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Medical treatment of lower urinary tract symptoms/benign prostatic hyperplasia: anything new in 2015

Schauer, Ingrid; Madersbacher, Stephan

doi: 10.1097/MOU.0000000000000120
MALE LOWER URINARY TRACT SYMPTOMS: Edited by Oliver Reich

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. 5α-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 α-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 α-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.

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: Stephan.madersbacher@wienkav.at

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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 underlines the need for a thorough diagnostic work-up 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.

Box 1

Box 1

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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 – α-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 α-blockers and were five times as likely to prescribe combination therapy (α-blocker and 5ARI) after level I evidence supported its use [3]. Ingimarsson et al. [4] reported on an increased use of α-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 α-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, prescription-based data demonstrate a continuously increased use of medical BPH/LUTS therapy in general and a rise in the use of combination therapy of α-blocker and 5ARIs as recommended by all major guidelines.

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α-BLOCKER MONOTHERAPY

The vast majority of studies published in the past 18 months concentrate on Silodosin, as it is the most recent selective α-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.

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5α-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 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 = 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 high-grade 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 α-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 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].

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α-BLOCKER AND 5α-REDUCTASE INHIBITOR

The role of the combination of α-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-of-life 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 Short-Form 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 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▪▪].

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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 placebo-controlled 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 +0.7 ml/s and for those with a voided volume more than 450 ml, the respective figures were –0.2 and +2.0 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 above-mentioned 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 <20/≥20), age (≤65/>65 years), previous use of α-blockers or phosphodiesterase-5 (PDE-5) inhibitors, low testosterone levels (<300/≥300 ng/dl) or PSA-predicted prostate volume Tadalafil was effective in improving LUTS [21].

The third publication of this integrated analysis assessed whether the effects of the treatment with Tadalafil for LUTS are independent of improvements in erectile dysfunction [22]. The authors have used various analytical approaches. Regardless of the approach, self-reported erectile dysfunction status did not appreciably influence Tadalafil response in men with LUTS supporting the dual action of Tadalafil on LUTS and erectile dysfunction [22].

Oelke et al. [23] reported on the treatment satisfaction rate following Tamsulosin, Tadalafil 5 mg/day and placebo based on a 3 months RCT using the Treatment Satisfaction Scale-BPH. Treatment satisfaction at 3 months was significantly better for Tadalafil 5 mg/day than placebo, although no difference between Tamsulosin and placebo was reported [23].

These studies provide further insights in the use of Tadalfil for male LUTS. This approach is particularly suitable for comorbid patients (i.e. those with BPH/LUTS and erectile dysfunction who request a therapy for both disorders) and those who develop sexual side-effects under α-blocker therapy. Yet, it needs to be emphasized that the study duration of the above-mentioned studies was limited to 3 months and that the effect of Tadalfil on the natural history of BPH/LUTS remains unclear.

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COMBINATION OF TADALAFIL AND FINASTERIDE

For several reasons, the combination of Tadalafil and 5ARI is an attractive approach: 5ARIs have a well documented positive effect on the natural history of the disease, yet are hampered by a delayed clinical efficacy and a negative effect on sexual function. Tadalafil, on the contrary, has a rapid clinical onset and a positive effect on sexual function, in particular, erectile dysfunction.

Casabe et al. [24▪▪] tested this approach in a large-scale, randomized, double-blind parallel study. Men had an IPSS at least 13 and a prostate volume at least 30 ml; the study duration was 26 weeks. Mean changes of the IPSS after 4, 12 and 26 weeks of Tadalafil/Finasteride coadministration were −4.0, −5.2 and −5.5, respectively; corresponding values for placebo/Finasteride were −2.3, −3.8 and −4.5, respectively. As expected, erectile function improved significantly under Tadalafil/Finasteride, although no relevant changes have been observed in the placebo/Finasteride arm. This study shows that the coadministration of Tadalafil/Finasteride provides early improvement of LUTS as well as an improvement in erectile function. This approach seems to be particularly interesting in men with LUTS and an increased risk of disease progression who suffer from erectile dysfunction or who fear or have developed sexual side-effects of 5ARI [24▪▪].

The combination of α-blocker and PDE5-inhibitor is less supported by the literature, as only small-sized RCTs with inconsistent results have been reported [25▪].

