Original Article Japanese Urological Association. International Journal of Urology (2006) 13,

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1 Blackwell Publishing AsiaMelbourne, AustraliaIJUInternational Journal of Urology Blackwell Publishing Asia Pty Ltd Original ArticleTamsulosin vs doxazosin in BPH D Rahardjo et al. International Journal of Urology (2006) 13, doi: /j x Original Article 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 DJOKO RAHARDJO, 1 DODDY M SOEBADI, 2 SUWANDI SUGANDI, 3 PONCO BIROWO, 1 WAHJOE DJATI 2 AND IRFAN WAHYUDI 3 1 Subdivision of Urology, Department of Surgery University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, 2 Department of Urology Airlangga University, Sutomo Hospital, Surabaya, and 3 Subdivision of Urology, Department of Surgery Padjadjaran University, Hasan Sadikin Hospital, Bandung, Indonesia 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. Key words benign prostatic hyperplasia, doxazosin, lower urinary tract symptoms, tamsulosin. Introduction Lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH) is a very common condition among older men throughout the world with approximately 25% of men over the age of 40 suffering from LUTS. 1,2 Selective alpha-1-adrenoceptors inhibit sympathetic stimulation of prostatic smooth muscle, thereby reducing prostatic tone and relieving urinary obstruction. Clinical studies with alpha-blockers (alfuzosin, doxazosin, prazosin, tamsulosin and terazosin) have demonstrated a significant beneficial effect on symptoms and uroflow. 3 Caine et al. proposed a hypothesis for the use of alphablockers in the treatment of bladder outlet obstruction due to BPH in By antagonizing the effect of noradrenaline at the alpha-1-adrenoceptor, the alpha-blockers Correspondence: Ponco Birowo MD, Subdivision of Urology, Department of Surgery, University of Indonesia, Cipto Mangunkusumo Hospital, Jl. Diponegoro no. 71, Jakarta 10430, Indonesia. ponco.birowo@gmail.com Received 8 December 2005; accepted 18 May reduce smooth muscle cell tone in the bladder neck, prostatic urethra, prostate capsule and prostatic adenoma (stroma) and, consequently, reduce the dynamic component of bladder outlet obstruction. 4 7 Thus, the short-acting alpha-1-blockers and the long-acting alpha-1-blockers (e.g. doxazosin) are effective in treating hypertension and in patients with symptomatic BPH. They improve symptoms and urinary flow rate and a favorable clinical response is achieved in about 70% of patients. 4,5 Although effective in reducing the muscle tone resulting in better urine flow, side-effects such as dizziness and a decrease in blood pressure have been reported. 8 Tamsulosin is known to have numerous advantages and disadvantages over doxazosin. Both tamsulosin and doxazosin offer significant improvement in symptom score and peak urinary flow rate. There is an increased incidence of ejaculatory dysfunction in patients receiving tamsulosin, while doxazosin is associated with a significantly raised incidence of dizziness, hypotension and asthenia. 3 It is important therefore to compare tamsulosin with other alpha blockers to evaluate the advantages and disadvantages of its use.

