Muscarinic receptor antagonists for overactive bladder

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1 Great drug classes ANTIMUSCARINIC DRUGS FOR OAB From time to time we publish a full review of drugs that are available for the treatment of common conditions. In this issue, the review is written by two of the leading authorities in the world, Paul Abrams and Karl-Erik Andersson, on the topic of overactive bladder and antimuscarinic agents. This in-depth review covers the entire range of questions that might be asked about this common area of interest. Muscarinic receptor antagonists for overactive bladder Paul Abrams and Karl-Erik Andersson* Bristol Urological Institute, Southmead Hospital, Bristol, UK and *Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA Accepted for publication 1 June 2007 Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M 2 and M 3 on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as α 3 -adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB. KEYWORDS antimuscarinic, darifenacin, muscarinic receptor antagonist, overactive bladder, oxybutynin, solifenacin, tolterodine, trospium INTRODUCTION Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence (UUI), usually with frequency and nocturia [1]. Population-based estimates suggest that OAB affects 12 17% of adults in Europe and the United States [2 4], and compromises healthrelated quality of life (HRQoL) [5 7]. Muscarinic receptor antagonists are a firstline pharmacotherapy for OAB. JOURNAL COMPILATION 2007 BJU INTERNATIONAL 100, doi: /j x x 987

2 BASIC SCIENCE MICTURITION REFLEX Bladder function during storage and voiding is regulated by the peripheral and central nervous systems (CNS), and bladder contraction is primarily under parasympathetic control [8 12]. In adults, the micturition reflex is mediated by a spinobulbo-spinal pathway, which passes through relay centres in the brain [13]. During bladder filling, afferent impulses generated by myogenic activity, bladder distension, and urothelial signals are conveyed to CNS centres via the pelvic and hypogastric nerves [13]. It has been proposed that the afferent neurones send information to the periaqueductal grey nucleus, which in turn communicates with the pontine tegmentum, where two different regions involved in micturition control have been described [14]. One is a dorsomedially located M region, corresponding to Barrington s nucleus or the pontine micturition centre. A more laterally located L region might serve as a pontine urine storage centre, which has been suggested to suppress bladder contraction and to regulate the activity of the striated musculature of the bladder outlet during urine storage [15] (Fig. 1) [10]. VOIDING Somatic activity Urethra Striated muscle Pelvic floor Suprapontine mechanisms PAG PMC Spinal control mechanisms Sympathetic activity Parasympathetic Ganglia activity ++ Detrusor Urethra Smooth muscle FIG. 1. Voiding reflexes involve supraspinal pathways and are under voluntary control. During bladder emptying, the spinal parasympathetic outflow is activated (+ +), leading to bladder contraction. Simultaneously, the sympathetic outflow to urethral smooth muscle and the somatic outflow to urethral and pelvic floor striated muscles are turned off, and the outflow region relaxes. PAG, periaqueductal grey; PMC, pontine micturition centre. Reprinted with permission: Andersson and Wein, 2004 [10]. FIG. 2. During filling, there is continuous and increasing afferent activity from the bladder. There is no spinal parasympathetic outflow that can contract the bladder. The sympathetic outflow to urethral smooth muscle (α-adrenoceptors, α + ), and the somatic outflow to urethral and pelvic floor striated muscles (nicotinic receptors, N + ) keep the outflow region closed. Whether the sympathetic innervation to the bladder contributes to bladder relaxation during filling (α-adrenoceptors, α + ) in humans has not been established. PAG, periaqueductal grey; PMC, pontine micturition storage centre. Reprinted with permission: Andersson and Wein, 2004 [10]. STORAGE Suprapontine mechanisms The efferent arm of the micturition reflex starts at the pontine micturition centre; the spinal parasympathetic outflow is activated and conveyed to the sacral (S2 S4) parasympathetic nucleus. This nucleus, which receives modulatory input from stimulatory and inhibitory neurones, contains the preganglionic neurones projecting to the bladder. In major parasympathetic ganglia, contact is made with the cholinergic neurones innervating the bladder. Detrusor contraction is initiated via release of acetylcholine and nonadrenergic noncholinergic (mainly ATP) transmitters [10] (Fig. 2). Somatic activity PAG PMC Spinal control mechanisms Parasympathetic activity Sympathetic activity Ganglia Centres rostral to the pons determine the start of micturition. Thus, even if the forebrain is not essential for the basic micturition reflex, it plays a role in decisions concerning when and where micturition should take place [16]. Furthermore, evidence suggests that γ-aminobutyric acid, opioid, serotonin, noradrenaline, dopamine, nitric oxide, histamine, and glutamate signalling are involved in the control of micturition [10]. Muscarinic receptors within the CNS might also influence micturition [17 19]. Urethra Striated muscle Pelvic floor CAUSES OF OAB Detrusor overactivity (DO) is frequently associated with OAB symptoms and is + + Detrusor Urethra Smooth muscle urodynamically characterized by involuntary detrusor contractions during bladder filling [1]. DO and OAB do not always coexist [20 22], but Hashim and Abrams [22] 988 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