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ANTIMUSCARINIC AND α-BLOCKER

The SATURN study evaluated the combination of Solifenacin with Tamsulosin versus Tamsulosin alone in the treatment of male LUTS [26]. A total of 937 men were randomized to one of eight treatment arms (placebo, 0.4 mg Tamsulosin, Solifenacin 3, 6 or 9 mg; Solifenacin 3, 6 or 9 mg and Tamsulosin 0.4 mg) to this 12 weeks study [26]. Combination therapy was associated with significant improvements in micturition frequency and voided volume versus Tamsulosin monotherapy, yet improvements in total IPSS were not significant. The most prominent advantage of combination therapy was seen in the subgroup of men with two or more urgency episodes in 24 h [26]. To further evaluate this approach, van Kerrebroeck et al. [27▪▪] randomized 1334 men into four study arms: placebo, 0.4 mg Tamsulosin, fixed-dose combination of 6 mg Solifenacin and 0.4 mg Tamsulosin and fixed-dose combination (FDC) of 9 mg Solifenacin and 0.4 mg Tamsulosin. This large-scale trial has shown that the FDC of 6 mg Solifenacin and Tamsulosin improved storage and voiding symptoms as well as quality of life-parameters [27▪▪]. Yet, the absolute differences of the FDC as compared with Tamsulosin monotherapy were modest [27▪▪]. The incidence of acute urinary retention was low [27▪▪].

Filson et al. [28▪] performed a meta-analysis on the role of combination therapy of seven RCTs. Combination therapy had a significantly greater reduction in IPSS storage subscores (−0.7) and voiding frequency (−0.7 voids) [28▪]. There was also a greater increase in Qmax (+0.6 ml/s) and reduction in postvoid residual volume (−12 ml) in the combination therapy arm [28▪].

It remains to be determined whether this approach will be established as a first-line therapy in men with BPH/LUTS and a predominance of storage symptoms or if it remains reserved as an add-on strategy for men with persistent storage symptoms after α-blocker monotherapy [15▪▪].

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β3-ADRENORECEPTOR AGONISTS

The β3-Adrenoreceptor subtype is the principal β-adrenoreceptor in the bladder. It has been shown that the stimulation of this receptor may increase bladder capacity without interference in micturition pressure, postvoid residual volume or voiding contraction.

Several phase-III trials, which enrolled more than 25% of male patients, confirmed efficacy, safety and tolerability of the β3-agonist Mirabegron in men with LUTS [29▪]. Nitti et al. [30▪] evaluated the urodynamic effect of Mirabegron in men with LUTS and BOO. A total of 200 men (≥45 years) with LUTS and urodynamically documented BOO were randomized to receive once-daily Mirabegron 50, 100 mg or placebo for 12 weeks [30▪]. Treatment with Mirabegron 50 and 100 mg was noninferior to placebo for Qmax and detrusor pressure at Qmax. Both active treatment arms showed a significant decrease in micturition frequency as compared with placebo [30▪]. These findings show that Mirabegron does not adversely affect voiding urdynamics in men with LUTS and BOO [30▪]. On the contrary, Mirabegron had no urodynamic demonstrable effect on the storage function, such as bladder capacity or the incidence and severity of detrusor overactivity.

In a nonrandomized study, Otsuki et al. [31] tested the efficacy of Mirabegron 50 mg in men with newly diagnosed OAB (n = 52) and in those who were unresponsive to antimuscarinics (n = 45) at 4 and 8 weeks. This cohort study firms the efficacy of Mirabegron in male OAB, also in those who were unresponsive to antimuscarinics.

These findings are promising and may open a new pathway in the individualized treatment of male LUTS and new options in combining medical treatment modalities.

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NEW STRATEGIES

Recently, Füllhase et al. [32▪] reviewed several novel medical strategies in this journal to manage male LUTS. It is beyond the scope of this review to discuss recent developments on intraprostatic injections, such as NX-1207 or PRX302 [32▪]. Potential novel medical approaches include Cannabinoids, transient receptor potential vanilloid channel blockers, Rho-kinase inhibitors, purinergic receptor blockers, selective oestrogen receptor modulators and endothelin converting enzyme inhibitors [32▪,33]. The vast majority of these substances are still in an experimental state of testing [32▪].

