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.

22nd Congress of the European Association of Urology

Berlin, Germany / March 21-24, 2007

The International Continence Society (ICS) defines overactive bladder (OAB) syndrome as urgency with or without incontinence, usually with frequency and nocturia, in the absence of any organic pathology or proven urinary tract infection. Nevertheless, as speakers here observed, urgency is the defining feature of OAB, driving all other symptoms. The effects of treatment on symptoms of urgency are thus important when assessing treatment benefit. As speakers noted, it is important to make a distinction between “urge”—namely, the desire to void that can usually be deferred and which is a normal physiological sensation—and “urgency,” a pathological sensation associated with abnormal bladder behaviour as the bladder is filling.

The extent of OAB prevalence was identified by the National Overactive Bladder Evaluation (NOBLE) study. According to NOBLE data, OAB affects 16.5% of the adult population, some two-thirds of whom remain continent despite the presence of an OAB, while approximately one-third are incontinent. These percentages vary depending on their source; among other experts, Prof. Philip van Kerrebroek, Chairman of Urology, University Hospital, Maastricht, The Netherlands, suggested that up to half of patients with OAB experience urgency without incontinence. Even when patients do not experience incontinence, Prof. Kerrebroek reaffirmed that urgency is still the most bothersome symptom of OAB as it often results in “fear of urgency” that can significantly affect quality of life.

Indeed, improved quality of life appears to be the most important factor in guiding treatment choice for practitioners, according to Prof. Ian Milsom, Chairman of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg, Sweden. At the same time, speakers here agreed that treatment of OAB must address not only the most bothersome symptom of the syndrome but all other accompanying symptoms as well, including frequency of micturition, urge incontinence, nighttime voiding and reduced volume of urine passed. To better assess treatment benefit, composite end points as measured by a scale such as the OAB-Symptom Composite Score are able to best determine the effect of treatment on each symptom associated with OAB.

A strategy that has been thoroughly evaluated using composite end points is the antimuscarinic agent solifenacin. As discussed by Prof. Milsom, an analysis of four double-blind, phase III studies demonstrated that treatment with once-daily solifenacin 5 and 10 mg was associated with significant improvements in all symptoms of OAB (Chapple et al. Int J Clin Pract 2006;60(8):959-66). As researchers reported, over 25% of patients receiving solifenacin experienced resolution of urgency, over 50% achieved continence and at least one-third of patients experienced “normalization” of micturition frequency to eight or fewer voids per day by study end.

In two studies that examined quality-of-life data, active treatment significantly improved quality-of-life scores from baseline in nine out of 10 domains compared to placebo. In all trials, the rate of adverse events was low and comparable to that of placebo at both treatment doses and few patients discontinued treatment due to adverse events.

“Composite end points accurately reflect the ICS definition of OAB which involves several factors, although urgency is the most important factor as it mirrors changes in quality of life, and I think this is important,” Prof. Milsom concluded.

Patient Perception of Treatment Impact

End point parameters, including the effect of treatment on frequency, urgency and incontinent episodes, number of pads, and urodynamics have traditionally been used to assess the benefit of various therapies in patients with OAB. In fact, because the degree of urgency can only be subjectively determined by patients, frequency and urge incontinence have traditionally been chosen as the primary end point in most OAB studies. Now, however, investigators are increasingly turning to patients’ perception of a treatment’s impact on their symptoms, and it is now felt that other end points such as quality of life and bother should be assessed in OAB trials in addition to urgency.

This was first analyzed in the large-scale SUNRISE (Solifenacin in the Treatment of Urgency Symptoms of Overactive Bladder in a Rising Dose) trial. As investigators pointed out, SUNRISE was the first trial in which the pivotal role of urgency in OAB was acknowledged, as well as patients’ perception of their symptoms, particularly urgency bother, a measure of the inconvenience and distress caused by urgency. These measures became the primary end point of the trial; specifically, change from baseline in mean urgency episodes per 24 hours at the end of the 16-week study, with urgency being defined as grades 3 and 4 of the patient perception of intensity of urgency scale (PPIUS).

In their first reported findings from this study, results from which were presented at the European Association of Urology Congress 2006, SUNRISE investigators showed that urgency episodes (grades 3 and 4) among almost 1000 patients enrolled in the study decreased by 2.58 points on the PPIUS among patients randomized to solifenacin 5 to 10 mg compared to 1.81 for placebo (P<0.001). For urgency bother, scores on the visual analogue scale (VAS 0 to 100) were also reduced by 35 points with solifenacin compared to 25 points for placebo (P<0.0001).

