Although α-blockers remains to be the first-line treatment for male with BPH, there are a subset of patients still having residue OAB symptoms, including urinary urgency, urge incontinence, frequency, and nocturia. OAB symptoms caused by consistent DO may be a possible reason for treatment failure, because DO was poorly associated with BOO affected by α-blockers. Thus, there is an increasing concern in add-on treatment of OAB symptoms in patients with BPH. The add-on treatment lead to a significant improvement in patients with BPH and concomitant OAB in the total IPSS, IPSS storage sub-score, IPSS voiding sub-score, mean number of micturition per day, urgency episodes per day, nocturia episodes per day, total Overactive Bladder Symptom Score (OABSS), and mean volume voided (MVV). In general, add-on treatment appeared superior to mono-treatment in many aspects. Despite adding a second medication to α-blockers may surely be helpful in patients experiencing residue OAB, evidence of comparative effectiveness of different add-on medications may be limited in the absence of published head-to-head trial. To compare multiple add-on treatments, a network meta-analysis was developed by using both direct comparisons of interventions among trials and indirect comparisons across RCTs. [16, 17] Hence, this systematic review and network meta-analysis has assessed the efficacy of a range of medications for treating OAB on clinical outcomes as add-on treatment for patients with BPH and residual OAB symptoms despite α-blockers prescription. We have included a total of 15 RCTs containing 7 add-on medications used in 4875 patients. Our results indicated that add-on treatment appeared more effective than α-blockers alone in improving total IPSS score, IPSS storage sub-score, the mean number of micturition per day, urgency episodes per day, and nocturia episodes per day.
Patients with BPH and refractory nocturia usually do not completely respond to α-blockers, because relief of bladder outlet obstruction is not sufficient to overcome nocturia. The reason may be because the multifactorial mechanism of nocturia in aging male [18]. Nocturnal polyuria (NP), which was defined as the voided urine volume during the hours of sleep exceeded 33% of the 24 hours output, was found to be the main etiology leading to nocturia. NP is a common condition in patients having nocturia (up to 82.9%) [18], and was found to be more prevalent in elderly population due to nocturnal urine production increases with aging. Yoong et al reported that 85% of male patients with nocturia and LUTS having poor response to α-blocker were identified to have NP [19]. NP should be considered as a possible cause of refractory nocturia despite α-blocker treatment.
In our analysis, we found that desmopressin adding to α-blockers had the greatest improvement in the total IPSS score and nocturia, and ranked second in improving the IPSS storage sub-score based on the SUCRA. Desmopressin, an arginine vasopressin synthetic analogue, causes similar inhibitory effects on diuresis. It can significantly decreased nocturnal urine output and the number of nocturia episodes [20], which may cause an subsequent improvement in storage symptoms and voiding symptoms resulting in decreased IPSS scores. A systematic review concluded that oral desmopressin added to α-blockers was more effective for improving the IPSS and nocturnal symptoms than using α-blockers alone, with a 64.3% reduction in frequency of nocturia in comparison with 44.6% [21]. Shin et al. reported a significant decrease in nocturnal urine volume, nocturia episodes, overactive bladder symptom score, urgency episodes,, and nocturnal bladder capacity index when using desmopressin plus α-blockers [22]. Bae et.al showed that mean number of nocturnal voids, total IPSS, and IPSS storage sub-score significantly improved after desmopressin add-on therapy [14]. In addition, add-on desmopressin could improve quality of life (QoL), with higher satisfaction with medication and more willing to continue the treatment for men with BPH [23]. As for the safety assessment, the most concerning adverse events of the add-on therapy with desmopressin was hyponatremia. Despite most patients who developed hyponatremia were asymptomatic, regular assessment of serum sodium after starting desmopressin add-on therapy is recommend, especially for men with advanced age. Owing to the clinical effectiveness and relative safety of desmopressin, the addition of desmopressin to α-blockers may be a suitable therapy for BPH patient with residue OAB symptoms, especially for nocturia.
