased bladder pressure to overcome the obstruction. The increased pressure results in progressive detrusor hypertrophy with a resulting decrease in compliance and capacity over time. Detrusor overactivity can arise from a similar process.

LUTS and overactive bladder (OAB) share certain pathophysiologic features. A growing volume of evidence suggests that LUTS evolves secondary to bladder outlet obstruction, which can also cause detrusor instability and lead to symptoms of OAB (Kaplan SA. Rev Urol 2006;8:14-22, Mirone et al. Eur Urol 2007;51:57-66, Greenland JE, Brading AF. J Urol 2001;165:245-8, Harrison et al. Br J Urol 1987;60:519-22). The International Continence Society defines OAB as urgency with or without urge incontinence, usually with frequency and nocturia (Abrams et al. Neurourol Urodyn 2002;21:167-78). The hallmark symptom of OAB is urgency, which to this day remains difficult to define, even for experts in the field.

OAB Not Gender-Specific

For years, OAB had been considered a women’s health issue, and research in the field had been focused accordingly, noted Dr. Claus Roehrborn, Professor and Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas. However, recent studies have documented conclusively that OAB affects men as well as women.

“In fact, OAB may be just as common in men as in women, and men appear to experience just as much bother from OAB as women do,” Dr. Roehrborn told delegates.

A four-country survey documented a growing prevalence of urinary incontinence in men, accompanied by increasing use of absorbent pads (Boyle et al. BJU Int 2003;92:943-7). The study also demonstrated that urge symptoms had the greatest impact on quality of life.

“In fact, some evidence has indicated that urge causes more impairment in health-related quality of life in men than in women,” Dr. Roehrborn remarked.

The prevalence of urge and incontinence in men might be underestimated, he continued. The four-country study showed that many men are reluctant to discuss incontinence, pad usage and related issues with their physicians.

A study of urinary incontinence, OAB and LUTS in five countries revealed the same symptomatology in almost two-thirds of study participants (Irwin et al. Eur Urol 2006;50:1306-14). Although LUTS in men typically has been associated with voiding dysfunction, an examination of LUTS prevalence in the five-country analysis showed that more than 50% of men studied reported storage-related problems and half of those individuals reported voiding problems.

Storage and voiding problems often occur together, confirmed Dr. Roehrborn. In one recent study, approximately two-thirds of men reported having both types of symptoms (Abrams et al. Urology 2003;61:28-37).

Implications for Therapy

Historically, clinicians have had two options for management of urinary symptoms in men secondary to BPH: alpha-blockers and 5-alpha reductase inhibitors (5ARIs). Both classes of drugs have evidence to support their efficacy in male LUTS, but the landmark VA Cooperative Study appeared to signal the end of 5ARI use in this therapeutic field (Lepor et al. N Engl J Med 1996;335:533-8). The trial showed that treatment with an alpha-blocker significantly improved urinary symptoms compared to placebo, but treatment with a 5ARI did not, reported Dr. Roehrborn. Moreover, adding a 5ARI to an alpha-blocker did not appear to improve symptom control over the use of an alpha-blocker alone.

However, Dr. Roehrborn subsequently performed a meta-analysis of trials of 5ARI therapy and found that the 5ARI finasteride (the only available drug in the class at the time) effectively relieved urinary symptoms in properly selected men, namely, those with larger prostates (Roehrborn C. Urology 1998;51:46-9). Conversely, the VA Cooperative Study involved men with smaller prostates.

The meta-analysis was followed by publication of data from the Medical Therapy for Prostatic Symptoms (MTOPS) study, which showed that a 5ARI, an alpha-blocker or the combination of the two prevented progression of BPH symptoms. However, only the 5ARI and the combination therapy prevented progression to the most serious complications of BPH: acute urinary retention and need for invasive therapy (McConnell et al. N Engl J Med 2003;349:2387-93).

“The VA Cooperative Study had a shorter follow-up than the MTOPS trial,” explained Dr. Roehrborn. “The longer follow-up demonstrated the long-term benefits of combination therapy, which had not been evident in the VA Cooperative Study.”

An Emerging Role for Antimuscarinics

The recognition that men develop OAB as often as women do has raised questions about available therapies, specifically, whether an agent used to treat OAB in women would also work in men. A strongly affirmative answer has emerged from studies of tolterodine, according to Dr. Steven A. Kaplan, Chief, Institute for Bladder and Prostate Health, New York Presbyterian Hospital, and Professor of Urology, Weill Medical College.

In one preliminary study, the alpha-blocker doxazosin was evaluated with and without tolterodine in men with symptomatic bladder outlet obstruction and OAB (Lee et al. BJU Int 2004;94:817-20). The results showed that almost three-quarters of men with bladder outlet obstruction and OAB who did not respond to doxazosin alone experienced significant symptomatic improvement when tolterodine was added. He cited a similar clinical investigation from Greece which yielded comparable findings (Athanasopoulos AA, Perimenis PS. BJU Int 2005;95:1117-8).

