Table 1 Summary Table of Oral Anticholinergics

Author Year

Country
Research Design
Score
Total Sample Size

Methods Outcome
Propiverine

Stohrer et al. 2013

Germany

RCT

PEDro=7

N=66

Population: Mean age: 41.2 yr; Gender: males=41, females=25; Injury etiology: traumatic (n=35, 57%), stroke (n=15, 23%), inflammable (n=12, 18%), degenerative (n=1, 2%); All individuals had urodynamically-confirmed neurogenic detrusor overactivity.

Intervention: Individuals were randomly allocated to either extended-release (ER, n=33) or immediate-release (IR, n=33) treatment groups: administration of propiverine either in ER capsules (45 mg BID) or coated IR tablets (15 mg TID).

Outcome Measures: Reflex volumes, Maximum detrusor pressure, Leak point volume, incontinence, all were measured at baseline and 21 d after treatment.

Adverse events were assessed as tolerability outcomes.

1.     Reflex volumes improved significantly in both the ER and IR groups, but intergroup differences were non-significant (p<0.0001).

2.     Leak point volume increased and maximum detrusor pressure decreased significantly in both treatment groups, without significant intergroup differences (p<0.0001; p<0.0043).

3.     Incontinence was significantly reduced in the ER group (p<0.0005), and there was a significant intergroup difference.

4.     16 individuals (48%) in the IR group and 12 individuals (36%) in the ER group experienced at least one adverse event.

5.     Treatment related adverse events occurred in 14 individuals (42%) in the IR group and 12 individuals (36%) in the ER group.

6.     Individuals related tolerability of both treatment groups worse in comparison to the investigators.

7.     Post void residual volume increased in both treatment groups.

Stohrer et al. 1999

Germany

RCT
PEDro=9

Initial N=124;

Final N=113

Population: Age range=29-30 yr; Gender: males=69, females=44; All individuals had NDO, suprasacral SCI and used IC for bladder management.

Intervention: 15 mg of propiverine or placebo were given 3x/d for 14 d.

Outcome Measures: Urodynamic parameters, individuals’ clinical symptoms, physician’s assessment of efficacy, adverse events and laboratory parameters (haematology, bleeding times, clinical chemistry etc.)

1.     Significant treatment increases:

·         Bladder capacity (p=0.006).

·         Maximal cystometric bladder capacity (p<0.0001).

·         Residual urine volume (p=0.01).

2.     Significant treatment decreases:

·         Maximal detrusor contractions (p<0.001).

·         Detrusor contraction duration (p<0.03).

3.     Improved clinical symptoms: Treatment=63.3%; placebo=22.6%.

Solifenacin

Chen et al. 2015

China

RCT

PEDro=6

Ninitial=100; Nfinal=98

Population: Neurogenic detrusor overactivity; Mean age: 33.2 yr; Gender: males=91, females=6; Level of injury: cervical=28, thoracic=47, lumbar=23; Severity of injury: complete=75, incomplete=23; Mean time post-injury: 3.4 yr.

Intervention: Individuals were randomized to receive 1) percutaneous tibial nerve stimulation (PTNS group), consisting of surface electrodes placed at the ankle over the course of the tibia nerve for 30 min, 2 times per week, for 4 weeks or 2) solifenacin succinate (SS group), with 5 mg once a day for 4 weeks.

Outcome Measures: Clean intermittent catherization (CIC) frequency, fluid intake, volume per catherization, total leakage volume per day, Incontinence Quality of Life (I-QOL), adverse events.

1.     No significant differences were observed post-treatment and between groups in terms of CIC frequency and fluid intake.

2.     Compared to baseline, the volume per catherization significantly increased (p<0.05), the total leakage volume per day decreased (p<0.05), and the I-QOL significantly improved (p<0.05) for both groups at 2 wk and 4 wk follow-up. However, no significant differences were observed between 2 wk and 4 wk follow-up within groups, or between groups.

3.     No adverse events were reported in PTNS group, compared to 5 participants in SS group reporting dry mouth (2 resulting in study discontinuation).

