Imidafenacin, a novel antimuscarinic agent, is alternative to antimuscarinic agents in patients with overactive bladder syndrome:An updated systematic review and Meta-analysis of randomized controlled trials

Purpose Previous study included limited number of randomized controlled trials (RCTs) and compared limited parameters post the treatment of imidafenacin and other anticholinergic drugs (ADs) for overactive bladder syndrome (OAB) and controversy about the superiority of those ADs still remains. We aim to update the evidence and provide better clinical guidance. A systematic search in PubMed, Embase, ClinicalTrial.gov, and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. Meta-analysis of all published RCTs comparing imidafenacin with other ADs in patients with OAB was performed. The primary outcomes were the changes in OAB symptoms and OAB Symptom Score (OABSS). Secondary outcomes included adverse events (AEs) and dropout rate related to AEs.


Introduction
Overactive bladder syndrome (OAB), usually accompanied by frequency and nocturia, is characterized by urinary urgency, with or without urgency urinary incontinence [1,2].
Etiology and pathologic mechanism remain unclear. OAB is a chronic and debilitating condition, whose overall prevalence is estimated 11.8%-16.9% in US [3,4]. OAB symptoms can usually affect work productivity, social relationships, and sleep patterns, causing anxiety and depression, and lead to decline of life quality [5].
Oral antimuscarinic agents (i.e., solifenacin, propiverine, darifenacin, and fesoterodine) have been the mainstay of pharmacotherapy for the treatment of OAB [6]. However, these antimuscarinics lack bladder selectivity and result in dry mouth, constipation, and other adverse events, decreasing patient satisfaction and leading to discontinuation or switching [7,8].
Imidafenacin, which is a novel antimuscarinic agent with high bladder selectivity, was used to treat OAB in Japan since 2007 and had higher affinity for the M1 and M3 muscarinic receptor subtypes and lower affinity for the M2 subtype [9,10]. Study had confirmed the efficacy and safety of imidafenacin compared with placebo [11]. However, whether it is a better choice for OAB patients compared with other anticholinergic drugs still remains unclear.
Huang et al. [12] analyzed only 4 randomized controlled trials (RCTs) in 2015, and captured limited parameters to compare the efficacy (without nocturia episodes) and safety (only dry mouth and constipation rate) of those antimuscarinic agents and controversy about the superiority of those antimuscarinics still remains.
Hence, this present study aims to include more relevant RCTs and analyze more parameters to compare the efficacy and safety of imidafenacin and other antimuscarinics for OAB, and provide updated evidence for clinical practice.

Search strategy
The current study was performed according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guideline [13]. A systematic search in PubMed, Embase, ClinicalTrial.gov, and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. The electronic search was performed to capture all relevant studies using the following search strategy: (Overactive bladder OR OAB) AND (Novel antimuscarinic agent OR Antimuscarinics OR Cholinergic drug OR Imidafenacin OR tolterodine OR darifenacin OR solifenacin OR fesoterodine OR propiverine OR botulinum toxin) AND Quality of life. The procedure of retrieving and evaluating the articles was conducted independently by two reviewers (JP-W and LP), and differences were solved through a discussion in group. The selection procedure was presented in Fig 1. This study did not need IRB approval because the data were directly obtained from studies freely available on the internet instead of being collected from institutions or patients.

Study selection and exclusion criteria
The Eligible for inclusion: (1) published RCTs compared imidafenacin with at least one anticholinergic drug (AD) in patients with OAB; (2) studies provided main outcome data evaluating the safety and tolerability of the these antimuscarinics.
The exclusion criteria: (1) descriptive studies without comparison between imidafenacin with other ADs; (2) a type of review, meta-analysis, letter, case report, or studies based on animals or on children; (3) duplications and repeated analyses. There were no exclusion criteria based on publication status or language.

Outcomes
The primary outcomes were used to evaluate the effectiveness including overactive bladder symptom score (OABSS) [14], and the change in OAB symptoms (urgency episode/day, nocturia episode/day, urgency incontinence episode/day, incontinence episode/day, urine volume voided per micturition, and micturition/day). Secondary outcomes were adverse events (AEs), such as dry mouth, constipation, prolongation of intervals of electrocardiogram (ECG), blurred version, headache, stomach discomfort, nausea, dry eyes, postvoid residual volume (PVR), urinary tract infection (UTI), abdominal pain, and dropout rate related to AEs.

Assessment for risk of bias
The risk of bias (ROB) across RCTs was assessed using a ROB graph generated through Review Manager software according to Cochrane hand book. ROB domains were judged as low, high, or unclear risk.

