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PRIORITY PRESS - 104th Annual Meeting of the American Urological Association

Chicago, Illinois / April 25-30, 2009

Overactive bladder (OAB) in men is underappreciated as a source of lower urinary tract symptoms (LUTS), which most often are attributed to benign prostatic hyperplasia (BPH). Despite its prevalence, OAB often goes untreated, according to the results of various surveys. “Historically, BPH and prostatism have been used to describe male LUTS, and the term OAB has been reserved mostly for women. These terms are no longer adequate to describe the range of symptoms presenting in patients,” stated Dr. Brian Helfand, Department of Urology, Northwestern University, Chicago, Illinois.

Recent data support the safety and efficacy of adding an antimuscarinic agent to a 5-alpha-reductase inhibitor (5-ARI) to treat OAB in men with larger prostates. A new study presented here reveals that extended-release (ER) tolterodine in combination with dutasteride was well tolerated and reduced micturition frequency in men with large prostates.

EpiLUTS: Measuring OAB Symptom Prevalence

A population representative survey carried out in the US, the UK, and Sweden found that OAB is highly prevalent in men yet seldom treated. Participants in the EpiLUTS trial were asked how often they had urinary symptoms during the past four weeks using a 5-point Likert scale: “never,” “rarely,” “sometimes,” “often” and “almost always.” The prevalence of urinary urgency incontinence was assessed with a “yes/no” questionnaire.

Twenty-two per cent of men in Sweden, 24% in the UK and 27% in the US reported having OAB symptoms at least sometimes; 13% in Sweden and the UK and 16% in the US reported having such symptoms often or almost always. The prevalence of OAB symptoms rose with increasing age. Less than 30% of those affected sought treatment for their symptoms, noted lead investigator Dr. Karin S. Coyne, Center for Health Outcomes Research, United BioSource Corporation, Bethesda, Maryland.

“About 60% of men said they were bothered somewhat or more by their urgency,” she reported. “A lot of people may have LUTS for which they are not seeking treatment. As a matter of assessing bladder health, it’s good to ask patients, especially older patients, if they are having urinary symptoms and their level of bother.”

She presented other data derived from the same survey showing that OAB in men was associated with diminished sexual health and a greater prevalence of erectile dysfunction, ejaculation dysfunction and premature ejaculation, and advised the assessment of sexual health in men who present with OAB.

Comorbidities Affect Physicians’ Treatment Decisions

Analysis of pharmacy claims data from 90 US healthcare plans shows that older men with comorbidities are more likely to receive treatment for symptoms related to OAB. Prescription data were drawn from more than 3.2 million men 45 years and older who were diagnosed with OAB.

“Only about 19% of men with OAB and BPH in the US are being treated medically, which is significantly lower than the same population of women,” observed Dr. Helfand, lead investigator of the analysis. “If you look at all causes of OAB, only 17% of men are being treated as opposed to about 25% of women.”

The percentage of men who received treatment with medical agents increased with age: 11% of men 45 to 54 years, 14% of those 55 to 64 years, and 21% of those 65 years and older. Those with BPH, diabetes or hypertension were significantly more likely to receive treatment than those without comorbidities. “We should be paying closer attention to men with OAB, who actually can be treated medically,” he told delegates.

The Option of Antimuscarinics

The combination of dutasteride, a 5-ARI, and tolterodine ER, an antimuscarinic, was significantly better than the 5-ARI alone on several measures of efficacy for persistent OAB symptoms in men with LUTS and prostates larger than 30 g in whom previous alpha-blocker (AB) therapy failed, Dr. Doreen Chung, Department of Urology, Weill Cornell Medical College, New York City, told attendees.