Commenting on results at the time, principal investigator Prof. Linda Cardozo, Professor of Urogynecology, King’s College Hospital, London, UK, noted that it is important to measure both the severity of the urgency and associated bother when assessing the effects of treatment on symptoms of OAB. Prof. Cardozo also underscored that SUNRISE findings demonstrated that solifenacin “really does have a significant effect” on reducing both the severity of urgency and associated bother. Here at this year’s meeting, Prof. Cardozo and colleagues also demonstrated that solifenacin not only improves urgency in OAB but it does so quickly.

Based on further analysis of the SUNRISE data, investigators determined the speed of onset of significant improvement in severe urgency and urge incontinence with solifenacin 5 mg. As they observed, significantly greater reductions in the incidence of severe urgency and urge incontinence as judged by the PPIUS grades 3 to 4 were apparent as early as the third day following initiation of treatment. Specifically, on the third day, there was a median 30.8% reduction in the number of episodes of PPIUS grades 3 to 4 from baseline for solifenacin patients compared to a median reduction of 14.3% for placebo controls (P=0.003).

In a separate study, investigators involved in the VENUS (Vesicare Efficacy and Safety in Patients with Urgency Study) also reported significant reductions in both urinary urgency and incontinence in patients treated with solifenacin vs. placebo, independent of their continence status. As reported by Dr. Rodney Appell, Professor of Urology, Obstetrics and Gynecology, Baylor Continence Center, Houston, Texas, VENUS enrolled 739 patients with at least one episode of urgency over a 24-hour interval, with or without urge incontinence, usually accompanied by eight or more micturitions over the same interval. Study participants also had a history of nocturia for at least three months prior to enrolment. Patients were followed for 12 weeks and episodes of urgency, as well as frequency of micturition, incontinence and nocturia, were noted by participants at baseline and at weeks 4, 8 and 12.

Two additional patient-reported outcome tools, the Indevus Urgency Severity Scale (IUSS) and the Urgency Perception Scale (UPS), were also used to assess urgency outcomes.

In an analysis of 463 patients in the incontinent cohort (234 of whom received solifenacin and the remaining 229 patients received placebo) and 244 patients in the continent group (123 of whom received solifenacin and 121 placebo), treatment with active therapy reduced mean urgency episodes in both continent and incontinent patients and improved urgency as measured by IUSS and UPS, irrespective of continence status. Furthermore, patients reporting incontinence at baseline in the solifenacin group achieved a mean decrease of 2.1 episodes of incontinence over 24 hours compared to a mean decrease of 1.24 episodes in placebo controls. Importantly, “58% of patients taking solifenacin who were incontinent at baseline became continent by study end,” investigators reported, adding that results from VENUS clearly support solifenacin as an effective agent in reducing both patient-reported outcome measures such as urgency as well as more classic OAB study end points such as incontinence.

The flexible-dosing VOLT (Vesicare Open-Label Trial), in which 2225 patients received solifenacin at either 5 or 10 mg, indicated that after 12 weeks of treatment, improvement was observed in mean values of the Patient Perception of Bladder Condition (PPBC) scale. Specifically, scores dropped from a mean baseline value of 4.4 to a mean value of 2.9 at study end. Significant reductions were similarly observed in subscales reflecting both the degree of bother caused by individual symptoms as well as quality-of-life indices.

Along with a growing consensus that patient perception of treatment benefit is an important measure in any OAB study is a recognition that self-reported therapy-induced improvements do not always correspond with physician perception of the benefits of treatment.

In a study designed to evaluate whether patient and physician perception of treatment benefit differ, investigators from the Belgian Evaluation of Solifenacin trial presented findings from their open-label, eight-week study comparing patient and physician perception of the benefit of treatment on a three-point scale. Patients filled in a three-day voiding diary before taking any medication and were subsequently started on solifenacin 5 mg with the option of having the dose increased to 10 mg after four weeks of treatment. Patients recorded their perception of treatment effects on the six-point PPBC scale. At baseline, almost half of the 252 patients enrolled in the trial had been previously treated for OAB. The mean number of micturitions per 24 hours was 12.4, while the mean number of incontinence episodes was 3.05. The baseline mean PPBC score was 4.8.

After four weeks of treatment, 35% of patients requested that their dose of solifenacin be increased to 10 mg, investigators noted. Almost one-half of physicians (47.6%) indicated that their patients had “benefited very much” from active therapy compared with 41.9% of patients, a difference which was statistically significant (P=0.008). Eight weeks after treatment had been initiated, the difference between patient and physician perception in terms of significant benefit from treatment did not differ at 60.8% and 63%, respectively. After eight weeks of treatment, patients in this trial also reported a mean reduction in symptom severity on the PPBC scale of 1.59 relative to baseline, a confirmation of PPBC-rated treatment benefit, investigators indicated.

