ABC (2012) Anticholinergic Therapy vs Botox for Incontinence

Anticholinergic Therapy vs. OnabotulinumtoxinA for Urgency Urinary Incontinence. A.G. Visco et al.

https://www.ncbi.nlm.nih.gov/pubmed/23036134 NEJM 2012

Clinical Question

In women with urgency urinary incontinence does OnabotulinumtoxinA compared with anticholinergic therapy reduce daily continence frequency?

Bottom Line

The bottom line of this study is that oral anticholinergic and intra-detrusor onabotulinumtoxinA were both associated with reductions in episodes of urinary urge incontinence and improvement in quality of life. OnabotuliniumtoxinA may be more likely to lead to complete resolution of urinary urgency incontinence, but it also has a higher rate of urinary tract infection and urinary retention.

Major Points

• 241 of the 247 treated patients had data available.
• Prior to beginning the trial, the participants had an average rate of 5 (+/-2.7) episodes of urinary urge incontinence per day. This was reduced by:
  • 3.4 episodes per day in the anticholinergic group (n=118)
  • 3.3 episodes per day in the onabotulinumtoxinA group (n=113)
  • P=0.81, no statistically significant difference between treatments in reduction of urinary urge incontinence episodes per day over a 6-month period.
  • Most women experienced this benefit within the first month.

• Women in the onabotulinumtoxinA group were significantly more likely than those in the anticholinergic group to report complete resolution of urgency urinary incontinence (27% vs. 13%, P=0.003)
• Both groups reported increased quality of life and reduction in symptom severity using QOL and symptom severity measurement scales. There was no significant difference in the improvements between the groups
• Adverse events:
  • Dry mouth reported more frequently in anticholinergic group (46% vs. 31%, P=0.02)
  • Higher instance of UTI in onabotulinumtoxinA group (33% vs. 13%, P<0.001)
  • No severe adverse events were attributed to the study

Guidelines

The NICE guidelines recommend the following escalation for management of women with urinary incontinence

1. Lifestyle modifications: weight loss if overweight, reduction in caffeine and alcohol consumption, smoking cessation

2. Pelvic floor exercises: needs to be continued for 3–4 months before determining its success. It should be done with three sets of 8–12 slow maximal contractions sustained for 6–8 seconds and repeated 3–4 times per week

3. Bladder retraining: initial bladder training involves a voiding interval of 1 hour during waking hours with a gradual increase by 15–30 minutes per week until a 2–3 hour voiding interval is reached (2 & 3 usually done together)

4. Pharmacotherapy (tends to work better for UI rather than SUI)

• Anticholinergic: most common oxybutynin 5mg PRN TDS
• Newer uroselective anticholinergic medications including tolterodine, solifenacin and darefenacin have similar efficacy to oxybutynin but an improved side effect profile. As yet they are not available on the Pharmaceutical Benefits Scheme
• Imipramine, a tricyclic antidepressant, may reduce detrusor contractility and increases outlet resistance and can be used in conjunction with anticholinergics

5. Intravesical botulinum toxin A injections or neuromodulation can be performed

6. Detrusor myomectomy or bladder augmentation

7. Sacral neuromodulation – it is hoped that the InterStim™ device for this problem will be shortly approved for usage in Australia

8. Ileal conduit urinary diversion

Design

• Trial type: multicentre, randomised, double blind, double placebo controlled trial
• N=number of patients randomized (often different from number of patients enrolled)
  • Experimental arm (n=127) - anticholinergic
  • Standard (n=122) - onabotulinumtoxinA
• Setting: 10 centres in USA
• Enrollment: Feb 2010 – May 2012
• Mean follow-up: not reported
• Analysis: modified intention-to-treat
• Primary outcome: change from baseline in mean number of episodes of urgency urinary incontinence over the course of 6 months (as reported for 3 day periods in monthly bladder diaries)

Population

Inclusion Criteria

Women with moderate to severe idiopathic urge urinary incontinence as defined by 5 or more episodes of incontinence per day over a 3 day period, recorded in bladder diary.

