In this systematic review update, we identified 20 new RCTs (in 38 records and 3 new publications for trials identified in the previous systematic review) [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69] published since the 31 RCTs included in the 2012 review . See Fig. 1 for the PRISMA flow diagram (see Table S2 for list of included studies). We also included the full publication and data from an RCT  comparing darifenacin vs. solifenacin that was only published as an abstract at the time of the 2012 review. This study and five others (in six records) were rated poor quality because of unclear allocation concealment, blinding, and issues related to missing data and were not discussed in this report [31, 36, 45, 49, 50, 64]. Five RCTs were rated good quality and 10 were fair quality. Since mirabegron was approved after the 2012 review, all evidence involving mirabegron is new (14 RCTs total). Two new comparisons added were fesoterodine vs. solifenacin  and darifenacin vs. trospium . Excluded studies with reasons for exclusion are listed in Table S3. Detailed study characteristics and quality assessments of included studies are in Tables S4 and S5.
Table 1 shows characteristics of new included studies. Considering fair- and good-quality RCTs identified in this update, trial sample size of included populations ranged from 60 to 3080. Trial durations ranged from 4 to 52 weeks (median 12 weeks). Of 12 trials that reported funding source, all but one were funded by industry. Mean age of patients was 57.4 (SD 13.4) years with a mean BMI of 28.4. Similar to RCTs included in the 2012 review, patients were predominantly female (77.7%) and White (89.7%). UUI was the most common form of OAB (58.6%), followed by mixed incontinence (22.2%) then OAB without incontinence (19.4%). Patients experienced mean 67.4 months of OAB symptoms and 59.2% had previous pharmacotherapy for OAB. At baseline, patients reported means of 3 incontinence episodes, 6.1 urgency episodes, and 2.5 UUI episodes per day. As with previously included RCTs, there was a wide range of baseline incontinence episodes per day (range 1.9 to 8.9 episodes per day, median 2.78). Baseline numbers of urgency and UUI episodes were more consistent, with a range of 4.2 to 8.2 urgency episodes and 1.7 to 3.9 UUI episodes per day.
Mirabegron plus solifenacin vs. solifenacin
Four trials (N = 6430 for included drug doses) compared the combination of mirabegron (25 to 50 mg) plus solifenacin 5 mg vs. solifenacin 5 mg, with three lasting 12 weeks [29, 37, 41] and one lasting 52 weeks . Two trials were rated good quality and two were fair quality. Table 2 shows change from baseline, pooled mean differences (MD), and risk ratio for efficacy outcomes for each drug comparison. The combination of mirabegron 50 mg with solifenacin 5 mg showed significant improvement on all efficacy outcomes compared with solifenacin 5 mg. However, patients still experienced more than one incontinence and about three urgency episodes per day. Moreover, the absolute difference between combination therapy and monotherapy was less than one episode of incontinence, urgency and micturitions per day (−0.18, −0.58, and − 0.41, respectively). There was moderate heterogeneity (I2 = 59%) in the pooled estimate of reduction of urgency episodes, but all trials consistently favored combination therapy. Of patients with incontinence at baseline, significantly more patients on combination therapy reported no incontinence over 3 days at end of treatment (45% vs. 36%). All four trials reported measures of patient-assessed change in symptoms using both the PPBC and the OAB-q Symptom Bother score, and pooled results favored combination therapy on both assessments (Table 3). On the OAB-q Symptom Bother score, both treatment groups achieved the MCID from baseline.
Table 4 shows pooled relative risks for adverse events. Combination therapy resulted in significantly higher incidence of constipation (3.8% vs. 2.4%) Combination therapy also showed higher rates of blurred vision (0.7–1.3% vs. 0–0.5%, Table S6) and tachycardia (1.3–10% vs. 0.3–0.7%) than monotherapy. Incidence of SAEs and other adverse events of interest were low and not significantly different between drugs.
