REVIEW URRENT C OPINION
Medical treatment of lower urinary tract symptoms/benign prostatic hyperplasia: anything new in 2015 Ingrid Schauer and Stephan Madersbacher
Purpose of review The purpose of this study is to provide an update on recent developments regarding the medical management of male lower urinary tract symptoms (LUTS). Recent findings Silodosin improves storage/voiding symptoms and nocturia and is effective within the framework of a trial without a catheter. 5a-reductase inhibitors (5ARIs) are not associated with male breast cancer development. Alcohol consumption seems to increase the risk of high-grade prostate cancer under 5ARIs. The combination of a-blocker and 5ARIs remains a well established concept for benign prostatic hyperplasia/ LUTS patients with an enhanced risk of disease progression. Tadalafil 5 mg/day monotherapy is a valid option particularly for men with LUTS and erectile dysfunction; the combination of Tadalafil 5 mg/day with a 5ARI is an interesting approach. The fixed-dose combination of a-blocker and antimuscarinic provides advantages regarding storage symptom improvement. This approach is currently primarily recommended as an add-on strategy. Mirabegron opens new horizons in the management of male LUTS and has no negative (but also no positive) urodynamic effects. Several encouraging novel approaches are currently in the experimental phase and might enhance our therapeutic armamentarium in the near future. Summary The recent literature refines our knowledge on current therapeutic options and provides further evidence for an individualized, risk-adapted approach for male LUTS mainly depending on symptoms status, comorbidities (i.e. erectile dysfunction) and risk of disease progression. Keywords benign prostatic hyperplasia, lower urinary tract symptoms, medical therapy, risk-stratified approach
INTRODUCTION Male lower urinary tract symptoms (LUTS) have a multifactorial pathogenesis [1 ]. Among the most important factors are benign prostatic hyperplasia (BPH)/benign prostatic enlargement (BPE), the adrenergic tone of the smooth muscles, inflammation, ultrastructural changes of the ageing detrusor, urothelial dysfunction, alterations in muscarinic receptor expression and atherosclerosis [1 ]. With respect to urodynamic findings, the most frequently observed pattern is detrusor overactivity, followed by bladder outflow obstruction and detrusor underactivity. LUTS are not uniform as well; some men present with a dominance of storage or voiding symptoms, although the majority have a combination of storage, voiding and postmicturition symptoms. This complex pathogenesis and urodynamic findings paralleled by a mixed clinical presentation &
&
www.co-urology.com
underlines the need for a thorough diagnostic workup and also emphasizes the need for an individualized, risk-adapted approach regarding the use of medical therapy. This review selectively focuses on recent publications regarding medical BPH/LUTS therapy. Although no new substance or concept has been introduced within the past 18 months, the data further support – as indicated above – the concept of an individualized approach regarding medical BPH therapy. Department of Urology, Kaiser-Franz-Josef Spital, Vienna, Austria Correspondence to Stephan Madersbacher, MD, FEBU, Department of Urology, Kaiser-Franz-Josef Spital, Kundratstrasse 3, A-1100 Vienna, Austria. Tel: +43 1 60191 4808; fax: +43 1 60191 4809; e-mail: [email protected] Curr Opin Urol 2015, 25:6–11 DOI:10.1097/MOU.0000000000000120 Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Treatment of lower urinary tract symptoms Schauer and Madersbacher
KEY POINTS Silodosin improves storage/voiding symptoms/nocturia and is effective within the framework of a trial without a catheter. 5a-reductase inhibitors (5ARIs) are not associated with male breast cancer development and the combination of a-blocker and 5ARIs remains a well established concept for patients with an enhanced risk of disease progression. Tadalafil 5 mg/day monotherapy is a valid option particularly for men with LUTS and erectile dysfunction. The fixed-dose combination of a-blocker and antimuscarinic provides advantages regarding storage symptom improvement. Mirabegron opens new horizons in the management of male LUTS.