3 ANTIMUSCARINIC DRUGS FOR OAB reported that 83% of patients with DO had symptoms of OAB, and 64% of patients with OAB symptoms had DO. The causes of DO are multifactorial and might involve both peripheral (urothelial, myogenic/autonomous) and central signalling [23,24]. Studies designed to investigate changes in neurotransmitter signalling that contribute to bladder dysfunction have often focused on acetylcholine. During the storage phase, the parasympathetic drive that causes acetylcholine release resulting in detrusor contraction is normally suppressed [9,25]. However, a basal release of acetylcholine from non-neuronal (i.e. urothelial) as well as neuronal sources has been shown in isolated human detrusor muscle [26]. This release, which is stimulated by stretch during filling and increases with age, increases bladder afferent activity during storage [27]. Such spontaneous activity can be seen in the whole bladder or as relatively isolated contractions in parts of the bladder wall. These contractions, or micromotions [28,29], have been studied in isolated guinea-pig and mouse bladders [30,31] and can be demonstrated in humans [32]. They are enhanced by muscarinic receptor stimulation [33]. Enhanced myogenic contractions can generate enhanced afferent activity, afferent noise, contributing to urgency and/or initiation of the micturition reflex [24,31,34]. Altered structure of the detrusor smooth muscle has also been implicated in DO [35]. Studies in humans and animal models of DO have shown infiltration of the smooth muscle of the bladder wall by elastin and collagen, denervation of the bladder wall, and changes in protrusion junctions that allow electrical activity to spread between smooth muscle cells [35]. Facilitation of electrical coupling between smooth muscle cells could result in a coordinated myogenic response [35,36]. BOO can also cause DO through cholinergic denervation of the detrusor [37] and subsequent supersensitivity of muscarinic receptors to acetylcholine [35]. However, data from the EPIC study, a recent large, multinational epidemiologic survey that used the current ICS definitions showed that the prevalence of OAB is similar in men and women across all age groups [4], suggesting that the role of BOO in causing DO in men might be overemphasized. Another source of neurogenic bladder dysfunction might be a change in the excitability of unmyelinated, capsaicin-sensitive C-afferents in the urothelium. C-fibre afferents might mediate the feeling of bladder fullness and sensation of urgency [38,39]. C-afferent signalling might initiate bladder contraction in response to chemical stimuli [40,41] before stretch receptors are activated. These events might contribute to urgency at low bladder volumes, a symptom characteristic of OAB. MUSCARINIC RECEPTORS Acetylcholine activates muscarinic receptors on detrusor myocytes and is the main contractile transmitter. Muscarinic receptors comprise five subtypes encoded by five distinct genes [42]. The mrnas for all muscarinic receptor subtypes have been detected in the human bladder [43,44], with mrna and protein levels of the M 2 subtype outnumbering the M 3 receptor subtype [43 46]. These receptors have been detected in the urothelium, interstitial cells, nerve fibres, and detrusor layers [47]. Detrusor smooth muscle contains muscarinic receptors mainly of the M 2 and M 3 subtypes [9,48 50]. Both subtypes are coupled to G proteins, but the signal transduction pathways differ [9,48,49]. Detrusor smooth muscle M 3 receptors in the human detrusor are thought to be most important for detrusor contraction [10]. Evidence for this functional role comes from studies in M 3 knockout mice. In the presence of carbachol, bladder strips from these mice had a maximal contractile response only 5% of that found in wild-type mice [51]. However, these mice have a nearly normal cystometric pattern due to the remaining purinergic activation mechanism [52]. Even in the obstructed rat bladder, M 3 receptors were found to play a predominant role in mediating detrusor contraction [53]. Stimulation of M 3 receptors is generally thought to cause contraction through phosphoinositide hydrolysis [54,55]. However, Jezior et al. [56] suggested that muscarinic receptor mediated detrusor contraction also includes both nonselective cation channels and activation of Rho-kinase. Wibberley et al. [57] reported that Rho-kinase inhibitors (Y-27632, HA 1077) inhibited contractions evoked by carbachol without affecting the contractile response to KCl in rat bladder strips. They also reported high levels of Rho-kinase isoforms (I and II) in rat detrusor muscle. A role for Rho-kinase in the regulation of rat detrusor contraction and tone is supported by other investigators. For instance, Schneider et al. [58] confirmed that, in the human detrusor, carbachol-induced contraction is mediated via M 3 receptors, and they concluded that detrusor contraction largely depends on Ca 2+ entry through nifedipine-sensitive channels and activation of the Rho-kinase pathway. Although there might be species differences in the signalling pathways used by the different muscarinic receptor subtypes [59], data suggests that the main pathways for M 3 receptor mediated contraction in the human detrusor are calcium influx via L-type calcium channels and inhibition of myosin light-chain phosphatase through activation of Rhokinase and protein kinase C, which leads to increased sensitivity of the contractile machinery to calcium [58,60] (Fig. 3). Inhibition of potassium channels might also be involved [10]. Although a functional role for the M 2 receptor has not been definitively identified, it has been suggested that stimulation of this receptor opposes sympathetically (βadrenoceptor) mediated smooth muscle relaxation by inhibition of adenylate cyclase [61]. M 2 receptor stimulation might also activate nonspecific cation channels [62] or inhibit K ATP channels through activation of protein kinase C [63,64]. An investigation using M 2, M 3, and M 2 /M 3 double knockout mice showed that the M 2 receptor might play an indirect role in mediating bladder contractions by enhancing the contractile response to M 3 receptor activation and that minor M 2 receptor mediated contractions might also occur [65]. Although the contribution of M 2 receptors to detrusor contraction may be less than that of M 3 receptors in the healthy bladder, in certain disease states, the contribution of M 2 receptors to detrusor contraction might increase. In the denervated rat bladder, M 2 receptors, or a combination of M 2 and M 3 receptors, mediated contractile responses [66 70]. In obstructed, hypertrophied rat bladders there was an increase in total muscarinic receptor and M 2 receptor density and a reduction in M 3 receptor density [71]. The functional significance of this change has not been established, and preliminary experiments on the human detrusor [72,73] could not confirm these observations. Pontari JOURNAL COMPILATION 2007 BJU INTERNATIONAL 989