Krebs et al. 2013

Switzerland

Case Series

N=35

Population: Median age at treatment initiation: 44.9 yr (IQR 34.4 – 56.3 yr); Gender: 25 male, 7 female

Injury Etiology: traumatic (n=30, 85.7%), non-traumatic (n=5,14.3%); Level of injury: complete SCI (ASIA A (N=15)), incomplete (N=20); Level of injury: 4 tetraplegic, 31 paraplegic (91.4% – suprasacral lesions); All individuals had urodynamically confirmed neurogenic detrusor overactivity (NDO).

Intervention: Solifenacin treatment initiated 7.3 yr after SCI (median, IQR 2.7 – 22.0 yr), 33 (94.3%) at 10 mg/d, 2 (5.7%) at 5 mg/d; All procedures were completed between Jan 2008 and Mar 2012

Outcome Measures: Bladder capacity, Detrusor compliance, Maximum detrusor pressure, Reflex volume, Risk of renal damage

1.     At 13.1 mo (median, IQR 6.1–19.5 mo) after treatment, solifenacin treatment significantly improved all urodynamic parameters. Bladder capacity increased by 6% (+30.0 mL (median, IQR 0.0 to 69.0 mL)), detrusor compliance increased by 66% (+25.0 mLcm-1 H2O (median, IQR -1.0 to 50.0 mlcm-1 H2O)), maximum detrusor pressure decreased by 39% (-7.0cm H2O (median, IQR -17.0 to -1.0cm H2O)) and reflex volume increased by 39% (+62.5 mL (median, IQR 12.5 to 101.0 mL)).

2.     Though not statistically significant (p>0.1), fewer individuals presented with a risk of renal damage based on maximum detrusor pressure (6 vs. 13) and detrusor compliance (8 vs. 11), and the majority of individuals (69%) continued solifenacin treatment.

Oxybutynin

Stőhrer et al. 2007

Europe

RCT
PEDro=9

N=131

Population: Mean age: 38.3yr; Gender: males=99, females=32; Injury etiology: Traumatic SCI=122, Myelitis=1, MS=2, Myelodysplasia=4, Spinal tumours=2; All individuals had NDO.

Intervention: To compare the efficacy and tolerability of propiverine and Oxybutynin for individuals with NDO. Individuals were randomized (1:1) to receive 15 mg TID propiverine or 5 mg tid Oxybutynin for 21 d.

Outcome Measures: Maximum cyctometric bladder capacity and bladder pressure.

 

1.     A significant increase was shown in the Max cystometric capacity (mL) for both the propiverine and Oxybutynin treatment groups (198±110 to 309±166 and 164±64 to 298±125, respectively).

2.     A significant decrease was shown in the Max detrusor pressure during the filling phase (cm H20) for both the propiverine and Oxybutynin groups (56.8±36.2 to 37.8±31.6 and 68.6±34.5 to 43.1±29.2, respectively).

3.     During filling cystometry, detrusor compliance showed significant improvements in both groups but no significant inter-group differences resulted.

4.     Residual urine for both groups was increased but the inter-group difference was not significant (p=0.13) (propiverine 72.6 mL±115 to 140.9 mL±167 versus Oxybutynin 65.3 mL±78 to 149 mL±133).

5.     The propiverine group reported less frequent adverse events compared to Oxybutynin (63.0% vs. 77.8%) – Dryness of mouth was most frequently reported (47.1% vs. 67.2% respectively (p=0.02).

Ersoz et al. 2016

Turkey

Pre-Post

N=27

Population: Lower urinary tract dysfunction; Mean age: 35 yr; Gender: males=22, females=5; Level of injury: cervical= 3, thoracic=19, lumbosacral=5; ASIA classification: A=19, B=1, C=6, D=1; Mean time post-injury: 110 d; Injury etiology: traumatic spinal cord injury.

Intervention: Oxybutynin HCl (10 mg/d in 15 cases and 15 mg/d in 12 cases).

Outcome Measures:  Meeting criteria for changing intermittent catheterization (IC) from 6/d to 4/d, maximum cystometric capacity.

