Background
The term ‘lower urinary tract symptoms’ (LUTS) is used to describe a condition that encompasses storage, voiding and post-micturition symptoms [
1,
2]. The aetiology of LUTS can be multifactorial [
2,
3], but BPH is a common cause in men. Storage symptoms (e.g. urgency, frequency, urgency incontinence and nocturia) and voiding symptoms (e.g. weak or intermittent urinary stream, straining, hesitancy, terminal dribbling and incomplete emptying) are common and frequently co-exist in men with LUTS [
4,
5]. Storage symptoms represent the most troublesome LUTS, reported in up to 42% of men aged ≥75 years [
4]. Storage symptoms are also reported to be the most bothersome LUTS [
6].
Overall, the recommended treatment options for men with moderate-to-severe LUTS include α-blockers, 5α-reductase inhibitors (in those with a large prostate, 30 g or 40 mL) and antimuscarinic (in those with predominant storage symptoms) [
2,
4,
7]. In addition, α-blocker plus antimuscarinic combination treatment should be considered for patients not adequately responding to monotherapy of either drug [
2,
4]. However, the majority of men with moderate-to-severe LUTS associated with BPH receive α-blocker monotherapy only [
8], whilst less than 25% are reported to receive an antimuscarinic [
8,
9]. Additionally, α-blocker monotherapy is reported to improve voiding and storage symptoms in men with LUTS/BPH [
10,
11]. However, storage symptoms may persist in some men after receiving α-blocker monotherapy, epitomised by data from Lee et al. that reported only 35% of men with storage symptoms were sufficiently controlled by this treatment strategy [
12].
Several trials have demonstrated that α-blocker plus antimuscarinic combination treatment is more effective than α-blocker monotherapy for men with moderate-to-severe LUTS and documented storage symptoms [
13-
19]. The most recent phase 3 trial (NEPTUNE), which included 1,334 men with LUTS/BPH who had moderate-to-severe storage symptoms and voiding symptoms, showed that solifenacin 6 mg plus an oral controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS) improved storage symptoms and quality of life compared with TOCAS alone [
18]. The combination treatment was also well tolerated and exhibited an adverse event profile similar to that reported for the individual monotherapies. A once-daily, FDC tablet of solifenacin 6 mg plus TOCAS 0.4 mg aimed at treating both storage and voiding symptoms in men with LUTS/BPH is licensed and available in several countries, including the UK [
20].
The aim of this study was to perform a cost-effectiveness analysis for a once-daily FDC tablet of solifenacin 6 mg plus TOCAS (0.4 mg) versus daily tolterodine extended release (ER, 4 mg) plus tamsulosin (0.4 mg) given concomitantly, in men with LUTS/BPH who have moderate-to-severe storage symptoms and voiding symptoms within the UK healthcare setting.
Discussion
There are a few reports of cost-effectiveness of drug treatment in LUTS, but this study represents the first cost-effectiveness analysis of a FDC tablet of solifenacin 6 mg plus TOCAS. Overall, the results of this analysis indicate that the FDC tablet of solifenacin 6 mg plus TOCAS is a cost-effective treatment option for men with LUTS/BPH who have moderate-to-severe storage symptoms and voiding symptoms. The base-case analysis showed that the FDC tablet of solifenacin 6 mg plus TOCAS is dominant (i.e. was associated with improved patient outcomes and lower costs) versus tolterodine plus tamsulosin over a 1-year time horizon.
The robustness of our cost-effectiveness model is demonstrated through the results of the univariate and probabilistic sensitivity analyses, as well as the scenario analyses. The univariate analysis showed that several of the main drivers for superior cost-effectiveness of FDC solifenacin 6 mg plus TOCAS versus tolterodine plus tamsulosin were inputs related to treatment persistence. Data from several areas of medicine describe that adherence/persistence with medication is a key driver of cost-effectiveness [
29-
32]. Two reports of real-world clinical practice data in the UK indicate improved persistence for solifenacin versus tolterodine in men with LUTS/BPH or overactive bladder (OAB). The THIN database reported that a lower proportion of men with LUTS/BPH discontinued and switched treatment (43% and 15%, respectively) compared with tolterodine (60% and 23%, respectively) over a median follow-up of 2 years [
8]. In addition, 35% of patients with OAB were still receiving solifenacin after 12 months compared with 28% for tolterodine ER [
28]. Further analyses should be conducted to confirm these observations, and various factors are likely to impact persistence. For example, solifenacin is reported to provide an improved efficacy (urgency and micturitions) and tolerability (dry mouth) profile compared with tolterodine [
33]. Subsequently, this may contribute to the increased persistence with solifenacin, resulting in fewer patients discontinuing medication, reduced switching and/or surgery costs, and improved quality of life. This is supported by the slightly better outcomes, QALY gains and lower overall costs, reported in our analysis.
