Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial

What’s known on the subject? and What does the study add? Treatment of benign prostatic hyperplasia (BPH) centres on two drug classes, 5α‐reductase inhibitors and α‐blockers. The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study investigated whether the combination of dutasteride and tamsulosin was more effective than either monotherapy in reducing the relative risk of AUR, BPH‐related surgery, and BPH clinical progression in men with moderate‐to‐severe LUTS who were at increased risk of disease progression. Data from the 2‐ and 4‐year, pre‐planned primary and secondary endpoint analyses for the CombAT study have been reported previously. This study reports the outcomes of post hoc analyses of the influence of baseline parameters on the incidence of AUR, BPH‐related surgery, and overall clinical progression in patients treated with tamsulosin, dutasteride, or combination therapy with both agents.

OBJECTIVE

? To investigate the influence of baseline variables on the 4‐year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)‐related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both.

PATIENTS AND METHODS

? The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double‐blind, parallel‐group study of clinical outcomes in men aged ≥50 years with symptomatic (International Prostate Symptom Score [IPSS]≥12) BPH, with prostate‐specific antigen (PSA) levels of ≥1.5 ng/mL and ≤10 ng/mL, and a prostate volume (PV) of ≥30 mL. ? Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. ? The primary endpoint was time to first AUR or BPH‐related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health‐related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q_max] and body‐mass index [BMI]) on the incidence of AUR or BPH‐related surgery, clinical progression of BPH, and symptoms were performed.

RESULTS

? There were 4844 men in the intent‐to‐treat population. Overall baseline characteristics were similar across all patient groups. ? Regardless of baseline subgroup, the incidence of AUR or BPH‐related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. ? Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH‐related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P≤ 0.001). ? Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of <20 or IPSS HRQL score of <4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of <40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. ? Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of <40 mL) and compared with dutasteride in most subgroups.

CONCLUSIONS

? Men with a baseline PV of ≥40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH‐related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. ? These analyses support the long‐term use of combined therapy with dutasteride plus tamsulosin in men with moderate‐to‐severe BPH symptoms and a slightly enlarged prostate.     

Effect of dutasteride,tamsulosin and the combination on patient‐reported quality of life and treatment satisfaction in men with moderate‐to‐severe benign prostatic hyperplasia: 2‐year data from the CombAT trial

OBJECTIVE

To investigate the effect of dutasteride and tamsulosin as combined therapy compared with each monotherapy for improving patient‐reported health outcomes in men with moderate‐to‐severe urinary symptoms and prostate enlargement, reporting the pre‐planned 2‐year analyses from the CombAT trial.

PATIENTS AND METHODS

The CombAT study is an ongoing, international, double‐blind, randomized, parallel‐group trial. Men aged ≥50 years with a clinical diagnosis of benign prostatic hyperplasia (BPH), an International Prostate Symptom Score (IPSS) of ≥12 units, a prostate volume of ≥30 mL, a total serum prostate‐specific antigen level of 1.5–10 ng/mL and a peak urinary flow of >5 and ≤15 mL/s, with a minimum voided volume of ≥125 mL, were randomized to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months. The primary endpoint at 2 years was the change in IPSS from baseline. Secondary endpoints included various measures of health outcomes, which included the BPH Impact Index (BII), IPSS Question 8 (Q8), and the Patient Perception of Study Medication (PPSM) questionnaire.

RESULTS

Combined therapy resulted in significantly greater improvements in BII and IPSS Q8 from baseline than did dutasteride from 3 months and compared with tamsulosin from 9 months (BII) or 12 months (IPSS Q8). Assessments using the PPSM questionnaire showed that a significantly higher proportion of patients were satisfied with and would request dutasteride and tamsulosin combined therapy than with each monotherapy at 24 months.

CONCLUSIONS

Dutasteride and tamsulosin combined therapy provides significantly greater improvements in patient‐reported quality of life and treatment satisfaction than both monotherapies at 2 years, following the trends for clinical improvements in symptom scores and peak urinary flow rates, in men with moderate‐to‐severe BPH symptoms.     