Mirabegron plus solifenacin vs. mirabegron
Three trials (N = 3677) compared mirabegron plus solifenacin vs. mirabegron [29, 40, 41, 58, 61, 62, 65, 68]. Two trials lasting 12 weeks were fair quality, and one trial lasting 52 weeks was rated good quality. With the exception of proportion of patients reporting no incontinence over 3 days, mirabegron 50 mg plus solifenacin 5 mg per day significantly improved all other efficacy outcomes more than mirabegron 50 mg per day at 12 weeks (Tables 2 and 3). The greatest difference was observed in number of urgency episodes, which decreased by a mean 3.47 episodes per day with combination therapy compared with a mean 2.73 episodes per day with mirabegron. All three trials reported patient-assessed symptoms using the OAB-q Symptom Bother score and the PPBC, both of which favored combination therapy (Table 3).
Incidence of dry mouth was significantly higher with combination therapy than with mirabegron alone (8% vs. 4%), but this did not lead to significantly greater participant withdrawal (3% vs. 3%, Table 4). There were no differences between combination therapy and mirabegron monotherapy in SAE and constipation (Table 4). Incidence of blurred vision was rare and similar between treatment groups (0.8% in combination therapy vs. 0.02% in mirabegron).
Mirabegron vs. solifenacin
Five RCTs in 11 records (N = 4279) compared mirabegron 50 mg with solifenacin 5 mg [29, 32, 40, 41, 58, 59, 61, 62, 65, 67, 68]. Two of the four larger RCTs were rated good quality, and a small, fair-quality study recruited only women. The pooled estimate based on the four larger RCTs (N = 3603) showed that solifenacin significantly reduced incontinence episodes more than mirabegron (Fig. 2), but there was no difference in the number of patients reporting no incontinence (51% vs. 50%, Table 2) [29, 32, 40, 41]. A significant difference was not found in reduction of urgency episodes from baseline. However, there was moderate heterogeneity (I2 = 52%) with three trials favoring solifenacin and one favoring mirabegron. The mean change in micturitions per day was not significantly different in individual studies, but the pooled mean difference showed solifenacin reduced micturition frequency significantly more than mirabegron (Table 2). In three RCTs, differences between the drugs in UUI (separate from overall incontinence) did not reach statistical significance.
Four trials reported patient-assessed symptoms using both the PPBC and OAB-q Symptom Bother score [29, 32, 40, 41]. There was moderate heterogeneity among trials (I2 = 50%) on the PPBC, though most trials and the pooled mean difference showed similar changes between treatments (Table 3). Both treatment groups achieved the MCID on the OAB-q Symptom Bother score, but solifenacin showed significantly greater improvement than mirabegron (Table 3).
Based on meta-analyses, differences in adverse events were not apparent except a small but statistically significant higher risk of dry mouth with solifenacin than with mirabegron (6.3% vs. 3.4%, Table 4). Constipation occurred at similar rates between mirabegron and solifenacin (2.2% vs. 2.1%). Pooled assessment of 12-week trials showed no difference in withdrawals due to adverse events [29, 32, 41, 67] or SAEs (Table 4) [29, 32, 41].