Time and quality of life utility values were also key drivers of cost-effectiveness in our model. The time horizon analysis showed that the FDC tablet of solifenacin 6 mg plus TOCAS remained dominant at the 3-year time horizon and within a generally acceptable range of cost-effectiveness for up to 10 years. The robustness of our model was also exemplified by data showing that the FDC tablet of solifenacin 6 mg plus TOCAS remained dominant when utilities were derived from both generic (EQ-5D) and disease-specific (OAB-5D) instruments. These data are underscored by the NEPTUNE study quality of life data, which reported significant improvements in International Prostate Symptom Score (IPSS) quality of life and OAB-q health-related quality of life total and coping, sleep, concern, and social subscores with FDC tablet of solifenacin 6 mg plus TOCAS compared with TOCAS monotherapy [
18].
Data suggest that first-line α-blocker monotherapy may not adequately control symptoms in men with LUTS associated with BPH [
12]. As such, current guidelines recommend α-blocker plus antimuscarinic combination as a treatment option for men with moderate-to-severe storage symptoms if symptom relief has been insufficient with the monotherapy of either drug [
2,
4]. This recommendation is supported by the results of several large randomised trials that have reported improved symptoms and quality of life with combination/add-on therapy compared with α-blocker monotherapy in patients with LUTS [
14,
15,
17,
18,
34,
35]. However, data from a large population-based study, THIN, indicate that α-blocker plus antimuscarinic combination treatment is used in only a small proportion (~15%) of patients with LUTS/BPH who have both storage and voiding symptoms [
8]. Overall, these data suggest that there may be an unmet need in this patient population, based on the low use of combination therapy in clinical practice despite its proven effectiveness in men with LUTS/BPH who have both storage and voiding symptoms.
This
de novo model may have some limitations. First, due to lack of published data, some assumptions were made using expert opinion only, including resource use and the proportion of patients going on to have surgery. Other key assumptions were required, for example due to the absence of persistence data on FDCs or free combinations in LUTS, and due to there being no head-to-head studies for the combinations assessed in the present study. Additionally, the primary trials for the combination therapies evaluated in our analysis had some notable differences in the patient populations and outcome measures that prohibit an indirect treatment comparison. Patients in these trials had IPSS ≥12 or 13, ≥2 or 3 urgency episodes/24 hours and ≥8 micturitions/24 hours. In contrast to NEPTUNE, TIMES had an inclusion criterion for overactive bladder symptoms but not one for voiding symptoms. In addition, the primary efficacy endpoint in TIMES was the Perception of Treatment benefit question [
36] and the secondary endpoints included bladder diary variables, and change in episodes/24 hours of urgency urinary incontinence, urgency, total micturitions and night-time micturitions. In NEPTUNE, the co-primary endpoints were total IPSS and TUFS.
Second, although the model included tamsulosin, solifenacin and tolterodine, which are commonly prescribed for men with LUTS [
8], other common α-blockers (e.g. alfuzosin) and antimuscarinics (e.g. oxybutynin) were not considered in our model. Additionally, although men with LUTS may receive α-blocker or antimuscarinic monotherapy, our model was restricted to evaluation of combination treatment only. Therefore, future models will be required to compare the cost-effectiveness of monotherapy versus combination therapy and to compare other feasible combination therapies.
Third, the model allowed treatment to be discontinued at any cycle (i.e. every 4 weeks), but switching of treatment was not allowed until 12 weeks; this cut-off is consistent with the assessment point of several recent large randomised clinical trials in LUTS [
14,
18]. However, it is feasible that switching could occur before Week 12 in clinical practice for tolerability, efficacy or other reasons.
Fourth, the switching and discontinuation rates applied to the model were based on data for antimuscarinics only. This was because, to our knowledge, there are no published data reporting the long-term (e.g. ≥1 year) persistence of α-blocker plus antimuscarinic combination therapy in men with LUTS/BPH.
There are a limited number of published cost-effectiveness analyses for combination treatment with α-blockers plus 5α-reductase inhibitors for men with BPH [
23,
37-
39], but only one published report of α-blockers plus antimuscarinic combination therapy in men with LUTS [
40]. The cost-effectiveness analyses in BPH found that combination treatment appears to be largely more cost effective than monotherapy [
37-
39]. Similarly, a secondary analysis of the TIMES study showed that tolterodine plus tamsulosin appears to be more cost-effective compared with tolterodine monotherapy (dominant) or tamsulosin monotherapy (ICER, 10,381/QALY) in patients with LUTS over a 1-year time horizon [
40]. Consistent with our analysis, the higher drug acquisition costs of tolterodine plus tamsulosin were offset by the improved efficacy (postponement of surgery) and quality of life benefits with combination treatment. However, there were some differences between these two cost-effectiveness analyses of combination treatment in LUTS, including that the TIMES model did not incorporate resources associated with GP visits.
Competing interests
Zalmai Hakimi is employed by Astellas Pharma Global Development and Jameel Nazir is employed by Astellas Pharma Europe Ltd. Lars Heemstra, Anke van Engen, and Cristina Ivanescu are employed by Quintiles Consulting.
Authors’ contributions
All authors contributed to the design of the study, interpretation of the data, critically revised the publication for important intellectual content; and approved the final version for publication. L, A and C collected the data and performed the analyses. All authors have read and approved this manuscript.