4 et al. [74] analysed bladder muscle specimens from patients with neurogenic bladder dysfunction to determine whether the muscarinic receptor subtype mediating detrusor contraction shifts from the M 3 to the M 2 subtype, as seen in the denervated, hypertrophied rat bladder. They concluded that, whereas normal detrusor contractions are mediated by the M 3 receptor subtype, in patients with neurogenic bladder dysfunction, contractions can be partly mediated by the M 2 receptors. FIG. 3. Acetylcholine (ACh) causes contraction of detrusor muscle by stimulation of M 3 receptors via activation of Rho-kinase and protein kinase C (PKC), and by increasing influx of Ca 2+. ACh also induces contraction indirectly by inhibiting the production of cyclic adenosine monophosphate (cyclic AMP) and reversing the relaxation induced by β-adrenoceptors after stimulation by noradrenaline (NA). ACh + ACh M 3 M 3 M 2 + Ca 2+ ACh + NA β + Presynaptic nerve terminals Muscarinic receptors might also be located on the presynaptic nerve terminals and contribute to the regulation of transmitter release. The inhibitory prejunctional muscarinic receptors have been classified as M 2 in the rabbit [75,76] and rat [77], and as M 4 in the guinea-pig [78], rat [79] and human [80] bladders. Prejunctional facilitatory muscarinic receptors appear to be the M 1 subtype in the rat and rabbit urinary bladder [75 77]. Prejunctional muscarinic facilitation has also been detected in human bladders [81]. The muscarinic facilitatory mechanism seems to be up-regulated in overactive bladders from chronic spinal cord transected rats. The facilitation in these preparations is primarily mediated by M 3 muscarinic receptors [81,82]. Urothelium and suburothelium Muscarinic receptors have also been detected on the urothelium/suburothelium [47,49,83], but their functional importance has not been definitively identified. In a study by Mukerji et al. [47], there was M 2 and M 3 receptor immunoreactivity in the urothelium, nerve fibres, and detrusor layers. In addition, strong myofibroblast-like cell staining was present in the suburothelial region and detrusor muscle. There was a significant increase in suburothelial myofibroblast-like M 2 and M 3 receptor immunoreactivity in patients with idiopathic DO compared with controls. M 2 and M 3 receptor immunoreactivities each significantly correlated with the urgency score, and M 2 immunoreactivity also correlated with the frequency score in these patients. The authors concluded that the increase in M 2 and M 3 receptor immunostaining in myofibroblast-like cells in clinical bladder syndromes, including painful bladder syndrome and idiopathic DO, and its correlation with clinical scores Rho-kinase Ca 2+ Contraction PKC suggests a potential role for these receptors in pathophysiological mechanisms and in the therapeutic effect of antimuscarinic agents. It has also been suggested that muscarinic receptors on structures other than the myocyte (e.g. urothelium/suburothelium) might be involved in the release of a factor that inhibits contractile responses [49,84,85]. ANTIMUSCARINIC MECHANISMS OF ACTION It has been suggested that antimuscarinics act at muscarinic receptors on detrusor smooth muscle cells to reduce spontaneous myocyte activity during the storage phase [86], eventually decreasing the frequency and intensity of detrusor contractions. Other evidence suggests that antimuscarinics affect micturition through additional mechanisms. Yokoyama et al. [87] administered tolterodine i.v. or intravesically to rats with DO induced by cerebral artery occlusion with and without pretreatment with resiniferatoxin, a capsaicin analogue that induces C-fibre afferent desensitization. At low doses, tolterodine increased bladder capacity in untreated rats but was ineffective in those that had received resiniferatoxin. The authors concluded that tolterodine exerted an inhibitory effect on C-fibre bladder afferent nerves, thereby reducing detrusor activity and improving bladder capacity. An effect on afferent mechanisms by tolterodine in rats was also reported by Hedlund et al. [88], who found an effect of this drug even after resiniferatoxin treatment. Antimuscarinic-mediated Cyclic AMP inhibition of afferent signalling from the bladder via effects on both Aδ- and C-fibres might explain this apparent discrepancy in results. Studies in which afferent activity has been directly recorded from the pelvic nerve of rats have shown that systemic oxybutynin [89] and darifenacin [90] reduce activity in both Aδ- and C-fibre bladder afferents. Boy et al. [91] studied the effect of tolterodine on sensations evoked by intravesical electrical stimulation and during bladder filling in healthy women and reported that the drug had a significant effect on afferent fibres, probably located in the suburothelium. These findings are consistent with the clinical observations that, at clinically recommended doses, antimuscarinics might increase bladder capacity largely during the bladder storage phase [92]. CLINICAL DATA Cyclic AMP Relaxation Pharmacological agents used in the past to treat OAB include antimuscarinics, such as propantheline, methantheline, emepronium, dicyclomine, terodiline, and oxybutynin; spasmolytics, such as flavoxate; tricyclic antidepressants, such as imipramine; and prostaglandin synthetase inhibitors, such as indomethacin. However, with the exception of oxybutynin, none of these agents remain commonly used owing to lack of efficacy and/or poor tolerability [93,94]. Newer antimuscarinic drugs, which have proven efficacy in patients that have OAB symptoms 990 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

5 ANTIMUSCARINIC DRUGS FOR OAB Drug USA UK European Union TABLE 1 Oxybutynin ER Key launch dates for Tolterodine ER antimuscarinics used to Trospium treat OAB Darifenacin 2005 NA NA Solifenacin 2005 NA 2004 Propiverine ER NA 2006 NA NA, drug not yet launched. FIG. 4. Antimuscarinic structures. with or without urodynamically confirmed DO, are a first-line treatment [92]. In addition to oxybutynin, several antimuscarinics, each with varied affinity for muscarinic receptor subtypes, are currently available, including propiverine, tolterodine, trospium, solifenacin, and darifenacin. Key approval dates for these agents are listed in Table 1, and their structures are depicted in Fig. 4. Structural differences between these two classes of amines affect their pharmacokinetic, pharmacodynamic, and adverse event (AE) profiles. OUTCOMES MEASURES Management of OAB should initially be based on the patient s report of symptoms. Clinical trials typically use objective measures of efficacy, including bladder diary variables. However, there is currently a growing appreciation of the importance of subjective patient-reported outcomes (PROs) in clinical research [95,96]. Objective measures of efficacy often correlate poorly with PROs, suggesting that objective and subjective assessments measure different aspects of the patient s clinical profile; they should not be interpreted as different methods for assessing the same