2 1406 D Rahardjo et al. The objective of the study was to compare the efficacy and safety of tamsulosin hydrochloride and doxazosin in patients with LUTS due to BPH. Methods Patients This 6-week, randomized, open label, multicenter study was authorized by the Institutional Review Board of the University of Indonesia, Airlangga University and Padjadjaran University. The study population was made up from male outpatients with LUTS due to BPH who visited the urology clinics at Cipto Mangunkusumo Hospital, Jakarta, Central Pertamina Hospital, Jakarta, Hasan Sadikin Hospital, Bandung, and Sutomo Hospital, Surabya. All subjects enrolled in the study met the inclusion and exclusion criteria. Subjects were informed of the details of the study by the study investigators, and also of possible adverse effects including ejaculatory dysfunction as well as dizziness, hypotension or asthenia, and all subjects gave their written informed consent to participate in the study. Subjects with moderate to severe symptomatic BPH were selected for enrollment in the study. BPH was diagnosed from patient history, symptoms, digital rectal examination and transrectal ultrasonic imaging. The inclusion criteria were men aged 40 years or over, with International Prostatic Symptom Score (IPSS) total symptom score of 13 or higher, maximum urinary flow rate (Qmax) 4 15 ml/s, voided volume 120 ml or higher, PSA level less than 8 ug/ml, residual urine <100 ml and prostate volume of less than 60 ml. The exclusion criteria were subjects who underwent prostatectomy during the period of 3 months prior to this study, concomitant neurogenic bladder, bladder neck sclerosis, urethral stricture, prostatic cancer, cystolithiasis, severe vesical diverticulum and urinary tract infection. Also excluded were those with severe hepatic or renal dysfunction, severe cardiovascular disorder, orthostatic hypotension, or senile dementia, subjects with a history of drug hypersensitivity or allergy to tamsulosin and doxazosin, and subjects with any other conditions that may result in voiding dysfunction. The number of patients with a clinically significant response to treatment with tamsulosin or doxazosin was determined and defined as improvement of more than 20% over baseline in Qmax or a total IPSS decrease of more than 20%. Possible and probable adverse events considered related to the medication were recorded during the course of treatment period. Intention-to-treat (ITT) analysis was performed. Study design Subjects were randomized into two groups, one receiving tamsulosin 0.2 mg daily orally after breakfast and the other doxazosin 2 mg daily orally before sleep for 6 weeks. Prior to the active treatment, the subjects underwent a 2-week wash-out period if they were given no medication for BPH. If the subjects were still being treated for BPH on the day of their first study visit, the wash out period was a minimum of 4 weeks. In the wash-out period the subjects were given no medication for BPH. Efficacy and safety were monitored every 2 weeks for all evaluated subjects in both groups. The primary parameters for assessment of efficacy were IPSS, Qmax, average urinary flow (Qave) and residual urine. Other baseline parameters included, age, weight, height, prostate specific antigen (PSA), and prostate volume, which was assessed by transrectal ultrasound. The primary parameters for assessment of safety were vital signs (blood pressure and heart rate) and adverse events. At every visit, the patients were asked about and assessed for any adverse events that had possibly occurred. Statistical analysis The baseline characteristics of the patients in both groups and differences in subjective and objective changes between the baseline and treatment periods were analyzed using the Student s t-test. Inter- and intra-group differences were evaluated using analysis of variance (ANOVA). The incidence of adverse events was analyzed by Fischer s exact test. All statistical analysis was performed using SPSS 12.0 (SPSS, Chicago, IL, USA). Statistical differences were considered significant at P < Results One hundred and nine patients were screened, of whom eight patients were excluded due to abnormal PSA (six patients), hematuria (one patient) and bladder stone (one patient). Therefore, 101 patients were enrolled and randomized into two treatment groups (50 patients in the tamsulosin group and 51 patients in the doxazosin group). Patient