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CONCLUSION

Although no new substance has been introduced into clinical practice within the past 2 years, the recent literature refines our knowledge on current therapeutic options and provides further evidence on an individualized, risk-adapted approach mainly depending on the symptoms status, comorbidities such as erectile dysfunction and risk of disease progression [15▪▪,34▪]. The updated eau-guidelines provide an excellent overview on current treatment recommendations [15▪▪].

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Acknowledgements

None.

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Conflicts of interest

Ingrid Schauer, MD, has no conflicts of interest.

Stephan Madersbacher, MD, FEBU, is a member of the international advisory boards of GSK, Lilly, Pfizer and Astellas. He received speaker honoraria from GSK, Astellas, Lilly, Pfizer.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1▪. Soler R, Andersson KE, Chancellor MB, et al. Future direction in pharmacotherapy for nonneurogenic male lower urinary tract function. Eur Urol 2013; 64:610–621.

An excellent review on future developments in the pharmacotherapy of male LUTS.

2▪▪. Lukacs B, Cornu JN, Aout M, et al. Management of lower urinary tract symptoms related to benign prostatic hyperplasia in real-life practice in France: a comprehensive population study. Eur Urol 2013; 64:493–501.

An excellent population-based description of BPH therapy, with a high rate of treatment modification and interruption; 40% of patients are taking BPH/LUTS medication 5 years after TURP.

3. Filson CP, Wei JT, Hollingsworth JM. Trends in medical management of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 2013; 82:1386–1392.
4. Ingimarsson JP, Isaksson HJ, Sigbjarnarson HP, et al. Increased population use of medications for male lower urinary tract symptoms/benign prostatic hyperplasia correlates with changes in indications for transurethral resection of the prostate. Scand J Urol 2014; 48:73–78.
5. Cindolo L, Pirozzi L, Fanizza C, et al. Actual medical management of lower urinary tract symptoms related to benign prostatic hyperplasia: temporal trends of prescription and hospitalization rates over 5 years in a large population of Italian men. Int Urol Nephrol 2014; 46:695–701.
6. Novara G, Chapple CR, Montorsi F. A pooled analysis of individual patient data from registration trials of silodosin in the treatment of nonneurogenic male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). BJU Int 2014; 114:427–433.
7. Eisenhardt A, Schneider T, Cruz F, et al. Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies. World J Urol 2014; 32:1119–1125.
8. Kumar S, Tiwari DP, Ganesamoni R, et al. Prospective randomized placebo-controlled study to assess the safety and efficacy of silodosin in the management of acute urinary retention. Urology 2013; 82:171–175.
9. Choo MS, Song M, Kim JH, et al. Safety and efficacy of 8-mg once-daily vs 4-mg twice-daily silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (SILVER Study): a 12-week, double-blind, randomized, parallel, multicentre study. Urology 2014; 83:875–881.
10▪. Bird ST, Brophy JM, Harzteme AG, et al. Male breast cancer and 5α-reductase inhibitors finasteride and dutasteride. J Urol 2013; 190:1811–1814.

This study based on the insurance data of 60mio persons suggests no association between 5ARIs intake and the development of male breast cancer.

11▪. Loke YK, Ho R, Smith M, et al. Systematic review evaluating cardiovascular events of the 5-alpha reductase inhibitor – dutasteride. J Clin Pharm Ther 2013; 38:405–415.

This systematic review underlines the cardiovascular safety of dutasteride.

12▪. Fowke JH, Howard J, Andriole G, et al. Alcohol intake increases high-grade prostate cancer risk among men taking dutasteride in the REDUCE-trial. Eur Urol 2014; [Epub ahead of print].

Patients should be informed about the association between alcohol intake, high-grade prostate cancer and 5ARI.

13. Oelke M, Roehrborn CG, D’Ancona C, et al. Impact of dutasteride on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): a pooled analysis of three phase III studies. World J Urol 2014; 32:1141–1147.
14. Wada N, Kita M, Hashizume K, et al. Urodynamic effects of dutasteride add-on therapy to alpha-adrenergic antagonist for patients with benign prostatic enlargement: prospective pressure-flow study. Neurourol Urodyn 2013; 32:1123–1127.
15▪▪. Oelke M, Bachmann A, Descazeaud A, et al. Eau guidelines on the treatment and follow-up of nonneurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013; 64:118–140.

