Mechanism of Action

Antimuscarinic agents act to some extent on the afferent (based on preclinical data) innervations, but probably principally on the parasympathetic (efferent) system. The chief functional receptor responsible for the motor activity of the detrusor muscle is the postjunctional muscarinic M ₃ receptor. Although the most numerous (75%) are the M ₂ receptors, their function in the bladder along with that of M ₄ and M ₅ remains undefined. The M ₁ muscarinic receptors predominate in the central nervous system; M ₁ and M ₃ in salivary glands, M ₂ and M ₃ in the gastrointestinal tract, M ₃ and M ₅ in the eyes, and M ₂ in the heart.

M ₃ receptor excitation leads to smooth muscle contraction via entry of extracellular calcium into the cell through L-type channels and activation of rho kinase. Although there has been discussion about the potential importance of activity on M ₂ receptors and sensory nerves and there is a body of literature to support this, these putative mechanisms of action still remain the subject of academic discussion.

In addition, neurotransmitters are released from the urothelium and suburothelium in response to distension and receptor activation. Acetylcholine (Ach) has been shown to be released in greater amounts when the urothelium of bladder strips is intact, suggesting nonneuronal crosstalk between the urothelium and detrusor muscle. It is also proposed that this nonneuronal Ach may enhance muscarinic receptor-mediated detrusor activity and may also be inhibited by antimuscarinic agents to different degrees. Therefore, inhibition of smooth muscle “micromotion” may occur, a phenomenon that is postulated to occur because of leak of Ach from postganglionic parasympathetic nerve during the storage phase of micturition leading to activation of sensory afferent fibers and the sensation of urgency. Recent work has also suggested that muscarinic activation also stimulates urothelial adenosine triphosphate release, which may be of importance given that changes in purinergic signaling have been implicated in the aging bladder and are postulated to occur in bladder dysfunction.

Current antimuscarinic agents approved by the regulatory authorities include oxybutynin, tolterodine, solifenacin, darifenacin, trospium, propiverine, and fesoterodine. The above antimuscarinic agents have different affinities for the different muscarinic receptors, and darifenacin is the only agent with a high selectivity for the M ₃ receptor over M ₂ . Fesoterodine is an oral antimuscarinic drug that is metabolized rapidly and extensively to 5-hydroxymethyl tolterodine, the main active metabolite of tolterodine. Tolterodine and its 5-hydroxymethyl metabolite (fesoterodine) do not discriminate between the receptor subtypes. Oxybutynin and solifenacin show fractional selectivity for M ₃ receptors.

In animal models, greater bladder selectivity has been shown for tolterodine, darifenacin, and solifenacin compared with oxybutynin. It should be noted that animal studies cannot be translated directly to the human situation, and this data should be interpreted with that in mind. Trospium chloride is a quaternary amine that is incompletely absorbed or metabolized, and the majority is excreted in the urine and therefore has a high bioavailability. In addition to antimuscarinic activity, propiverine has been shown to antagonize Ca ²⁺ channels, which may suppress smooth muscle contraction resistant to atropine.

Clinical Efficacy

Two meta-analyses have reviewed anticholinergic medication use in patients with LUTS. Some of the drugs are available as immediate release or once daily preparations, such as oxybutynin, propiverine, tolterodine, and trospium. In addition, oxybutynin is available as a transdermal patch and as a topical gel. Most of the trials in the meta-analyses had a placebo arm, and patient inclusion criteria were often diverse. The proportion of patients having received prior therapy was also variable. Median follow-up was 12 weeks.

The Chapple meta-analysis reported pooled differences, which showed a reduction of 0.5 to 1.3 micturition episodes per day and 0.4 to 1.1 incontinence episodes per day. Some trials reported changes in urodynamic parameters, such as the maximum cystometric capacity, which increased by 90 mL on average. In addition to this, QOL questionnaires, such as the Incontinence Impact Questionnaire, King’s Health Questionnaire, and Urogenital Distress Inventory, were used to show significant benefits over placebo.

With very few trials comparing selective antimuscarinic agents against each other, a meta-analysis of these was not possible. Most patients in the randomized controlled trials (RCTs) were women, and men with a post void residual (PVR) urine volume of more than 200 mL were mostly excluded. This cutoff is rather arbitrary because there are no clear data to support that this is the clinically relevant threshold. In addition, men with voiding symptoms and poor flow were also excluded in most of the trials.

