ÉZER A. MELO, DEMERVAL MATTOS JR., LUIS A. S. RIOS. Division of Urology, Hospital do Servidor Público Estadual de São Paulo, São Paulo, SP, Brazil

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1 Clinical Urology Brazilian Journal of Urology Official Journal of the Brazilian Society of Urology Vol. 28 (1): 25-32, January - February, 2002 A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY, TO ASSESS THE EFFICACY OF ALFUZOSIN IN THE TREATMENT OF PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA ÉZER A. MELO, DEMERVAL MATTOS JR., LUIS A. S. RIOS Division of Urology, Hospital do Servidor Público Estadual de São Paulo, São Paulo, SP, Brazil ABSTRACT Introduction: The alpha-blockers are currently the drug of choice for the clinical management of patients with benign prostatic hyperplasia (BPH). The authors present the results of a prospective, randomized, double-blind and placebo-controlled study of alfuzosin in the treatment of patients with BPH. Material and Methods: A total of 31 patients were randomized to either the selective alpha blocker alfuzosin, 5 mg twice a day (n = 16), or placebo (n = 15), for 12 weeks. Patients were selected according to the established inclusion and exclusion criteria which overall included patients 50 years old, international prostate symptom score (IPSS) of 12 points, quality of life index (QLI) 3 points and maximum flow rate (Qmax) between 5 and 15 ml/s. Results: There were no differences in the improvement rate of IPSS (37% vs. 29%, p = 0.446) and QLI (15% vs. 21%, p = 0.446) between alfuzosin and placebo. In contrast, although marginally significant, the Qmax showed a marked improvement after alfuzosin compared to placebo (50% vs. 5.5%, p = 0.06). The incidence of side effects was similar between alfuzosin and placebo (43.8% vs. 40%, respectively). Conclusions: The alpha-blocker alfuzosin is not a panacea and, in some patients, the clinical improvements are largely due to the placebo effect which, in this study, produced approximately a 30% improvement in the IPSS (p = 0.001), a 21% improvement in the QLI (p = 0.017), and a Qmáx increase 50% in 26.5% of the patients. However, the alpha-blocker alfuzosin has an important role in the clinical management of BPH, since this drug s mechanism of action of does alleviate the dynamic component of the prostatic obstruction, as shown by the improvement in Qmáx. Key words: prostate; prostatic hyperplasia; alpha-blockers; alfuzosin Braz J Urol, 28: 25-32, 2002 INTRODUCTION Phenoxibenzamine was the first alphablocker used in the clinical treatment of benign prostatic hyperplasia (BPH). However, due to the high incidence of side effects, it has not been accepted in the daily clinical practice (1-5). These events were associated with the simultaneous blockade of the α 1 and α 2 adrenergic receptors. Because of that, selective drugs which act predominantly on the α 1 adrenergic receptors came up. They provide the same clinical improvement, but with fewer side effects (6). Nowadays, the α-blockers are the most used drugs for the clinical treatment of BPH, according to many published studies showing its presumed clinical efficacy (7). The alfuzosin consists in a quinazolin derivate which acts selectively on the contraction mediated by the α 1 adrenergic receptor of the prostate, proximal urethra and bladder neck smooth muscle, and has been used mainly in European countries (8). The new slow release formula reaches maximum plasmatic levels 3 hours after oral absorption, with 49% relative bioavailability and 8-hour half-life (8). The usual 25

2 dose recommended is 5 mg twice a day. This compound has already been tested in many studies, where it demonstrated its clinical and urodynamics improvement potential, and favorable side effects profile (9-11). The authors present a clinical study with the α-blocker alfuzosin (SR - slow release) in the clinical treatment of patients with BPH, in a prospective, randomized, double-blind, and placebo controlled protocol. MATERIAL AND METHODS The clinical trial was elaborated to include only patients with more than 50 years, with BPH based on the clinical history, physical examination, including digital rectal examination, voiding symptoms evaluated by the International Prostate Symptom Score (IPSS) with minimum score of 12 points, Quality of Life Index (QLI) with a minimum punctuation of 3 points, and peak urinary flow rate (Qmax) between 5 and 15 ml/s with minimum voiding volume of 150 ml. Patients with prostate specific antigen (PSA) over 4 ng/ml (AXSYM system Abbot Laboratories) were submitted to a prostate biopsy to exclude prostate cancer. The exclusion criteria were: patients using α-adrenergic blockers and/or anti-androgenic medications (including 5α-reductase inhibitors), α- adrenergic agonists, diuretics, anticholinergics, cholinergics, androgens, LH-RH analogues, macroscopic hematuria, patients with severe renal, hepatic or cardiac failure, neurogenic bladder, inferior urinary tract infection, vesical calculus and acute urinary retention (patients with catheters). Patients with history of dizziness, arterial hypotension or hypersensitivity to α-blockers were also excluded. The protocol of this study has been approved by the ethics and research committee of this institution and all patients signed an informed consent. The active drug was provided by the responsible laboratory, being this the only link established, and not having any communication, support or budget after that. The placebo was produced in the hospital pharmacy as well as the randomization in similar flasks and cover. Patients were directed to return after 4, 8 and 12 weeks of treatment, when they answered the IPSS and the QLI. The Qmax was measured in the initial screening appointment and after the end of the treatment. The cardiovascular effects were evaluated by measuring the arterial blood pressure (BP) and the heart rate (HR), in sitting and supine positions, in the initial appointment and in each following return appointment. The prostate volume was determined by abdominal ultrasonography in the first appointment only. Alfuzosin (5 mg) or placebo were administered at random and following the double-blind protocol. The posology was 1 tablet twice a day. The alfuzosin group (AG) had 16 patients and the placebo group (PG) 15. The main variables analyzed were changes in the IPSS, QLI, Qmax, effects on BP and HR. Reduction 30% and 50% in IPSS and QLI, respec- Table 1 - Demographic data of the alfuzosin and placebo groups. Alfuzosin Group Placebo Group p Value Age 64.7 ± ± Race 14 whites/2 blacks 12 whites/3 blacks Duration of symptoms 43.6 ± 40.9 m 40.5 ± 43.7 m 0.74 Hypertension Diabetes Creatinine 1.22 ± 0.25 mg% 1.15 ± 0.28 mg% PSA 3.76 ± 2.83 ng/ml 1.15 ± 0.28 ng/ml Prostatic size 46.9 ±19.8 g 50.1 ± Postvoid residual 79.8 ± ±