outcome. Subjective and objective measures have limitations, and investigators should carefully consider the outcome H 3 C O O H 3 C Acetylcholine N CH 3 CH 3 H 3 C H 2 N O O O OH N N N Oxybutynin OHH 3 C Tolterodine Darifenacin CH 3 CH 3 CH 3 CH 3 O C O C O CH 2 O O of interest when choosing a means of assessment. However, studies that include assessments of both subjective and objective outcomes can yield results that represent a more global patient experience than can be captured by evaluating either type of measure alone. Furthermore, the overall patient experience can be better understood by identifying the relative contribution of objective endpoints to treatment-related changes in HRQoL, symptom bother, and patient satisfaction. The most common method of objective assessment in clinical trials of antimuscarinics is the bladder diary. Bladder diaries document voiding patterns during a patient s routine activities and can be completed for any duration. Bladder diaries differ between studies, but generally require a patient to keep records of micturition frequency, number of urgency and incontinence episodes, and volume voided per micturition. Urodynamic studies are another common means of objective assessment and provide a graphical representation of intravesical pressure as a function of bladder volume [97]. Conventional studies usually involve artificial bladder filling, and ambulatory studies use natural bladder filling [1]. Bladder volume at first involuntary detrusor contraction, involuntary detrusor contraction amplitude, postvoid residual CH 3 O Propiverine N + N Trospium H O N O Solifenacin N + H Cl CH 2 CH 3 CH 3 OH urine volume (PVR), maximum cystometric capacity, and maximum urinary flow rate (Q max ) are frequent urodynamic endpoints. Pad tests represent another type of objective measure and are used to quantify the volume of urine lost during incontinence episodes [98]. Common subjective endpoints include investigator- and patient-assessed variables such as HRQoL impact, symptom severity, and perceived treatment benefit. PROs include many different questionnaires designed to evaluate various aspects of OAB symptoms and their impact on HRQoL. The International Consultation on Incontinence (ICI) is developing a range of questionnaires (ICIQ modules) for use in patients with LUTS and other pelvic conditions. The ICIQ-OABq (OAB questionnaire), is a disease-specific tool that assesses symptom bother and HRQoL in those with OAB [99]. Another questionnaire, the Patient Perception of Bladder Condition ([100], provides a more general assessment of bladder function. The ICIQ-LUTSqol (King s Health Questionnaire) includes 21 questions in eight domains and is validated for assessment of QoL in patients with OAB [101]. EFFICACY There is ample evidence to support the efficacy of all of the antimuscarinics considered here in the treatment of OAB. Large-scale, randomized, placebo-controlled studies have shown that patients receiving these agents report significant reductions in urinary frequency, urgency episodes, and UUI episodes [102,103]. Two published systematic reviews have examined the efficacy of these agents in detail, but these reports possess important methodological differences that influenced their conclusions. Herbison et al. [102] included data from 32 randomized, placebo-controlled trials of antimuscarinics used to treat OAB. The included studies were published between January 1966 and January 2002 and involved all routes of administration. The data from all of the trials were combined for efficacy comparisons of antimuscarinic vs placebo. Weighted mean differences in the change in incontinence episodes per 24 h, micturitions per 24 h, and maximum cystometric capacity were calculated. Patients receiving antimuscarinics reported a weighted mean difference (vs placebo) of 0.56 (95% CI 0.93 to 0.15) for the change in incontinence episodes and 0.59 ( 0.83 to 0.36) for the change in JOURNAL COMPILATION 2007 BJU INTERNATIONAL 991

6 micturitions per 24 h. The changes in maximum cystometric capacity, at weighted mean difference (95% CI) of +54 ml (43 66) also favoured active treatment. Although these were statistically significant differences and favoured antimuscarinic treatment over placebo, the authors challenged the clinical significance of the efficacy findings because the magnitude of improvement in these endpoints was small. However, the clinical significance of the efficacy of individual antimuscarinics in patients with OAB is supported by a 2005 meta-analysis by Chapple et al. [103] that included data published from 1966 to August 2004 and that permitted the inclusion of studies evaluating the efficacy and tolerability of two new antimuscarinics, darifenacin and solifenacin. This meta-analysis also assessed the effects of antimuscarinics on PROs, which are increasingly being evaluated in clinical trials of OAB. Chapple et al. [103] included data from 56 blinded, randomized, placeboand active-controlled trials of oral and transdermal antimuscarinics used to treat OAB. Importantly, whereas Herbison et al. [102] combined data for all antimuscarinics, Chapple et al. [103] did individual comparisons between each antimuscarinic and placebo or active controls. The weighted mean difference (95% CI) vs placebo for the change in incontinence episodes per 24 h was significant for oxybutynin immediate release (IR) ( mg/day; 0.72, 1.09 to 0.34), transdermal oxybutynin ( 0.55, 1.05 to 0.04), solifenacin (5 mg/day; 0.66, 1.13 to 0.19; 10 mg/day, 0.69, 1.19 to 0.19), tolterodine IR (4 mg/day, 0.50, 0.70 to 0.30), and tolterodine extended release (ER) ( 0.73, 0.93 to 0.53). For changes in micturition frequency per 24 h, there were significant improvements vs placebo for transdermal oxybutynin ( 0.55, 1.03 to 0.07), solifenacin (5 mg/day, 0.99, 1.52 to 0.46; 10 mg/day, 1.41, 1.97 to 0.85), tolterodine IR (2 mg/day, 0.68, 1.15 to 0.22; 4 mg/day, 0.67, 0.92 to 0.42), and tolterodine ER ( 0.73, 0.96 to 0.49). Chapple et al. [103] found some evidence suggesting that propiverine IR and ER might also reduce incontinence episodes and micturition frequency [104,105] relative to placebo; however, these data were not suitable for inclusion in the meta-analysis. The changes in urgency episodes per 24 h vs placebo were significant for solifenacin (5 and 10 mg/day) and tolterodine ER. Improvements in volume voided per micturition were significant for oxybutynin IR ( mg/ day), transdermal oxybutynin, solifenacin (5 mg and 10 mg/day), tolterodine IR (2 mg and 4 mg/day), and tolterodine ER. The relative risk (RR, 