Given most patients in OAB trials are women, urologists have debated the utility of antimuscarinics in men; this is especially important given the potential risk of precipitating urinary retention. The TIMES (The tolterodine and tamsulosin in men with LUTS including OAB: evaluation and efficacy study) trial randomized men with both storage and voiding LUTS to tamsulosin or tolterodine monotherapy or a combination. A PVR greater than 200 was an exclusion criterion. By 12 weeks, tolterodine monotherapy significantly reduced urgency urinary incontinence episodes versus placebo, but no other parameters were improved. By comparison, combination therapy led to significant reductions in OAB symptom outcomes, including bladder diary variables, International Prostate Symptom Score (IPSS) total, and storage subscores, including reduction in each of the individual storage symptom scores.

In another study, Kaplan and colleagues were unable to demonstrate efficacy with tolterodine in men with storage symptoms. However, Herschorn and colleagues have conducted a meta-analysis of fesoterodine 4 and 8 mg and found a reduction in frequency, urgency, and voided volumes. The risk of retention was not apparently increased in these. Solifenacin has also been shown to be efficacious in men with LUTS.

Kaplan and colleagues have systematically reviewed the evidence for antimuscarinics in men and reported a rate of urinary retention in less than 3% with nonsignificant changes in post void residue. A combination of antimuscarinic and α-antagonist was found to lead to greater symptomatic improvements than antimuscarinics alone, although antimuscarinics alone are efficacious and safe. The variable results with antimuscarinic agents alone probably boil down to patient selection and whether the patient has an element of bladder outlet obstruction contributing to their symptoms.

Combination therapy is considered a useful treatment option in men with both storage and voiding symptoms. Seven RCTs have shown the superiority of combination treatment over single-agent treatment and placebo. It is argued that the symptomatic differences are small but significant. Also, a trial powered to assess perception of treatment benefit showed a significant difference, suggesting this difference is still important to patients.

Combination therapy has been investigated as sequential therapy, like in the ADAM (The tolterodine XL ADd-on to an Alpa-blocker in Men) and VICTOR (Vesicare in combination with tamsulosin in overactive bladder residual symptoms) studies, where the antimuscarinic was added later to tamsulosin or as a combination strategy from the outset, such as in the NEPTUNE (Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS [oral controlled absorption system] in Males with Lower Urinary Tract Symptoms) study. Sequential therapy is useful in men where the α-antagonist has not alleviated the patients’ storage symptoms.

In the ADAM study, a significant advantage over placebo was found in total number of voids, day and nighttime frequency, Overactive bladder questionnaire (OAB-q) symptoms scores, and IPSS storage subscore. In terms of total urgency episodes, there was a significant improvement in the add-on antimuscarinic group compared with placebo (−2.9 vs −1.8; P = .0010).

In the VICTOR study, a significant reduction in total number of urgency episodes for solifenacin/tamsulosin versus solifenacin/placebo was observed (−2.18 vs −1.10, P <.001), although there was no statistically significant difference between the groups in terms of total number of voids. Approximately 1.5% of the tamsulosin/solifenacin group developed acute urinary retention (AUR) versus none in the tamsulosin/placebo group.

The NEPTUNE study was interesting because it included men with urodynamically proven bladder outlet obstruction with storage and voiding symptoms. Men received solifenacin 6 or 9 mg with 0.4 mg tamsulosin. At 12 weeks, there was no significant difference in terms of Qmax, Pdet@Qmax , and bladder contractility index between the treatment groups and placebo.

A small randomized study including 107 men compared tolterodine, solifenacin, and darifenacin. All 3 agents were effective in reducing total daily voids and IPSS. In terms of improvement in IPSS and urgency, tolterodine and solifenacin had an advantage over darifenacin. Overall, the PVR increased significantly (>50 mL) in the darifenacin group, while the rates of acute retention requiring catheterization and constipation were also higher, leading the investigators to conclude that darifenacin was not an optimal agent to use in men with LUTS/BPH. Further larger studies are needed to definitively establish whether there is differential efficacy across agents in this patient group.

Clinical Safety

The Chapple meta-analysis reported that trial withdrawal rate was only significant in patients taking oxybutynin immediate release at 15 mg/d and 7.5 to 10 mg/d over placebo and was not significant for any of the other drugs. However, most RCTs are conducted over only a 12-week period, and the natural history of the OAB syndrome complex seems to fluctuate, probably because of its multifactorial nature. Therefore, discontinuation rates, which are obtained from after-market analysis, are actually up to 50%.

