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.     

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.     

Outcomes and complications of naftopidil versus tamsulosin for elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis

We conducted a systematic review and meta-analysis to assess the outcomes and complications of naftopidil in treating elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and compared them with those administered with tamsulosin. A literature review was performed to identify the available randomised controlled trials concerning the comparison between naftopidil and tamsulosin for men with LUTS/BPH. We searched the following databases: the Cochrane Library Database, PubMed, Embase and Web of Science. Eleven publications involving 1,114 men (557 in the naf group and 557 in the tam group) were pooled in our analysis. We found no significant differences in the total IPSS, IPSS storage score, IPSS voiding score, quality of life index, peak urinary flow rate, average flow rate and post-void residual volumes. We assessed cardiovascular and sexual adverse events, acute urinary retention, surgical intervention, withdrawals due to any reason and withdrawals due to adverse events. The incidence of adverse events was similar among patients in naf and tam groups. In conclusion, naftopidil shared comparable efficacy and similar incidence of adverse events with tamsulosin and appears to be a promising agent for and alternative to tam. However, more prospective trials with high quality and long-term treatment duration are needed to verify this observation.     

Sexual dysfunction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Sexuality is an essential aspect of a couple's relationship and has a significant impact on life satisfaction. Benign prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. Men with moderate-to-severe LUTS are at increased risk for sexual dysfunction, including moderate-to-severe erectile dysfunction (ED), ejaculatory dysfunction (EjD), and hypoactive desire (HD). The results of several recent large-scale studies have shown a consistent and strong relationship between LUTS and both ED and EjD. It appears that the pathophysiological mechanisms of LUTS and the related prostatic enlargement of BPH as well as certain treatments for this condition may have an impact on both the erection and ejaculation components of the sexual response. Validated questionnaires that assess sexual function provide clinicians with valuable information to help guide treatment selection decisions. Effective medical therapies for LUTS associated with BPH include alpha(1)-adrenergic receptor antagonists (i.e., alfuzosin, doxazosin, tamsulosin, and terazosin) and 5alpha-reductase inhibitors (i.e., finasteride and dutasteride). The side effects of these medications, including sexual dysfunction, are important distinguishing features. The successful management of patients with LUTS associated with BPH should include assessments of sexual function and monitoring of medication-related sexual side effects. For men with LUTS and sexual dysfunction, an appropriate integrated management approach, based on each patient's symptoms and outcome objectives, is warranted.     

Efficacy and safety of tamsulosin hydrochloride compared to doxazosin in the treatment of Indonesian patients with lower urinary tract symptoms due to benign prostatic hyperplasia

AIM: The objective of the study was to compare the efficacy and safety of tamsulosin hydrochloride and doxazosin in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). METHODS: The safety and efficacy of tamsulosin (0.2 mg) and doxazosin (2 mg) was determined after once daily administration for 6 weeks in an open-label, randomized, multicenter study of 101 men with BPH. The International Prostatic Symptom Score (IPSS), maximal urinary flow rates (Qmax), average urinary flow rates (Qave) and residual urine were determined at baseline and again at 6 weeks as efficacy parameters. The primary parameters used for safety evaluation were vital signs (blood pressure and heart rate) and adverse events. The number of patients with a clinically significant response to treatment with tamsulosin or doxazosin was determined and defined as those with >20% improvement from the baseline Qmax or >20% decrease in total IPSS. RESULTS: The total IPSS decreased significantly in both the tamsulosin and doxazosin groups compared to baseline. There was a significant difference in the decrease in total IPSS between two groups. Qmax, Qave and residual urine significantly improved only in the tamsulosin group. There were no significant differences in systolic blood pressure, diastolic blood pressure or heart rate profile in the tamsulosin group; however, doxazosin resulted in a significant difference in systolic and diastolic blood pressure. Tamsulosin was well tolerated; only three patients (6%) in the tamsulosin group reported an adverse event (dizziness) while 11 patients (22%) in the doxazosin group reported an adverse event (dizziness), one of whom withdrew from the study. CONCLUSIONS: Tamsulosin was shown to be more effective than doxazosin in the treatment of LUTS due to BPH.     