The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Long‐term treatment with combination therapy (dutasteride plus tamsulosin) is significantly superior to tamsulosin but not dutasteride at reducing the relative risk of AUR or BPH‐related surgery. Furthermore, combination therapy is significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression, and provides significantly greater reductions in IPSS. In addition, combination therapy significantly improves patient‐reported, disease specific QoL and treatment satisfaction compared with either monotherapy. Two‐year results from the CombAT study showed that combination therapy was more effective than either monotherapy in controlling both storage and voiding symptoms, irrespective of baseline prostate volume (for men with prostate volume ≥30 cc). This post‐hoc two‐year analysis also showed that treatment with dutasteride not only improved voiding symptoms, as would be expected from its effects on prostate volume, but was also as effective as the α‐blocker tamsulosin in the control of storage symptoms.

OBJECTIVE

• ? To assess the effects of combined therapy with dutasteride and tamsulosin on voiding and storage symptoms compared with those of dutasteride or tamsulosin alone, using 4‐year data from the Combination of Avodart and Tamsulosin (CombAT) study.

PATIENTS AND METHODS

• ? Men (n = 4844) aged ≥50 years with moderate‐to‐severe lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH), a prostate volume of ≥30 mL, and a serum prostate‐specific antigen level of 1.5–10 ng/mL.
• ? CombAT was a multicentre, double‐blind, parallel‐group study.
• ? Oral dutasteride (0.5 mg) or tamsulosin (0.4 mg) alone or in combination was taken daily for 4 years.
• ? Mean changes from baseline in storage and voiding symptoms at 4 years were assessed using subscales of the International Prostate Symptom Score.

RESULTS

• ? At 4 years, the mean reduction in the storage subscore was significantly greater in the combined therapy group vs the dutasteride (adjusted mean difference ?0.43) and tamsulosin (adjusted mean difference ?0.96) monotherapy groups (P < 0.001).
• ? Also at 4 years, the mean reduction in the voiding subscore was significantly greater in the combined therapy group vs the dutasteride (adjusted mean difference ?0.51) and tamsulosin (adjusted mean difference ?1.60) monotherapy groups (P < 0.001).
• ? The improvement in the storage subscore with combined therapy was significantly better (P < 0.001) than dutasteride and tamsulosin from 3 months and 12 months, respectively. Similarly, the improvement in the voiding subscore with combined therapy was significantly better than dutasteride (P < 0.001) and tamsulosin (P ≤ 0.006) from 3 months and 6 months, respectively.
• ? Improvements in the storage and voiding symptom subscores with combined therapy were achieved irrespective of prostate volume, although in men with the highest baseline prostate volumes (≥58 mL), combined therapy was not better than dutasteride.

CONCLUSIONS

• ? In men with a prostate volume of ≥30 mL, combined therapy with dutasteride plus tamsulosin provided better long‐term (up to 4 years) control of both storage and voiding LUTS compared with tamsulosin monotherapy.
• ? Combined therapy was better than dutasteride monotherapy in men with prostate volumes of ≥30 to <58 mL, but not in men with a prostate volume of ≥58 mL.

     

Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial

Background

A 23% relative risk reduction (RRR) in prostate cancer (PCa) was shown in men receiving dutasteride in the 4-yr Reduction by Dutasteride of Prostate Cancer Events study, in whom biopsies were protocol dependent.

Objective

Our aim was to explore PCa risk reduction in men with benign prostatic hyperplasia (BPH) from the Combination of Avodart and Tamsulosin (CombAT) study, in which biopsies were undertaken for cause.

Design, setting, and participants

CombAT was a 4-yr randomized double-blind parallel group study in 4844 men ≥50 yr of age with clinically diagnosed moderate to severe BPH, International Prostate Symptom Score ≥12, prostate volume ≥30 ml, and serum prostate-specific antigen (PSA) 1.5–10 ng/ml. Men underwent annual PSA measurement and digital rectal examination (DRE), and prostate biopsies were performed for cause.

Intervention

All patients took tamsulosin 0.4 mg/d, dutasteride 0.5 mg/d, or a combination of both.

Measurements

The primary end point was incidence of PCa. Secondary end points included postbaseline prostate biopsy rates and Gleason score of cancers.

