The Journal of International Medical Research 2012; 40:

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1 The Journal of International Medical Research 2012; 40: Comparison of α-blocker Monotherapy and α-blocker Plus 5α-Reductase Inhibitor Combination Therapy Based on Prostate Volume for Treatment of Benign Prostatic Hyperplasia K-J JOO 1, W-S SUNG 2, S-H PARK 3, W-J YANG 4 AND T-H KIM 5 1 Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2 Department of Urology, Seoul Red Cross Hospital, Seoul, Republic of Korea; 3 Department of Urology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 4 Department of Urology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea; 5 Department of Urology, Chung-Ang University College of Medicine, Seoul, Republic of Korea OBJECTIVE: This study compared a-blocker monotherapy with combination therapy involving an a-blocker and a 5-a reductase inhibitor for benign prostatic hyperplasia (BPH), according to baseline prostate volume. METHODS: Korean men diagnosed with BPH were randomized to 12 months treatment with 0.2 mg tamsulosin or 0.2 mg tamsulosin plus 0.5 mg dutasteride. Prostate specific antigen (PSA), prostate volume, transition zone volume (TZV), International Prostate Symptom Score (IPSS), maximal urinary flow rate (Q max ), postvoid residual urine volume and sexual function were assessed at baseline and after 12 months treatment. Variables were analysed based on baseline prostate volumes of 35 ml or > 35 ml. RESULTS: In total, 216 men with BPH were included. Combination therapy resulted in significant improvements in prostate volume, TZV, PSA, IPSS and Q max, which were most pronounced in men with a prostate volume > 35 ml. CONCLUSIONS: Tamsulosin mono - therapy was sufficient treatment for BPH in Korean men with a prostate volume 35 ml. Combination tamsulosin and dutasteride therapy provided greater benefits than tamsulosin monotherapy in men with BPH whose prostate volume was > 35 ml. KEY WORDS: PROSTATIC HYPERPLASIA; PROSTATE; TAMSULOSIN; DUTASTERIDE Introduction Benign prostatic hyperplasia (BPH) is a progressive disease that causes lower urinary tract symptoms (LUTS) which substantially affect quality of life for many patients. 1 Progression of BPH results in more severe LUTS, as well as other symptoms and episodes such as reduction of urinary flow rate, increased incidence of urinary infection, acute urinary retention 899

2 and increased incidence of surgery for BPH. 1,2 The α-adrenergic blockers (α-blockers) and 5α-reductase inhibitors (5-ARIs) are commonly used to treat patients with BPH. Prostatic smooth muscle plays a key role in the development of prostatic urethral pressure, which results in LUTS in patients with BPH. Since there are many α-adrenergic receptors within the prostatic smooth muscle, blocking the α-adrenergic receptor signal relieves the symptoms of BPH. The use of 5-ARIs reduces prostate volume by 20 30%, thereby relieving obstructive symptoms in BPH patients. 3,4 α-blocker monotherapy is commonly used to treat BPH patients who have a small prostate volume, whereas α-blocker/5-ari combination therapy is commonly used to treat BPH patients who have a large prostate volume. The Medical Therapy of Prostatic Symptoms (MTOPS) study indicated that combination therapy was beneficial when the prostate volume was > 40 ml and the serum prostate specific antigen (PSA) concentration was > 4.0 ng/ml. 5 It is unknown whether these standards also apply to the Korean population. The CombAT study suggested that combination therapy with 0.4 mg tamsolusin and 0.5 mg dutasteride was effective in patients with a prostate volume > 30 ml. 6 Unlike Western countries, where 0.4 mg tamsulosin once daily therapy is used, in Asian countries such as the Republic of Korea, China, Japan, Taiwan and Singapore, 0.2 mg tamsulosin once daily is the recommended dosage for treating BPH. The present study compared the efficacy and safety of monotherapy (0.2 mg tamsulosin, once daily) with combination therapy (0.2 mg tamsulosin/0.5 mg dutasteride, once daily), according to baseline prostate volume, in Korean men with BPH. Patients and methods STUDY POPULATION This randomized, controlled, open-label, multicentre study was performed between June 2008 and March 2010, and included consecutive patients diagnosed with BPH. The study was conducted at the following institutes in the Republic of Korea: Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; Department of Urology, Seoul Red Cross Hospital, Seoul; Department of Urology, Haeundae Paik Hospital, Inje University College of Medicine, Busan; Department of Urology, Soonchunhyang University College of Medicine, Seoul; Department of Urology, Chung-Ang University College of Medicine, Seoul. Patient inclusion criteria were: age 40 years; diagnosis of BPH; International Prostate Symptom Score (IPSS) 13 points; 6 9 maximal urinary flow rate (Q max ) of 4 15 ml/s in a total voided volume 150 ml. Patients who had been treated previously for BPH were excluded from the study, as were patients diagnosed with prostate cancer, bladder cancer or other progressive diseases that could cause LUTS. Patients with > 200 ml of residual urine were also excluded. Approval for the study was granted by the Ethics Committee and Institutional Review Board at Chung-Ang University (reference No ). Written informed consent was obtained from all patients prior to the investigation. STUDY TREATMENT AND ASSESSMENTS Selected patients were randomized into one of the two treatment groups according to a computer-generated randomization schedule at study entry, and treated either with α- blocker monotherapy (0.2 mg tamsulosin, orally, once daily; Group 1) or with α- 900