TRENDS IN MEDICAL MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA/ LOWER URINARY TRACT SYMPTOMS Several studies on population-based trends of medical BPH/LUTS management have recently been published. Lukacs et al. [2 ] described the prescription pattern in France by analysing all prescriptions in the years 2004–2008. The most frequently prescribed drugs were – as expected – a-blockers (60.3%), followed by phytotherapy (31.8%) and 5 ARIs [2 ]. Treatment modification was high within the first 12 months (9–15%) and 16% interrupted medical therapy [2 ]. The incidence of medical BPH/LUTS therapy after surgery for BPH was high as well, 14% after 12 months and up to 40% 5 years after surgery [2 ]. Filson et al. [3] reported on national US trends by analysing 101 million outpatient visits for men with BPH/LUTS between 1993 and 2010. Among these visits, the use of BPH-medication increased from 14% in 1993–1995 to over 40% in 2008–2010. Following approval of Tamsulosin, providers were twice as likely to prescribe a-blockers and were five times as likely to prescribe combination therapy (a-blocker and 5ARI) after level I evidence supported its use [3]. Ingimarsson et al. [4] reported on an increased use of a-blockers and 5ARI at almost linear rates in Island. There was an inverse correlation between LUTS/BPH medication use and the TURP-rate [4]. Finally, Cindolo et al. reviewed the prescription data of approx. 1 500 000 patients over 40 years in some regions of Italy from 2004 to 2008 [5]. Within these 5 years, there was an increase of 49% for a-blockers and of 41% for 5ARI. The use of combination therapy also increased substantially and reached a value of 25% &&
&&
&&
&&
in patients aged more than 75 years [5]. Within the same time period, the hospitalization rate for BPH/LUTS declined per year by 8% for nonsurgical and by 3% for surgical reasons [5]. In summary, these large-scale, prescriptionbased data demonstrate a continuously increased use of medical BPH/LUTS therapy in general and a rise in the use of combination therapy of a-blocker and 5ARIs as recommended by all major guidelines.
a-BLOCKER MONOTHERAPY The vast majority of studies published in the past 18 months concentrate on Silodosin, as it is the most recent selective a-blocker introduced into clinical practice. Novara et al. [6] published a pooled analysis of individual data from registration trials of Silodosin. A total of 1494 patients included into three randomized controlled trials (RCTs) with a study duration of 3 months were analysed [6]. Silodosin was more effective than placebo in improving International Prostate Symptom Score (IPSS), storage and voiding symptoms, quality of life and Qmax. The most frequently reported adverse event was ejaculatory dysfunction by 22% under Silodosin and 0.9% under placebo [6]. Dizziness and orthostatic hypotension rates were comparable to placebo. A further pooled analyses revealed a – moderate – positive effect on nocturia [7]. In men with more than two voids/night at baseline, 61% under Silodosin and 49% under placebo reported on a reduction of nocturia episodes [7]. The well established concept of a trial without a catheter (TWOC) was tested by Kumar et al. [8] using Silodosin 8 mg/day. A total of 60 men with acute urinary retention entered this randomized trial. The success rate of a TWOC was 77% under Sildosin, while only 37% under placebo [8]. A retention volume more than 800 ml and a high IPSS (>25) had significantly greater odds of failure [8]. In a Korean study, Choo et al. [9] have shown similar efficacy and safety profile of Silodosin 8 mg/day versus 2 4 mg/day. In this large RCT, a total of 532 patients were randomized, and the study duration was 12 weeks [9]. Silodosin is effective in managing male LUTS with an excellent cardiovascular safety yet a substantial rate of retrograde ejaculation.