In the mainstream trials included in the Chapple meta-analysis, dry mouth is the most commonly reported adverse event (AE) at 30% and 8% in treatment and placebo arms, respectively, followed by pruritus in 15% and 5%. In the meta-analysis, dry mouth rates were higher in active drug groups than the placebo groups. Other AEs included blurred vision, headache, constipation, erythema, fatigue, and urinary retention.

Meta-analysis of patients taking anticholinergic medications reported odds ratios of 1.36 for tolterodine, 1.93 for darifenacin, 2.07 for fesoterodine, 2.34 for oxybutynin, 2.93 for trospium, and 3.02 for solifenacin. This meta-analysis suggests that the receptor selective agents may increase the risk of constipation over nonreceptor selective agents. The major limitation of this meta-analysis was the combination of nondirect comparison studies and the combination of data of different dosages and formulations.

Cognitive impairment is often not thoroughly assessed in many trials involving anticholinergic medications. It is, however, considered to pose a significant risk in the elderly population and in those with conditions such as diabetes, Alzheimer disease, stroke, trauma, multiple sclerosis, and Parkinson disease because of increased permeability of the blood-brain barrier. Therefore, this needs assessing in this at-risk population with longer-term studies.

Another consideration in men is the risk of precipitating urinary retention. The limitation of most studies is that they are short term (12 weeks) ( Table 1 ), and also most studies excluded men with larger PVRs (usually >200 mL) who would be at higher risk due to a presumed reduction in the detrusor contractile function. Furthermore, in the studies that measured prostate size, volumes were generally low. As such, antimuscarinics are generally not recommended in men with PVR greater than 200 mL, in men who have low peak flow rates, or in men who have larger prostates or a previous history of AUR.

In a population-based study, the relative risk of urinary retention was increased to 8.3 in the first 30 days after commencing antimuscarinic therapy and thereafter decreased to a relative risk of 2 with longer-term use. These data need to be interpreted with a degree of caution, because the participant characteristics are unclear. In the 12-week RCTs with selected patients, the risk is reported at 1% to 2%. There remains a need for longer-term studies to better assess the risk of urinary retention and determine the safe upper limit in terms of baseline PVR.

Summary

Antimuscarinic agents have long been used to treat bladder storage symptoms in women. Their safety profile is well known among urologists. Similarly, their use in men is advocated by multiple RCTs. They are also beneficial in combination with an α-antagonist in men with mixed storage and voiding symptoms. In these men, they can be used as add-on therapy or as a combination with an α-antagonist from the outset. In men with urodynamically proven bladder outflow obstruction, they should only be used in combination.

The risk of urinary retention is low if men are selected appropriately as they are done for the RCTs. Specific exclusions should be PVR greater than 200 mL, Qmax 10 mL/s, large prostate, or a previous history of AUR.

Mechanism of Action

Mirabegron is the first agent in a new therapeutic class introduced for the treatment of OAB that works by specific agonisms of the β-3 adrenoreceptor. Mirabegron is thought to enhance relaxation of the detrusor muscle and facilitate urine storage without affecting the detrusor contractile function during micturition. The detrusor relaxes mainly through the cyclic adenosine pathway, during which norepinephrine binds to the β-adrenoceptors. Within the detrusor muscle and the urothelial layer, 3 subtypes of β-adrenoceptors are present (β1, β2, and β3). The vast majority are β3-adrenoceptors (more than 95%), which are thought to be the most important functionally. The exact mechanism is not yet established but may include adenylyl cyclase activation with resulting increase in the intracellular cyclic adenosine phosphate as well as calcium channels. It is currently hypothesized that a significant part of the efficacy is manifest on afferent pathways; hence, the apparent lack of voiding dysfunction in reported studies.

Clinical Efficacy

Several industry-sponsored studies conducted over the past 10 years have assessed the efficacy and safety of mirabegron in a total of more than 10,000 patients. The phase III program consisted of three 12-week double-blind placebo RCTs that took place in Europe, North America, and Australia. Mirabegron was compared with a placebo or active comparator, tolterodine. The inclusion criteria consisted of adults (men and women older than the age of 18) with daytime frequency (≥8) and urgency with or without urgency incontinence (≥3 leakage episodes in a period of 3 days). The vast majority of patients studied were women (approximately 70%). The change in mean number of incontinence episodes and the mean number of micturitions in a 24-hour period were the primary end points. The mean number of urgency episodes per 24 hours and mean volume voided/micturition were the secondary endpoints.

