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.     

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.     

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.

     

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 alpha-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 > or =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.     

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.     

Comparison of the response to treatment between Asian and Caucasian men with benign prostatic hyperplasia: Long‐term results from the combination of dutasteride and tamsulosin study

The Combination of Avodart and Tamsulosin study was a 4‐year, randomized, double‐blind study of the efficacy and safety of dutasteride and tamsulosin, alone or in combination, in men with moderate‐to‐severe benign prostatic hyperplasia. In this post‐hoc investigation, we analyzed primary and secondary end‐points from the Combination of Avodart and Tamsulosin study in Asian (n = 325) and Caucasian men (n = 4259). The incidence of acute urinary retention or benign prostatic hyperplasia‐related surgery did not differ significantly between treatment groups in the Asian subpopulation. In Caucasian men, the incidence of acute urinary retention/benign prostatic hyperplasia‐related surgery was significantly lower in the combination therapy group compared with the tamsulosin monotherapy group (P < 0.001), but not compared with dutasteride monotherapy. Combination therapy significantly increased the time to benign prostatic hyperplasia clinical progression and resulted in improved International Prostate Symptom Score, maximum urinary flow rate, quality of life, and reduced prostate volume in Asian and Caucasian men who received combination therapy compared with tamsulosin monotherapy. Combination therapy also significantly improved (P < 0.05) time to benign prostatic hyperplasia clinical progression, International Prostate Symptom Score, maximum urinary flow rate and quality of life versus dutasteride in the Caucasian subpopulation. The adverse‐event profile was comparable between subpopulations. In conclusion, Asian and Caucasian men respond similarly to these treatments, despite apparent racial differences in 5α‐reductase activity.     

The effects of dutasteride on voiding and storage symptoms in men with benign prostatic hyperplasia

We investigated the effects of dutasteride on voiding and storage symptoms by a post-hoc analysis from two randomized, placebo-controlled, parallel-group studies (Japanese phase II study and phase III study) which assessed the efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia (BPH). Men aged 50 years and older, with a prostate volume of 30 cc or greater, an International Prostate Symptom Score (IPSS) of 8 or higher and maximal urinary flow rate of 15 ml/sec or lower were randomized to placebo or dutasteride groups. The number of subjects for the placebo and dutasteride groups was respectively 72 and 72 in the phase II study, and 185 and 193 in the phase III study. Questions 1, 3, 5 and 6 of IPSS were related to voiding symptoms, and Questions 2, 4 and 7 were related to storage symptoms. Changes between pre- and post-treatments were evaluated. In the phase II study, dutasteride significantly improved voiding symptoms and numerically improved storage symptoms compared with the placebo at week 24. In the phase III study, dutasteride significantly improved voiding and storage symptoms compared with the placebo after 52 weeks. These consistent results suggest that dutasteride is effective for both voiding and storage symptoms in Japanese men with BPH.     

Combination therapy with curcumin plus tamsulosin and finasteride in the treatment of men with benign prostatic hyperplasia: a single center,randomized control study

BackgroundTo perform a prospective, randomized, single center study to investigate the efficacy of combined use of curcumin, an anti-inflammatory agent, with the best standard management (BSM, tamsulosin and finasteride) in benign prostatic hyperplasia (BPH) patients.MethodsOne hundred and twenty-two consecutive patients were randomized to receive tamsulosin 0.2 mg, finasteride 5 mg, and curcumin 2,250 mg once a day (curcumin + BSM group, n=61) versus tamsulosin 0.2 mg, finasteride 5 mg, and placebo (BSM group, n=61) for 6 months. The safety of treatments and their efficacy on improving waist circumference (WC), periprostatic fat thickness (PPFT), lower urinary tract symptoms (LUTS), and sexual function were assessed at baseline and month 6.ResultsOne hundred and sixteen patients completed the whole procedure (116/122, 95.1%). There were significant improvements in prostate volume (PV), maximum flow rate (Qmax), the International Prostate Symptom Score (IPSS), IPSS-voiding subscore (IPSS-V), IPSS-storage subscore (IPSS-S), and quality of life (QoL) from baseline after treatment in both groups. Additionally, both WC and PPFT decreased significantly after treatments than those at baseline in the curcumin + BSM group. Also, WC and PPFT in the curcumin + BSM group were significantly lower than those in the BSM group. In addition, IPSS-S, QoL score, and the 5-item version of the International Index of Erectile Function (IIEF-5) in the curcumin + BSM group improved significantly compared with those in the BSM group.ConclusionsWe conclude that curcumin combined with tamsulosin and finasteride has more beneficial effects in reducing PPFT, protecting erectile function, improving urinary retention symptoms, and QoL scores in BPH patients compared to tamsulosin and finasteride alone.Trial RegistrationChinese Clinical Trial Registry ChiCTR2100043800.     