5a-REDUCTASE INHIBITOR: MONOTHERAPY There is a long-standing controversy regarding the development of male breast cancer under 5ARIs. Bird et al. [10 ] analysed this issue by the US IMD
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-urology.com
7
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Male lower urinary tract symptoms
LifeLink Health Plan claims database between 2001 and 2009. This database contains information regarding the use of 5ARI and male breast cancer incidence regardless of exposure assessment before the index date (1 year or more, 2 years or more, 3 years or more). Each subsequent 180 days and 365 days of cumulative 5ARI therapy also showed null associations [10 ]. This – by far the largest study on this topic – strongly suggests that 5ARIs have no impact on the development of male breast cancer [10 ]. The CombAT trial brought into question the safety of Dutasteride, as an increased risk of ‘cardiac failure’ was noted in the Dutasteride arm compared with placebo. To further address this issue, Loke et al. [11 ] performed a meta-analysis that included 12 RCTs with a total of 18 802 patients with a study duration of 6–208 weeks. Dutasteride was not associated with a statistically significant increased risk of heart failure [relative risk (RR) 1.05], myocardial infarction (RR 1.00) and stroke (RR 1.20) [11 ]. The authors concluded that they did not find consistent evidence of a significant association between Dutasteride and the risk of cardiovascular adverse events [11 ]. The association between 5ARI and development of high-grade prostate cancer is another controversial issue. Recent analysis of the prostate cancer prevention trial found that high alcohol intake significantly increased prostate cancer among men randomized to 5ARIs. Fowke et al. [12 ] assessed this issue using the data generated within the REDUCE study. Of 6374 participants in this analysis, approximately 25% reported no alcohol consumption, 49% were moderate drinkers (one to seven drinks per week) and 26% were heavy drinkers (more than seven drinks per week) [12 ]. Alcohol intake was not associated with low or high-grade prostate cancer (PCa) in the placebo arm and was not associated with low-grade PCa among men taking Dutasteride. In contrast, men randomized to Dutasteride and reporting more than seven drinks per week were 86% more likely to be diagnosed with high-grade PCa (P ¼ 0.01). Among alcohol abstainers, Dutasteride was associated with significantly reduced risk of high-grade PCa [odds ratio (OR) 0–59; 95% confidence interval (95% CI) 0.38–0.90], but Dutasteride was no longer associated with reduced high-grade PCa among men reporting high alcohol intake. Obviously, alcohol consumption negated a protective association between Dutatasteride and highgrade PCa [12 ]. The impact of Dutasteride on nocturia was studied in a pooled analysis of several phase III trials that included 4321 patients and a follow-up of 24 months [13]. At 24 months, Dutasteride resulted &
&
&
&
in a greater proportion of individuals with nocturia improvement than placebo (P < 0.05), with the largest treatment group differences in individuals with a baseline nocturia score of 2 or 3 [13]. Little is known on the urodynamic effect of Dutasteride if assessed by pressure flow studies. Wada et al. [14] tested this issue in 52 consecutive patients who have not been satisfied with a-blocker monotherapy. Dutasteride was given as an add-on strategy and all patients underwent a multichannel pressure before Dutasteride administration and after 24 months [14]. Maximum bladder capacity did not change significantly (baseline: 221 97 versus 240 104 ml). All of the 41 patients with detrusor overactivity before Dutasteride add-on therapy showed a reduction in the amplitude of involuntary detrusor contraction [14]. The PDetQmax declined significantly from 71.5 30.1 to 59.1 24.9 cmH2O O after 24 months of Dutasteride; the bladder outlet obstruction index (BOOI) also decreased significantly from 55.2 31.9 to 42.3 27.9. The data demonstrate that long-term treatment of Dutasteride as an add-on strategy resulted in a moderate relief of BOO [14].