Short‐term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia

Objectives: To compare the efficacy and safety of silodosin and tamsulosin in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) by a randomized crossover method. Methods: BPH patients with the complaint of LUTS were included in this study, and were randomly divided into two groups: a silodosin‐preceding group (4 weeks of twice‐daily administration of silodosin at 4 mg, followed by 4 weeks of once‐daily administration of tamsulosin at 0.2 mg) or a tamsulosin‐preceding group (4 weeks' administration of tamsulosin, followed by 4 weeks' administration of silodosin). No drug withdrawal period was provided when switching the drug. Results: In the first treatment period, both drugs significantly improved the International Prostate Symptom Score total score, but the improvement by silodosin was significantly superior to that by tamsulosin. After crossover treatment, significant improvement was observed only with silodosin treatment. Moreover, intergroup comparison of changes revealed that silodosin showed significant improvement of straining and nocturia with first and crossover treatments, respectively, compared with tamsulosin. Silodosin also significantly improved quality of life (QOL) score in both treatment periods, while tamsulosin significantly improved QOL score only in the first treatment period. The most frequent adverse drug reaction was ejaculatory disorder with silodosin; however, the incidence of dizziness with silodosin was similar to that with tamsulosin. Conclusions: In BPH/LUTS patients, silodosin exhibits excellent efficacy in improving subjective symptoms in both initial and crossover treatment, and it appears to improve the QOL of patients.     

Efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia

Objectives:   To assess the efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia (BPH).
Methods:   This was a randomized, double-blind, placebo-controlled, parallel-group study. A total of 378 subjects with clinical BPH having an International Prostate Symptom Score (IPSS) of 8 points or greater, a prostate volume of 30 mL or greater, and a maximal urinary flow rate (Qmax) of 15 mL/s or less were randomized to receive placebo or dutasteride once daily for 52 weeks. Subjects were stratified according to tamsulosin use at baseline. The numbers of subjects with and without tamsulosin use were 242 and 136, respectively. IPSS, Qmax, prostate volume and drug safety were evaluated.
Results:   Continued improvement in IPSS was noted in the dutasteride group, and dutasteride significantly decreased IPSS compared with placebo. At week 52, dutasteride significantly improved Qmax and prostate volume compared with placebo. Drug-related sexual function events in the dutasteride group were infrequent and generally were not treatment limiting.
Conclusions:   Dutasteride improves urinary symptoms and flow rate and reduces prostate volume. In Japanese men with BPH, it is effective and generally well tolerated during the one-year treatment period.     

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.     

Relationship between lower urinary tract symptoms and serum levels of sex hormones in men with symptomatic benign prostatic hyperplasia

Study Type – Aetiology (case series)
Level of Evidence 4

OBJECTIVES

To investigate a possible association between the severity of lower urinary tract symptoms (LUTS) and the serum levels of sex hormones in men with symptomatic benign prostatic hyperplasia (BPH) that underwent surgery for severe benign prostatic obstruction.

PATIENTS AND METHODS

In all, 127 selected men with symptomatic BPH attending our urology clinic were recruited. The clinical conditions of BPH were assessed by digital rectal examination, serum prostate‐specific antigen (PSA) determination, International Prostate Symptom Score (IPSS), transrectal ultrasonography and maximum urinary flow rate (Q_max) value at uroflussimetry. Before surgery, we measured the serum concentrations of total testosterone (TT) and free testosterone (FT), oestradiol, prolactin, luteinizing hormone and follicle‐stimulating hormone. We excluded men with endocrine diseases, those with prostate disease who were receiving antiandrogen therapy and those with psychological diseases. The relationships between the IPSS score and serum sex hormone levels were determined.

RESULTS

The final study population consisted of 122 men (mean age of 70.66 years), as five were excluded (three due to incomplete evaluation and two who were diagnosed with prostate cancer). On statistical analysis, the total IPSS was significantly associated with age (r= 0.405, P < 0.001) and TT (r= 0.298, P= 0.020) but not with FT or the serum levels of the other sex hormones. The serum levels of testosterone and IPSS did not correlate with prostate volume and Q_max. PSA level and age correlated with prostate volume (r= 0.394, P < 0.001; r = 0.374, P < 0.001, respectively). We distinguished two subgroups of patients: the first group of 40 men with an IPSS of <19 and the second group of 82 with an IPSS of >19, and we evaluated the median levels of TT in each group. There was an increased risk of LUTS in men with a greater serum concentration of TT (P= 0.042), although the mean TT level was in the normal range.

CONCLUSIONS

In the present study, the severity of LUTS was associated with age and serum levels of TT but only age correlated with the measures of BPH, especially prostate volume. The potential effects of testosterone on LUTS may well be indirect. Additional large studies are needed to confirm these preliminary results.     