Combination Therapy Outcome

Subsequently, a number of other reports confirmed the efficacy of tolterodine in men with OAB. Most recently, Drs. Kaplan and Roehrborn and their collaborators reported encouraging results when the antimuscarinic was used in combination with the alpha-blocker tamsulosin to treat LUTS and OAB in men (Kaplan et al. JAMA 2006; 296:2319-28).

“We now have very good evidence that tolterodine can relieve symptoms of LUTS and OAB in men and that the agent is well tolerated,” stated Dr. Kaplan.

He and colleagues reported results on its effects in an extended-release formulation, with or without tamsulosin, on bladder diary variables of men with LUTS, including OAB. The four-arm study involved almost 900 men with BPH and OAB who were randomized to one of four treatment arms for 12 weeks: placebo, tolterodine, tamsulosin or combination tamsulosin/tolterodine. The primary end point was treatment benefit reported at 12 weeks .

Outcome variables assessed included daily urgency episodes, daily urge urinary incontinence episodes, 24-hour micturitions and micturitions per night. Both monotherapies demonstrated efficacy vs. placebo but the combination achieved the most robust and consistent effects. “These data suggest that men with LUTS, including OAB, may benefit more from dual therapy with an alpha-receptor antagonist and an antimuscarinic agent than from either treatment alone,” Dr. Kaplan concluded.

Dr. Roehrborn reported data from the same study, focusing on effects of therapy on the International Prostate Symptom Score (IPSS) (Table 1). The change in IPSS at 12 weeks was a secondary outcome, whereby patients rated how frequently they were bothered by seven different LUTS symptoms on a scale of 0 (not at all) to 5 (almost always). Additionally, they answered a quality-of-life question: “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?” Response options ranged from 0 (delighted) to 6 (terrible).

Table 1. IPSS Scores

By the end of the study, the combination of tolterodine and tamsulosin significantly improved total IPSS and storage subscale scores vs. placebo. Tamsulosin monotherapy significantly improved total and voiding subscale scores. The combination also significantly improved all storage symptoms.

All of the active treatments were well tolerated. The incidence of acute retention was low in men treated with tolterodine, alone or in combination with tamsulosin.

“Only the combination significantly improved the IPSS quality of life vs. placebo,” Dr. Roehrborn commented. “On the basis of these results, we can conclude that treatment with tolterodine and tamsulosin significantly improved LUTS and associated symptom bother.”

A third study was reported at the World Chinese Urological Society meeting during the AUA. Researcher Dr. Zhonghong Guan, New York, New York, presented updated findings reported last year by Kaplan and colleagues (Kaplan et al. JAMA 2006).

The updated report confirmed the efficacy of tolterodine in men with BPH and LUTS, regardless of whether the antimuscarinic agent was used alone or in combination with tamsulosin.

Dr. Guan reported that combination therapy achieved the best results vs. placebo. Tolterodine monotherapy was more efficacious than placebo with respect to urge urinary incontinence episodes, and tamsulosin demonstrated superiority to placebo on the total IPSS score and the subscale focusing on voiding dysfunction. Dr. Guan indicated that the results also showed that tolterodine was effective in men with either small or large prostates.

Other Strategies

In addition to antimuscarinics, the phosphodiesterase type 5 inhibitors, used widely in the treatment of male erectile dysfunction, have attracted interest as therapy for LUTS and OAB. The interest has evolved from evidence that LUTS secondary to BPH and erectile dysfunction might share a common pathophysiologic pathway, explained Dr. Kevin McVary, Center for Genetic Medicine, Associate Professor of Urology, Northwestern University, Chicago, Illinois.

Here at the AUA meeting, Dr. McVary reported findings from a multicentre, placebo-controlled clinical trial of sildenafil in men with erectile dysfunction and concomitant LUTS which was moderate or severe in intensity. The patients received placebo or sildenafil 50 mg nightly or one hour before sexual activity. After 12 weeks of treatment, 16% fewer men taking active treatment had severe LUTS compared to baseline vs. 4% of the placebo group. Among patients with moderate LUTS upon enrolment, 57% of the active treatment cohort improved from moderate to mild LUTS, compared to 36% of the placebo group (P<0.0001). Peak urinary flow did not improve during treatment.

Reported Dr. McVary, “The improvement in LUTS correlated with improvement in erectile function scores. Although this trial did not have an active comparator, the improvement in IPSS for men with moderate and severe LUTS appears to be comparable to that achieved with alpha-blockers and 5-ARIs.”

In addition, researchers presented clinical studies of tadalafil and vardenafil which also demonstrated evidence of efficacy for treatment of men with LUTS. The vardenafil study involved men who did not have a history of erectile dysfunction at enrolment.