Mirabegron vs. tolterodine ER
Six RCTs in 11 publications (N = 4904) of mirabegron and tolterodine met the inclusion criteria for this review [30, 34, 35, 47, 48, 51, 54,55,56,57, 63, 66, 69]. All but one trial were fair quality. Meta-analyses showed no difference in any efficacy outcome between drugs. Pooling data from five trials reporting incontinence at 8 to 12 weeks found no difference between mirabegron 50 mg and tolterodine ER 4 mg (Table 2) [35, 48, 51, 66, 69]. Forty-seven percent of patients in both treatment groups reported no incontinence over 3 days at the end of treatment. In the 52-week trial, interim results at 3 months showed no significant difference between the drugs on incontinence (MD –0.01, 95% CI –0.24 to 0.22), but tolterodine ER showed greater reduction from baseline than mirabegron at study end point (MD 0.25, 95% CI 0.01 to 0.49) . Change from baseline number of urgency episodes was not statistically significantly different between mirabegron and tolterodine at 8 to 12 weeks [35, 48, 51, 66, 69] and at 52 weeks . Pooling six RCTs with data at 8 to 12 weeks found no significant difference between mirabegron 50 mg and tolterodine ER 4 mg in number of micturitions per day (Table 2, Fig. 3) [34, 35, 48, 51, 66, 69]. Sensitivity analysis, removing two outlier studies, did not resolve the heterogeneity. However, the difference between the drugs was very small; at 52 weeks, one study found a small, non-significant change in micturitions between mirabegron 50 mg and tolterodine ER 4 mg (MD 0.12, 95% CI –0.11 to 0.35) . Three trials reported patient-assessed symptoms using the OAB-q Symptom Bother score and two also reported the PPBC, neither of which found significant differences between mirabegron 50 mg and tolterodine ER 4 mg at 8 to 12 weeks (Table 3) [35, 48, 66] or at 52 weeks . All relevant treatment arms achieved the MCID on the OAB-q Symptom Bother score [35, 48, 66]. One trial also found no difference in the King’s Health Questionnaire mean change in bladder problem score .
Pooling results from four short-duration RCTs showed a statistically significantly higher rate of dry mouth with tolterodine 4 mg than with mirabegron 50 mg (11.7% vs. 4.6%, Table 4) [48, 51, 66, 69]. Higher incidence of dry mouth with tolterodine was also observed in the 52-week trial (8.6% vs. 2.8%) . The incidence of cardiac arrhythmia was similar at 12 weeks in two trials (2.6% vs. 2.8%) [48, 51], but higher with tolterodine ER 4 mg at 12 months in a single trial (3.9% vs. 6.0%; P = 0.0547) . However, there was no difference in the proportion of patients who withdrew because of adverse events (Table 4). Incidences of constipation, SAEs, and dizziness were similar between the drugs at both 8 to 12 weeks (Tables 4 and S6) and 52 weeks.
Fesoterodine vs. solifenacin
One fair-quality trial (N = 119) compared fesoterodine 4 mg per day with solifenacin 5 mg per day . The study reported only the OABSS for assessment of benefits. While fesoterodine and solifenacin each significantly improved scores from baseline at 12 weeks (−9.4 vs. −8.2) and achieved an MCID of 3 points, the difference between drugs was small and not statistically significant. Significantly more patients receiving fesoterodine compared with solifenacin withdrew because of adverse events (10.2% vs. 0.0%). Fesoterodine also resulted in higher incidence of constipation (5.1% vs. 1.7%) and dry mouth (13.6% vs. 5.0%), though differences did not reach statistical significance (P = 0.256 and P = 0.186, respectively). Other adverse events of interest were not reported.
Fesoterodine vs. tolterodine
We did not identify any new trials that compared fesoterodine with tolterodine. The 2012 review included three 12-week trials comparing fesoterodine 8 mg per day vs. tolterodine ER 4 mg per day (N = 4148) . Although fesoterodine led to statistically fewer incontinence and urgency episodes per day, the absolute differences were small at less than one-half episode per day for each efficacy outcome. Patients reporting no incontinence at end of treatment also favored fesoterodine (64% vs. 58%, Table 2). Fesoterodine 8 mg resulted in significantly more withdrawals due to adverse events than tolterodine ER 4 mg (4.9% vs. 3.3%, Table 4). Incidence of constipation and dry mouth was also significantly higher with fesoterodine 8 mg than with tolterodine ER 4 mg (Table 4), while there was no difference in dizziness (Table S6).