&
&
&
&
8
www.co-urology.com
a-BLOCKER AND 5a-REDUCTASE INHIBITOR The role of the combination of a-blocker and 5ARIs is firmly established and recommended by all major BPH/LUTS guidelines for moderately/severely symptomatic men with an enhanced risk of disease progression [15 ]. This concept is based on several large-scale RCTs such as the MTOPS or the CombAT trial [15 ]. Although first published more than 10 years ago, Fwu et al. [16] published two further analyses of the first landmark trial on combination therapy, that is the MTOPS study [17]. In the first analysis, the authors assessed the impact of mono and combination therapy on several quality-oflife instruments. The authors demonstrated an improvement of disease-specific quality-of-life measures (BPH index II and the IPSS-Ql) in all three active arms, although no improvement of the nondisease-specific Medical Outcomes Study ShortForm 36 has been observed [17]. The same group evaluated changes in sexual function assessed by the Brief Male Sexual function Inventory during the 4 years study period [16]. Treatment with Finasteride and combination therapy was associated with a worsening of sexual function, whereas treatment with Doxazosin monotherapy had no or only a minimal negative impact. Roehrborn et al. [18 ] reported on the influence of baseline variables on IPSS changes after Dutasteride, Tamsulosin or &&
&&
&
Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Treatment of lower urinary tract symptoms Schauer and Madersbacher
combination monotherapy based on the 4 years CombAT trial. These data further support the use of long-term combination therapy with Dutasteride and Tamsulosin in patients considered at risk of disease progression (prostate volume >30 ml) [15 ]. &&
TADALAFIL MONOTHERAPY On the basis of a series of placebo-controlled trials, it was shown that Tadalafil improves LUTS and therefore was approved for the medical management of male LUTS. The impact of Tadalafil on urodynamic parameters, such as Qmax, is less clear. Therefore, Roehrborn et al. [19] performed an integrated analysis of the four large, international placebocontrolled trials of Tadalafil for male LUTS. A total of 1500 patients with a follow-up of 3 months were included. At a baseline voided volume of 125–250 ml, the median Qmax increased by 0.9 ml/s under placebo and 1.2 ml/s under Tadalafil; the respective figures for patients with a voided volume of 250–450 ml were –0.3 and þ0.7 ml/s and for those with a voided volume more than 450 ml, the respective figures were –0.2 and þ2.0 ml/s [19]. This integrated analysis revealed a small, but statistically significant median Qmax improvement of Tadalafil over placebo. The numerical differences increased with increasing voided volume [19]. The moderate changes of uroflow parameters, however, have to be interpreted in the light of a recent uodynamic-based study [20]. In this study, Tadalafil induced no significant changes of any urodynamic parameter [20]. Hence, the pathomechanisms leading to this Qmax improvement in this integrated analysis remain poorly understood. Using the same database of the abovementioned pooled analyses, Porst et al. [21] performed a subgroup analysis to assess efficacy and safety of Tadalafil in several clinical scenarios. The authors have shown that regardless of baseline LUTS severity (IPSS 65 years), previous use of a-blockers or phosphodiesterase-5 (PDE-5) inhibitors, low testosterone levels (
Medical treatment of lower urinary tract symptoms/benign prostatic hyperplasia: anything new in 2015 Ingrid Schauer and Stephan Madersbacher
Purpose of review The purpose of this study is to provide an update on recent developments regarding the medical management of male lower urinary tract symptoms (LUTS). Recent findings Silodosin improves storage/voiding symptoms and nocturia and is effective within the framework of a trial without a catheter. 5a-reductase inhibitors (5ARIs) are not associated with male breast cancer development. Alcohol consumption seems to increase the risk of high-grade prostate cancer under 5ARIs. The combination of a-blocker and 5ARIs remains a well established concept for benign prostatic hyperplasia/ LUTS patients with an enhanced risk of disease progression. Tadalafil 5 mg/day monotherapy is a valid option particularly for men with LUTS and erectile dysfunction; the combination of Tadalafil 5 mg/day with a 5ARI is an interesting approach. The fixed-dose combination of a-blocker and antimuscarinic provides advantages regarding storage symptom improvement. This approach is currently primarily recommended as an add-on strategy. Mirabegron opens new horizons in the management of male LUTS and has no negative (but also no positive) urodynamic effects. Several encouraging novel approaches are currently in the experimental phase and might enhance our therapeutic armamentarium in the near future. Summary The recent literature refines our knowledge on current therapeutic options and provides further evidence for an individualized, risk-adapted approach for male LUTS mainly depending on symptoms status, comorbidities (i.e. erectile dysfunction) and risk of disease progression. Keywords benign prostatic hyperplasia, lower urinary tract symptoms, medical therapy, risk-stratified approach