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.     

西地那非联合坦索罗辛治疗LUTS/BPH的对比研究

目的 观察西地那非联合坦索罗辛及单独应用坦索罗辛治疗良性前列腺增生症(BPH)所致下尿路症状(LUTS)的临床疗效.方法 国际前列腺症状评分(IPSS)≥12分的本院2010年7月～2011年6月BPH患者50例,随机分为两组,每组25例.治疗组口服西地那非25mg,每日一次+坦索罗辛0.2mg,每日两次;对照组服用坦索罗辛0.2mg,每日两次,疗程8周.治疗后组间比较IPSS、最大尿流率(Qmax)、残余尿量(PVR)、生活质量(QOL)和勃起功能国际问卷(IIEF-5),并进行统计学分析.结果 与对照组比较,治疗组IPSS明显下降,IIEF-5明显改善,QOL明显改善(P＜0.05),两组Qmax和PVR无明显差异(P＞0.05).结论 西地那非联合坦索罗辛治疗前列腺增生症所致下尿路症状优于单独应用坦索罗辛,并可以改善患者的勃起功能.     

Benign prostatic hyperplasia (BPH) and prostatitis: prevalence of painful ejaculation in men with clinical BPH

OBJECTIVES: To determine the prevalence and importance of pain/discomfort on ejaculation (prostatitis-like symptom) in men with lower urinary tract symptoms (LUTS) diagnosed with clinical benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Baseline data from 5096 men reporting LUTS suggestive of BPH, and enrolled in the ALF-ONE study by general practitioners and urologists in Europe, Asia, Latin America, the Middle East and Canada, were analysed to determine the prevalence and significance of pain/discomfort on ejaculation. All the men were asked to complete the International Prostate Symptom Score (IPSS) questionnaire, the bother score (IPSS question 8), and the Danish Prostate Symptom Score sexual-function questionnaire (DAN-PSSsex) which assesses three symptoms (rigidity of erection, amount of ejaculate and pain/discomfort on ejaculation) and their bothersomeness. RESULTS: There were 3700 sexually active men who had an evaluable answer to the DAN-PSSsex question related to pain/discomfort on ejaculation. Of these, 688 (18.6%) reported pain/discomfort on ejaculation and 609 (88%) considered it was a problem. Patients with painful ejaculation had more severe LUTS and reported greater bother (P < 0.001). Of men with painful ejaculation, 72% reported erectile dysfunction, of whom 91% considered it a problem, and 75% reported reduced ejaculation, of whom 81% considered it a problem. By contrast, of men with no ejaculatory discomfort, 57% reported erectile dysfunction, of whom 79% considered it a problem, and 56% reported reduced ejaculation, of whom 57% considered it a problem. A history of urinary tract infection was reported by 12% of men in the ejaculatory pain group, compared with 7% in the LUTS-only group, while 5% of men in the ejaculatory pain group reported macroscopic haematuria, compared to 3% in the LUTS-only group. Men with ejaculatory pain were slightly younger, but there were no significant differences in duration of LUTS, history of acute urinary retention, prostate-specific antigen concentrations or maximum urinary flow rate compared to the LUTS-only group. CONCLUSIONS: Of sexually active men with LUTS suggestive of BPH, approximately 20% complain of specific prostatitis-like symptoms of pain/discomfort on ejaculation, and these men clearly differ from those who present with LUTS only. For most the symptom is a significant bother. Men with BPH and painful ejaculation have more severe LUTS and reported greater bother, and had a higher prevalence of erectile dysfunction and reduced ejaculation, than men with LUTS only. Evaluation and treatment strategies should address this population of men with symptoms suggestive of both prostatitis and BPH.     

Assessment of possible effects for testosterone replacement therapy in men with symptomatic late-onset hypogonadism

We herein report clinical assessments of efficacy and side effects of T replacement therapy (TRT) in men with late-onset hypogonadism (LOH). The study included 56 patients who were diagnosed with LOH and treated with TRT for at least 6 months at our institution. Age, ageing male symptom (AMS) scale, and androgen decline in the ageing male (ADAM) questionnaires were examined. Fasting blood samples were analysed for sex hormones, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), red blood cell count (RBC), haemoglobin (Hb), haematocrit (Ht), and prostate-specific antigen (PSA). Total and psychological symptoms scores were measured by the AMS scale and the ADAM questionnaire score, demonstrating that the sum of positive responses to the questions were significantly improved after TRT (P < 0.05). TC, HDL, and LDL cholesterol, TG, AST, ALT, γ-GTP, RBC, Hb, Ht, and PSA were not significantly different between before and after TRT. Although TRT for men with LOH may cause favorable changes in psychological conditions, it may not have effects on lipid metabolism, liver function, RBC, and PSA level.