Hypothesis / aims of study
Overactive bladder syndrome (OAB) is a very common problem with high social-economical impact. This condition is often idiopathic, with no responsible anatomical substrate. Urodynamic testing is used to evaluate bladder function in these patients. Detrusor overactivity can be demonstrated during filling cystometry in these patients, but in asymptomatic patients as well. The involuntary initiation of voiding phase can lead to urge urinary incontinence. A sudden fall in urethral outlet resistance because of urethral pressure variations could result in stimulation of urethral afferents by leakage of urine into the urethra, thereby inducing OAB as well. Urge urinary incontinence only due to sudden fall in urethral pressure has in the past been defined as urethral instability (UI). The definition was abandoned shortly after because of the rarity of this condition and lack of consensus in clinical studies. A recent systematic review on UI concluded however that UI may be regarded a potential pathophysiological entity of its own within cohorts of patients with OAB. A beta 3 adrenoreceptor agonist (mirabegron) is approved for the treatment of overactive bladder symptoms. The beta 3 adrenoreceptor agonist stimulates inhibition of detrusor overactivity and is clinically and urodynamically effective in this regard. Theoretically beta 3 adrenoreceptor agonists may, apart from inhibition of detrusor overactivity, stimulate the urethra to maintain closure contraction. Patients with urethral pressure variations might therefore especially benefit from beta 3 adrenoreceptor agonist since theoretically the treatment might ‘stabilize’ the urethral pressure and therefore reduce symptoms of ‘urinary urgency’. The effect of a beta 3 adrenoreceptor agonist on the urethral pressure and or on urethral pressure variations during filling cystometry is however unknown. In this study, we prospectively explored the association of symptoms and voiding diary data before and on treatment with a beta 3 adrenoreceptor agonist with significant urethral pressure variations/ urethral pressure drops during urodynamic investigation (before and on treatment).
Study design, materials and methods
Between may 2015 and may 2018, a prospective cohort of 51 consecutive female patients suffering from bothersome OAB symptoms were included. Patients were included in two centers. Exclusion criteria were cystocele POP-Q stage 2 or more and neurogenic bladder dysfunction. Urinary tract infection, urolithiasis and bladder neoplasm were excluded. At entry of the study patients were evaluated with a voiding diary, two validated questionnaires and urodynamic investigation. The used questionnaires were the Urogenital Distress Inventory - 6 (UDI-6) and Incontinence Impact Questionnaire - short form (IIQ-7). After urodynamic investigation, patients started with a daily dosis of 50 mg mirabegron. After six weeks, second evaluation was performed with voiding diary, questionnaires and urodynamic investigation. Urodynamic investigation was performed according to ICS standard good urodynamic practices and terms 2016. Urethral instability (UI) was defined as urethral pressure drop exceeding 40 cmH2O. The main endpoint was defined as the number of patients with a reduction of significant urethral pressure variations on urodynamic investigation while on treatment with beta 3 adrenoreceptor agonist.
Forty-nine patients underwent complete evaluation at entry, two patients never showed up anymore. Forty-two patients completed the study with two urodynamic investigations. One patient discontinued because of side effects of mirabegron. Treatment with mirabegron resulted in a significant reduction of symptoms in the questionnaires on the domains of active relaxation (IIQ p=0,005, UDI-6 p=0,031) and emotional health (IIQ, p=0,011) and in frequency of small amounts urinary incontinence (UDI-6 p=0,011). There was also a significant improvement of first desire (p=0,019), normal desire (p=0,015) and strong desire (p=0,020) demonstrated in urodynamic investigation. Results of urodynamic investigation before and after mirabegron are shown in table 1. Prevalence of UI was in 15/49 patients (31%) at initial urodynamic investigation, and in 8/42 patients (19%) at second urodynamic investigation. These results are shown in table 2.
Interpretation of results
Urethral instability is a more common urodynamic phenomenon than detrusor overactivity, demonstrated in one third of the female patients at presentation with OAB. Treatment with beta 3 adrenoceptor agonist results in a significant subjective improvement of OAB, as well as in a significant improvement in urodynamic parameters. Although the prevalence of UI was reduced after six weeks of treatment, this difference was not significant.