Effectiveness of Solifenacin and Trospium for Managing of Severe Symptoms of Overactive Bladder in Patients With Benign Prostatic Hyperplasia

Abstract

This research is aimed to study the possibility of management of severe symptoms of overactive bladder (OAB) with solifenacin and trospium in patients who receive treatment with tamsulosin due to benign prostatic hyperplasia (BPH). The 338 men more than 50 years old (average age 58.4 years) diagnosed with BPH and severe symptoms of OAB were enrolled in the study. Over three episodes of urinary incontinence per day (registration according to bladder diaries), International Prostate Symptom Score over 19, OAB-V8 questionnaire score over 32, and urodynamic disorders diagnosed using cystometry and uroflowmetry were taken as a criterion of severe symptoms of OAB. Patients of the main group during 2 months received treatment with daily combination of solifenacin 5 mg and trospium 5 mg simultaneously with tamsulosin 0.4 mg. Patients of the control group were treated only with tamsulosin. First endpoint is a quantitative assessment of patients with BPH having severe symptoms of OAB. Second endpoint is a state of the patients’ lower urinary tract after the treatment. In the main group, most of urodynamic indices normalized significantly. Number of episodes of incontinence reduced from middle level 3.4 (0.8) per day to 0.9 (0.7) per day. In the control group changes of urodynamic indices were not significant. Quantity of side effects did not exceed the level which is common for antimuscarinic monotherapy. Therefore, percentage of patients with severe symptoms of OAB is not less than 44% of all cases of prostatic hyperplasia accompanied by OAB symptoms. Combination of trospium and solifenacin in standard doses is an efficient and safe method of management of severe symptoms of OAB in the course of the treatment of with tamsulosin in patients more than 50 years of age.

Keywords

overactive bladder beginning hyperplasia prostate solifenacin trospium tamsulosin

Introduction

Benign prostatic hyperplasia (BPH) is a formation of glandular epithelium or stromal component of prostate. It is generally thought that BPH is caused by chronic infection, hypercholesterolemia, and hormonal disorders. Under influence of these factors unregulated proliferation of connective tissue, smooth muscle, and glandular epithelium develops in prostate (Auffenberg, Helfand, & McVary, 2009; Vignozzi et al., 2014).

Prevalence rate of BPH is10.3% and above in population, and significantly increases with age reaching 24% by 80 years of age. BPH risk for 46-year-old man during next 30 years is more than 45% (Verhamme et al., 2002). According to other data, prevalence of urethral obstruction associated with BPH increases from 1.2% at the age of 40 to 49 years to 36% in patients more than 70 years of age (Safarinejad, 2008). Also, there is information that 8% of 40-year-old men, 50% of 50-year-old men, and 90% of men more than 90 years of age suffer from BPH (Dimitropoulos & Gravas, 2015).

Average growth rate of prostate is from 2.0% to 2.5% in elderly people, and BPH risk significantly increases in persons more than 45 to 50 years of age (Bosch, Bangma, Groeneveld, & Bohnen, 2008; Bosch, Tilling, Bohnen, Bangma, & Donovan, 2007; Loeb et al., 2009).

Symptoms of overactive bladder (OAB) pose serious problem for patients with BPH. More than 67% of men suffering from BPH report urination disorders, mainly in the phase of accumulation and excretion of urine (Rana et al., 2014). According to other data, approximately 50% of men more than 50 years of age have BPH and approximately half of them complain of symptoms of OAB with different severity (Roehrborn, 2012). Other research groups report the same data (Roehrborn, 2008; Shahab et al., 2009).

Combined therapy with α-blockers and antimuscarinic drug (Hanuš, Zámečník, Doležal, & Karmazínová, 2011), in particular 5-α-reductase and antimuscarinic agents (Chung & Sandhu, 2011), is used to manage symptoms of overactive detrusor. Several researches have confirmed that simultaneous use of tamsulosin and solifenacin in patients with BPH is efficient and safe (Gao et al., 2014; Lee, Byun, Lee, Kim, & Lee, 2014). But in both researches, authors did not use cystometry as one of the method for assessing state of lower urinary tract (LUT) in their patients. Meanwhile, Chen et al. (2010), based on results of his research, insist on necessity to use this method and refers to significant differences of urodynamic profile in patients with BPH and value of such information for choosing treatment and predicting results. Besides, issue on efficacy of such therapy in patients with severe, steady, unmanageable symptoms of OAB still remains open.