While studies have shown that the addition of antimuscarinics to α-blockers was recommended for persistent OAB symptoms associated with BPH [24], comparisons among antimuscarinics were currently unclear. Based on our results, imidafenacin adding to α-blockers make greatest reduction in the IPSS storage sub-score and micturition, and also presented as a second best choice in improving nocturia and urgency based on the SUCRA. The Good-Night study showed that add-on imidafenacin caused a significant reduction in frequencies of 24-h and nocturnal micturition, and significantly reduced nocturnal urine volume in imidafenacin nightly group (α1-blocker plus 0.1 mg imidafenacin nightly) [25]. Similarly, the ADDITION study reported that add-on imidafenacin (tamsulosin 0.2 mg/d + imidafenacin 0.1 mg twice per day) resulted in significant improvements in frequencies of daytime urination, night-time urination, urinary urgency, IPSS, and total OABSS. A recent meta-analysis also concluded that adding imidafenacin to α-blockers significantly improve OAB symptoms, with a greater reduction in OABSS compared with alpha-blocker monotherapy [26]. Imidafenacin, as a antimuscarinic agent, has high affinities to the M3 and M1 muscarinic receptor subtypes and a low affinity to M2 receptors [27]. Meantime, in clinical experiments, imidafenacin also has an inhibitory effect on the contractions of detrusor smooth muscles by blocking both the postjunctional M3 receptors and the prejunctional M1 receptors in humans [28]. The reasons of superior efficacy of add-on imidafenacin over other antimuscarinics for treating OAB symptoms may be explained by its unique pharmacological effect. Imidafenacin featured by shorter half-life (2.9 hours), relatively greater selectivity and longer duration of receptor binding in the bladder than in the salivary gland and other organs in rats (6–9 hours in the bladder, 1–3 hours in the submaxillary gland; no observation in the brain) [29, 30] compared with other antimuscarinic agents. Interestingly, our results also revealed that add-on imidafenacin has greatest improvement in nocturia than other antimuscarinics. This finding was consistent with previous studies, which speculated that imidafenacin may reduce the number of nighttime voids, increase bladder capacity and improve sleep disorders [25, 31]. In an animal experiment, Watanabe et.al showed that imidafenacin decreased urine volume by suppressing the C-fibers in the rat bladder [32]. The possible mechanism for how imidafenacin improving nocturia is that it decreases the nocturnal urine volume by the inhibition of bladder afferent nerves, causing subsequent improvement in nocturia and sleep disturbance [25]. In terms of safety, imidafenacin has fewer adverse events such as dry mouth and constipation than other antimuscarinic agents [33, 34], which could be explained because it was higher selective to the bladder. Furthermore, Wu et.al reported that imidafenacin was associated with a statistically lower withdrawal rate related to adverse events [34]. There have been concerns that antimuscarinic add-on may theoretically aggravate voiding symptoms by inhibiting detrusor muscle contraction, resulting in reducing Qmax improvements, increased PVR, and, in particular, cause of acute urinary retention. However, there were no significant differences with respect to the Qmax or the PVR after adding imidafenacin to α-blockers [26, 35]. Collectively, imidafenacin add-on treatment was effective, safe, and well-tolerated for residual OAB symptoms in patients with BPH already receiving α-blockers, with the superior efficacy on micturition, urgency, and nocturia than other antimuscarinic agents.
Our results indicated that add-on mirabegron was effective in treating residual OAB symptoms such as micturition, urgency, and nocturia in patients already receiving α-blockers, ranking second in improving IPSS score and third in IPSS storage sub-score based on the SUCRA. Previous works have corroborated our findings. Two RCTs have reported that adding mirabegron to tamsulosin showed significant improvement in total IPSS, IPSS storage sub-score, and total OABSS [12, 36]. Kaplan et al. described that adding mirabegron to tamsulosin had significant improvements in micturition, urgency, and Total Urgency and Frequency Score [11]. A recent meta-analysis showed that add-on mirabegron therapy significantly reduce the mean number of micturition, urgency episodes per day, and total OABSS compared with tamsulosin monotherapy [10]. Mirabegron was also proved to be urodynamically efficacious and safe in treating men with BPH and OAB. Add-on mirabegron treatment significantly increased Qmax and voided volume [37, 38]. This finding could possibly be interpreted by the pharmacology characteristics of mirabegron. Mirabegron, as a β3-agonist, not only promoted relaxation of detrusor smooth muscle to increases bladder capacity [39], but also showed competitive antagonist activity on the α1-adrenoceptors in the urethra, resulting in urethral smooth muscle relaxation [40]. As for the safety assessment, the incidence rate of treatment-emergent adverse event (TEAE) of the adding mirabegron to α-blockers and α-blockers were similar, and TEAEs were mild in severity [10, 41]. Although increase in PVR was observed for add-on mirabegron treatment in some studies, the change of PVR was not clinically meaningful [41]. Mirabegron appeared to be a safe treatment option for patients with predominant co-existing OAB and BPH after receiving α-blockers. Furthermore, patient receiving mirabegron have significantly higher persistence and adherence rates than those treating with antimuscarinics, with lower occurrence of TEAEs including dry mouth and constipation [42, 43]. Because add-on mirabegron treatment exhibited satisfactory efficacy and safety with well-tolerance, it could be an alternative choice for residual OAB symptoms in patients not satisfied with other add-on medications with BPH having previous treatment of α-blockers.