95% CI) for return to continence was significant for oxybutynin IR ( mg/day; 3.53, ), transdermal oxybutynin (1.75, ), tolterodine ER (1.72, ), and trospium (2.00, ). Thus, patients receiving these antimuscarinics were nearly twice as likely to return to continence compared with placebo-treated patients. HRQoL data were available for transdermal oxybutynin, tolterodine IR (4 mg/day), tolterodine ER, and trospium. The meta-analysis revealed significant weighted mean differences vs placebo for 27 of 37 HRQoL domains [106]. For example, the weighted mean differences for change in overall HRQoL assessed by the Incontinence Impact Questionnaire were significant and favoured transdermal oxybutynin, tolterodine ER, and trospium vs placebo. Weighted mean differences for the change in ICIQ-LUTSqol domains for incontinence impact, role limitations, physical limitations, and sleep/energy were significant and favoured patients treated with tolterodine IR or ER vs placebo. A metaanalysis of three active-controlled studies of tolterodine ER and tolterodine IR revealed no significant differences in the change in HRQoL measures between active treatments [106]. Twenty-four of the 56 trials included in the Chapple et al. [103] meta-analysis were active-controlled. Most comparisons that resulted in significant findings were based on one study alone, and none of the significant comparisons came from studies that were powered to show a significant difference between active treatments. The authors reported that patients receiving solifenacin (5 or 10 mg/day) had up to one fewer urgency episodes per day than did those receiving tolterodine IR (4 mg/day). Solifenacin (10 mg/ day) was also associated with significantly fewer micturitions per 24 h than was tolterodine IR (4 mg/day). Oxybutynin ER (10 mg/day) was associated with approximately two fewer incontinence episodes per week than was tolterodine ER (4 mg/day). A greater proportion of patients treated with oxybutynin ER (10 mg/day) returned to continence compared with those receiving tolterodine ER (4 mg/day). Finally, volume voided was significantly greater in patients treated with oxybutynin IR (15 mg/ day) or solifenacin (5 and 10 mg/day) compared with patients receiving tolterodine IR (4 mg/day). Unlike the report by Herbison et al. [102], the Chapple et al. [103] meta-analysis permitted the discernment of within-class differences in efficacy. Although data for each drug were not available for each endpoint, this study might help clinicians select the most appropriate antimuscarinic for individual patients depending on their most bothersome symptoms. The return to continence and HRQoL data presented in the Chapple et al. [103] report are particularly important to consider when evaluating the conclusion by Herbison et al. [102] that the benefits of antimuscarinics are of limited clinical significance. Responder analyses are a recent trend in evaluating efficacy of antimuscarinics for OAB. These analyses, which provide a comprehensive survey of benefit by examining the proportion of patients who achieve various levels of improvement, also support the clinical significance of improvements in OAB symptoms with antimuscarinic treatment. For instance, in one study 57% of patients receiving darifenacin (15 mg) reported a 70% reduction in incontinence episodes from baseline compared with 39% receiving placebo (P < 0.001), and 28% of patients receiving darifenacin had a 90% reduction compared with 17% in the placebo group (P < 0.005) [107]. Similarly, Sussman et al. [108] reported that after 12 weeks of treatment with tolterodine ER (4 mg), 78%, 66%, and 54% of patients had reductions of 50%, 70%, and 100% in urgency episodes, respectively, and 75%, 61%, and 51% of patients had reductions of 50%, 70%, and 100% in UUI episodes, respectively. Such analyses represent an alternative to the expression of efficacy in terms of whole-group mean numeric or median percentage changes and might better reflect the likelihood of specific levels of treatment benefit with antimuscarinics. ONSET OF ACTION Few studies have specifically examined the onset of therapeutic efficacy of an antimuscarinic for OAB, and between-study comparisons should be made with caution because of differences in study designs and populations. A post hoc analysis of an openlabel study showed that tolterodine ER 992 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

7 ANTIMUSCARINIC DRUGS FOR OAB TABLE 2 Factors contributing to the pharmacokinetic profiles of antimuscarinic treatments for OAB Darifenacin Oxybutynin IR/ER Oxybutynin transdermal Propiverine IR/ER Solifenacin Tolterodine IR/ER Trospium Molecular weight Relative lipophilicity Highly lipophilic Lipophilic Lipophilic NA Lipophilic Slightly lipophilic Not lipophilic Polarity (9.20 pka) Positive Neutral Neutral NA NA (9.87 pka) Positive polar Highly Metabolizing enzymes Metabolites contributing to clinical effect CYP2D6, CYP3A4 CYP3A4 CYP3A4 CYP2D6, CYP3A4 CYP3A4 CYP2D6, CYP3A4 dependent mechanism None Propiverine N-oxide None Ester hydrolysis by noncyp450- Desethyloxybutynin Desethyloxybutynin 5-hydroxy-methyltolterodine Compound excreted intact (urine),% Intact compound 3 <0.1 <0.1 <1 <15 <1 3* Active metabolite NA NA < NA 5 14 NA Half-life, h 12 2/ /8 20 CYP, cytochrome P450; NA, not available; *Evidence suggests that trospium is primarily excreted in feces [112]. None reduced micturitions, urgency episodes, and UUI episodes as early as treatment day 5 [108]. In a trial of darifenacin, patients with OAB had significant reductions in micturitions, urgency episodes, UUI episodes, and urgency severity compared with placebo after 2 weeks of treatment [109]. Patients with OAB who were treated with trospium showed significant improvements in the frequency of UUI episodes, urgency episodes, and micturitions as early as day 1, 3, and 5, respectively [110]. However, it should be noted that patients in this study were required to have 7 UUI episodes per week for enrolment. Thus, these results should be interpreted in light of the fact that increased symptom severity at baseline is directly related to the magnitude of potential symptom improvement [111]. PHARMACOKINETICS Structural differences in the tertiary and quaternary amines impart pharmacokinetic heterogeneity among the antimuscarinics (Table 2) [112]. Tertiary amines bear no charge and are therefore more lipophilic than the positively charged quaternary amines [113]. Tertiary amines are more easily absorbed from the gastrointestinal tract, have greater oral bioavailability, and more easily cross the blood brain