3 blocker/5-ari combination therapy (0.2 mg tamsulosin, orally, once daily plus 0.5 mg dutasteride, orally, once daily; Group 2) for 12 months. Patients were asked to attend follow-up appointments at their treatment centres every 3 months. Prostate volume, transition zone volume (TZV), uroflowmetry and residual urine volume were measured before and after 12 months treatment. In addition, participants were asked to complete the following questionnaires: the IPSS, with symptoms classified as mild (scores 0 7), moderate (scores 8 19), or severe (scores 20 35); 9 the International Index of Erectile Function (IIEF), which classifies the severity of erectile dysfunction into five categories (severe [scores 5 7], moderate [scores 8 11], mild to moderate [scores 12 16], mild [scores 17 21], and no erectile dysfunction [scores 22 25]); 10 and the Male Sexual Health Questionnaire (MSHQ: 11 out of the 25 items, only the seven items for ejaculation were assessed in the present study). Each questionnaire was completed before and after 12 months treatment and scores were compared to determine whether there were any significant changes over time. Treatment effects of mono- and combination therapy on prostate volume were compared in patients, divided into those with a baseline prostate volume 35 ml and those with a baseline volume > 35 ml. The primary endpoint was the change in IPSS or Q max from baseline for monotherapy versus combination therapy in patients with a baseline prostate volume 35 ml or > 35 ml. Adverse events were assessed by the investigator at every 3-month follow-up visit. STATISTICAL ANALYSES Statistical analyses were carried out using SPSS statistical software, version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows. Differences between the two treatment groups were compared using Student s t-test and the incidence of adverse events was analysed using Pearson s χ 2 -test. A P-value < 0.05 was considered to be statistically significant. Results In total, 216 participants met the inclusion criteria and were enrolled. Of these, 23 (10.6%) were unable to complete the study: eight (3.7%) dropped out due to a desire to stop treatment; five (2.3%) were excluded due to modification of the treatment plan to surgical intervention; five (2.3%) dropped out due to adverse events such as impotence and retrograde ejaculation; four (1.9%) dropped out due to orthostatic hypotension; one (0.5%) dropped out due to dyspepsia. A total of 95 patients in Group 1 and 98 patients in Group 2 completed the trial. Baseline parameters are shown in Table 1. There were no significant between-group differences in terms of baseline parameters. After 12 months treatment, patients in Group 1 showed a significant reduction in IPSS and residual urine volume, and a significant increase in Q max (Table 1; P < 0.05, all comparisons). In Group 2, a significant reduction in PSA concentration, prostate volume, TZV, IPSS and residual urine volume, and a significant increase in Q max, were observed (Table 1; P < 0.05, all comparisons). IIEF and MSHQ scores did not change significantly in either group across the study period (Table 1). In total, 52 patients from Group 1 and 51 patients from Group 2 had a baseline prostate volume 35 ml, whereas 43 patients from Group 1 and 47 patients from Group 2 had a baseline prostate volume > 35 ml. At baseline there were no significant differences between Groups 1 and 2, stratified by prostate volume (Tables 2 and 3). 901