Treatment of LUTS

A constellation of symptoms, including urgency, frequency, nocturia and incontinence, are often found in men with enlarged prostates as well as OAB, and lower urinary tract symptoms (LUTS) are highly prevalent in men as they age. Historically, LUTS are treated with alpha-adrenergic receptor antagonists such as tamsulosin and antimuscarinic agents such as tolterodine. But as investigators of a placebo-controlled study suggested, a combination from both classes appears to be more effective for men with LUTS suggestive of benign prostatic hyperplasia and OAB.

In the study, a total of 851 men 40 years of age and over with a total International Prostate Symptom Score (IPSS) of at least 12 and an IPSS quality-of-life item score of at least 3 were randomized to either extended-release tolterodine 4 mg (n=217), tamsulosin 0.4 mg (n=215), placebo (n=222) or tolterodine/tamsulosin (n=225). All patients were followed for 12 weeks, during which time they recorded the number of urgency episodes and micturitions over a 24-hour interval as well as the number of nocturnal micturitions. Episodes of urgency with or without urinary incontinence were recorded for five days prior to baseline and at various time points to week 12.

Based on patient perception of treatment benefit, study authors found that by week 12, a “significantly greater percentage” of patients randomized to the combination arm reported treatment benefit (80%) compared with patients in either the tolterodine arm (65%) (P<0.01), the tamsulosin arm (71%) (P<0.05) or the placebo arm (62%) (P<0.0001). The differences between either monotherapy arm and placebo did not achieve statistical significance by study end, although transient and significant improvements were noted over the course of the study. There were no significant changes in safety end points between any of the groups and the incidence of acute urinary retention requiring catheterization was low in all groups as well.

As suggested by Dr. David Sussman, Clinical Associate Professor of Urology, University of Medicine and Dentistry of New Jersey, Stratford, findings from this study indicate that men who have both storage and voiding symptoms likely respond best to a combination of agents that address both an enlarged prostate and OAB.

Summary

Urgency has been singled out as the most bothersome symptom in patients with an OAB and patient as well as physician perception of treatment benefit clearly must address this important symptom. At the same time, treatment should lead to improvement in other symptoms of OAB and ultimately improve quality of life for patients with this distressing syndrome. The antimuscarinic agent solifenacin has been shown to decrease not only episodes of urgency but all symptoms of OAB and it is well tolerated. The combination of an antimuscarinic agent and an alpha-adrenergic receptor antagonist may prove particularly effective in men with symptoms of both an enlarged prostate and OAB.

Questions and Answers

This question-and-answer session was conducted with Prof. Linda Cardozo, Professor of Urogynecology, King’s College Hospital, London, UK.

Q: In OAB, what is the most bothersome symptom to most patients and how much does it affect quality of life?

A: All symptoms of OAB—urgency, frequency, nocturia, incontinence—are bothersome, but the most bothersome symptom is the one that impacts the most on an individual’s lifestyle. Because of the definition of OAB, urgency must be present for the syndrome to exist so as the universal symptom, it is the one most prevalent and therefore perhaps the one that management should be geared to.

Q: Could you comment on the importance of having a treatment that has both a rapid onset of action (i.e. within three days of initiating treatment) as well as on severe symptoms?

A: It is very important for patients that a drug has a rapid onset of action because they like to know if it is working or not, and it is also very important to treat symptoms of all severity. Some patients are bothered by relatively minor symptoms while others tolerate quite severe symptoms, so it is important for a medication to treat the whole range.

Q: Does solifenacin have a role in men with LUTS, including those with in OAB?

A: About 20% of all subjects in the overall clinical trial program were men. Very often, it is difficult to differentiate between symptoms of an enlarged prostate and symptoms of OAB because they often co-exist. So yes, it can be used in men with LUTS and often it can be used in combination with other drugs such as tamsulosin.

Q: How important is it for physicians to take into consideration patients’ perception of the benefits of treatment rather than just tabulate “harder” clinical end points such as incontinence episodes?

A: Until recently, clinical trial end points have been tied to objective end points and numbers such as frequency of incontinence episodes that could be documented on charts. But what actually matters to patients is what bothers them the most and therefore, their individual problems need to be addressed. It is much better to have patients reporting on how much better their bladder condition is than have a number on a chart which may be meaningful for physicians but not for patients.

Q: Would you consider solifenacin as first-line therapy for OAB? If so, what advantages do you see in its use as opposed to other therapies? A: We have used solifenacin as first-line therapy since the findings from the STAR trial, which showed that it had greater efficacy for most symptoms than the control arm. No medication is available that adequately treats all individuals and no medication is completely free of side effects but on balance, solifenacin has decent efficacy and good acceptability.