Nitti and colleagues presented results of a pooled analysis of efficacy data from the pivotal phase III studies. At 12 weeks, there was a significant reduction in the primary endpoint of mean incontinence episodes per 24 hours for mirabegron 50 mg and mirabegron 100 mg compared with placebo, −1.49, −1.50, and 1.10, respectively ( P <.05). In terms of mean number of voids, reductions of −1.20, −1.75, and −1.74 were observed for placebo, Mirabegron 50 mg, and Mirabegron 100 mg, respectively ( P <.05 for all comparisons). The mean number of micturitions per 24 hours was also significantly reduced for Mirabegron 50 mg and Mirabegron 100 mg compared with placebo, −0.55 and −0.54, respectively. For all the secondary endpoints of mean volume/micturition and mean number of urgency episodes (grade 3 or 4) per 24 hours, a significant reduction at 12 weeks for both doses of Mirabegron in comparison to placebo was noted. The higher dose of mirabegron did not add any discernible additional benefit over the lower dose.

Around half of the patients in the pooled analysis had had prior treatment with an antimuscarinic, which had been stopped due to either a lack of efficacy or a lack of tolerability. Mirbegron was efficacious in both those who had received prior antimuscarinics and those who had not.

Clinical Safety

The pooled analysis of safety data of the 3 pivotal phase III studies by Nitti and colleagues showed the most common treatment-emergent adverse event (TEAE) to be hypertension and headache. These both occurred at a similar frequency to the both the placebo and the tolterodine groups. The development of dry mouth is one of the most bothersome TEAE with antimuscarinic therapy; the incidence of this problem with mirabegron (2%) was placebo level (2.1%), while with tolterodine it occurred 5 times as often (10.1%). Mirabegron was associated with approximate increases of 1 mm Hg or less in blood pressure and 1 bpm or greater in pulse rate as compared with placebo. Although these rates are acceptable, pharmacovigilance data will be essential in confirming safety in real life practice.

The 12-month study by Chapple and colleagues demonstrated a similar incidence of TEAEs for mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg. Again dry mouth was more frequent in the tolterodine group (8.6%) in comparison to mirabegron (2.3%–2.8%). However, all the groups had a similar rate of subjects discontinuing the medication because of TEAEs, 6.4%, 5.9%, and 6.0% for mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg, respectively.

An important issue in men with LUTS is the risk of urinary retention; hence, in the phase III studies, PVR volume was included as a safety endpoint. In the pooled analysis, the overall occurrence of urinary retention was low, and lowest in mirabegron-treated patients (placebo 0.5%, mirabegron 25 mg 0%, mirabegron 50 mg 0.1%, mirabegron 100 mg 0%, tolterodine 0.5%). No clinically relevant changes in PVR, from baseline to last visit, occurred in any group. Similarly, in the 12-month study by Chapple and colleagues, the incidence of urinary retention was low across the groups, occurring in 1, 1, and 3 patients in the mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg groups. Nitti and colleagues sought to further assess the effect of mirabegron on voiding parameters by assessing more than 200 men (>45 years) with LUTS and bladder outlet obstruction with urodynamic studies pretreatment and posttreatment with placebo or mirabegron. They found that mirabegron (50 or 100 mg) did not adversely affect maximal flow or detrusor pressure at maximal flow after 12 weeks of treatment.

Summary

Mirabegron was shown to be safe and effective in the treatment of patients with OAB. There is no evidence of a greater efficacy at the higher dose of 100 mg compared with 50 mg. Mirabegron was associated with levels of dry mouth similar to placebo, while the safety profile appears to be acceptable. Mirabegron is therefore a treatment option in patients with men with OAB, with or without a history of prior antimuscarinic use. Most patients studied in the phase III program are women, and so there is a need for further studies to better characterize the features of men who respond to treatment. In the future, it will be interesting to see whether the low rate of dry mouth translates to any significant difference in discontinuation rates compared with antimuscarinics in real clinical practice. However, there remains the important future need for adequate studies evaluating the use of this therapy in the male population affected by storage LUTS/BPH.