Statistical analysis
Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) was used to perform all analyses. Mean difference (MD) and relative risk (RR) with 95% confidential interval (CI) were calculated for continuous and dichotomous outcomes, respectively. Heterogeneity was evaluated by I² test, with significance set at P < 0.05. I² values of 25, 50, and 75 % corresponded to low, medium, and high levels of heterogeneity, respectively. The fixedeffect method was used for studies without significant heterogeneity (I² values<50%), and random-effect method was used with I² values ≥50%. Sensitivity analyses were performed If a huge heterogeneity was detected. Publication bias was calculated using funnel plot in Review Manager.

Literature search and study characteristics
Totally, 138 records have been searched using the items in searching strategies from January 2007 to May 2019. Duplications(n=20) and non-comparative articles(n=53) were excluded, respectively. Then, 65 full-text papers were assessed independently by two reviewers (L P and X Z) for eligible according to previous inclusion criteria. Finally, 6 studies published in English including 7 RCTs [15][16][17][18][19][20] with mean follow-up of 23.43  weeks were captured and included in our meta-analysis. According to the study design in LIST study [17], there were two RCTs in this study regarding long-term and short-term follow-up, with different baseline and endpoints. 7 RCTs included very overall outcome data regarding both efficacy and safety of those ADs. Moreover, the ROB across included studies was relatively low as depicted in Fig 2. Characteristics of included RTCs were presented in Table 1.

Micturition per day and urine volume voided per micturition
Similarly

OABSS
OABSS, integrating four symptoms into a single score, was a useful tool to evaluate the improvement of OAB symptoms and life quality [14].
In the current study, OABSS was reported in 4 RCTs involving 465 patients (Fig 9). There was no statistically differences between imidafenacin and other ADs throughout the administration period ranging from 2-52 week ( (Fig 10).
Simultaneously, imidafenacin did not show a higher risk in blurred vision, dry eyes, UTI, headache, stomach discomfort, nausea, and abdominal pain (Fig 11), as well as in PVR (4   weeks (Fig 13).

Principal findings
OAB is a chronic and debilitating disease. The long-term efficacy and tolerability of treatments will be very important regarding it is a QOL-related disease. Antimuscarinics (i.e., solifenacin, propiverine, and tolterodine) have been used as first-line pharmacotherapy for OAB, however, a current study reported that discontinuation rate was 84% and switching rate was 4% in 12-month follow-up duo to AEs [21]. Thus, it is necessary to find a novel anticholinergic drug with higher tolerability in the long-term follow-up. Imidafencin compared with other ADs presented a lower AE-related withdrawal rate in this study (RR=0.51, P=0.02), indicating that imidafenacin had higher tolerability and adherence in 23.43-week follow-up. 0.1 mg twice daily or 0.2 mg once daily was recommended clinical dosage for the treatment of OAB.
It is clear that imidafenacin has more efficacy than placebo [11]. However, controversy about priority of imidafenacin and other antimuscarinics still unclear although Huang et al.
(published in 2015) [12] had conducted a meta-analysis previously. Researcher included only 4 articles and captured limited parameters to compare the efficacy and safety of three antimuscarinic agents (imidafenacin vs. solifenacin and propiverine). The advantage of the current meta-analysis is that we included three more high-quality RCTs with totally 5 antimuscarinics and overall analyzed parameters (2-52 weeks) regarding both efficacy and safety of those drugs, especially adding overall indicators to evaluate the safety. One serious problem in previous study was authors used data from each visit rather than variation compared with baseline, and there was no comparability if the primary data were not consistent. Another advantage of present study was that heterogeneity was generally low across all analyses.  [24]. Moreover, the imidafenacin excreted in urine also play an important role in pharmacokinetic and pharmacological selectivity [24].
In terms of safety, Huang et al. only reported dry mouth rate, constipation rate and total number of AEs. However, significant lower dry mouth rate and lower constipation rate were accordant with Huang΄s data. We believed the higher selectivity in bladder than salivary gland and digest system could explain for the results. As expected, these was no statistically difference in PVR, QT intervals, blurred version, headache, stomach discomfort, nausea, dry eyes, and abdominal pain. Blood-brain barrier blocks the binding to the brain's anticholinergic receptor [24], suggesting imidafenacin will not increase the risk for patient with cardiovascular diseases [25]. Similarly, imidafenacin bound rarely to the agents on stomach and colon resulting in less digest-system-related AEs [24]. Taken together, these findings confirmed the safety of imidafenacin.