1.     At a mean follow-up of 30 d, there were 25 participants that had a maximum cystometric capacity of 400 ml or more, meeting the criteria for changing IC from 6/d to 4/d. Among the 2 cases that did not meet the criteria, one had not taken the medication after meals and one had only increased to 350 ml.

2.     There was a significant increase in maximum cystometric capacity after treatment (p<0.001).

Kennelly et al. 2009

USA

Pre-Post

N=24

Population: SCI individuals with neurogenic detrusor overactivity and incontinence. Mean age: 41.9 yr; Gender: males=21, females=3; Severity of injury: AIS A=17, B=2, C=5.

Intervention: To evaluate the efficacy and safety of Oxybutynin transdermal system (Oxybutynin-TDS) in people with SCI with neurogenic detrusor overactivity and incontinence 8-wk dose titration period, Oxybutynin-TDS doses adjusted every 2 wk.

Outcome Measures: Change in daily number of clean Intermittent catheterization (IC) periods without leakage, from baseline – 8 wk or last observation using 3-d voiding diary, clean intermittent catheterization (IC) volume and urodynamic parameters

1.     Baseline mean daily total clean IC frequency=5.3±1.4

2.     Mean daily number of clean IC periods without leakage=2.4±1.8 (all other were associated with leakage)

3.     During the study, overall mean daily clean IC frequency (observed cases) remained constant

4.     Significant improvements were seen in:

·         Reflex volume (p=0.0466)

·         Maximal cystometric bladder capacity (p=0.0009)

·         Residual urine volume (p=0.0023).

·         Detrusor pressure (p=0.0457).

O’Leary et al. 2003

USA

Pre-Post

N=10

Population: SCI: Age range35-77 yr; Gender: males=2, females=8; Severity of injury: AIS: A-D.

Intervention: Initial 10 mg of Oxybutynin (extended release) daily; increased by 5 mg daily until symptoms were controlled or until a max dosage of 30 mg per d.

Outcome Measures: Micturition frequency diaries and urodynamics were completed at baseline and repeated at wk 12. Tolerability info was also collected.

1.     Mean cystometric bladder capacity volume significantly increased (p=0.008).

2.     Mean number of voids in a 24 hr period decreased (p=0.003).

3.     Residual urine increased (p=0.02).

4.     Nocturia decreased but not by a significant amount.

5.     Incontinence episodes per wk significantly decreased (p=0.03)

Tolterodine

Ethans et al. 2004 Canada

RCT (Tolterodine vs. placebo)

Prospective controlled trial (Oxybutynin vs. tolterodine)
PEDro=6

N=14

Population: Mean age: 40.5 yr; Gender: males=9, females=1; Mean time post-injury=13.7 yr. Injury etiology: SCI, MS.

Intervention: Neurogenic detrusor overactivity tx. Double-blind design with tolterodine (T) 2 mg twice daily vs. placebo (P). Open label: tolterodine self-selected dose (TSSD) vs. Oxybutynin SSD (OSSD).

Outcome Measures: Cystometric capacity, catheterization volumes, number of episodes of urinary incontinence/d, degree of mouth dryness per d using visual analog scale (VAS).

1.     No significant difference between T vs. P groups in:

·         mean cystometric capacity

·         degree of mouth dryness

2.     T vs. P significantly improved:

·         mean catheterization volume (263 mL vs. 188 mL, p<0.001)

·         Number of incontinence episodes/d (1 vs. 2.8, p<0.005)

3.     No significant difference between TSSD vs. OSSD in:

·         mean cystometric capacity

·         catheterization volume

·         number of incontinence episodes/d.

4.     TSSD<OSSD for:

5.     dry mouth (VAS 2.6 vs. 4.4, p<0.05).

Amend et al. 2008

Germany

Prospective Controlled Trial

N=27

Population: SCI individuals with hyperreflexia, Mean age: 35.7yr; Gender: males=21, females=6

Level of injury tetraplegia=15, paraplegia=6.

Intervention: Individuals from a previous study continued treatment in 3 groups: Group A (n=8) received 8 mg of tolterodine and Oxybutynin (15-30 mg); Group B (n=11) received 90 mg of trospium (TCL) and tolterodine (4-8 mg); Group C (n=8) received 30 mg of Oxybutynin and TCL (45-90 mg) for 4 weeks.