Previously, we achieved satisfactory results from use of combination of two antimuscarinic drugs (trospium and solifenacin), which influence mainly on different types of muscarinic receptors for management of OAB in elderly patients (Kosilov, Loparev, Ivanovskaya, & Kosilova, 2013a, 2013b, 2013c). Then, we made an attempt to study efficacy and safety of use of these drugs in the course of the treatment with tamsulosin in the patients suffering from BPH with severe symptoms of OAB (objective of the study). Results of this study are described below.

Patients and Method

This study was carried out in Urology Department of Gerontological Inpatient Hospital of Vladivostok city from March 2012 to May 2014 using principles of randomization involving 388 men more than 50 years old (average age 58.4 years).

Who had been initially diagnosed with BPH (8-19 points for International Prostate Symptom Score [IPSS], residual urine volume ≤ 100 ml) and who had not taken tamsulosin and antimuscarinics before were enrolled in the study.

Preliminary stage of the study consisted in selection of patients with BPH (ICD-9-CM, Code 600), who suffered severe OAB symptoms besides underlying disease (ICD-9-CM, Codes 596.51, 596.59, 788.30, 788.31, 788.33, 788.36, 788.41, or 788.43). Randomization was performed by method of simple probability sampling with use of random number table. Criterion of enrollment in the main and control groups were as follows: age over 50 years, male, presence of BPH, and severe symptoms of OAB, duration of symptoms not less than 1 year before enrollment. Distribution of patients according to their income or social status was outside the scopes of this research.

Criterion of exclusion while selecting patients included abnormalities of LUT and prostate not related to the studied diseases. Patients with concomitant chronic internal diseases in acute phase or cancer, solifenacin, trospium, or tamsulosin intolerant patients, patients who had taken antimuscarinic drugs less than 6 months before the beginning of the study, patients who take other drugs due to any chronic diseases, and patients who voluntarily refused to participate in the study and did not sign informed consent were eliminated from the study.

More than three episodes of urinary incontinence per day were taken as a criterion of OAB symptoms severity (Dmochowski, Larson-Peters, & Aronstein, 2009; Wu, Fulton, Amundsen, Knight, & Kuppermann, 2011). Patients selected in such a way were randomly divided into two groups—main and control groups. The first endpoint is a number of patients with BPH having severe symptoms of OAB. Besides, criteria of symptoms severity included IPSS score (over 19—high level of disorder), OAB-V8 score (over 30), and level of measured urodynamic disorders.

At the next stage, the patients of the main group were treated with one dose of tamsulosin 0.4 mg (Athanasopoulos et al., 2011; Shalaby et al., 2013), solifenacin 5 mg, trospium 5 mg per day within 8 weeks (Biastre & Burnakis, 2009; Chapple, 2010; Horstmann, Schaefer, Aguilar, Stenzl, & Sievert, 2006; Ohtake et al., 2004). Patients of control group took tamsulosin 0.4 mg/day within 8 weeks and two placebo medicines. The second endpoint is a LUT urodynamic condition of patients in the course of treatment with tamsulosin and two antimuscarinic drugs (Figure 1).

Figure 1.

The algorithm of distribution of the group, examination, and treatment.

Tools for assessment of the patients’ condition were as follows:

IPSS (score over 19—severe symptoms; Rizzo, Tosto, Benvenuti, & Del Popolo, 1995; Ruffion, Marionneau, Taïeb, & Perrin, 2005)

OAB–Awareness Tool (AT) questionnaire–V8 (total OAB signs score over 8; Coyne, Margolis, Bavendam, Roberts, & Elinoff, 2011; Coyne, Zyczynski, Margolis, Elinoff, & Roberts, 2005)

Bladder diaries with registration of urination volumes, number of urge episodes, incontinence episodes, episodes of nighttime urination (Amundsen et al., 2006; Okamura et al., 2006; Parsons et al., 2007)

Cystometry with registration of postvoid residual urine volume, bladder volume at first desire to void, bladder capacity, detrusor compliance

Uroflowmetry with registration of average and maximum flow rate (Q_aver, Q_max; Singh et al., 2010; Thüroff et al., 2011)

Information was processed with JMP SAS Statistical Discovery 8.0.2 (SAS Institute, Cary, NC, USA). Wilcoxon and Kruskal–Wallis criteria were used to compare data of both groups. Spearman criterion was applied to study dependence between processes. Values of standard deviation p < .05 were considered statistically significant.

