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103rd Annual Meeting of the American Urological Association

Orlando, Florida / May 17-22, 2008

It is estimated that 60% of men who present with lower urinary tract symptoms (LUTS) have symptoms of an overactive bladder (OAB) either as an independent or co-existing condition. More evidence presented here supports a combination strategy consisting of an antimuscarinic agent plus an alpha-blocker for superior relief of LUTS compared with an alpha-blocker alone if men also have OAB symptoms.

Findings corroborate growing evidence that some—although not all—antimuscarinics are safe to use in men who have symptoms of urgency, increased daytime frequency, nocturia and urgency urinary incontinence in addition to LUTS if symptoms are poorly relieved with alpha-blockers alone. “Therapy with alpha-blockers is the standard of care for men with LUTS, but they may not effectively relieve urgency and frequency if these LUTS are related to the OAB syndrome,” Dr. Sender Herschorn, Professor and Chair, Department of Urology, University of Toronto, Ontario told delegates.

Evidence provided by Kaplan et al. (JAMA 2006; 296:2319-28) suggests extended-release tolterodine can relieve symptoms of LUTS and OAB when used in combination with the alpha-blocker tamsulosin. In the latest study, Dr. Herschorn and colleagues randomized 652 men 40 years of age and older with symptoms of OAB who had been on a stable dose of an alpha-blocker for at least one month. Men received extended- release tolterodine, 4 mg/day or placebo for 12 weeks while continuing on alpha-blocker therapy. Mean age was approximately 65 years, 70% of the cohort were Caucasian, and the mean time from diagnosis of OAB was between 3.6 and 3.8 years.

Participants recorded every micturition and noted whether it occurred with or without urgency urinary incontinence. They also rated the urgency sensation associated with each micturition using a validated 5-point Urinary Sensation Scale (ranging from “no urgency” or “normal desire to void” to “severe urgency”). In addition, subjects were given the International Prostate Symptom Score (IPSS) and the Patient Perception of Bladder Condition (PPBC) scale to rate the severity of their bladder conditions—the primary end point of the 12-week trial.

Investigators also had patients fill out the OAB questionnaire, a symptom bother scale that includes several domains, including coping, concern, sleep and social interaction.

Virtually identical numbers of men at 329 received add-on extended-release tolterodine, while 323 remained on tamsulosin alone. At baseline, there were no differences between the two groups in bladder variables, as Dr. Herschorn noted.

Men had an average of between 11 and 12 micturitions per day, and about six to seven urgency episodes per 24 hours. Only 14% of men in the add-on antimuscarinic arm and 17% of men in the placebo group had a history of urgency urinary incontinence, he added. Mean baseline total index on the IPSS as well as storage and voiding subscales were well matched between the two groups as were measures of quality of life.

At the end of 12 weeks, changes in bladder diary variables favoured the combination extended-release tolterodine/alpha-blocker arm, with fewer micturitions per 24 hours (1.8 fewer) compared with placebo controls at 1.2 fewer episodes (P=0.0079). There were also fewer urgency episodes at -2.9 in the extended-release tolterodine group compared with -1.8 fewer episodes in placebo controls (P=0.0010) and fewer severe urgency episodes per 24 hours at -1.1 episodes in the dual agent arm vs. -0.7 episodes in the alpha-blocker arm (P=0.0495) (Figure 1).