4 TABLE 1: Baseline parameters and changes after 12 months treatment with a-blocker monotherapy (Group 1) compared with combination therapy with an a-blocker plus a 5a-reductase inhibitor (Group 2) for the treatment of benign prostatic hyperplasia in Korean patients Group 1 Group 2 n = 95 n = 98 Parameter Baseline 12 months Difference Baseline 12 months Difference Age, years ± ± 7.77 PV, ml ± ± ± ± ± ± 6.14* TZV, ml ± ± ± ± ± ± 2.32* PSA, ng/ml 1.70 ± ± ± ± ± ± 0.68* IPSS ± ± ± 3.93* ± ± ± 2.91* Q max, ml/s ± ± ± 3.45* ± ± ± 2.07* PVR, ml ± ± ± 17.51* ± ± ± 15.52* IIEF score ± ± ± ± ± ± 5.28 MSHQ score ± ± ± ± ± ± 3.75 Data presented as mean ± SD. *P < 0.05, baseline versus after 12 months treatment; Student s t-test. Group 1, monotherapy with 0.2 mg tamsulosin, orally once daily; Group 2, combination therapy with 0.2 mg tamsulosin, orally once daily plus 0.5 mg dutasteride, orally once daily. PV, prostate volume; TZV, transition zone volume; PSA, prostate specific antigen; IPSS, International Prostate Symptom Score; 6 9 Q max, maximal urinary flow rate; PVR, postvoid residual urine volume; IIEF, International Index of Erectile Function; 10 MSHQ, Male Sexual Health Questionnaire

5 TABLE 2: Baseline parameters and changes after 12 months treatment in Korean patients with benign prostatic hyperplasia with a baseline prostate volume 35 ml who were treated with either a-blocker monotherapy (Group 1) or combination therapy with an a-blocker plus a 5a-reductase inhibitor (Group 2) Group 1 Group 2 n = 52 n = 51 Parameter Baseline 12 months Difference Baseline 12 months Difference Age, years ± ± 7.42 PV, ml ± ± ± ± ± ± 0.41* TZV, ml ± ± ± ± ± ± 0.10* PSA, ng/ml 1.23 ± ± ± ± ± ± 0.05* IPSS ± ± ± ± ± ± 0.40 Q max, ml/s ± ± ± ± ± ± 0.22 PVR, ml ± ± ± ± ± ± 2.19 IIEF score ± ± ± ± ± ± 0.81 MSHQ score ± ± ± ± ± ± 0.44 Data presented as mean ± SD. *P < 0.05, difference in Group 1 versus difference in Group 2; Student s t-test. Group 1, monotherapy with 0.2 mg tamsulosin, orally once daily; Group 2, combination therapy with 0.2 mg tamsulosin, orally once daily plus 0.5 mg dutasteride, orally once daily. PV, prostate volume; TZV, transition zone volume; PSA, prostate specific antigen; IPSS, International Prostate Symptom Score; 6 9 Q max, maximal urinary flow rate; PVR, postvoid residual urine volume; IIEF, International Index of Erectile Function; 10 MSHQ, Male Sexual Health Questionnaire

6 TABLE 3: Baseline parameters and changes after 12-months treatment in Korean patients with benign prostatic hyperplasia with a baseline prostate volume > 35 ml who were treated with either a-blocker monotherapy (Group 1) or combination therapy with an a-blocker plus a 5a-reductase inhibitor (Group 2) Group 1 Group 2 n = 43 n = 47 Parameter Baseline 12 months Difference Baseline 12 months Difference Age, years ± ± 7.66 PV, ml ± ± ± ± ± ± 0.76* TZV, ml ± ± ± ± ± ± 0.40* PSA, ng/ml 2.25 ± ± ± ± ± ± 0.12* IPSS ± ± ± ± ± ± 0.43 Q max, ml/s ± ± ± ± ± ± 0.32* PVR, ml ± ± ± ± ± ± 2.26 IIEF score ± ± ± ± ± ± 0.65 MSHQ score ± ± ± ± ± ± 0.63 Data presented as mean ± SD. *P < 0.05, difference in Group 1 versus difference in Group 2; Student s t-test. Group 1, monotherapy with 0.2 mg tamsulosin, orally once daily; Group 2, combination therapy with 0.2 mg tamsulosin, orally once daily plus 0.5 mg dutasteride, orally once daily. PV, prostate volume; TZV, transition zone volume; PSA, prostate specific antigen; IPSS, International Prostate Symptom score; 6 9 Q max, maximal urinary flow rate; PVR, postvoid residual urine volume; IIEF, International Index of Erectile Function; 10 MSHQ, Male Sexual Health Questionnaire