barrier (BBB) than do the hydrophilic quaternary amines. Tertiary amines undergo significant metabolism via the cytochrome P450 enzymes, whereas trospium has little P450 metabolism. Consequently, 80% of trospium is excreted unchanged in the urine compared with <5% of oxybutynin or tolterodine. The lack of P450 metabolism also reduces the potential for drug drug interactions with trospium [113]. Elimination half-lives for antimuscarinics range from 2 h for oxybutynin IR [114] and tolterodine IR [115] to h for solifenacin. The half-life of solifenacin probably exceeds that of the other antimuscarinics because of its comparatively large volume of distribution [116]. ADMINISTRATION Of the antimuscarinics considered, only oxybutynin can be administered transdermally. The sustained-delivery patch allows for more stable serum concentrations of oxybutynin than oral formulations and avoids presystemic metabolism [117]. The implications of these altered pharmacokinetic parameters are discussed in more detail below. TOLERABILITY AND SAFETY RECEPTOR AND ORGAN SELECTIVITY Muscarinic receptor and organ selectivities are key components of the therapeutic potential for antimuscarinics and affect their AE profiles. As mentioned, the M 2 and M 3 receptors are the main muscarinic receptors involved in bladder control. Antimuscarinic agents might block acetylcholine binding at more than one muscarinic receptor subtype. Furthermore, receptor-selective agents might block muscarinic receptors outside the bladder and cause AEs. For example, blockade of M 3 receptors in the salivary gland, lower bowel, and ciliary smooth muscle are thought to contribute to three of the most frequently reported AEs associated with antimuscarinics: dry mouth, constipation, and blurred vision, respectively [118]. Estimates of binding affinity of antimuscarinics for human muscarinic receptor subtypes are provided in Table 3 [118,119]. Trospium and propiverine are the least selective, but trospium has the highest affinity for each of the muscarinic receptor subtypes. Darifenacin is clearly M 3 selective, and oxybutynin and solifenacin have a moderate selectivity for the M 3 receptor over the M 2 receptor. Tolterodine shows a similar degree of selectivity for all five muscarinic receptor subtypes. It has been suggested that tolterodine [ ] and solifenacin [121,123] have greater selectivity for muscarinic receptors of the bladder than for those in the salivary gland. Reports differ for the organ selectivity of oxybutynin [ ], darifenacin [120,121,124], and propiverine [124,125]; to our knowledge, organ selectivity data for trospium have not been published. It is important to note that information on JOURNAL COMPILATION 2007 BJU INTERNATIONAL 993

8 organ selectivity is based mainly on studies using animal models and in vitro experiments. Apparent organ selectivity might in fact be model specific and might not necessarily be valid in humans. ADVERSE EVENTS AND WITHDRAWALS Dry mouth, constipation, headache, and blurred vision are generally the most frequently reported AEs among patients treated with oxybutynin, tolterodine, trospium, propiverine, darifenacin, and solifenacin in clinical trials (Table 4 [109,112,116, ] and Table 5 [ ]). Chapple et al. [103] reported that the RR (95% CI) of reporting any AE was significantly greater for darifenacin (7.5 mg/ day; 1.24, ; 15 mg/day, 1.35, ), oxybutynin IR ( mg; 1.39, ), propiverine IR (30 mg/day; 1.90, ), and propiverine ER (30 mg/day; 1.69, ). There were no differences in the RR for any AE between placebo and the other antimuscarinic agents. Dry mouth, constipation, and blurred vision are consistent with the mechanism of action of antimuscarinics. Dry mouth Dry mouth is the most commonly reported AE in clinical trials of oral antimuscarinic therapies for OAB and is listed among the AEs in the full prescribing information for each agent. Dry mouth is probably a consequence of antagonism of the M 3 receptors that regulate salivary secretion in the parotid glands [8,117]. In placebo- and activecontrolled trials, the incidence of dry mouth in patients taking oxybutynin IR was 17 97%, oxybutynin ER 23 68%, transdermal oxybutynin 4 39%, propiverine IR 20 47%, propiverine ER 22%, tolterodine IR 8 50%, tolterodine ER 7 34%, trospium 3 41%, solifenacin 8 30%, and darifenacin 18 31% generally exceeded the combined incidence of constipation, headache, and abnormal vision (Table 4 [109,112,116, ] and Table 5 [ ]). In the Chapple et al. [103] metaanalysis the RR (95% CI) for dry mouth was significantly greater than placebo for patients receiving all of the antimuscarinics considered here with the exceptions of lowdose oxybutynin IR ( mg/day; 1.06, ), transdermal oxybutynin (1.35, ), and propiverine IR (45 mg/day; 3.00, ). Herbison et al. [102] reported a RR (95% CI) for dry mouth of Molecule M 1 M 2 M 3 M 4 M 5 Oxybutynin Tolterodine Darifenacin Solifenacin NR NR Trospium Propiverine NR, not reported. *Binding affinity estimates (K i in nm). Adapted from Hegde et al., 2004 [118]. Propiverine data from Wuest et al., 2006 [119] ( ; P < 0.001) in patients receiving any antimuscarinic vs placebo. Transdermal oxybutynin circumvents first-pass metabolism and results in lower concentrations of the active metabolite N-desethyloxybutynin. This metabolite has a greater affinity than oxybutynin for muscarinic receptors in the parotid gland and might contribute to dry mouth reported by many patients receiving oral oxybutynin [117]. In a study of 76 patients randomized to oxybutynin IR or transdermal oxybutynin, the incidence of dry mouth was 94% and 38%, respectively [146]. Constipation Constipation is generally the second most common AE reported by patients receiving oxybutynin IR (4 50%), transdermal oxybutynin (1 21%), propiverine IR (4 17%), propiverine ER (3%), tolterodine ER (3 8%), solifenacin (3 13%), and darifenacin (14 22%). Constipation was reported by 0 8% of patients administered tolterodine IR and 7 10% of those receiving trospium (Table 4 [109,112,116, ] and Table 5 [ ]). The higher rates of constipation in patients treated with darifenacin compared with other antimuscarinics might be explained by its relatively high selectivity for the M 3 receptor [163], which regulates contraction of intestinal smooth muscle [140]; however, withdrawal rates due to constipation and laxative use among patients who received darifenacin were similar or only mildly elevated compared with those who received placebo [109,141]. It should be noted that elderly patients account for a large percentage of the OAB population and are at higher