Results and limitations

Dutasteride (alone or in combination with tamsulosin) was associated with a 40% RRR of PCa diagnosis compared with tamsulosin monotherapy (95% confidence interval, 16–57%; p = 0.002) and a 40% reduction in the likelihood of biopsy. There were similar reductions in low- and high-grade Gleason score cancers. The biopsy rate in the groups receiving dutasteride trended toward a higher diagnostic yield (combination: 29%, dutasteride: 28%, tamsulosin: 24%). One limitation was the lack of a standardized approach to PCa diagnosis and grading.

Conclusions

Dutasteride, alone or in combination with tamsulosin, significantly reduced the relative risk of PCa diagnosis in men with BPH undergoing annual DRE and PSA screening. Consistent with the increased usefulness of PSA for PCa detection, men receiving dutasteride had a numerically lower biopsy rate and higher yield of PCa on biopsy.

Trial registration

Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).     

Nocturia improvement in the combination of Avodart® and tamsulosin (CombAT) study

Purpose

The purpose of the study was to assess the impact of dutasteride plus tamsulosin combination therapy, compared with dutasteride or tamsulosin monotherapy, on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) using data from the 4-year CombAT study.

Methods

Nocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included as follows: mean change in nocturia at 3-month intervals up to 48 months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with a baseline score ≥2.

Results

In total, 4,722 patients with a mean age of 66 years were included. Mean nocturia improvements were significantly superior (p ≤ 0.01) with combination therapy than with either monotherapy (adjusted mean change from baseline in IPSS Question 7 score at month 48: combination therapy ?0.5, dutasteride ?0.4, tamsulosin ?0.3). Reduction in nocturia score with combination therapy was significantly (p ≤ 0.01) better than tamsulosin monotherapy across all baseline subgroups tested, except for men with previous 5ARI use. Among those with a baseline IPSS Q7 score ≥2, more patients with combination therapy had a score <2 at month 48 (34 %) compared with dutasteride (30 %, p = 0.018) or tamsulosin (26 %, p < 0.0001).

Conclusions

Combination therapy provided greater improvements and less worsening of nocturia compared with both dutasteride and tamsulosin monotherapies. These analyses are the first to show greater improvement with a 5ARI/α-blocker combination versus either agent alone for the management of nocturia in patients with LUTS/BPH.     

Efficacy and safety of dutasteride, tamsulosin and their combination in a subpopulation of the CombAT study: 2-year results in Asian men with moderate-to-severe BPH

Although ethnicity-based differences in prostate size and physiology have been reported, results of benign prostatic hyperplasia (BPH) treatment trials in predominantly Caucasian patients are assumed to be applicable to non-Caucasian populations. This post hoc analysis investigated whether an Asian subpopulation of men with moderate-to-severe BPH in the CombAT study achieves treatment responses in line with those of the overall study population. In this double-blind, randomized, parallel-group trial, 325 Asian men were assigned to treatment with 0.5 mg dutasteride once daily, 0.4 mg tamsulosin once daily or the combination. Decrease in international prostate symptom score (IPSS) at month 24 from baseline (the primary endpoint) was significantly greater with combination treatment compared with tamsulosin (P<0.05), and numerically, but not statistically significantly, greater compared with dutasteride. Mean IPSS was reduced from baseline by 7.5 (+/-0.84) in the combination group, by 6.3 (+/-0.86) in the dutasteride group and by 4.5 (+/-0.78) in the tamsulosin group, resulting in respective mean IPSS at months 24 of 11.4 (+/-0.60), 12.7 (+/-0.70) and 14.3 (+/-0.74). The adverse event profile was similar to that observed in the overall CombAT population, and drug-related adverse events were more common with combination therapy (26%) than with tamsulosin (15%) or dutasteride (9%). No unexpected adverse events emerged. In conclusion, in Asian men with moderate-to-severe lower urinary tract symptoms and an enlarged prostate, combination therapy achieved significantly greater improvements from baseline BPH symptoms, flow rate, quality of life, reduced prostate volume and improved treatment satisfaction compared with tamsulosin monotherapy.     

Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride

OBJECTIVES: The Symptom Management After Reducing Therapy (SMART-1) study examined the combination of the dual action 5alpha-reductase inhibitor (5ARI) dutasteride, and alpha(1)-blocker tamsulosin, followed by withdrawal of tamsulosin in men with symptomatic BPH. METHODS: 327 BPH patients were randomised to 0.5mg dutasteride and 0.4 mg tamsulosin for 36 weeks (DT36) or 0.5 mg dutasteride and 0.4 mg tamsulosin for 24 weeks followed by dutasteride and tamsulosin matched placebo for the remaining 12 weeks (DT24+D12). Patients' assessment of their symptoms, IPSS at weeks 24, 30, and drug safety were evaluated. RESULTS: 77% of DT24+D12 patients felt the same/better at week 30 compared with week 24 (changes in IPSS were consistent with this finding). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms. In the 27% of men with severe baseline symptoms (IPSS >or=20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms compared with 14% in the DT36 group. The regimens were well tolerated. CONCLUSIONS: Dutasteride can be used in a 24-week combination with tamsulosin, to achieve rapid onset of symptom relief in patients at risk of underlying disease progression. This symptom relief is maintained in the majority of patients after the alpha(1)-blocker is removed from the combination. Patients with severe symptoms may benefit from longer-term combination therapy.     

The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia

The dual 5alpha-reductase inhibitor, dutasteride has been shown to suppress serum dihydrotestosterone (DHT) by >90%. In the present study, the effect of dutasteride 0.5 mg/day on intraprostatic DHT levels was investigated. In this multicenter, double-blind trial, 43 men with benign prostatic hyperplasia (BPH) scheduled to undergo transurethral resection of the prostate (TURP) were randomized to receive dutasteride, 0.5 mg/day or placebo for 3 months before surgery. Intraprostatic DHT, testosterone and dutasteride levels were determined at the time of TURP. Changes in serum DHT and testosterone from baseline, and both serum and intraprostatic dutasteride levels at the time of TURP were also assessed. Dutasteride reduced intraprostatic DHT by 94% relative to placebo (P<0.001); the adjusted mean intraprostatic DHT concentration was 3.23 and 0.209 ng/g in the placebo and dutasteride groups, respectively. In the dutasteride group, serum DHT was reduced from baseline by 93% at month 3, a significantly greater reduction (P<0.001) than the 15% decrease observed in the placebo group. There was a reciprocal increase in intraprostatic testosterone but the level of intraprostatic testosterone in the dutasteride group tended to be lower than the intraprostatic DHT level in the placebo group (P=0.06). Significant intraprostatic DHT suppression was achieved in all subjects who received dutasteride, regardless of the level of intraprostatic dutasteride. There was a strong positive correlation between serum and intraprostatic dutasteride concentrations (R(2)=0.73). After 3 months of treatment, dutasteride 0.5 mg/day provided near-complete suppression of both intraprostatic and serum DHT in men with BPH.     

α‐Blockers to assist stone clearance after extracorporeal shock wave lithotripsy: a meta‐analysis

Study Type – Therapy (meta‐analysis)
Level of Evidence 1a

OBJECTIVE

To review the evidence for the use of α‐blockers after extracorporeal shock wave lithotripsy (ESWL) in enhancing the effectiveness of renal and ureteric stone clearance.

METHODS

We searched MEDLINE, Embase and the Cochrane Library up to January 2009. All randomized controlled trials in which α‐blockers were evaluated after ESWL were eligible for the analysis. Outcome measures assessed were clearance rate (primary) and expulsion time (secondary). Two authors independently assessed study quality and extracted data. All data were analysed using RevMan 5.

RESULTS

Of the 29 identified papers, seven trials with a total of 484 patients met the predefined criteria. These studies evaluated the effectiveness of the α‐blocker tamsulosin, and studied clearance rate as the primary outcome. There was large heterogeneity between trials, but their methodological quality was adequate. The pooled absolute risk difference of clearance rate was 16% (95% confidence interval 5–27%) in favour of the tamsulosin group, i.e. an average of six patients have to be treated with tamsulosin after ESWL to achieve clearance in one. Subgroup analysis for the six studies that used a dose of 0.4 mg tamsulosin showed a pooled risk difference of 19 (10–29)%. The expulsion time was analysed in three studies and the pooled mean difference was 8 (?3–20) days in favour of the tamsulosin group. Pain and analgesic usage was reported to be lower with tamsulosin. Adverse effects of tamsulosin, mainly dizziness, were reported in eight patients (3%).