他汀类药物的使用与良性前列腺增生和下尿路症状相关性的临床研究

目的:探讨服用他汀类药物是否可延缓良性前列腺增生(BPH)和下尿路症状的临床进展。方法:选择2003年1月至2008年12月于我院体检中心体检的50~69岁男性作为研究对象,制定纳入标准,随访5年,通过比较IPSS评分、最大尿流率(Qmax)和前列腺体积(PV)探讨他汀类药物的使用与前列腺增生和下尿路症状临床进展的相关性。结果:总共有653例男性纳入本研究,其中他汀类药物使用组(1组)283例,他汀类药物未使用组(2组)370例,两组入选时的年龄、IPSS评分、Qmax和PV差异均无显著性(P0.05),随访过程中因出现明显的排尿困难各剔除24例(1组)和35例(2组)。5年随访过程中1组和2组的IPSS评分都逐渐升高,但1组升高程度明显低于2组(P0.01),1组和2组的Qmax都逐渐下降,但1组下降程度明显低于2组(P0.01);1组[PV5年分别为(22.60±4.99)、(25.80±5.20)、(27.92±5.05)、(29.11±5.24)、(29.97±5.26)ml]和2组[5年分别为(24.30±4.98)、(28.50±5.14)、(32.84±4.77)、(36.99±4.78)、(40.90±4.78)ml]的PV都逐渐增大,但1组增大程度明显小于2组(P0.01)。结论:使用他汀类药物可明显延缓BPH和下尿路症状的临床进展,且长时间服用疗效更显著。     

他达拉非治疗继发于良性前列腺增生下尿路症状的研究进展

他达拉非作为新一代的选择性磷酸二酯酶-5抑制剂(PDE5Is)为男性勃起功能障碍(ED)的治疗带来了全新的理念。继发于男性良性前列腺增生症(BPH)的下尿路症状(LUTS)由于其病因的复杂性,治疗效果受到多因素的影响,使得传统的临床治疗方法不可避免地存在各种难以预测的并发症。目前日益受到关注的他达拉非每日一次口服方案(OAD)治疗ED的新方案在临床研究中表现出了对继发于BPH的LUTS的显著的疗效,在治疗的早期,国际前列腺症状评分(IPSS)就得以显著改善。还有研究表明在同时存在ED和LUTS症状的BPH患者中,他达拉非也显著有效。本文旨在回顾PDE5Is对BPH相关症状治疗的相关研究进展,综述他达拉非治疗继发于BPH的LUTS的有效性和安全性证据。     

Clinical guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia

The present article is the abbreviated English translation of the Japanese guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia updated as of the end of 2016. The target patients are men aged >50 years complaining of lower urinary tract symptoms, with or without benign prostatic hyperplasia, and the target readers are non‐urological general physicians and urologists. Mandatory assessment for general physicians is medical history, physical examination, urinalysis and measurement of serum prostate‐specific antigen. Additional mandatory assessment for urologists is symptoms and quality of life assessment by questionnaires, uroflowmetry, residual urine measurement, and prostate ultrasonography. Nocturia requires special attention, as it can result from nocturnal polyuria and/or sleep disturbance rather than lower urinary tract disorders. Functional lower urinary tract disorders with or without benign prostatic hyperplasia are primarily managed by conservative therapy and medications, such as α₁‐blockers and phosphodiesterase‐type 5 inhibitors. Use of other medications or combination pharmacotherapy is to be reserved for urologists. 5α‐Reductase inhibitors and anticholinergics or β3 agonists are indicated for men with enlarged prostates and overactive bladder symptoms, respectively. Surgical intervention for bladder outlet obstruction is considered for persistent symptoms or benign prostatic hyperplasia‐related comorbidities. Surgical modalities should be optimized by the patient's characteristics, performance of equipment and the surgeon's experience.     

Influence of hypertension on lower urinary tract symptoms in benign prostatic hyperplasia

AIM: To clarify the influence of hypertension on lower urinary tract symptoms (LUTS) we examined the relationship between blood pressure, LUTS, and the effect of terazosin on LUTS in patients with benign prostatic hyperplasia (BPH). METHODS: The subjects were patients who had LUTS and BPH. They were treated with terazosin (1 mg, twice-a-day) for 12 weeks. Calculation of the International Prostate Symptom Score (IPSS), measurement of blood pressure, and uroflowmetry were performed before and after 12 weeks of therapy. Patients were divided into a normotensive (NT) group and a hypertensive (HT) group at the time of first examination. RESULTS: The IPSS for urinary frequency and nocturia in BPH-HT patients (n = 21; mean age, 71 years) were significantly higher than those in the BPH-NT patients (n = 21; mean age, 69 years) before the administration of terazosin. The total IPSS the BPH-HT patients was also significantly higher than that of the BPH-NT patients. There were no differences of uroflowmetric parameters between the two groups. After 12 weeks of therapy, systolic and diastolic blood pressure decreased in the BPH-HT patients, but not in the BPH-NT patients. However, the systolic pressure of the BPH-HT patients was still significantly higher than that of the BPH-NT patients. The score for each IPSS parameter decreased in both groups, but the difference of the score between the two groups increased. CONCLUSION: Hypertension may worsen LUTS and may decrease the improvement of symptoms by terazosin.