risk for pharmacotherapy-related constipation than are younger patients. Constipation might cause or exacerbate urinary symptoms [164], which makes this AE an important consideration in the development of pharmacotherapies for OAB. Blurred vision M 3 receptors mediate constriction [51] and are the predominant muscarinic receptor subtype in the cells of the human ciliary and iris sphincter muscles [165]. Thus, abnormal or blurred vision in patients taking antimuscarinics is consistent with their mechanism of action. The results of placebo-controlled trials to date indicate that incidence rates of abnormal vision were 15% for oxybutynin IR, 0% for transdermal oxybutynin, 4% for propiverine IR, 5% for propiverine ER, 0 5% for tolterodine IR, 0 2% for tolterodine ER, and 4 6% for solifenacin (Table 4 [109,112,116, ]). Activecontrolled studies have also provided incidence rates for abnormal vision in patients administered oxybutynin IR (3 24%), oxybutynin ER (3 28%), transdermal oxybutynin (18%), tolterodine IR (1 5%), tolterodine ER (1 2%), trospium (3%), and solifenacin (1 6%) (Table 5 [ ]). Withdrawals TABLE 3 Affinity* of antimuscarinics for human muscarinic receptor subtypes Withdrawals due to AEs have generally been infrequent in placebo- and active-controlled trials of oral antimuscarinic treatments for OAB. Herbison et al. [102] reported that patients receiving placebo were equally likely to withdraw owing to AEs as were those receiving antimuscarinics (RR 1.01, 95% CI, ). In the Chapple et al. [103] metaanalysis, the RR (95% CI) for all-cause withdrawals was significantly greater in patients receiving oxybutynin IR ( mg/day, 1.40, ) compared with placebo. On the other hand, the risk of all-cause withdrawal for patients receiving tolterodine ER (0.71, ) was significantly less than placebo. There were no 994 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

9 ANTIMUSCARINIC DRUGS FOR OAB TABLE 4 Percentage of patients reporting common AEs in double-blind, placebo-controlled trials* of antimuscarinics for OAB Daily dose, mg Dry mouth Constipation Headache Abnormal vision Oxybutynin IR Burgio et al [126] 2.5, 5, 7.5, 10, NR 15 Oxybutynin transdermal Dmochowski et al [127] NR 0 Oxybutynin PI [128] NR NR NR Tolterodine IR Jonas et al [129] Malone-Lee et al [130] Tolterodine IR PI [131] Tolterodine ER Abrams et al [132] Tolterodine ER PI [133] Rackley et al [134] Zinner et al [135] Trospium Alloussi et al [136] 40 3 NR NR NR Cardozo et al [137] 40 Trospium PI [112] NR 24 NR Zinner et al [138] NR Solifenacin Cardozo et al [139] NR NR 6 Solifenacin PI [116] NR NR 5 Darifenacin Haab et al [109] NR NR Darifenacin PI [140] 7.5, NR Steers et al [141] NR NR NR, not reported; PI, prescribing information. *Limited to randomized, double-blind, placebo-controlled phase III or postmarketing trials of oral antimuscarinic agents used to treat OAB. other statistically significant differences in RR for all-cause withdrawal between placebo and antimuscarinics. Only patients receiving oxybutynin IR ( mg/day; 1.82, ) had a significantly greater risk of withdrawal due to AEs compared with placebo. In summary, an extensive literature supports the tolerability of antimuscarinics for the treatment of OAB symptoms. The AE profiles of antimuscarinics are determined by their organ and muscarinic receptor subtype selectivities and pharmacokinetic parameters. The most commonly reported AEs associated with antimuscarinics are dry mouth, constipation, headache, and blurred vision. The favourable AE profiles of antimuscarinics are supported by low withdrawal rates due to AEs in clinical studies. CARDIAC EFFECTS Among the more serious concerns related to antimuscarinic use is the risk of cardiac AEs, particularly increases in heart rate and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). It should be emphasized that QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the herg potassium channel in the heart [166]. Thus, QT prolongation is not a class effect of antimuscarinics, despite the fact that terodiline was withdrawn from the market owing to an association with QT prolongation [167]. It is well established that classical (nonsubtype receptor selective) antimuscarinics may increase heart rate through blockade of vagal inhibitory input [168,169]. Although cardiac arrhythmia and tachycardia are among the precautions listed in the full prescribing information for oxybutynin IR, a study of 21 elderly patients with OAB who had been treated with oxybutynin IR for 4 weeks had no significant change from baseline for heart rate, PR interval, or QTc parameters [170]. JOURNAL COMPILATION 2007 BJU INTERNATIONAL 995

10 TABLE 5 Percentage of patients reporting common AEs in active-controlled studies* of antimuscarinics for OAB Daily dose, mg Dry mouth Constipation Headache Abnormal vision Oxybutynin IR Abrams et al [142] 7.5, NR NR 7 Anderson et al [143] 5, 10, 15, NR 17 Barkin et al [144] 5, 10, 15, NR Birns et al [145] NR 5 5 Davila et al [146] 10, 15, NR 24 Drutz et al [147] 10, NR 10 NR Halaska et al [148] Homma et al [149] Lee et al [150] NR 5 NR Malone-Lee et al [151] 5, Stöhrer et al [157] Versi et al [152] 5, 10, 15, NR NR NR Oxybutynin ER Anderson et al [143] 5, 10, 15, 20, 25, NR 28 Barkin et al [144] 5, 10, 15, NR Birns et al [145] NR 0 7 Diokno et al [153] NR Sand et al [154] Versi et al [152] 5, 10, 15, NR NR NR Oxybutynin transdermal Davila et al [146] NR 18 Dmochowski et al [155] NR NR Propiverine IR Junemann et al [156] NR NR NR Stöhrer et al [157] Junemann et al [158] Propiverine ER Junemann et al [158] Tolterodine IR Abrams et al [142] 2, 4 50 NR NR 3 Chapple et al [159] NR 2 Drutz et al [147] 2, 4 30 NR 15 NR Junemann et al [156] 4 19 NR NR NR Lee et al [150] 4 35 NR 4 NR Malone-Lee et al [151] Sand et al [154] Swift et al [160] van Kerrebroeck et al [161] Tolterodine ER Chapple et al [162] NR 2 Diokno et al [153] NR Dmochowski et al [155] NR NR Homma et al [149] Swift et al [160] van Kerrebroeck et al [161] Trospium Halaska et al [148] Solifenacin Chapple et al [159] NR NR 6 Chapple et al [162] 5, NR 1 NR, not reported; *Limited to active-controlled phase III or postmarketing trials of oral antimuscarinic agents used to treat OAB; Placebo- and active-controlled studies. 996 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

