A significant proportion of patients with acontractile/underactive detrusor due to a conus/cauda lesion will develop high end filling pressures (EFP) and low compliance over time, potentially risking the upper tracts. While mirabegron is now an established therapy in idiopathic over active bladder, its role in the neurogenic bladder population is still to be defined. To our knowledge, this is the first prospective study evaluating the role of mirabegron in the specific subset of patients with low compliant acontractile/underactive detrusor due to conus/cauda lesion.

This prospective study was performed at our institute after obtaining ethical clearance from institute ethics committee. Written Informed consent was taken from all study participants.
Inclusion criteria: Adult patients (>18 years) who had a low compliant(defined as <40ml/cm H2O for study purposes) acontractile/underactive detrusor due to a conus/cauda lesion. Exclusion criteria: Patients with symptomatic urinary tract infection, gross hydroureteronephrosis, previous urologic surgery, prior treatment with intradetrusor botulinum toxin injection, history of pelvic radiation, uncontrolled hypertension (systolic >180mmHg and/or diastolic >110mmHg), unstable cardiac disease or abnormal electrocardiogram (ECG), deranged kidney or liver function tests, history of glaucoma, and those unwilling to do clean intermittent catheterization (CIC) 

For eligible patients (those meeting inclusion exclusion criteria) detailed history including the diagnosis and duration of disease, mode of emptying, use of antimuscarinics, physical findings including pulse and blood pressure, along with baseline investigations including urine routine and culture, kidney and liver function tests, ECG, ultrasonography of kidney bladder prostate with post void residual urine estimation, micturating cystourethrography, and invasive urodynamic data pertaining to filling phase were recorded. Newly diagnosed cases/those who were not employing CIC as the bladder emptying method were instructed to start performing CIC 6th hourly. Those already on CIC were allowed to continue their previous schedule. All patients were asked to make a CIC diary of 48 hours duration and this baseline data was also recorded. Those patients who were already on an antimuscarinic were advised to continue the drug in the same dosage as before, for the duration of the study. 

All patients were started on tab mirabegron 50mg once daily for 6 weeks. At 6 weeks, all patients made another 48 hour CIC diary and were subjected to general examination and a repeat invasive urodynamic evaluation. Side effects, if any, were noted. The primary outcome analysis included CIC diary parameters and urodynamic variables whereas the tolerability/side effect profile constituted the secondary outcomes. The data was analyzed using SPSS 20 and variables at the baseline were compared to that at 6 weeks using the paired t test and a p value of <0.05 was considered statistically significant.

A total of 20 patients were included, 17 males and 3 females, with a mean age of 34.1 years (19-60 years). The mean duration of symptoms prior to inclusion into this study was 77.7 months (6-276 months). Six patients were already on CIC, the rest 14 were started on CIC after inclusion in the study and the mean post void urine volume (in those not on CIC) was 245 ml (10-634ml). Four patients were already on antimuscarinics. 

Primary Outcomes:
a)CIC diary: After 6 weeks of mirabegron therapy, the mean urine volume per CIC was 280.7 ml (36.1 - 711 ml) as compared to 268.2ml (55-495ml) at baseline, the total 24 hr CIC volume (urine output) was 1735.5 ml (250 -4010 ml) as compared to 1954.5 ml (445-3950 ml) at baseline , change in both parameters being statistically insignificant. At 6 weeks, only 2 patients recorded leakage in the intervening time between CIC as compared to 7 at the baseline (p value 0.02). 
b) Invasive Urodynamics: Various urodynamic parameters recorded at the baseline and at 6 weeks follow-up are summarized in Table 1. While the mean volume at first sensation, mean volume at strong desire and mean volume at cystometric capacity did not change significantly, the end filling pressures and compliance showed a significant improvement post therapy. An improvement in compliance was noted in all but 3 patients in whom it deteriorated further (from 18 ml/cmH2O to 12.7 ml/cmH2O).The storage detrusor pressure exceeded 40cmH2O in 8 patients at baseline ( at mean volume of 249.6ml) as compared to 2 patients at 6 weeks(at mean volume of 381 ml) ( p = 0.058). 4 patients had leak during urodynamics at baseline (with mean DLPP of 37.05 cmH2O) while none leaked during urodynamic study at 6 weeks. 
Secondary Outcomes: On evaluation of the side effects of mirabegron, none of the patients discontinued the medication or developed intolerable untoward effects. There were no significant changes in pulse rate, systolic BP or diastolic BP. Six patients reported dry mouth at the baseline, which was perceived to be similar in intensity at 6 weeks in 4 and increased in intensity 2 patients. Four patients developed new onset dry mouth during the treatment. Ten patients had constipation at baseline, which was perceived to be same at the end of the study, no patient developed new onset constipation.
Failed antimuscarinic subgroup receiving mirabegron as add on therapy : Out of the total 20 patients included, four patients were already on antimuscarinics which were continued in the same doses during the study. Various urodynamic parameters recorded at the baseline and at 6 weeks follow-up in failed antimuscarinic group are presented in Table 2.

In this study, we evaluated the efficacy of mirabegron in patients with low compliant underactive/acontractile detrusor due to  a conus/cauda lesion. In so far as the bladder filling pressures are concerned, we noted a significant improvement in end filling pressures (reduced by nearly 60%). The bladder compliance improved (increased nearly 9 times) and overall, 85% of patients responded. This is in contrast with findings reported in patients with neurogenic detrusor overactivity in recently published randomized control trials, where the peak detrusor pressure did not reduce significantly and an improvement in compliance was not universally seen (1,2). In our study, patients who had failed antimuscarinic therapy also showed equally good improvements in bladder pressure parameters, when compared to the antimuscarinic naïve patient, as was previously reported in a retrospective study, underlying the fact that both these drugs have different mechanisms of actions(3). Mirabegron did not significantly improve bladder capacity in our study and this is in accordance with what other authors have found in their experience of mirabegron usage in neurogenic bladder patients (1, 2). One of the limitations of this study: It is possible that introduction of intermittent catheterization in the catheterization naive group may itself have contributed to the improvement in EFP/ compliance.

Mirabegron is safe and effective in patients with poorly compliant acontractile/underactive detrusor due to a conus/cauda lesion. It reduces end filling pressures and improves compliance in majority of the patients but does not significantly affect the cystometric capacity. Mirabegron therapy is equally effective and similarly well tolerated when prescribed as add on therapy to patients with inadequate response to antimuscarinics when compared to antimuscarinic naïve patients.

Krhut J, Borovicka V, Bílková K, Sýkora R, Míka D, Mokriš J, et al. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity—Prospective, randomized, double-blind, placebo, controlled study. NeurourolUrodyn. 2018; 37:2226-33.
Welk B, Hickling D, McKibbon M, Radomski S, Ethans K. A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction. NeurourolUrodyn. 2018; 37:2810-17.
Wada N, Okazaki S, Kobayashi S, Hashizume K, Kita M, Matsumoto S, et al. [Efficacy of combination therapy with mirabegron for anticholinergic-resistant neurogenic bladder: videourodynamic evaluation]. Hinyokika Kiyo. 2015; 61:7-11.