Combining an antimuscarinic with a beta-3 adrenoceptor agonist could improve the symptoms of overactive bladder (OAB), while allowing a lower dose of antimuscarinic and thus reducing side effects, results of an early study suggest.

The double blind randomised trial used a number of arms. There were six combination groups: solifenacin (an antimuscarinic) at 2.5 mg, 5 mg and 10 mg, plus mirabegron (a beta-3 adrenoceptor agonist) at 25 mg or 50 mg; five monotherapy groups: solifenacin 2.5 mg, 5 mg or10 mg; mirabegron 25 mg or 50 mg; or placebo.

A total of 1,306 patients, at 141 centres across 20 European countries, were randomised to one of these groups. Two-thirds of the patients were women, and all had had symptoms of OAB for 3 months or longer.

The primary outcome measure was mean volume voided per micturition – patients with OAB will typically have lower values due to the number of voids at low bladder volume when patients experience an urgent desire to void despite a relatively empty bladder.

Secondary endpoints were possibly more clinically meaningful – mean numbers of micturitions per 24 hours, incontinence and urgency episodes per 24 hours.

Safety analysis showed that the combination therapies were well tolerated, with only a small increase in constipation rates.

All combinations involving doses of solifenacin 5 mg or 10 mg were more effective than 5 mg solifenacin monotherapy, significantly increasing mean voided volume, with adjusted differences ranging from: 18 ml per void (95% CI:5.4-30.0) to 26.3 ml per void (95% CI:12.0-41.0).

Three of the six combinations significantly reduced urinary frequency compared with solifenacin 5 mg, ranging from:

-0.80 (95% CI:-1.39 to -0.22) to

-0.98 (95% CI:-1.68 to -0.27).

Five of the six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from:

-0.98 (95% CI:-1.78 to -0.18) to

-1.37 (95% CI:-2.03 to -0.70).

Mirabegron has recently been licensed for treating patients with OAB. After a review of the evidence for this ‘first in class’ treatment, NICE concluded that it should be reserved for patients with symptoms of OAB for whom antimuscarinics are contraindicated, or where two or more antimuscarinics have failed, either because of lack of efficacy or lack of tolerability.

Antimuscarinic drugs therefore remain the mainstay of treatment for OAB. However, this drug class can be hard for patients to tolerate because of side effects, particularly dry mouth, making it difficult for patients to remain on a therapeutic dose.

Clearly, the use of this combination may be an option in the future for patients with OAB that is difficult to control with standard doses of an antimuscarinic.

While this study shows statistically significant differences between the combinations when compared with monotherapy or placebo, the outcome measures are difficult to translate into an understanding of how clinically useful this combination will be.

Further studies are required to ascertain if the improvements on this combination are both detectable to patients in improving their quality of life, and also regarding the cost effectiveness compared with current treatment regimens. Until then, it is unlikely that this combination will be initiated for patients with OAB in primary care.

Dr Jonathan Rees