CONCLUSIONS

Treatment with tamsulosin after ESWL appears to be effective in assisting stone clearance in patients with renal and ureteric calculi. To make a definite clinical recommendation to use tamsulosin after ESWL for renal and ureteric calculi, a high quality confirmatory trial is warranted.     

Influence of dutasteride treatment on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement

Objectives

To clarify the effects of dutasteride on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement.

Methods

The present prospective study was carried out in 110 symptomatic benign prostatic enlargement patients treated with daily administration of 0.5 mg dutasteride. We analyzed serum hormonal levels and aging related symptoms using a validated Aging Male Symptom questionnaire at baseline and after 3 months of dutasteride treatment.

Results

The mean total testosterone, free testosterone and luteinizing hormone levels after dutasteride treatment were approximately 20% higher than those at baseline. The percentage increases in total and free testosterone levels were negatively correlated with these baseline levels. Baseline age, levels of total testosterone and free testosterone, and the changes in the rate of luteinizing hormone after dutasteride treatment tended to be correlated with an increase in the rate of total testosterone and free testosterone after dutasteride treatment. In a subgroup of 26 patients with moderate‐to‐severe aging male symptoms, poor morning erection and free testosterone levels <8.5 pg/mL, total aging male symptoms, and somatic symptoms scores significantly decreased after dutasteride treatment with an increase of total and free testosterone.

Conclusions

The increase of endogenous free testosterone and total testosterone by dutasteride might bring additional benefits of improvement of aging male‐related symptoms, especially in patients with lower free testosterone baseline levels and moderate‐to‐poor aging‐related symptoms.     

Low serum testosterone levels are poor predictors of sexual dysfunction

Study Type – Prognosis (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Sexual dysfunction is a common problem in elderly men, especially if they also have LUTS. Serum testosterone likewise decreases with aging, and a common conclusion from this is that low serum testosterone levels are a main cause for this. This is by far the largest population‐based study correlating sexual dysfunction with serum testosterone levels. Whereas age, body mass index and the severity of LUTS were independent risk factors for sexual dysfunction, serum testosterone levels were not. Treating sexual dysfunction only based on a low serum testosterone level therefore appears unjustified. There is a trend towards sexual dysfunction with S. testosterone levels <200 ng/dl, but only 4% of the 8231 older men studied were in this range.

OBJECTIVE

? To identify predictors of sexual dysfunction using baseline data from the reduction by dutasteride of prostate cancer events (REDUCE) study.

PATIENTS AND METHODS

? REDUCE was a 4‐year randomized, double‐blind, placebo‐controlled study evaluating the efficacy and safety of once‐daily dutasteride 0.5 mg in over 8000 men aged 50–75 years with a prostate‐specific antigen (PSA) level of 2.5–10 ng/mL (50–60 years) or 3.0–10 ng/mL (>60 years) and a negative prostate biopsy within 6 months of enrolment. ? Baseline values (mean serum testosterone, age, International Prostate Symptom Score [IPSS], total prostate volume [TPV], body mass index [BMI], and presence of diabetes/glucose intolerance) were compared in subjects with and without sexual dysfunction (sexual inactivity, impotence, decreased libido or a Problem Assessment Scale of the Sexual Function Index [PAS‐SFI] score <9).

RESULTS

? Multivariate logistic regression showed that baseline age and IPSS were significant predictors of all four sexual function criteria examined (P < 0.0001). ? BMI was a significant predictor of decreased libido, impotence and a PAS‐SFI score <9, while diabetes/glucose intolerance was a significant predictor of sexual inactivity, impotence and a PAS‐SFI score <9. ? Testosterone and TPV were not significant predictors of any sexual function criterion examined.