Results

At the preliminary stage of the study (the first endpoint), it was identified out that among patients having BPH and symptoms of OAB, percentage of persons with severe OAB symptoms is at least 44%.

Information about urodynamic condition of LUT prior and after medical treatment (the second endpoint) was analyzed. The results of comparative analysis of LUT condition according to IPSS and OAB questionnaire, bladder diaries, and urodynamic symptoms are shown in Table 1. It is obvious that average values of majority of compared parameters prior and after treatment are significantly different. Comparison of the results in main and control groups after the treatment (not represented in the table) allowed revealing not only absence of considerable differences but closeness of values by many parameters. For example, Incomplete emptying value in main group equals to 1.3 (0.5) points, and in the control group it was 1.1 (0.4). Calculation of correlation of IPSS parameters variability by Spearman criterion allowed detecting its high level (r = .6-.9, p < .05).

Table 1.

Change in IPSS and OAB Questionnaire, Diaries of Urination, and Urodynamic Symptoms at the Start of and After Treatment (n = 172).

Observation period	Before treatment		After treatment
Parameters	Main group (n = 91)	Control group (n = 81)	Main group (n = 91)	Control group (n = 81)	Pearson correlation coefficient between the variability of parameters in groups
IPSS questionnaire (in scores)
Incomplete emptying	2.4 (0.7)	2.1 (0.4)	1.3 (0.5)*	1.1 (0.4)*	.82, p ≤ .05
Intermittency	1.9 (0.6)	1.9 (0.4)	0.7 (0.3)*	1.1 (0.6)	.72, p ≤ .05
Weak stream	2.7 (0.7)	2.8 (0.7)	1.7 (1.1)	1.3 (0.5)*	.79, p ≤ .05
Straining	3.1 (0.5)	2.7 (0.8)	1.4 (0.5)**	1.3 (0.4)*	.81, p ≤ .05
Nocturia	2.9 (0.8)	2.2 (0.8)	1.6 (0.4)*	0.9 (0.7)*	.67, p ≤ .05
OAB-AT questionnaire (in scores)
Daytime frequency	3.8 (1.3)	3.6 (1.5)	1.3 (1.0)**	3.3 (0.9)‖*	.31, p ≤ .05
Nighttime frequency	2.9 (0.8)	3.2 (1.1)	2.1 (0.6)	2.6 (0.7)	.49, p ≥ .05
Urgency	4.7 (0.7)	4.9 (1.4)	2.4 (1.2)*	3.9 (0.7)	.29, p ≤ .05
Urgency incontinence	4.5 (0.9)	4.3 (0.8)	2.1 (0.6)*	3.6 (0.7)‖*	.44, p ≤ .05
Diaries of urination (the number of episodes per day)
Daytime frequency	9.2 (1.9)	8.7 (1.6)	5.7 (1.2)*	8.3 (2.3)	.17, p ≥ .05
Nighttime frequency	3.5 (2.0)	3.3 (1.2)	1.3 (0.4)	2.8 (1.1)	.30, p ≤ .05
Urgency	6.2 (1.4)	6.5 (1.8)	2.0 (1.4)**	5.9 (2.1)‖*	.15, p ≤ .05
Episodes of incontinence	3.4 (0.8)	3.2 (1.2)	0.9 (0.7)**	2.5 (0.9)‖*	.36, p ≥ .05
Urodynamic parameters
PVR (ml)	18.1 (7.4)	19.0 (5.4)	21.2 (5.2)	19.9 (6.8)	.21, p ≤ .05
Q_aver (ml/sec)	10.4 (2.9)	12.0(4.9)	17.8 (3.2)*	19.5 (5.0)	.81, p ≤ .05
Q_max (ml/sec)	18.0 (4.1)	17.6 (5.0)	24.4 (7.7)	24.9 (4.9)	.67, p ≤ .05
Bladder volume (ml)	164.5 (28.2)	178.9 (31.9)	221.4 (26.6)*	192.3 (24.7)	.45, p ≤ .05
Bladder capacity (ml)	233.7 (19.9)	219.5 (27.3)	372.8 (41.8)**	250.7 (17.8)‖*	.49, p ≤ .05
Detrusor compliance (ml/cm H₂O)	18.3 (4.1)	20.8 (2.9)	29.1 (4.8)*	23.9 (3.9)	.39, p ≤ .05