INTRODUCTION Male lower urinary tract symptoms (LUTS) have a multifactorial pathogenesis [1 ]. Among the most important factors are benign prostatic hyperplasia (BPH)/benign prostatic enlargement (BPE), the adrenergic tone of the smooth muscles, inflammation, ultrastructural changes of the ageing detrusor, urothelial dysfunction, alterations in muscarinic receptor expression and atherosclerosis [1 ]. With respect to urodynamic findings, the most frequently observed pattern is detrusor overactivity, followed by bladder outflow obstruction and detrusor underactivity. LUTS are not uniform as well; some men present with a dominance of storage or voiding symptoms, although the majority have a combination of storage, voiding and postmicturition symptoms. This complex pathogenesis and urodynamic findings paralleled by a mixed clinical presentation &
&
www.co-urology.com
underlines the need for a thorough diagnostic workup and also emphasizes the need for an individualized, risk-adapted approach regarding the use of medical therapy. This review selectively focuses on recent publications regarding medical BPH/LUTS therapy. Although no new substance or concept has been introduced within the past 18 months, the data further support – as indicated above – the concept of an individualized approach regarding medical BPH therapy. Department of Urology, Kaiser-Franz-Josef Spital, Vienna, Austria Correspondence to Stephan Madersbacher, MD, FEBU, Department of Urology, Kaiser-Franz-Josef Spital, Kundratstrasse 3, A-1100 Vienna, Austria. Tel: +43 1 60191 4808; fax: +43 1 60191 4809; e-mail: [email protected] Curr Opin Urol 2015, 25:6–11 DOI:10.1097/MOU.0000000000000120 Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Treatment of lower urinary tract symptoms Schauer and Madersbacher
KEY POINTS Silodosin improves storage/voiding symptoms/nocturia and is effective within the framework of a trial without a catheter. 5a-reductase inhibitors (5ARIs) are not associated with male breast cancer development and the combination of a-blocker and 5ARIs remains a well established concept for patients with an enhanced risk of disease progression. Tadalafil 5 mg/day monotherapy is a valid option particularly for men with LUTS and erectile dysfunction. The fixed-dose combination of a-blocker and antimuscarinic provides advantages regarding storage symptom improvement. Mirabegron opens new horizons in the management of male LUTS.
TRENDS IN MEDICAL MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA/ LOWER URINARY TRACT SYMPTOMS Several studies on population-based trends of medical BPH/LUTS management have recently been published. Lukacs et al. [2 ] described the prescription pattern in France by analysing all prescriptions in the years 2004–2008. The most frequently prescribed drugs were – as expected – a-blockers (60.3%), followed by phytotherapy (31.8%) and 5 ARIs [2 ]. Treatment modification was high within the first 12 months (9–15%) and 16% interrupted medical therapy [2 ]. The incidence of medical BPH/LUTS therapy after surgery for BPH was high as well, 14% after 12 months and up to 40% 5 years after surgery [2 ]. Filson et al. [3] reported on national US trends by analysing 101 million outpatient visits for men with BPH/LUTS between 1993 and 2010. Among these visits, the use of BPH-medication increased from 14% in 1993–1995 to over 40% in 2008–2010. Following approval of Tamsulosin, providers were twice as likely to prescribe a-blockers and were five times as likely to prescribe combination therapy (a-blocker and 5ARI) after level I evidence supported its use [3]. Ingimarsson et al. [4] reported on an increased use of a-blockers and 5ARI at almost linear rates in Island. There was an inverse correlation between LUTS/BPH medication use and the TURP-rate [4]. Finally, Cindolo et al. reviewed the prescription data of approx. 1 500 000 patients over 40 years in some regions of Italy from 2004 to 2008 [5]. Within these 5 years, there was an increase of 49% for a-blockers and of 41% for 5ARI. The use of combination therapy also increased substantially and reached a value of 25% &&
&&
&&
&&
in patients aged more than 75 years [5]. Within the same time period, the hospitalization rate for BPH/LUTS declined per year by 8% for nonsurgical and by 3% for surgical reasons [5]. In summary, these large-scale, prescriptionbased data demonstrate a continuously increased use of medical BPH/LUTS therapy in general and a rise in the use of combination therapy of a-blocker and 5ARIs as recommended by all major guidelines.