demographics and baseline characteristics for age, weight, total IPSS, Qmax, Qave, prostate volume, and PSA level are presented in Table 1. There were no significant differences between the two groups in any baseline parameters. Efficacy The efficacy data refer to the ITT population. The total IPSS after 6 weeks of treatment had decreased significantly in both the tamsulosin and doxazosin groups compared to baseline. However, there was a significant difference in the total IPSS decrease after 6 weeks of treatment between the two groups. The Qmax, Qave and residual urine after 6 weeks treatment were significantly improved only in the tamsulosin group (Table 2). Safety There was no significant difference in systolic blood pressure, diastolic blood pressure or heart rate profile after 6 weeks of treatment in the tamsulosin group compared to baseline. However, there was a significant difference in the doxazosin group in both systolic and diastolic blood pressure after treatment compared to baseline. The only adverse event noted in the study was dizziness (Table 3). Tamsulosin was well tolerated, with dizziness observed in three patients (6%) while in the doxazosin group 11 patients (22%) reported dizziness, one of whom discontin-

3 Tamsulosin vs doxazosin in BPH 1407 Table 1 Baseline characteristics of men with benign prostatic hyperplasia according to treatment group Characteristic Tamsulosin (n = 50) Doxazosin (n = 51) Total (n = 101) P-value* Age (years) 63.7 ± ± ± Weight (kg) 63.4 ± ± ± Height (cm) ± ± ± IPSS total score (0 35) 18.6 ± ± ± Maximum urinary flow rate (ml/s) 9.9 ± ± ± Average urinary flow rate (ml/s) 4.5 ± ± ± Prostate volume (ml ) 32.6 ± ± ± Prostate-specific antigen level (ng/ml) 2.3 ± ± ± Data expressed as mean ± SD. *Student s t-test; estimated by transrectal ultrasonography. IPSS, International Prostatic Symptom Score. Table 2 Mean and percentage change from baseline of efficacy parameters Parameter Tamsulosin Doxazosin P-value IPSS (0 35) Baseline 18.6 ± ± weeks 13.3 ± (28.4)** 14.5 ± (22.9)** weeks 11.0 ± (40.1)** 12.9 ± (31.4)** weeks 9.4 ± (49.4)** 11.6 ± (38.2)** Qmax (ml/s) Baseline 9.9 ± ± weeks 12.6 ± (27.2)** 11.3 ± (6) NS Qave (ml/s) Baseline 4.5 ± ± weeks 5.7 ± (22.8)** 5.0 ± (2) NS Residual urine (ml) Baseline ± weeks (18.7)* 44.2 ± (4.5) NS Statistical significance within groups (paired student s t-test): *P < 0.05 vs baseline; **P < 0.01 vs baseline. Statistical significance between groups (ANOVA). IPSS, International Prostatic Symptom Score; NS, not significant; Qave, average urinary flow rate; Qmax, maximum urinary flow rate. ued the study as they could not tolerate the adverse event. The difference in the incidence of adverse events between the two groups was significant (P < 0.05; Table 4). Discussion To our knowledge there is no prior published study that has directly compared the efficacy and safety of tamsulosin 0.2 mg daily and doxazosin 2 mg daily in the treatment of BPH. The results of this study confirmed the efficacy of tamsulosin and doxazosin in patients with BPH. After 6 weeks of treatment, there was a clinically and statistically significant decrease in total IPSS in both groups compared to baseline. In the tamsulosin group, the total IPSS had decreased by 49.4% compared to baseline, while in the doxazosin group the decrease was 38.2%. This finding was clinically and statistically significant as the difference was more than 20% and P < A statistically significant difference therefore exists between the two treatment groups. This result was better than that obtained by Lee, who previously reported a decrease of 34.7% for tamsulosin. 9 However, the results for the doxazosin group were similar to data from a previous study published by Fawzy et al. who reported a decrease of 39% in total IPSS, 10 while another study reported a decrease of 30 45%. 11 A clinically and statistically significant improvement in Qmax and Qave compared to baseline were only observed in the tamsulosin group with improvements of 27.7% and 22.8%, respectively. The improvement in the doxazosin group for Qmax was only 0.7% while for Qave there was a slight decrease ( 0.1%). These results were not as significant as those previously reported, which found an improvement in Qmax of 30 35% for the tamsulosin group 12,13 and 20 36% for doxazosin group. 14,15 These differences are probably due to the duration of the study and the dose of the drugs administered.