Darifenacin vs. trospium
A small, fair-quality trial (N = 60) compared darifenacin 7.5 mg with trospium ER 60 mg over 4 weeks . Both darifenacin and trospium ER significantly improved the OABSS composite score and achieved an MCID of 3 points, but the difference between the groups was not significant (P = 0.654). Similarly, both drugs significantly improved the OABSS subscales of urinary frequency (−0.80 vs. −0.47), urgency (−1.87 vs. −2.40), nocturia (−0.87 vs. −0.93), and UUI (−2.27 vs. −1.47). These differences did not reach statistical significance between drugs on these OABSS subscales. There were no SAEs or withdrawals due to adverse events. Using the McMillan & Williams Constipation Assessment Scale (0 to 16), both darifenacin and trospium significantly increased constipation compared with baseline, but there was no difference between drugs (0.93 vs. 0.60; P = 0.944).
Solifenacin vs. tolterodine
Five RCTs (N = 2555) that compared solifenacin and tolterodine were included in the 2012 review, ranging in duration from 4 to 12 weeks, with no new studies found for this review . Meta-analysis of four studies indicated that solifenacin 5 mg significantly improved incontinence and urgency episodes per day (Table 2). The difference in micturitions did not reach statistical significance (Table 2). There was no difference in withdrawals due to adverse events (3.5% for solifenacin 5 mg vs. 2.5% for tolterodine 4 mg, Table 4). There was also no difference in incidence of dry mouth, but there was high heterogeneity (I2 = 74%) with three trials favoring solifenacin and two favoring tolterodine. Both solifenacin 5 mg and tolterodine 4 mg resulted in blurred vision (6.2% vs. 3.8%) though the difference did not reach statistical significance. We identified one additional study  that compared solifenacin with tolterodine, which was not included in the 2012 systematic review, but it was rated poor quality .
Solifenacin vs. oxybutynin
The 2012 review included one trial (N = 132) comparing solifenacin 5 mg with oxybutynin immediate release (IR) 15 mg that mainly focused on adverse effects , and no new evidence was found in this review. Additional data from ClinicalTrials.gov found no difference in urgency episodes per day or number of micturitions (Table 2) . Fewer patients treated with solifenacin 5 mg withdrew because of adverse events than patients treated with oxybutynin IR 15 mg (Table 4). There was no difference in incidence of constipation but significantly fewer patients reported dry mouth with solifenacin than with oxybutynin (Table 4).
Tolterodine vs. oxybutynin
The 2012 review included 14 trials (N = 3627) comparing tolterodine with oxybutynin . We identified two subsequently published RCTs (in three publications), of which one was fair quality (N = 301)  and the other one poor quality [31, 45]. Single trials evaluated tolterodine IR 4 mg vs. oxybutynin 10 mg IR and ER, oxybutynin 9 mg IR, and transdermal oxybutynin 3.9 mg. The other trials compared IR formulations with each other: tolterodine 4 mg vs. oxybutynin 10 mg (4 RCTs), tolterodine 4 mg vs. oxybutynin 15 mg (4 RCTs), and tolterodine 1 mg vs. oxybutynin 5 mg (1 RCT). The new trial compared tolterodine IR 4 mg with oxybutynin IR 15 mg . Meta-analyses for this drug comparison considered any reported daily dose.
Pooled estimates did not find statistically significant differences between drugs related to incontinence episodes per day or change in micturition frequency (Table 2), although one trial found that significantly more patients reported no incontinence with oxybutynin ER 10 mg than with tolterodine ER 4 mg (23% vs. 17%, Table 2) . Only the newly identified RCT reported change in urgency episodes with no difference between tolterodine 4 mg and oxybutynin 15 mg (Table 2) . Tolterodine resulted in fewer withdrawals due to adverse events compared with oxybutynin (9 RCTs, N = 2987) and significantly lower incidence of dry mouth (10 RCTs, N = 3140). Few RCTs reported on other typical anticholinergic adverse effects, with two reporting that constipation was similar between tolterodine ER/IR 4 mg and oxybutynin 10 mg (Table 4) and a single study reporting no differences between drugs related to blurred vision and dizziness (P = 0.393 and P = 0.736, respectively, Table S6).