11 ANTIMUSCARINIC DRUGS FOR OAB Furthermore, a postmarketing study of patients receiving tolterodine IR identified only 17 cases (0.1%) of tachycardia or palpitations that were possibly or probably related to the drug [171]. Four of 29 other arrhythmias were judged to be possibly or probably related to tolterodine. None represented a serious arrhythmia, such as ventricular tachycardia or fibrillation. The full prescribing information for tolterodine ER [172] states that there has been no association of torsade de pointes in the international postmarketing experience with tolterodine IR or tolterodine ER. Results of cardiac electrophysiology studies are included in the full prescribing information for tolterodine IR, tolterodine ER, trospium, solifenacin, and darifenacin. The full prescribing information for tolterodine IR and tolterodine ER include the results of a study of the IR formulation in healthy volunteers. In this study, treatment with the recommended (2 mg twice a day) and supratherapeutic (4 mg twice a day) doses of tolterodine IR for 4 days was not associated with clinically significant QTc interval prolongation in healthy adults. Treatment with trospium for 5 days was not associated with prolongation of the QTc interval [112], and electrocardiogram variables for trospiumtreated patients in a 12-week placebocontrolled trial raised no concerns [138]. QTc interval prolongation did not occur in patients treated with darifenacin for 6 days [140], nor was darifenacin treatment associated with clinically relevant changes in vital signs during a 12-week, placebo-controlled study [141]. QTc interval changes with 10-mg (2 ms) or 30-mg (8 ms) daily doses of solifenacin were not clinically significant [116]. Similarly, a placebo-controlled study of propiverine IR (45 mg) found no changes in heart rate, P Q interval, QRS interval, QT interval, or QTc interval after 4 weeks of treatment [173]. Thus, there is little evidence to suggest that antimuscarinics increase the risk of cardiac AEs when administered at recommended therapeutic doses. SAFETY AND EFFICACY IN SPECIAL POPULATIONS Men with BOO There is concern among clinicians that the inhibitory effect of antimuscarinics on detrusor muscle contraction could theoretically impair detrusor contractility and thus cause urinary retention in men with OAB symptoms and possible BOO. However, there is little published evidence to support the concern. Kaplan et al. [174] reported a significant increase in Q max, a decrease in PVR, and no incidence of acute urinary retention (AUR) in men with suspected benign prostatic obstruction (BPO), a form of BOO caused by prostatic enlargement due to BPH, and LUTS who had failed α-receptor antagonist therapy and were subsequently treated with tolterodine ER for 6 months. A 12-week, double-blind, placebo-controlled study designed to evaluate the safety of tolterodine ER in men (aged >40 years) with symptoms of OAB and urodynamic evidence of DO and BOO was also performed. Changes in Q max and detrusor pressure at Q max were comparable to placebo, and volume to first detrusor contraction and maximum cystometric capacity were significantly improved in men receiving tolterodine ER. A statistically significant increase in PVR (+33 ml vs placebo) was not considered clinically significant, and tolterodine ER was not associated with an increased incidence of symptoms suggestive of AUR (placebo 3%; tolterodine ER 3%). Micturition disorders led to withdrawals in one of 72 (1%) patients receiving placebo and three of 150 (2%) patients receiving tolterodine ER [132]. Several studies have also suggested that antimuscarinics can be safely combined with α 1 -receptor antagonists to treat OAB symptoms and other LUTS in men who were either known to have or suspected of having BOO [ ]. In fact, studies have shown that combination treatment might be more effective for reducing LUTS than α 1 -receptor antagonists alone. Athanasopoulos et al. [176] treated 50 men with BOO and DO with tamsulosin for 1 week and then randomly assigned them to 3-month therapy with tamsulosin/tolterodine combined therapy or tamsulosin alone. There were significant reductions from baseline for maximum detrusor pressure during micturition and maximum involuntary contraction pressure in men who received the combined treatment. Combined therapy was also associated with significantly increased Q max and volume at first involuntary contraction, as well as improvements in QoL measures from baseline. Changes from baseline in maximum detrusor pressure, maximum involuntary contraction pressure, and QoL measures did not reach statistical significance in men receiving tamsulosin alone. There was no incidence of urinary retention in either treatment group [176]. Thirty-two of 44 men (73%) with DO and BOO who failed treatment with doxazosin monotherapy had symptomatic improvements after 3-month treatment with doxazosin and tolterodine [175]. Combined treatment was not associated with an increased incidence of AUR (Lee 2005, personal communication). It should be noted that the three studies [132,175,176] used urodynamic criteria for patient enrolment, which might limit their applicability to clinical practice, where patients are initially treated based on symptoms rather than urodynamic findings. More recently, Kaplan et al. [179] studied the efficacy and safety of tolterodine ER and/or the α 1 -receptor antagonist tamsulosin in 879 men who met research criteria for both OAB and BPO. A significantly greater proportion of patients receiving combined therapy (80%) reported treatment benefit by week 12 compared with placebo (62%), tamsulosin (71%), or tolterodine ER (65%). Combined therapy also resulted in significant improvements in bladder diary variables (i.e. UUI, urgency, 24-h micturition frequency, and nocturnal frequency) and the IPSS total and QoL scores vs placebo. The incidence of AUR requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; placebo, 0%). Similarly, Lee et al. [177] reported significantly greater improvements in micturition frequency, volume voided per micturition, and the IPSS Storage Index among men with OAB symptoms and BPO treated with doxazosin plus propiverine than among those treated with doxazosin alone; there was no difference between the two groups in the rate of AUR. There remains a need for similar large-scale, placebo-controlled studies evaluating the efficacy and safety of other antimuscarinics in men with OAB and possible BOO. Elderly patients Because the prevalence of OAB is greatest among the elderly, it is important that OAB pharmacotherapies are safe for older patients. Safety considerations specific to the elderly include increased permeability of the BBB, altered hepatic and renal function, and coadministration of other drugs with antimuscarinic properties [180]. Of the JOURNAL COMPILATION 2007 BJU INTERNATIONAL 997