7 After 12 months treatment in patients with a baseline prostate volume 35 ml, prostate volume increased by 2.4% in Group 1 but decreased by 20.6% in Group 2, TZV increased by 2.0% in Group 1 but decreased by 17.0% in Group 2, and PSA concentration decreased by 2.4% in Group 1 and by 38.5% in Group 2 (Table 2). There was a significant between-group difference in the change from baseline at 12 months for all three parameters (Table 2; P < 0.05). After 12 months treatment in patients with a baseline prostate volume > 35 ml, prostate volume increased by 1.6% in Group 1 but decreased by 31.0% in Group 2, TZV increased by 1.4% in Group 1 but decreased by 21.3% in Group 2, PSA concentration decreased by 4.0% and by 42.6% in Groups 1 and 2, respectively, and Q max increased by 22.4% and by 41.5% in Groups 1 and 2, respectively (Table 3). There was a significant between-group difference in the change from baseline at 12 months for all four parameters (Table 3; P < 0.05). There were no significant between-group differences for the remaining variables after 12 months in men with a baseline prostate volume of 35 ml or > 35 ml (Tables 2 and 3). The incidence of adverse events recorded during the study is reported in Table 4; there were no significant between-group differences. Discussion The clinical effects of α-blockers in relieving obstructive symptoms in patients with BPH, by relaxing prostatic smooth muscles, are well defined. 7,12 Tamsulosin, a selective α 1a - adrenergic receptor blocker, is a commonly used treatment for BPH and has proven efficacy and a good safety profile. 8,13 15 The 5-ARIs block the action of the 5α-reductase enzymes that convert testosterone into dihydrotestosterone (DHT, which normally promotes prostate growth) and reduce prostate size to relieve obstructive symptoms. 3 Dutasteride inhibits both isoforms of 5α-reductase (types I and II), and has a 45-fold greater affinity for type I and a 2.5-fold greater affinity for type II than finasteride. As a result of this higher affinity, dutasteride effectively inhibits DHT much more rapidly than finasteride. 16 The management of BPH focuses not only on reduction of LUTS, but also on prevention of BPH progression. Several studies have demonstrated that the use of 5-ARIs reduces adverse events in the progression of BPH. 3,5,7 The PREDICT study and the Veterans Affairs Cooperative Study reported that 12 months TABLE 4: Adverse events recorded during 12 months treatment with a-blocker monotherapy (Group 1) compared with combination therapy with an a-blocker plus a 5a-reductase inhibitor (Group 2) for the treatment of Korean men with benign prostatic hyperplasia Group 1 Group 2 Event n = 95 n = 98 Erectile dysfunction 3 (3.2) 8 (8.2) Decreased libido 4 (4.2) 9 (9.2) Retrograde ejaculation 8 (8.4) 9 (9.2) Dizziness 2 (2.1) 3 (3.1) Data presented as n (%) of patients. There were no statistically significant difference between groups (P 0.05 for all comparisons); Pearson s χ 2 -test. Group 1, monotherapy with 0.2 mg tamsulosin, orally once daily; Group 2, combination therapy with 0.2 mg tamsulosin, orally once daily plus 0.5 mg dutasteride, orally once daily. 905

8 combination therapy with an α-blocker plus a 5-ARI was no more beneficial than α- blocker monotherapy in terms of symptom relief and urine flow rate. 7,17 The 4-year PLESS study, however, 18 reported that finasteride therapy reduced the need for surgical treatment by 50%. Moreover, according to the MTOPS study (which lasted for 4.5 years), the risk of acute urinary retention was lower in groups treated with finasteride or with the combination of an α- blocker and 5-ARI, compared with groups treated with doxazosin. 5 The MTOPS study also reported that α-blocker monotherapy only delayed BPH-associated adverse events (such as acute urinary retention), whereas combination therapy with an α-blocker and a 5-ARI reduced both the risk of adverse events and the need for surgical intervention. 5 Combination therapy with an α-blocker and a 5-ARI is theoretically ideal because α- blockers treat biokinetic factors associated with prostatic smooth muscle and 5-ARIs treat anatomical factors associated with BPH. The optimal combination has, however, yet to be determined. In patients from the Republic of Korea, it has been reported that there are no significant differences between combination therapy and monotherapy in terms of treatment effects for a prostate volume < 40 ml. 19 The MTOPS study reported that combination therapy was effective in patients with a prostate volume 40 ml. 5 Even though the frequency of LUTS in the Korean population is the same as that in Western populations, prostate volume and PSA concentrations are lower in the Korean population. Multicentre research in Korean patients indicates that the 40-ml standard for a large prostate in Western populations can be translated to 35 ml in the local Korean population. 20 Thus, the present study used 35 ml as the standard prostate volume to differentiate large and small prostates when comparing the treatment effects of monotherapy and combination therapy. In patients with a baseline prostate volume 35 ml, prostate volume, TZV and PSA concentrations were significantly reduced after 12 months combination therapy compared with monotherapy. Symptoms were relieved in both groups and changes in the IPSS, Q max, residual urine volume and other variables were not significantly different. In patients with a baseline prostate volume > 35 ml, decreases in prostate volume, TZV and PSA concentrations after combination therapy were greater than those observed in the group with a baseline prostate volume 35 ml. Thus, the reductions in PSA and prostate volume were greater in patients with an initially larger prostate volume. In addition, Q max was significantly increased in the combination therapy group compared with the monotherapy group with a baseline prostate volume > 35 ml. Most of the adverse events reported in the present study were related to sexual function and were more frequently observed in the combination therapy group, although such symptoms were minimal and were not significantly different between the two groups. The frequency of retrograde ejaculation (which is a known side-effect of α 1a -selective blockers) was the same in both groups. Adverse events observed with 5-ARIs (such as erectile dysfunction and decreased libido) were more frequently reported in patients receiving combination therapy, although the difference was not significantly different between the two groups. In addition, there were no significant betweengroup differences in the IIEF and MSHQ scores. It could be inferred that psychological factors play a role in the development of 906