a-BLOCKER MONOTHERAPY The vast majority of studies published in the past 18 months concentrate on Silodosin, as it is the most recent selective a-blocker introduced into clinical practice. Novara et al. [6] published a pooled analysis of individual data from registration trials of Silodosin. A total of 1494 patients included into three randomized controlled trials (RCTs) with a study duration of 3 months were analysed [6]. Silodosin was more effective than placebo in improving International Prostate Symptom Score (IPSS), storage and voiding symptoms, quality of life and Qmax. The most frequently reported adverse event was ejaculatory dysfunction by 22% under Silodosin and 0.9% under placebo [6]. Dizziness and orthostatic hypotension rates were comparable to placebo. A further pooled analyses revealed a – moderate – positive effect on nocturia [7]. In men with more than two voids/night at baseline, 61% under Silodosin and 49% under placebo reported on a reduction of nocturia episodes [7]. The well established concept of a trial without a catheter (TWOC) was tested by Kumar et al. [8] using Silodosin 8 mg/day. A total of 60 men with acute urinary retention entered this randomized trial. The success rate of a TWOC was 77% under Sildosin, while only 37% under placebo [8]. A retention volume more than 800 ml and a high IPSS (>25) had significantly greater odds of failure [8]. In a Korean study, Choo et al. [9] have shown similar efficacy and safety profile of Silodosin 8 mg/day versus 2 4 mg/day. In this large RCT, a total of 532 patients were randomized, and the study duration was 12 weeks [9]. Silodosin is effective in managing male LUTS with an excellent cardiovascular safety yet a substantial rate of retrograde ejaculation.
5a-REDUCTASE INHIBITOR: MONOTHERAPY There is a long-standing controversy regarding the development of male breast cancer under 5ARIs. Bird et al. [10 ] analysed this issue by the US IMD
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-urology.com
7
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Male lower urinary tract symptoms
LifeLink Health Plan claims database between 2001 and 2009. This database contains information regarding the use of 5ARI and male breast cancer incidence regardless of exposure assessment before the index date (1 year or more, 2 years or more, 3 years or more). Each subsequent 180 days and 365 days of cumulative 5ARI therapy also showed null associations [10 ]. This – by far the largest study on this topic – strongly suggests that 5ARIs have no impact on the development of male breast cancer [10 ]. The CombAT trial brought into question the safety of Dutasteride, as an increased risk of ‘cardiac failure’ was noted in the Dutasteride arm compared with placebo. To further address this issue, Loke et al. [11 ] performed a meta-analysis that included 12 RCTs with a total of 18 802 patients with a study duration of 6–208 weeks. Dutasteride was not associated with a statistically significant increased risk of heart failure [relative risk (RR) 1.05], myocardial infarction (RR 1.00) and stroke (RR 1.20) [11 ]. The authors concluded that they did not find consistent evidence of a significant association between Dutasteride and the risk of cardiovascular adverse events [11 ]. The association between 5ARI and development of high-grade prostate cancer is another controversial issue. Recent analysis of the prostate cancer prevention trial found that high alcohol intake significantly increased prostate cancer among men randomized to 5ARIs. Fowke et al. [12 ] assessed this issue using the data generated within the REDUCE study. Of 6374 participants in this analysis, approximately 25% reported no alcohol consumption, 49% were moderate drinkers (one to seven drinks per week) and 26% were heavy drinkers (more than seven drinks per week) [12 ]. Alcohol intake was not associated with low or high-grade prostate cancer (PCa) in the placebo arm and was not associated with low-grade PCa among men taking Dutasteride. In contrast, men randomized to Dutasteride and reporting more than seven drinks per week were 86% more likely to be diagnosed with high-grade PCa (P ¼ 0.01). Among alcohol abstainers, Dutasteride was associated with significantly reduced risk of high-grade PCa [odds ratio (OR) 0–59; 95% confidence interval (95% CI) 0.38–0.90], but Dutasteride was no longer associated with reduced high-grade PCa among men reporting high alcohol intake. Obviously, alcohol consumption negated a protective association between Dutatasteride and highgrade PCa [12 ]. The impact of Dutasteride on nocturia was studied in a pooled analysis of several phase III trials that included 4321 patients and a follow-up of 24 months [13]. At 24 months, Dutasteride resulted &
&
&
&
in a greater proportion of individuals with nocturia improvement than placebo (P < 0.05), with the largest treatment group differences in individuals with a baseline nocturia score of 2 or 3 [13]. Little is known on the urodynamic effect of Dutasteride if assessed by pressure flow studies. Wada et al. [14] tested this issue in 52 consecutive patients who have not been satisfied with a-blocker monotherapy. Dutasteride was given as an add-on strategy and all patients underwent a multichannel pressure before Dutasteride administration and after 24 months [14]. Maximum bladder capacity did not change significantly (baseline: 221 97 versus 240 104 ml). All of the 41 patients with detrusor overactivity before Dutasteride add-on therapy showed a reduction in the amplitude of involuntary detrusor contraction [14]. The PDetQmax declined significantly from 71.5 30.1 to 59.1 24.9 cmH2O O after 24 months of Dutasteride; the bladder outlet obstruction index (BOOI) also decreased significantly from 55.2 31.9 to 42.3 27.9. The data demonstrate that long-term treatment of Dutasteride as an add-on strategy resulted in a moderate relief of BOO [14].