Note. IPSS = International Prostate Symptom Score; OAB-AT = overactive bladder–Awareness Tool; Reduction in title urodynamic parameters, PVR = postvoid residual urine volume, Q_aver = average flow rate; Q_max = maximum flow rate; Bladder volume = bladder volume at first desire to void (ml). Main group (tamsulosin 0.4 mg + solifenacin 5 mg + trospium 5 mg—per day), Control group (tamsulosin 0.4 mg). Standard deviation is indicated in parentheses; the accuracy of the differences in the parameters between the groups before and after treatment are marked with *<.05; **<.01; the accuracy of the differences in the parameters between the main and control groups are marked with ‖*<.05; ‖<**<.01.

Comparative analysis of dynamics of key parameters of OAB-AT questionnaire allows observing sharp decrease of score given by patients after the treatment in main group. The most exponential was the decrease of Daytime frequency score—from 3.8 (1.3) to 1.3 (1.0), at p < .01. Definitely fewer patients gave score to such parameters as Urgency and Urgency incontinence. Decrease of score in control group after the treatment was almost unremarkable. Significant difference was detected for Daytime frequency parameter in comparison of the results of the groups. In all the rest cases, considerable decrease of median number of points was noted, but differences proved to be insignificant. Correlation between dynamics of similar parameters in groups prior and after the treatment proved to be within the range of r = .2 to .5, p < .05.

Direction of changes dynamics is well observed in case of analysis of studied parameters in absolute values according to bladder diaries. Daytime frequency decreases from 9.2 (1.9) prior to the treatment to 5.7 (1.2) after its completion (p < .05). The greatest changes are noted in parameters Urgency, 6.2 (1.4) → 2.0 (1.4), p < .01, and Episodes of incontinence, 3.4 (0.8) → 0.9 (0.7), p < .01. It should be noted that the latter parameter was the marker of severity of OAB symptoms during selection of patients, and its dynamics pretty well illustrates general tendency of reversibility of symptoms. Analysis of changes contingency between parameters in main and control groups showed weak form of positive correlation (r = .1-.4, p < .01). Changes of studied parameters in control group proved to be insignificant.

Changes of urodynamic parameters are in good agreement with clinical data of bladder diaries and questionnaires. In main group, Bladder capacity parameter demonstrated the most significant changes under the influence of medical treatment, 233.7 (19.9) → 372.8 (41.8), p < .01. Urodynamic parameters Q_aver, Bladder volume at first desire to void, Detrusor compliance improved considerably (statistically significant). By contrast, in the control group most of urodynamic parameters after the treatment remained at the same level. Correlation between changes of parameters in both groups proved to be weak in most comparisons.

Comparison of results in the main and control groups showed significant differences in such parameters as Daytime frequency and Urgency incontinence (OAB-AT-V8), Urgency and Episodes of incontinence (Diaries of urination), and in such urodynamic indicator as Bladder capacity (statistical significance for all paired comparisons is p < .05). At the same time, indicators of state of LUT in patients of the main group after the treatment were within normal range or close to normal range.

Six patients from the main group (3—due to intolerable dryness of the mouth, 2—due to repeated hypertension episodes, 1—without assigning any reasons) and three patients from the control group (2—due to absence of expected effect, 1—due to dryness of the mouth and faintness) stopped participating in the study. Besides, in 17 cases patients reported side effects, but their intensity was insignificant, and the treatment was not stopped. In the main group, among 12 such episodes in eight cases it was dry mouth, in one case—accommodation disorder and dry eyes, in one case—rash, and in one more case patient complained of decreased libido. In the control group all five patients, who reported side effects, complained of dry mouth (one of them reported sharp thirst in the morning).