Outcome Measures: Incontinence events, bladder capacity, reflex volume, detrusor compliance were all measured at baseline, 4 wk and 6 mo post treatment

1.     No significant difference in outcomes was seen between 4 wk and 6 mo follow up.

2.     Number of incontinence events decreased significantly in all three groups at 4 wk follow up (Group A p<0.001; Group B p<0.0005; Group C p<0.001).

3.     Bladder capacity significantly increased at 4 wk follow up in Groups A (p<0.005), B (p<0.0005), C (p<0.001).

4.     Reflex volume increased in all three groups post 4 wk follow up (Group A p<0.005, Group B p<0.0001, Group C p<0.001).

5.     Detrusor compliance increased after 4 weeks of treatment in Groups A (p<0.005), B (p<0.0001), C (p<0.001)

6.     No significant difference was found among the treatments in detrusor compliance (p=0.97) or incontinence events (p=0.11).

7.     Group A had significantly lower improvement in bladder capacity compared to the other groups (p<0.002).Group C had significantly higher reflex volume than group B.

Horstmann et al. 2006

Germany

Prospective controlled trial

N=21

Population: Mean age:34 yr; Gender: males=15, females=6; Level of injury: paraplegia=7, tetraplegia=10.

Intervention: Individuals were placed into one of two groups: 1) 4 mg of tolterodine once a d; 2) 15 mg of trospium (TCL) 3 times/d. After 4 wk, the dosage was doubled to either 4 mg of tolterodine ER twice/ d or 30 mg of TCL three times/d. Follow-up was monitored by a bladder diary and urodynamic evaluation.

Outcome Measures: Average reflex volume, detrusor pressure, cystometric capacity,

1.     The average reflex volume and cystometric capacity increased significantly (p<0.001).

2.     The maximum detrusor pressure dropped from 60 to 47cm H2O (p<0.05).

3.     Individuals treated with TCL:

·    Average reflex volume increase from 177 to 314 mL (p<0.05)

·    An average cystometric capacity enlargement from 271 to 430 mL (p=0.0005)

·    Maximum detrusor pressure decreased from 66 to 51cm H2O (p<0.05).

4.     Individuals treated with tolterodine:

·    Significant increase was seen in average reflex volume (p<0.05) and bladder capacity (p<0.001).

·    Average maximum detrusor pressure dropped from 54 to 43 cm H2O (p<0.05).

5.     One individual had to stop the medication because of intolerable side effects and five individuals did not experience satisfactory benefits.

Trospium Chloride

Madersbacher et al. 1995

Germany

RCT

PEDro=8

N=95

Population: Trospium chloride (TCL; n=52): Mean age: 32.8 yr (range 16-56); Gender: male=28, females=24; Maximum cystometric bladder capacity: 215.5 mL; Maximum voiding detrusor pressure: 82.1 cmH2O; Compliance: 74.6 mL/cmH2O; Residual urine: 49.2 mL. Oxybutynine (Oxy; n=43): Mean age: 31.3 yr (range 18-54); Gender: male=19, females=24; Maximum cystometric bladder capacity: 185.mL; Maximum voiding detrusor pressure: 82.1 cmH2O; Compliance: 59.5 mL/cmH2O; Residual urine: 48.1 mL; All individuals had NDO.

Intervention: Over a two wk period individuals in the TCL group took TCL (20 mg) twice daily with additional placebo midday. The oxybutynin group took three doses of oxybutynin(5 mg) daily.

Outcome Measures: Maximum bladder capacity, maximum voiding detrusor pressure, bladder compliance, residual urine, hyper-reflexive waves, tolerance variables (dryness of mouth). Urodynamic evaluation taken at baseline and follow-up.

 

1.     Maximum bladder capacity increased significantly in both TCL (215.5 mL to 311.9 mL) and Oxybutynin(187.8 mL to 350.9 mL) treatment groups (p<0.001), the difference between the two treatment groups was not statistically significant (p=0.057).

2.     Maximum detrusor pressure decreased significantly in both treatment groups (p<0.001), difference between the two was not statistically significant (p=0.63).