Figure 1. Improvements in Bladder Diary Variables

Mean reductions in total IPSS were also greater for the combination arm at 4.5 points compared with 3.8 points for the placebo arm (P=0.4223), as were reductions in IPSS storage and voiding subscales at 2.6 points and 1.8 points for the extended-release tolterodine add-on arm vs. 1.9 for each of the two domains in the placebo arm (P=0.0370 and P=0.7655, respectively). Regarding improvement in the PPBC scale, the difference between the two arms was not significant, with approximately one-third of each group not noticing any change from baseline, approximately 35% noted a 1-point improvement and approximately 27% noted a 2-point improvement (Fig
Improvements in IPSS

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Several domains on the OAB questionnaire, including symptom bother and coping domains, were significantly greater in the extended-release tolterodine add-on arm (P=0.0086 and P=0.0491 vs. placebo, respectively). Importantly, no significant increase in post-void residual urine or in the Qmax was seen in the antimuscarinic arm, at a mean increase from 13.6 mL vs. 1.0 mL in placebo patients—“not deemed to be clinically significant,” Dr. Herschorn observed. Rates of adverse events suggestive of AUR were identical at six patients (1.8% ) in both groups.

“LUTS in men is primarily treated with drugs that target the prostate so the prostate is responsible for a lot of LUTS,” explained Dr. Herschorn. Nevertheless, there are some patients who either do not need drugs that target the prostate, as they may not have a prostate, or they still have bladder symptoms that do not respond to prostate medication.

With the antimuscarinics working on the bladder and the alpha-blockers on the prostate, “men receiving an alpha-blocker for LUTS who are also reporting OAB symptoms may benefit from the addition of extended-release tolterodine for their OAB symptoms,” Dr. Herschorn concluded.

Antimuscarinic Profile Investigation

According to Dr. Steven Kaplan, Chief, Institute for Bladder and Prostate Health, New York Presbyterian Hospital and Professor of Urology, Weill Medical College, New York, if AUR does not seem to be clinically significant with extended-release tolterodine over the short term, the same cannot be said of all antimuscarinics. The investigating team noted that there have been no studies comparing various antimuscarinics with respect to safety and efficacy in men. To that end, they carried out a fixed-dose study in men with LUTS and persistent OAB symptoms during which three antimuscarinics were compared: extended-release tolterodine 4 mg; solifenacin 5 mg and darifenacin 7.5 mg.

The study population consisted of about 100 men 45 years of age and older, with an IPSS score of at least 12 plus diary-documented micturition frequency of at least eight voids per 24 hours accompanied by at least three urgency episodes a day; they were randomized in equal numbers to one of the three antimuscarinics. Patients had all been on either tamsulosin 0.4 mg or alfuzosin 10 mg for a minimum of three months. Investigators evaluated the efficacy of each of the three treatments by assessing urgency, 24-hour daytime and nighttime micturitions, and changes in the IPSS score, including both storage and voiding components. Safety was assessed by evaluating men for changes in post-void residual urine, episodes of urinary retention requiring catheterization and other adverse events.

As Dr. Kaplan reported, mean reductions from baseline to study end at 12 weeks were similar for 24-hour frequency at 3.1 for extended-release tolterodine, 3.0 for solifenacin and 3.0 for darifenacin, all of which were significant compared to baseline (P<0.5). Urgency was improved to a greater extent with extended-release tolterodine at 2.7 (P<0.1 vs. baseline) compared with solifenacin at 2.4 (P<0.5 vs. baseline) and 1.9 for darifenacin (not significant). Improvements in the IPSS total score were again in favour of both extended-release tolterodine and solifenacin at 6.6 and 6.1, respectively, compared with 5.6 for darifenacin (all P<0.5 vs. baseline). A similar pattern was seen in the IPSS storage subscale at an improvement of 4.2 from baseline for extended-release tolterodine (P<0.1), 4.0 for solifenacin (P<0.5) and 2.9 for darifenacin (not significant).

Of note, there was a major difference in both constipation rates and post-void residual urine between darifenacin and the other two antimuscarinics. At 12 weeks, the post-void residual urine had increased by 17.2 mL in men treated with darifenacin (P<0.001) vs. 3.5 mL for extended-release tolterodine and 3.3 mL for solifenacin (the latter two not being significant) (Table 1).