CONCLUSIONS

? Age, IPSS, BMI and diabetes/glucose intolerance, but not serum testosterone or TPV, were significant independent predictors of sexual dysfunction in the REDUCE study population. ? The lack of association between sexual dysfunction and serum testosterone questions the value of modestly reduced or low normal testosterone levels as criteria for choosing testosterone replacement in older men with sexual dysfunction.     

Effects of hexanic extract of serenoa repens (permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia

Background

Chronic prostatic inflammation (CPI) could be a cause of symptomatic or complicated benign prostatic hyperplasia (BPH). In previous in vitro and in vivo studies, Hexanic Extract of Serenoa repens (HESr) namely Permixon^® has demonstrated potent anti‐inflammatory properties. With the aim to provide new insight onto HESr anti‐inflammatory properties in human we explore its effect on CPI biomarkers in men with lower urinary tract symptoms (LUTS) related to BPH using a non‐invasive method and investigate links between biomarkers and clinical symptoms.

Methods

An international, randomized, double‐blind, parallel‐group, tamsulosin‐controlled study was carried out in 206 men with BPH‐related LUTS. Patients received oral daily HESr 320mg or tamsulosin 0.4 mg during 3 months. The first urine stream after digital rectal examination (DRE) was collected at Day 1 and Day 90 and mRNA was extracted from prostatic epithelial cells desquaming in the lumen of the glands and seminal plasma fluid after DRE. mRNA quantification of the 29 most significant published inflammation markers in BPH and protein detection in urine was performed.

Results

At D90, a decrease in mean gene expression was observed for 65.4% of the markers detected in the HESr group versus 46.2% in the tamsulosin group. In the 15 most frequently expressed genes, this difference was higher (80% vs. 33% respectively). Three proteins (MCP‐1/CCL2, IP‐10/CXCL10, and MIF) were detected. At D90, a decrease in the number of patients who expressed MCP‐1/CCL2 and IP‐10/CXCL10 was observed only in the HESr group. Moreover, MIF expression was significantly reduced by HESr compared with tamsulosin (P = 0.007). Finally, in contrast to tamsulosin, the subgroup of patients treated by HESr and who over expressed MIF at baseline, had a higher response to the International Prostate Symptom Score (I‐PSS) than those who did not over express this protein (mean I‐PSS change: ?6.4 vs. ?4.5 respectively). As the study is exploratory, results should be confirmed in a powered clinical study.

Conclusions

These results showed for the first time at clinical level the anti‐inflammatory properties of HESr, already indicated in BPH‐related LUTS. Thus, HESr could be of interest to prevent unfavourable evolution in patients with CPI. Prostate 75:1857–1867, 2015. © 2015 The Authors. The Prostate Published by Wiley Periodicals, Inc.

     

Improvements in benign prostatic hyperplasia-specific quality of life with dutasteride,the novel dual 5alpha-reductase inhibitor

OBJECTIVES: To examine the effect of the dual-action 5alpha-reductase inhibitor dutasteride on benign prostatic hyperplasia (BPH)-specific health status, as measured by the BPH Impact Index (BII), and to identify baseline and treatment risk factors for those most bothered by their BPH symptoms at the end of the protocol. PATIENTS AND METHODS: Data were derived from three randomized, double-blind, placebo-controlled, 2-year studies conducted in 4325 men with lower urinary tract symptoms caused by benign prostatic enlargement. Each study comprised a 1-month single-blind placebo run-in period, followed by randomization to oral dutasteride 0.5 mg once daily or placebo for 2 years. Patients eligible for inclusion were consenting men aged >/= 50 years with moderate to severe symptoms (American Urological Symptom Index, AUA-SI, score >/= 12), a prostate volume of >/= 30 mL, a serum prostate-specific antigen (PSA) level of >/= 1.5 or < 10 ng/mL, and a maximum urinary flow rate (Qmax) of /= 5 (greatest symptomatic burden) treatment with dutasteride improved the scores by 2.41, while the scores in placebo-treated patients only improved by 1.64. Dutasteride-treated patients with a baseline BII score of < 5 (least symptom burden) had a clinically significant improvement in health status, while placebo-treated patients deteriorated. Regression analysis showed that men with a combination of a baseline BII item-3 score of 3 (bothered a lot) and a high symptom score (AUA-SI >/= 20) were more likely to be bothered by their symptoms at the end of the study. Men receiving placebo were also more likely to be bothered at the end of the study than were those receiving dutasteride. CONCLUSIONS: Dutasteride treatment is associated with clinically significant improvements in BII score, reflecting improvements in the quality of life of men with BPH. Taken together with previously reported improvements in prostate volume, lower urinary tract symptoms and urinary flow, and diminution of the risk of acute urinary retention and the need for BPH-related surgery, dutasteride offers demonstrable efficacy in the management of BPH.     

Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH. Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment.

OBJECTIVE

? To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH).

PATIENTS AND METHODS

? At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks. ? The primary efficacy measure was the mean change from baseline to endpoint in IPSS. ? The non‐inferiority margin of the IPSS change was set at 1.0. ? Secondary efficacy measures included change in maximal urinary flow rate (Q_max) and health‐related quality of life (HRQL) score.

RESULTS

? Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥25% decrease in IPSS (P= 0.53). ? The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was ?0.60 (95% confidence interval ?2.15, 0.95), inferring the non‐inferiority of silodosin to tamsulosin. ? The mean changes in the Q_max and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P= 0.009), only 1.9% discontinued treatment. ? Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure (?4.2 mmHg, within‐group P= 0.004) relative to the negligible change of silodosin (?0.1 mmHg, within‐group P= 0.96)

CONCLUSION

? The trial shows the non‐inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH.     

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS)

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α‐reductase, the dominant form of 5α‐reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half‐life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double‐blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one‐year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α‐reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long‐term, progressive nature of BPH, the one‐year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment.

OBJECTIVE

• ? To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months.

PATIENTS AND METHODS

• ? The Enlarged Prostate International Comparator Study was a multicentre, randomized, double‐blind, 12‐month, parallel‐group study.
• ? Men aged ≥50 years with a clinical diagnosis of BPH received once‐daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4‐week placebo run‐in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24‐month, open‐label phase, during which patients received dutasteride 0.5 mg once daily.
• ? The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA‐SI) scores, improvement in maximum urinary flow rate (Q_max) and long‐term safety in the 24‐month open‐label phase.

RESULTS

• ? Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study.
• ? Similar reductions in mean AUA‐SI scores and Q_max were also observed for men in both treatment groups.
• ? A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open‐label phase.

CONCLUSION

• ? Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q_max and urinary symptoms associated with BPH in men with an enlarged prostate.

     

The effects of combination therapy with dutasteride plus tamsulosin on clinical outcomes in men with symptomatic BPH: 4-year post hoc analysis of European men in the CombAT study

CombAT (Combination of Avodart and Tamsulosin) was a randomised, double-blind study in men (n=4844) aged ≥ 50 years with a clinical diagnosis of BPH. Patients were randomised to daily tamsulosin 0.4 mg, dutasteride 0.5 mg or both for 4 years. The primary endpoint was time to acute urinary retention (AUR) or BPH-related surgery. Secondary endpoints included BPH clinical progression, symptoms and maximum urinary flow rate. A post hoc analysis of data from the European subgroup was conducted. A total of 2925 men were randomised to treatment in Europe as part of CombAT (tamsulosin, n=972; dutasteride, n=970; combination, n=983). Combination therapy significantly reduced the relative risk of AUR or BPH-related surgery compared with either monotherapy at 4 years, and also significantly reduced the risk of BPH clinical progression. Combination therapy also provided significantly greater symptom improvement than either monotherapy at 4 years. Safety and tolerability of dutasteride plus tamsulosin was consistent with previous experience of this combination and with the monotherapies. These data provide further evidence to support the use of long-term combination therapy (dutasteride plus tamsulosin) in men with moderate-to-severe lower urinary tract symptoms because of BPH and prostatic enlargement. The results in the European subgroup are generally consistent with those in the overall study population.     