3.     Bladder compliance significantly increased in the TCL group (74.62 ml/cmH2O to 92.75 ml/cmH2O; p<0.001).

4.     Residual Urine increased significantly in both groups (TCL: 49.2 ml to 128.33 ml; Oxy: 48.14 ml to 154.36 ml) with no significant intergroup differences (p=0.19).

5.     Frequency of hyper-reflexive waves decreased in both groups, with no significant intergroup differences (p=0.16).

6.     Reported severe dryness of mouth was considerably lower in TCL group (4%) compared to the Oxybutyningroup (23%).

7.     Withdrawal from treatment occurred less in those receiving TCL (6%) compared to those receiving Oxybutynin(16%).

Stohrer et al. 1991 Australia

RCT

PEDro=6

N=61

Population: SCI with detrusor hyperreflexia.

Intervention: Trospium chloride (20 mg bid, 3weeks) vs. placebo.

Outcome Measures: Pre-/post-treatment max cystometric capacity (MCC); max detrusor pressure (MDP), urinary flow rate and residual urine volumes, adverse events.

1.     Statistical improvements (p<0.001) in the treatment group vs. placebo:

·  increased MCC

·  decreased MDP

2.     No effect in either group on:

·  max flow rate

·  residual urine volume

·  Side effects low and no difference between groups.

Hadiji et al. 2014

France

Pre-Post

N=231

Population: Neurogenic detrusor overactivity; Mean age=38.4 yr; Gender: males=195, females=36; Level of injury: paraplegia=169, tetraplegia=62; ASIA classification: A=172, B-D=59.

Intervention: Either oxybutynin (15 mg/d) or trospium chloride (40 mg/d) was prescribed as a monotherapy. For those already on an anticholinergic agent, the other drug was added as bitherapy.

Outcomes: Maximum bladder capacity (BCmax), involuntary detrusor contraction (IDC), complete continence.

1.     At a mean follow-up of 1 mo, the mean BCmax significantly increased by 216 mL (p<0.01) and the mean amplitude of IDC significantly decreased by 26 cm H2O (p<0.01).

2.     No significant associations were found between the type of anticholinergic therapy (mono- or bi-therapy) and urodynamic balance.

3.     Only 75 (32%) of participants were fully continent at a mean follow-up of 1 mo.

Cisapride (FDA removal from market on July 14, 2000).

Wyndaele & Kerrebroeck 1995

Belgium

RCT

PEDro=5

N=21

Population: Mean age: 32 yr (range 17 -59); Gender: males=17, females=4; Etiology of SCI: traumatic (n=18, 86%), medical cause (n=3, 14%). All individuals had complete SCI and were out of spinal shock for 1.5 mo before entering the study.

Intervention: Individuals were randomly allocated to receive cisapride or a placebo for 4 wk. Cystometry was performed at baseline and during the testing period.

Outcome Measures: Maximum cystometric capacity, Volume at the first sensation of filling, Volume at the sensation to void, Maximum detrusor pressure, Compliance, Bladder Capacity at the first involuntary detrusor contraction, and Residual volume.

1.     There were no significant differences in urodynamic parameters between baseline and the end of the study in either group, nor were there any differences found in any of the parameters between groups.
Imidafenacin

Sugiyama et al. 2017

Japan

Case Series

N=34

Population: Mean age=60±15yr; Gender: males=29; females=5; Etiology: SCI=34; Time since injury=102±45d; Inclusion criteria: SCI with low cystometric volume and/or detrusor compliance.

Intervention: Individuals were administered 0.2mg imidafenacin/d. If cystometric capacity and/or detrusor compliance remained low at first follow-up (4 wk), dosage was escalated to 0.4mg imidafenacin/d. Individuals managed their bladders with transurethral catheters during the treatment period. Outcome measures were assessed at baseline, 4 wk, and 8 wk.

Outcome Measures: Bladder capacity; detrusor compliance; maximum detrusor pressure.

1.     There was a significant increase in bladder capacity and compliance post-imidafenacin (p=0.002; p=0.012)

2.     Imidafenacin had no effect on maximum detrusor pressure (p>0.05).

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