Exclusion Criteria

Previous or current solifenacin, darifenacin, or trospium; previous botox; Post Void Residual 150m; Inability to self catheterise (patient or caregiver)

Baseline Characteristics

No differences were noted between the treatment arms of the trial. The following are described for the Anticholinergic group.

• Age - 56.7 years
• Hispanic - 17%
• BMI - 32.9
• Married - 45%
• College education - 71%
• Private health insurance - 48%
• Never smoked - 59%
• Post menopausal - 73%
• No prior anticholinergic therapy - 43%
• Episodes of Urge Urinary Incontinence per day 5.2
• Episodes of Stress Urinary Incontinence per day 6.1
• Residual volume after voiding 35.4mL

Interventions

• Oral anticholinergics + placebo intra-detrusor injection
  • 5mg solifenacin (M3 cholinergic receptor antagonist) daily
  • Dose could be increased to 10mg daily if, at 2 months, 5mg daily was not providing subjective benefit to the patient
  • If 10mg daily was not sufficient to provide subjective benefit at 4 months, then 60mg trospium XR (non-selective muscarinic antagonist) daily was commenced in place of solifenacin
  • A single saline injection into detrusor muscle was also performed at the commencement of the study

• Intra-detrusor injection of Botox + placebo oral tablet
  • 100 U onabotulinum toxin injected into detrusor muscle (prevents release of acetylcholine at neuromuscular junction)
  • Single oral placebo tablet daily for 6 months

Outcomes

Primary Outcomes

• Mean reduction in episode of urge incontinence
  • Solifenacin 3.4 vs Botox 3.3 (p = 0.81)

Secondary Outcomes

• Complete resolution of incontinence
  • Solifenacin 13% vs Botox 27% (p=0.003)
• QoL Improvement score
  • Solifenacin 37.05 vs Botox 37.13 (p=0.98)
• Severity of symptom score
  • Solifenacin -44.55 vs Botox -44.08 (p=0.98)
• Adequate symptom control
  • 6 month – Solifenacin 71% vs Botox 70%
  • 1 month after ceasation of oral medication – solifenacin 50% vs Botox 62% (p = 0.006)
  • 12 months after ceasation – solifenacin 25% vs botox 38% (p =0.61)

Subgroup Analysis

Description provided of clinically relevant subgroup analyses.

• Subgroup analysis based on prior anticholinergic use and baseline frequency of urgency urinary incontinence (5-8 episodes vs 9+ episodes); nil difference between the 2 groups when stratified for these
• Higher baseline frequency of episodes of incontinence associated with greater reduction in episodes of urge incontinence

Adverse Events

• Any Adverse Events
  • Solifenacin 69% vs Botox 73% (p =0.79)

• Dry Mouth
  • Solifenacin 46% vs Botox 31% (p =0.02)
• Intermittent Catheterisation at 2 months
  • Solifenacin 0% vs Botox 5% (p =0.01)
• UTI
  • Solifenacin 13% vs Botox 33% (p <0.001)

No significant difference in constipation, dry eyes, serious adverse events

Criticisms

• Inclusion of patients who had previously used anticholinergic medication may had created a bias in terms of outcomes, because it may affect the way they respond to the anticholinergics in this study compared with participants who have never used the medication. For example, those who have used a medication previously will possibly develop a greater tolerance to its effects, including side-effects.

• Two different types of anticholinergic agents were used in this study whereas only one type of onabotulinum injection was used, creating a difference in the way each intervention was administered, and thus creating a direction of bias towards the anticholinergic group.

Funding

The trial was funded through academic grants from a number of sources. Some authors declared consulting fees from industry.

Further Reading

Study design paper: https://www.ncbi.nlm.nih.gov/pubmed/22008247

Medication adherence in this cohort: https://www.ncbi.nlm.nih.gov/pubmed/26516810

Health economics analysis: https://www.ncbi.nlm.nih.gov/pubmed/27564385