9 side-effects, but that these events are not substantial enough to affect daily life. In conclusion, in the population of Korean men that was studied, α-blocker monotherapy was a suitable treatment for BPH patients with a prostate volume 35 ml. In Korean BPH patients with a prostate volume > 35 ml, α-blocker plus 5-ARI combination therapy was more beneficial than α-blocker monotherapy. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 23 January 2012 Accepted subject to revision 5 February 2012 Revised accepted 13 April 2012 Copyright 2012 Field House Publishing LLP References 1 Welch G, Weinger K, Barry MJ: Quality-of-life impact of lower urinary tract symptom severity: results from the Health Professionals Follow-up Study. Urology 2002; 59: Roehrborn CG, Bruskewitz R, Nickel GC, et al: Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37: McConnell JD, Wilson JD, George FW, et al: Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992; 74: Roehrborn CG, McConnell J, Bonilla J, et al: Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR longterm efficacy and safety study. J Urol 2000; 163: McConnell JD, Roehrborn CG, Bautista OM, et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: Roehrborn CG, Siami P, Barkin J, et al: The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008; 179: Kirby RS, Roehrborn C, Boyle P, et al: Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003; 61: Lapitan MC, Acepcion V, Mangubat J: A comparative study on the safety and efficacy of tamsulosin and alfuzosin in the management of symptomatic benign prostatic hyperplasia: a randomized controlled clinical trial. J Int Med Res 2005; 33: Abrams P, Chapple C, Khoury S, et al: Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009; 181: Rosen RC, Riley A, Wagner G, et al: The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: Rosen RC, Catania J, Pollack L, et al: Male Sexual Health Questionnaire (MSHQ): scale development and psychometric validation. Urology 2004; 64: Lepor H, Williford WO, Barry MJ, et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335: Wilt TJ, MacDonald R, Nelson D: Tamsulosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. J Urol 2002; 167: Lyseng-Williamson KA, Jarvis B, Wagstaff AJ: Tamsulosin: an update of its role in the management of lower urinary tract symptoms. Drugs 2002; 62: Watanabe T, Ozono S, Kageyama S: A randomized crossover study comparing patient preference for tamsulosin and silodosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. J Int Med Res 2011; 39: Bartsch G, Rittmaster RS, Klocker H: Dihydrotestosterone and the concept of 5alphareductase inhibition in human benign prostatic hyperplasia. Eur Urol 2000; 37: Flanigan RC, Reda DJ, Wasson JH, et al: 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs Cooperative Study. J Urol 1998; 160:

10 18 McConnell JD, Bruskewitz R, Walsh P, et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998; 338: Jung SI, Kim SO, Min KD, et al: Efficacy of α- blocker and finasteride combination therapy for benign a prostatic hyperplasia with a prostate volume less than 40 grams. Korean J Urol 2003; 44: [in Korean, English abstract]. 20 Cho JS, Kim CI, Seong DH, et al: Cut-off point of large prostate volume for the patients with benign prostatic hyperplasia. Korean J Urol 2005; 46: [in Korean, English abstract]. Author s address for correspondence Professor Tae Hyoung Kim Department of Urology, Chung-Ang University College of Medicine, Heuksuk-dong, Dongjak-gu, Seoul , Republic of Korea. kthlmk@nate.com 908