Evaluation of the Clinical Benefit of Permixon and Tamsulosin in Severe BPH Patients—PERMAL Study Subset Analysis

Objective: To compare the efficacy of the lipido-sterolic extract of Serenoa repens, Permixon, to that of the α–blocker, tamsulosin, in the treatment of severe low urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH).Methods: In a 12-month, double-blind, randomized study that showed equivalent efficacy of Permixon 320 mg/day and tamsulosin 0.4 mg/day (“PERMAL study”), 685 BPH patients with IPSS ≥10 had been analyzed for efficacy. Of these, the 124 patients with severe LUTS (IPSS >19) at randomization were retained for this subset analysis. After a 4-week run-in period, 59 and 65 patients had been randomized to tamsulosin and Permixon groups, respectively. Both treatment groups were compared regarding the evolution from baseline of total IPSS and its irritative and obstructive subscores, LUTS-related QoL, prostate volume, Q_max and MSF-4 (sexual activity questionnaire) at different time points over 1 year. An analysis of variance of changes from baseline to end point was performed for all the parameters. The over-time evolutions of total, irritative and obstructive IPSS were further compared using a variance analysis for repeated measurements.Results: At 12 months, total IPSS decreased by 7.8 with Permixon and 5.8 with tamsulosin (p=0.051); the irritative symptoms improved significantly more (p=0.049) with Permixon (−2.9 versus −1.9 with tamsulosin). The superiority of Permixon in reducing irritative symptoms appeared as soon as month 3 and was maintained up to month 12 (p=0.03).Conclusion: Permixon 320 mg/day was shown to be slightly superior to tamsulosin 0.4 mg/day in reducing LUTS in severe BPH patients after 3 months and up to 12 months of treatment.     

Effects of dutasteride on serum free‐testosterone and clinical significance of testosterone changes

Sixty‐two patients with benign prostate hyperplasia (BPH) who were being treated with dutasteride participated in this study. Prostate volume, uroflowmetry, blood tests, the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF‐5) were determined before and 1, 3 and 12 months after the treatment with dutasteride. Patients were divided into two groups based on changes in serum testosterone after 1 month: Group A (>20% increase; n = 33) or Group B (<20% increase; n = 29). Serum free‐testosterone levels were 20.4% higher after 1 month and remained constant thereafter. When Groups A and B were compared, baseline free‐testosterone levels were significantly lower in Group A, IPSS QOL was significantly better in Group A at 3 and 12 months, and no significant differences were observed in uroflowmetry, prostate volume, IPSS or IIEF‐5. A univariate analysis identified serum free‐testosterone levels and the IPSS storage symptom subscore as significant factors influencing IPSS QOL at 12 months, and only the IPSS storage symptom subscore appeared to be independently related to IPSS QOL. These results indicate that dutasteride increases serum free‐testosterone levels in BPH patients, particularly with low baseline free‐testosterone levels, and the increase in free‐testosterone may have further add‐on impacts on their urinary tract symptoms.     

中断非那雄胺治疗对前列腺增生病情的影响

目的 通过监测前列腺增生患者中断使用非那雄胺前后,下尿路症状、血清PSA值和前列腺体积的改变,了解停用非那雄胺对患者病情的影响。方法 从2011年12月到2016年6月,收集本院83例55岁以上有中度以上临床症状（IPSS评分≥8）患者的资料。根据使用非那雄胺情况将患者分为两组,A组43例,B组40例。首先对所有患者每日联合使用非那雄胺5 mg和坦索罗辛0.2 mg治疗,持续1年时间。自第2年开始,A组患者继续接受两种药物联合治疗,B组患者仅使用坦索罗辛继续治疗。在研究开始时对所有入组的患者进行IPSS评分、PSA水平及前列腺体积测定,作为基线水平,然后在第1年和第2年末再进行评估,比较其差异。结果 停止非那雄胺治疗后,患者下尿路(LUTS)症状加重,PSA水平增高及前列腺体积继续增大。重复测量方差分析显示两组之间IPSS评分、PSA及前列腺体积水平均有较大差异。结论 在联合治疗后,停止非那雄胺使用,将会导致患者前列腺再度增生及LUTS症状加重,PSA水平再次升高。因此,定期监测IPSS评分及PSA水平对于患者是否继续或停用5α还原酶抑制剂都有意义。