Recent update of the EAU guidelines providing excellent evidence-based recommendations for the management of male LUTS.

16. Fwu CW, Eggers PW, Kirkali Z, et al. Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy. J Urol 2014; 6:1828–1834.
17. Fru CW, Eggers PW, Kaplan SA, et al. Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia. J Urol 2013; 190:187–193.
18▪. Roehrborn CG, Barkin J, Tubaro A, et al. Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT study. BJU Int 2014; 113:623–635.

This analysis confirms once more the concept of progression and risk stratification.

19. Roehrborn CG, Chapple C, Oelke M. Effects of Tadalafil once daily on maximum flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol 2014; 191:1045–1050.
20. Dmochowski R, Roehrborn C, Klise S, et al. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized controlled 12-week clinical trial. J Urol 2013; 189 ((Suppl 1)):S135–S140.
21. Porst H, Oleke M, Godlfischer ER, et al. Efficacy and safety of tadalafil 5mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology 2013; 82:667–673.
22. Brock GB, McVary KT, Roehborn CG, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol 2014; 191:405–411.
23. Oelke M, Giuliano F, Baygani SK, et al. Treatment satisfaction with tadalafil or tamsulosin versus placebo in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results from a randomized, placebo-controlled study. BJU Int 2014; 114:568–575.
24▪▪. Casabe A, Roehrborn CG, DaPozzo LF, et al. Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia. J Urol 2014; 191:727–733.

The first large-scale RCT on the combination of Tadalafil 5 mg/day and 5ARI confirming safety and efficacy of this approach.

25▪. Füllhase C, Chapple C, Cornu JN, et al. Systematic review of combination drug therapy for nonneurogenic male lower urinary tract symptoms. Eur Urol 2013; 64:228–243.

An in-depth review of the current role of combination therapy in managing male LUTS.

26. Van Kerrebroeck P, Haab F, Angulo JC, et al. Efficacy and safety of solifenacin plis tamsulosin OCAS in men with voiding and storage lower urinary tract symptoms: results from a phase 2 dose-finding study (SATURN). Eur Urol 2013; 64:398–407.
27▪▪. van Kerrebroeck P, Chapple C, Drogendijk T, et al. Combination therapy with Solifenacin and Tamsulosin oral controlled absorption system in a single tablet for lower urinary tract symptoms in men: efficacy and safety results from the randomised controlled NEPTUNE trial. Eur Urol 2013; 64:1003–1012.

The largest study available to date demonstrating that a fixed-dose combination is superior to α-blocker monotherapy particularly regarding improvement of storage symptoms.

28▪. Filson CP, Hollingsworth JM, Clemens JQ, et al. The efficacy and safety of combined therapy with α-blockers and anticholinergics for men with benign prostatic hyperplasia: a meta-analysis. J Urol 2013; 190:2153–2160.

A well written meta-analysis on the role of combined therapy with α-blockers and anticholinergics for male LUTS.

29▪. Silva J, Silva CM, Cruz F. Current medical treatment of lower urinary tract symptoms/BPH: do we have a standard? Curr Opin Urol 2014; 24:21–28.

A thorough review of recent developments regarding the medical management of male LUTS.

30▪. Nitti W, Rosenberg S, Mitcheson DH. Urodynamics and safety of the β3-adrenoreceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol 2013; 190:1320–1327.

This study demonstrates the urodynamic safety of mirabegron, yet also no positive urodynamic effects of mirabegron.

31. Otsuki H, Kosaka T, Nakamura K. β3-adrenoreceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men. Int Urol Nephrol 2013; 45:53–60.
32▪. Füllhase C, Soler R, Gratzke C. New strategies in treating male lower urinary tract symptoms. Curr Opin Urol 2014; 24:29–35.

An in-depth review on new strategies in improving male LUTS.

33. Garg M, Dalela D, Dalela D, et al. Selective estrogen receptor modulators for BPH: new factors on the ground. Prostate Cancer Prostatic dis 2013; 16:226–232.
34▪. Füllhase C, Chapple C, Cornu JN, et al. Systematic review of combination drug therapy for nonneurogenic male lower urinary tract symptoms. Eur Urol 2013; 64:228–243.
Keywords:

benign prostatic hyperplasia; lower urinary tract symptoms; medical therapy; risk-stratified approach

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