Combination therapy with tamsulosin and solifenacin for male lower urinary tract symptoms with predominant filling symptoms: a new approach to an old problem

Abstract

Benign prostatic enlargement is the main cause of male lower urinary tract symptoms (LUTS). The distinction and quantification of voiding, storage and postmicturition symptoms help clinicians decide on a modern pharmacological therapeutic approach for male LUTS. Muscarinic receptors antagonists are now considered safe therapy in males and a fixed-dose combination of oral controlled absorbed system solifenacin and tamsulosin is advantageous compared to tamsulosin monotherapy in males with predominant storage symptoms when validated instruments such as International Prostatic Score Symptoms (IPSS) or Total Urgency Frequency Score (TUFS) are used. This combination therapy is well tolerated and maintains symptomatic improvement in the long term. Different options of managing male LUTS with predominant storage symptoms include a combination of tamsulosin and solifenacin, antimuscarinics alone – some with flexible dosing, and the beta-3 agonist mirabegron. Tailored pharmacological therapy for the particular patient is not a reality yet, but judicious use of the different alternatives could bring varied new therapeutic solutions for male LUTS including benign prostatic enlargement and benign prostatic obstruction.

Keywords: :

• Benign prostatic hyperplasia
• Lower urinary tract
• Solifenacin
• Tamsulosin

The classical concept of benign prostatic hyperplasia (BPH) has progressively evolved for urologists and general practitioners to a wider view of male lower urinary tract symptoms (LUTS) including voiding, storage and postmicturition symptoms. Although the predominant cause of male LUTS is benign prostatic enlargement or benign prostatic obstruction, other factors including dysfunction of the urinary bladder or urethra also play an important role. In fact, EPILUTS, a large survey conducted upon 30,000 men and women in the USA, the UK and Sweden revealed an enormous overlap between storage, voiding and postmicturition symptoms and this fact may have great implications for the choice of appropriate treatment1. Storage or filling symptoms following the International Continence Society definition are far from being sex specific and occur in 45.7% of men over 40 years of age despite the prostate being the most probable cause of such symptoms in males. Growing recognition of the complexity of the pathophysiology of the male lower urinary tract as an integrated functional unit has important implications leading to a modern pharmacological therapeutic approach to male LUTS2. Male LUTS with predominant filling symptoms and male overactive bladder (OAB) can be considered the same problem. The pharmacology for this condition has evolved a great deal in the last decade and drug therapy tailored to different population groups has become a reality. First, use of muscarinic receptor antagonists in males conceptually moved to the consideration of safe therapy3.

A dose finding study for a fixed-dose combination (FDC) tamsulosin oral controlled absorbed system (OCAS) plus solifenacin was conducted (Saturn Trial)4. Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone, despite improvements in total International Prostatic Score Symptoms (IPSS) not being significant. However, the population included did not have predominant storage symptoms. The findings of this proof of concept and dose finding phase II study led to the design of a solid phase III study with FDC tamsulosin OCAS (TOCAS) plus solifenacin 6 mg, controlled with tamsulosin and placebo (Neptune Trial) to evaluate the efficacy and safety of the combination in men with moderate to severe storage and voiding symptoms5. The benefit of the combination in patients with predominant filling symptoms was confirmed. Solifenacin 6 mg plus TOCAS met success criteria for total IPSS and Total Urgency Frequency Score (TUFS), both primary efficacy endpoints. TUFS is a useful tool for the assessment of improvements in urgency and frequency in patients with storage symptoms attributable to LUTS6. In the Neptune trial TUFS correlated with treatment-related changes in a range of health related quality of life (HRQoL) endpoints, including the Patient and Clinician Global Impression, the IPSS HRQoL score and the OAB questionnaire symptom bother score, irrespective of treatment received5. From a practical point of view, patients with higher TUFS may benefit more from combination therapy. Long-term safety was defined in an extension trial (Neptune II)7. Long-term treatment with solifenacin plus TOCAS was well tolerated, with a low incidence of acute urinary retention. Symptomatic improvement was achieved after 4 weeks of treatment, with further improvement at 16 weeks, maintained for up to 52 weeks.

Gong et al. present the most current meta-analysis regarding tamsulosin combined with solifenacin versus tamsulosin monotherapy in male LUTS that reveals significant benefits of tamsulosin and solifenacin combination therapy in storage IPSS, QoL, micturitions per 24 hours and urgency episodes per 24 hours compared to tamsulosin monotherapy8. This extensive study is in consonance with other recently conducted meta-analyses9–12. However, we should admit that comparative evidence between combination therapy and muscarinic receptors antagonists alone for the treatment of male LUTS has not been properly addressed4^,10 and also that the advent of the beta-3 adrenoceptor agonist mirabegron as a new therapeutic option in the field makes further studies mandatory to recognize which is the best tailored therapy for the specific patient13. Mirabegron could also be a valuable option in combination or sequential treatment with alpha-blockers, especially considering its lack of effect on maximum urinary flow and detrusor pressure at maximum urinary flow14^,15. Based on the different mechanisms of action mirabegron could also be combined with antimuscarinics to treat OAB, both in males and females. Combinations based on reduced doses may bring a better tolerability profile and increased efficacy in some patients16.

Unfortunately, despite accumulated experience there is no robust data to define the usefulness of combination therapy for male LUTS with predominant filling symptoms in patients secondary to factors other than BPH, such as neurogenic bladder or sphincter dysfunction. Similarly, the optimum treatment for patients suffering side effects due to a combination therapy of solifenacin and alpha-blocker, mainly dry mouth and constipation4^,5, remains to be defined. In this sense, expected side effects could be better tolerated in males than females and both adherence and good global satisfaction as perceived in patient reported outcomes need a better definition in the male population with LUTS7.

In summary, different options are recommended to manage male LUTS with predominant storage symptoms and they include a combination of tamsulosin and solifenacin, solifenacin alone with flexible dosing, other antimuscarinics, and also the beta-3 agonist mirabegron17^,18. Tailored pharmacological therapy for the particular patient is still far from being a reality but surely judicious use of the different alternatives could bring varied new therapeutic solutions for this old problem (male LUTS including benign prostatic enlargement or benign prostatic obstruction).

Transparency

Declaration of funding

No funding is reported for this editorial.

Declaration of financial/other relationships

J.C.A. has disclosed that he has received educational grants for research from Astellas and Pfizer, and has received payment from Astellas, Pfizer and GSK as a lecturer/faculty member.

Acknowledgments

None.