4 1408 D Rahardjo et al. Table 3 Mean and percentage change from baseline of safety parameters Parameter Tamsulosin Doxazosin P-value Systolic blood pressure (mmhg) Baseline ± ± weeks ± (0.8) NS ± (1.7) NS weeks 6 weeks ± ± (0.5) NS 0.7 (0.5) NS ± ± (4.6)** 5.6 (4.0)** Diastolic blood pressure (mmhg) Baseline 82.2 ± ± weeks 81.2 ± (1.2) NS 80.7 ± (4.7)* weeks 82.0 ± (0.2) NS 80.3 ± (5.2)* weeks 82.2 ± (0) NS 82.0 ± (3.2) NS Heart rate (b.p.m.) Baseline 78.8 ± ± weeks 78.1 ± (0.9) NS 80.1 ± (2.4) NS weeks 78.6 ± (0.2) NS 79.8 ± (2.0) NS weeks 78.7 ± (0.1) NS 78.4 ± (0.3) NS Statistical significance within groups (paired Student s t-test): *P < 0.05 vs baseline; **P < 0.01 vs baseline. Statistical significance between groups (ANOVA). NS, not significant (P > 0.05). Table 4 Incidence of adverse events Tamsulosin Doxazosin Number of patients Incidence of adverse events 3 (6) 11 (22)* (Dizziness) Discontinuation due to adverse events 0 1 *P < 0.05, significantly different from the values in the tamsulosin group (Fisher s exact test). Data expressed as n (%). The duration of this study was 6 weeks, while previous studies have run for 12 weeks or more, with one study lasting a year. 15 A 6-week treatment phase was employed in this study as we wanted to investigate the rapid response of the drugs and to prevent a high number of dropouts. A 6-week treatment phase was also employed in studies conducted in other Asian countries (Japan and China). They were able to observe the improvement of IPSS and Qmax in a 6-week treatment phase or in an even shorter period (4 weeks) The dosages of tamsulosin and doxazosin administered in our study were 0.2 and 2 mg, respectively. In previous studies, the dose of tamsulosin was 0.4 mg or 0.8 mg, 12,13 and for doxazosin it was 4 mg or 8 mg. 14,15 Our study showed a significant decrease in residual urine in the tamsulosin group but not in the doxazosin group. No significant changes in residual urine volume had previously been reported for either drug. 19 There were no significant differences in blood pressure or heart rate in tamsulosin group compared to baseline. This result was similar to previously published data, which also indicated no significant difference in blood pressure in normotensive, controlled hypertensive and uncontrolled hypertensive patients taking tamsulosin. 20,21 In a previous 4-year study, tamsulosin showed a small influence on the mean diastolic blood pressure both in supine and standing positions compared with baseline, but no influence on systolic blood pressure or heart rate in supine and standing positions compared with baseline. 22 In the doxazosin group, there was a significant difference in both systolic and diastolic blood pressure but not in heart rate compared to baseline. The difference in diastolic blood pressure was present after 4 and 6 weeks with P < 0.001, whereas for systolic blood pressure, the difference was observed at both 2 and 4 weeks with P < This result is similar to that from a previous study that found a significant difference in blood pressure in a hypertensive population, 23,24 but not in a normotensive population. 25 The only adverse event reported in the study was dizziness, although in the informed consent process, the possibility of other adverse events such as hypotension and ejaculatory dysfunction was also explained in detail. Dizziness was observed in three patients (6%) in the tamsulosin group and 11 patients (22%) in the doxazosin group. The adverse event rate in the doxazosin group is significantly higher than in the tamsulosin group (P < 0.05). Previously reported adverse events for tamsulosin include dizziness, nausea, palpitations, headache, lassitude, hypotension, drowsiness, dry mouth, rash, retrograde ejaculation, depression, impotence, malaise, and pruritus. These adverse events were reported in 226 of the patients enrolled in that study. 26 The fact that there were no discontinuations in the tamsulosin group indicates the high safety and tolerability of tamsulosin. This is probably related to the dose of tamsulosin of only 0.2 mg and the duration of the study of only 6 weeks. Previously reported adverse events for doxazosin have included dizziness,

5 Tamsulosin vs doxazosin in BPH 1409 headache, hypotension, peripheral edema, somnolence, fatigue, nausea, palpitations, abdominal pain, abnormal vision, asthenia and chest pain, with the incidence of the adverse events due to doxazosin ranging from 16 to 48%. 10,14,23,24 In conclusion, tamsulosin was shown to be more effective than doxazosin in the treatment of LUTS due to BPH. The tamsulosin group had a significant improvement in Qmax and Qave compared to the doxazosin group. There was an improvement in residual urine in the tamsulosin group compared to baseline, while in the doxazosin group there was no significant difference. In addition, tamsulosin had less of an adverse impact on blood pressure than doxazosin and was well tolerated. Acknowledgment This study was supported by Yamanouchi Pharmaceutical Co., Ltd, Japan. References 1 Chute CG, Panser LA, Girman CJ et al. The prevalence of prostatism: a population-based survey of urinary symptoms. J. 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