&
&
&
&
8
www.co-urology.com
a-BLOCKER AND 5a-REDUCTASE INHIBITOR The role of the combination of a-blocker and 5ARIs is firmly established and recommended by all major BPH/LUTS guidelines for moderately/severely symptomatic men with an enhanced risk of disease progression [15 ]. This concept is based on several large-scale RCTs such as the MTOPS or the CombAT trial [15 ]. Although first published more than 10 years ago, Fwu et al. [16] published two further analyses of the first landmark trial on combination therapy, that is the MTOPS study [17]. In the first analysis, the authors assessed the impact of mono and combination therapy on several quality-oflife instruments. The authors demonstrated an improvement of disease-specific quality-of-life measures (BPH index II and the IPSS-Ql) in all three active arms, although no improvement of the nondisease-specific Medical Outcomes Study ShortForm 36 has been observed [17]. The same group evaluated changes in sexual function assessed by the Brief Male Sexual function Inventory during the 4 years study period [16]. Treatment with Finasteride and combination therapy was associated with a worsening of sexual function, whereas treatment with Doxazosin monotherapy had no or only a minimal negative impact. Roehrborn et al. [18 ] reported on the influence of baseline variables on IPSS changes after Dutasteride, Tamsulosin or &&
&&
&
Volume 25 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Treatment of lower urinary tract symptoms Schauer and Madersbacher
combination monotherapy based on the 4 years CombAT trial. These data further support the use of long-term combination therapy with Dutasteride and Tamsulosin in patients considered at risk of disease progression (prostate volume >30 ml) [15 ]. &&
TADALAFIL MONOTHERAPY On the basis of a series of placebo-controlled trials, it was shown that Tadalafil improves LUTS and therefore was approved for the medical management of male LUTS. The impact of Tadalafil on urodynamic parameters, such as Qmax, is less clear. Therefore, Roehrborn et al. [19] performed an integrated analysis of the four large, international placebocontrolled trials of Tadalafil for male LUTS. A total of 1500 patients with a follow-up of 3 months were included. At a baseline voided volume of 125–250 ml, the median Qmax increased by 0.9 ml/s under placebo and 1.2 ml/s under Tadalafil; the respective figures for patients with a voided volume of 250–450 ml were –0.3 and þ0.7 ml/s and for those with a voided volume more than 450 ml, the respective figures were –0.2 and þ2.0 ml/s [19]. This integrated analysis revealed a small, but statistically significant median Qmax improvement of Tadalafil over placebo. The numerical differences increased with increasing voided volume [19]. The moderate changes of uroflow parameters, however, have to be interpreted in the light of a recent uodynamic-based study [20]. In this study, Tadalafil induced no significant changes of any urodynamic parameter [20]. Hence, the pathomechanisms leading to this Qmax improvement in this integrated analysis remain poorly understood. Using the same database of the abovementioned pooled analyses, Porst et al. [21] performed a subgroup analysis to assess efficacy and safety of Tadalafil in several clinical scenarios. The authors have shown that regardless of baseline LUTS severity (IPSS 65 years), previous use of a-blockers or phosphodiesterase-5 (PDE-5) inhibitors, low testosterone levels (