Clinical decision and limitations
Since the prevalence of OAB increases with age, elderly individuals often associated with polypharmacy might experience a higher antimuscarinics burden [26]. What is worse, nocturia, greatly under-reported by both physicians and OAB patients, was perceived as a normal part of the aging process [27]. Nocturia was associated with increased overall mortality in patients voiding at least three times nightly [28] and was an important risk factor for nighttime falls in the elderly [29]. In the present study, imidafenacin compared with other antimuscarinics had better efficacy in reduction of nocturia episodes ranging from 4-12 weeks. Nevertheless, the cause of nocturia was multifactorial, which included low bladder capacity (including OAB), nocturnal overproduction of urine (NP), and a combination of NP and low bladder capacity. A prospective study concluded that imidafenacin led to an increase in bladder capacity and a decrease in nocturnal urine volume [23]. Another result from a phase III RCT drew the same conclusion that imidafenacin improved both nocturia and nocturnal polyuria [22]. Nevertheless, Linda et al.
reported that solifenacin could not improve nocturia symptoms in OAB patients with NP [30]. The findings suggested that imidafenacin may be a potential choice for elders with refractory nocturia caused by OAB, despite the evidence directly compared imidafenacin with other ADs on nocturia affected by OAB was lacking.
OAB syndrome often affects elderly patients who may present cardiovascular comorbidities [25]. According to our analysis, imidafenacin had no influence on the prolongation of 4,12,52-week QT intervals of ECG and all the RCTs reported few imidafenacin-related cardiovascular events. Therefore, we recommend imidafenacin as a preferable treatment for elder patients with cardiovascular diseases for the benefits of pharmacokinetics and pharmacodynamics [24]. Of course, regular follow-ups and ECG monitoring are necessary throughout the administration period in selected populations such as patients aged > 80 years, accompanied by coronary heart disease or congestive heart failure.
Despite a network meta-analysis [31] was performed recently, only few included articles studied the effect of imidafenacin and only voids, leaks, and dry mouth were analyzed in their study. Considering that imidafenacin was not the main body of study and important outcomes, such as OABSS, urgency episodes, nocturia episodes, and drug-related adverse events, were lacking, we included more RCTs and analyzed overall parameters in an updated meta-analysis that chiefly investigated the effects of imidafenacin to provide a better clinical guidance.
Our study should not be interpreted without limitations. First, although we have included very comprehensive evaluation parameters regarding both efficacy and safety, only imidafenacin vs. solifenacin, propiverine, tolterodine and fesoterodine were performed.
Future studies should focus on the comparison between imidafenacin and other antimuscarinics, such as botulinum toxin and darifenacin. Second, the current research mainly focuses on Asian patients (Japan, Korea, and Russia). Considering that patients have their own characteristics in different countries, the researches in other regions are also needed, especially in western countries. Third, the data on nocturia were available in only one RCT ranging from 4-12 weeks, and there was no difference between two groups in the original article. However, imidafenacin had a better performance by our statistical analysis using the same data. There may be some statistic errors in the original study.
Thus, to confirm the effects of imidafenacin compared with other ADs on nocturia, more high-quality long-term RCTs are needed.

Conclusion
In the present study, we founded that patients treated with imidafenacin and other antimuscarinics had similar efficacy in regard to OABSS and improvements of OAB symptoms, except imidafenacin had less nocturia episodes, suggesting that imidafenacin may be a potential choice for patients with nocturia caused by OAB. Duo to lower dry month rate, lower constipation rate and less withdrawals, imidafenacin is preferable for patients who need long-term medications. Moreover, imidafenacina, without increasing cardiovascular risk, is an optimal therapy for elder patients accompanied with cardiovascular diseases.

Conflict of Interest:
The authors declare that they have no conflict of interest.
Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent: Not applicable.                Figure 1 PRISMA flowchart of study selection.

Figure 2
Results of assessment of risk of bias (ROB). ROB domains were judged as low(green), high(red), or unclear risk(yellow).  Forest Plot for urgency incontinence episodes per day.

Figure 5
Forest Plot for micturition per day.

Figure 6
Forest Plot for urine volume voided per micturition.   Forest Plot for overactive bladder symptom score (OABSS).

Figure 11
Forest Plot for overall adverse events post the treatment of antimuscarinics.

Figure 12
Forest Plot for dropout rate related to adverse events for the treatment of imidafenacin and other antimuscarinics.

Figure 14
Forest Plot for prolongation of QT intervals of electrocardiogram (ECG).