Constipation rates were also significantly higher in the darifenacin arm at 25% compared with 2.9% (one patient) in the extended-release tolterodine arm and 8.3% or three patients in the solifenacin arm (P<0.001). Nine out of 36 men receiving darifenacin developed constipation, five of whom progressed to AUR requiring catheterization. Other adverse events were roughly comparable with dry mouth being reported by 8.5%, 13.9% and 11% of men on extended-release tolterodine, solifenacin and darifenacin, respectively, and blurred vision in 2.9%, 0% and 2.8%
ms, respectively.

Table 1. Change in Post-void Residual Urine

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“All of the patients who had constipation had an increase in [post-void] residual urine of greater than 50% at week 12 and this is very very unusual,” remarked Dr. Kaplan. “So we believe that what this shows is that constipation is a risk factor for AUR and darifenacin may not be the best drug to use in men.”

Summary

The authors concluded that on the basis of their results, treatment with extended-release tolterodine and tamsulosin significantly improves LUTS and associated symptom bother. In older men presenting with urinary symptoms, most physicians think first of an enlarged prostate, but if urgency is cited as an important part of the problem and there is no history of voiding issues, then it is reasonable to focus on OAB as the root problem.

Questions and Answers

The following section is based on discussions with Dr. Sender Herschorn, Professor and Chair, Department of Urology, University of Toronto, Ontario, and Dr. Steven A. Kaplan, Chief, Institute for Bladder and Prostate Health, New York Presbyterian Hospital and Professor of Urology, Weill Medical College, New York, during the AUA scientific sessions.

Q: In the study you mentioned earlier on, why do you think there was no difference between the extended-release tolterodine arm and the placebo arm in the PPBC questionnaire?

Dr. Herschorn: I think maybe it was the wrong scale. Men did respond in terms of the micturition diary variables. But they didn’t seem to respond differently based on the PPBC scale, so it could be the instrument; it could be the degree of response; maybe they weren’t thinking about their bladders, they were thinking about their prostates, so perhaps it was not the right scale to use in this population, although we know that they did respond in terms of their bladder diary variables.

Q: What about the long-term safety of using an antimuscarinic for OAB symptoms?

Dr. Herschorn: Most of the studies have only been done for 12 weeks except for one small study, so we don’t really know about the long-term safety effects. So if you are going to use this combination, physicians should see patients after three months and then maybe three months later and keep following them every three to six months, and monitor their response. Patients also need to know that if they notice a deterioration in their symptoms, it may be an indication they are at risk for urinary retention, so they need to be aware of this as well.

Q: Was your sample size significant enough to show the differences between the three treatment arms?

Dr. Kaplan: Yes. An earlier analysis showed that you needed about 30 patients to show a statistical significance with this hypothesis so it was large enough to show significant differences. But we actually thought the rates of constipation would be higher with darifenacin: if you look at the package inserts for the various antimuscarinic agents, darifenacin has the highest rates of constipation—anywhere from 17% to 25%. Q: In your opinion, why is constipation more prevalent among certain antimuscarinics?

Dr. Kaplan: It’s felt that darifenacin is more M3-specific, so it affects the M3-receptors to a greater extent than the other two agents and these receptors affect the bowel more and cause constipation which induces AUR. I believe we under-emphasized and under-represented the effect of constipation on voiding symptoms—whether it’s urinary retention or OAB symptoms, constipation is a major risk factor and in fact one could argue that it is the second most reversible risk factor for OAB symptoms after urinary tract infections. So we need to pay more attention to it. But it does make sense because darifenacin was originally looked at for irritable bowel syndrome (IBS) and it works—it constipates you—which is fine for IBS, but a bad side effect for voiding symptoms in men.

Q: What about men with prostate volumes under 30 cc. Does size always drive symptoms?

Dr. Kaplan: Just because the prostate shrinks in response to treatment doesn’t mean that patients always get better. That really is the take-home message for all of us. Patients who have smaller prostates might have their symptoms not because of prostate enlargement, but because they have bladder dysfunction, and we have to keep in mind that smaller prostates may be a different case than larger prostates.