Discussion

Severe symptoms of OAB in patients with BPH still pose serious problem both for patients and practicing urologists (Cam et al., 2013; Spångberg & Dahlgren, 2013). In this study, attempt was made to assess effectiveness of management of such symptoms with combination of two antimuscarinic drugs influencing mainly on different muscarinic receptors. At the time of the study design, it was understood that the task of objective estimation of efficacy of three medicines simultaneously was rather difficult, and can be criticized. Why such a design was considered to be reasonable? On the one hand, available databases (PubMed, PubMed Central, Scopus, CrossRef, etc.) give information about relative efficacy of simultaneous treatment of patients with BPH with solifenacin and tamsulosin. However, it is known that correction of severe OAB symptoms with only one medicine even among the newest generations (e.g., solifenacin) often causes difficulties. Considerable number of patients is not satisfied with the results of treatment (Abrams, Kaplan, De Koning Gans, & Millard, 2006; Athanasopoulos et al., 2011; Lee et al., 2014; Masumori, Tsukamoto, Yanase, Horita, & Aoki, 2010; Shalaby et al., 2013). At the same time, there is information about rather high efficacy of combinatory action of antimuscarinics in case of severe OAB symptoms. And the number of side effects in case of such combination does not increase significantly (Amend et al., 2008; Kosilov et al., 2013a). To our opinion, in this situation combination of trospium and solifenacin can be conventionally considered as one combined antimuscarinic with expended spectrum of action—efficient inhibitor of mainly М₁ and М₃—cholinergic receptors of bladder capable of suppressing severe symptoms of OAB accompanying BPH. Understanding of redundancy of separation of intermediate groups with one-medicine treatment is based on the results of previous observations (Abrams et al., 2006; Athanasopoulos et al., 2011; Masumori et al., 2010; Shalaby et al., 2013).

Besides, in design of the study, it was assumed that formation of only placebo group was unreasonable. It is connected with the fact that nowadays efficacy of treatment with both tamsulosin (reduction of BPH symptoms; De Mey, 2000; Eghbali, Shayegan, & Kianoush, 2013; Masumori, Tsukamoto, & Horita, 2013; Milicevic, 2012) and combination of trospium and solifenacin (reduction of OAB symptoms; Amend et al., 2008; Kosilov et al., 2013a) is considered to be definitely established. So, control group had another function. It allowed to identify efficacy of taking of combination of antimuscarinic and imitation of such taking on OAB symptoms on the background of tamsulosin taking.

The efficacy of proposed treatment scheme proved to be rather high. Average score of most parameters according to IPSS and OAB questionnaire was significantly decreased. Changes in the test results and information of bladder dairies corresponded with objective evidences received through urodynamic examination. The number of side effects does not exceed the level common for antimuscarinic monotherapy.

Probably, obtained result can be explained by expansion in the number of functionally active М₁ and М₃ receptors, which are stimulated by trospium and solifenacin. Function of receptor apparatus of such patients suffers both due to natural bladder “fading” (in particular, quantity reduction of active М₂ and other receptors) and due to change of pathway and perceiving structures in case of hyperplasia of prostate. Tamsulosin selectively and viably blocks postsynaptic α-1a-adrenoreceptors located in unstriated muscles of prostate, neck of the urinary bladder, and prostatic part of urethra. At the same time, trospium and solifenacin deal with muscarinic (М₁ and М₃) bladder receptors. Data obtained as a result of the examination, perhaps allow supposing synergistic effect of action of combined medications. Certainly, in this case study, configuration and sample volume keep from examining an emergence as one of key mechanisms of increase of efficacy of OAB severe symptoms therapy to the full extent. However, perhaps examination of this interpretation could become one of the directions for further study. Another direction for further study could become clarification of optimal doses of combined antimuscarinics. Probably, small doses of trospium and solifenacin could prove to be not less effective in such a situation.

Conclusion

Percentage of patients with severe symptoms of OAB comprises as many as 44% from all cases of hyperplasia of prostate accompanied by development of OAB.

High and average degrees of correlation between dynamics of clinical and instrumental markers are registered during study of LUT condition of BPH patients with severe OAB symptoms in the course of treatment with tamsulosin and combination of antimuscarinics.

Trospium and solifenacin combination in standard doses is an effective and safety method of managing severe symptoms of OAB in the course of treatment of BHP with tamsulosin in persons more than 50 years of age.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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