In the study, 51 men (mean age: 64.3 years) with persistent OAB symptoms despite treatment with the 5-ARI 0.5 mg for at least three months were given open-label tolterodine ER 4 mg/day. To be eligible for the study, men had to have an International Prostate Symptom Score (IPSS) of 12 or greater, an IPSS quality of life item of 3 or greater, diary-documented micturition frequency of at least 8 voids per 24 hours, urgency (three or more episodes per 24 hours) with or without urinary incontinence, and a self-rated bladder condition of at least moderate bother.

Three-day micturition diaries were completed prior to dutasteride initiation (baseline) and at week-12 visits in order to evaluate treatment-related changes from baseline to week 12 and to assess efficacy. Prior to being treated with the 5-ARI, all 51 men had been on an AB, which failed to control symptoms and which was discontinued before they started on dutasteride. Prostate volume at baseline was a mean of 54.3 mL.

At baseline, IPSS was 19.3, which decreased to 14.3 following three months of dutasteride, and decreased further, to 7.1, with the addition of tolterodine ER (P<0.001). The storage symptom component of the IPSS decreased from 9.8 at baseline to 8.3 on dutasteride followed by a further decline to 3.5 with the addition of tolterodine ER (P<0.01). The IPSS voiding component declined from 9.8 at baseline to 6.0 on dutasteride and 3.6 following tolterodine ER (P<0.001). Twenty-four hour frequency (P<0.01) and nighttime frequency (P<0.001) also declined significantly from baseline with combination therapy. A similar pattern was observed for daytime and nighttime urgency.

Adding tolterodine ER to dutasteride was safe: there were no significant changes in postvoid residual or peak flow between the combination and 5-ARI monotherapy. Urinary retention has been a theoretical concern with the medical treatment of OAB in men, but no patient in this study suffered urinary retention.

Sexual dysfunction occurred in three patients on dutasteride monotherapy and the same three patients experienced sexual dysfunction on the combination. There were four cases of dry mouth with combination therapy compared to one with 5-ARI monotherapy.

In Support of TIMES

The results of this study are consistent with those of the previously reported TIMES (Tolterodine and Tamsulosin in Men with LUTS including OAB) study, in which the combination of tolterodine ER and tamsulosin was superior to placebo and to either monotherapy in reducing symptoms in men with both BPH and OAB.

“A subanalysis of TIMES demonstrated that in patients with smaller prostates or with a low prostate-specific antigen (PSA), treatment with tolterodine alone provided benefit, but patients with larger prostates required an AB in addition to tolterodine to improve their symptoms,” indicated Dr. Chung.

According to the senior investigator Dr. Steven A. Kaplan, Department of Urology, Weill Cornell Medical College, “In patients with larger prostates with predominant persistent urgency symptoms, instead of adding an AB to a 5-ARI, it may be another option to add an antimuscarinic.” He noted that in general, antimuscarinics alone might not work as well to control symptoms in men with larger prostates.

Decreasing OAB Symptoms

In TIMES, tolterodine monotherapy was effective at relieving LUTS when prostate size and/or PSA levels were relatively small/low. When PSA levels rose or the prostate was larger, combination therapy became optimal. These results were also confirmed recently at the annual meeting of the European Urological Association in Stockholm, where Dr. Christopher Chapple, Department of Urology, The Royal Hallamshire Hospital, Sheffield, UK, presented data from a randomized trial of tolterodine ER in men OAB symptoms who were already being treated with an AB.

Men in the study had at least moderate OAB symptoms despite treatment for at least one month with an AB. They were randomized to tolterodine or placebo while continuing on their AB. The data were stratified by the median baseline PSA level (<1.41 ng/mL and <u>></u>1.41 ng/mL).

Tolterodine was associated with a reduction in OAB symptoms compared to placebo regardless of baseline PSA levels. Compared with placebo plus an AB, combination therapy with tolterodine and an AB significantly improved daytime micturitions and 24-hour urgency in men with lower and higher baseline PSA levels. The rate of acute urinary retention requiring catheterization was low in cohorts who were treated either with an AB alone or with tolterodine plus an AB.