3 Table 2 - Changes in IPSS of the alfuzosin and placebo groups after 3 months of treatment. IPSS Alfuzosin Group Placebo Group Comparison Mean ± SD Mean ± SD between Groups Median Median Minimum / Maximum Minimum / Maximum Baseline 21.4 ± ± 6.3 U = p = / / 35 1 month 15.8 ± ± 6.5 U = p = / 30 7 / 24 2 months 14.9 ± / 22 U = ± 6.6 p = / months 13.9 ± ± 6.6 U = p = / 27 2 / 22 Comparison - baseline vs. χ²r = χ²r = final outcome p = p = IPSS = International Prostate Symptom Score; SD = standard deviation; U = Mann-Whitney test; χ²r = Friedman test tively, were the parameters used to define a clinically significant response. We also analyzed increases in the Qmax 30% and 50%. Statistical Method Qualitative variables association was verified by the chi-square test (χ²) or Fisher exact test, and the comparison between the two groups concerning the quantitative variables was performed with the Student s t test and with the nonparametric Mann-Whitney test (U). The comparison inside groups was made with the repeated measures analysis of variance (F), being the differences found with multiple comparison tests and the comparison between the evaluations was made with the nonparametric Friedman test (χ² r ). The comparison between the initial and final measures inside each group was made with the nonparametric Wilcoxon test (z). Values of p< 0.05 were considered significant. RESULTS There were no significant differences in the demographic data of AG and PG patients shows (Table-1). Only the PSA values of AG were significantly higher than those of PG. Despite this difference, only 3 AG patients and 2 GP were submitted to prostate biopsy due to high PSA, being the result BPH. There was also no difference in prostate volume between groups. The IPSS analysis showed no statistically significant difference between AG and PG in the initial analysis and after each treatment period (Table- 2). By the end of the treatment, we observed statistically significant decrease in the IPSS of both AG (p = 0.011) and PG (p = 0.001). However, comparing the percent change of the IPSS decrease, no significant difference was found between groups (p = 0.446). The QLI evaluation showed no statistically significant difference between AG and PG in the 27

4 beginning as well as at the end of the treatment period (Table-3). Similarly to the change observed in IPSS, we also found a statistically significant decrease in the QLI in both AG (p = 0.047) and PG (p = 0.017) after the 3- month treatment period. However, once again there was no significant difference in the QLI percent change decrease between groups by the end of treatment (p = 0.470). Statistically significant difference was found between the Qmax of AG and PG at the initial evaluation (p = 0.041). GA patients presented Qmax values significantly lower than GP Table-4). However, patients who received alfuzosin presented statistically significant Qmax increase by the end of the study (p = 0.003). In the PG, no Qmax alteration was observed after the treatment (p = 0.932). Besides, the analysis of the Qmax percent change increase showed marginally significant difference (p = 0.060), indicating a tendency to higher Qmax increase in AG patients compared to PG. As for the clinically significant response evaluation, we found no statistically significant difference between AG and PG related to the IPSS decrease 30% and 50% (p = and p = 1.000) and QLI (p = and p = 1.000), respectively (Table-5). The Qmax alterations considering the increase 30% in AG patients were marginally significant (p = 0.083). However, we found no difference between groups regarding the Qmax increase 50% (p = 0.183) (Table-5). The cardiovascular evaluation revealed that neither the α-blocker nor the placebo caused significant changes in sitting and supine heart rate (Table- 6). BP changes were also very similar in both groups, with a tendency to arterial hypotension. This is strengthened by the lack of significant difference in side effects occurrence between groups (Table-7). Seven AG patients (43.8%) and 6 PG patients (40%) presented side effects. Dizziness was the most frequently observed side effect. Most of the adverse reactions were mild, and any patient stopped the medication due to the side effects. DISCUSSION Many published studies have shown better alfuzosin clinical results when compared to placebo. Table 3 - Changes in QLI of the alfuzosin and placebo groups after 3 months of treatment. QLI Alfuzosin Group Placebo Group Comparison Mean ± SD Mean ± SD Between Groups Median Median Minimum / Maximum Minimum / Maximum Baseline 4.44 ± ± 0.93 U = p = / 6 3 / 6 1 month 3.81 ± ± 1.32 U = p = / 6 0 / 5 2 months 3.5 ± ± 1.22 U = p = / 6 0 / 5 3 months 3.63 ± ± 1.19 U = p = / 6 0 / 5 Comparison - baseline vs. χ²r = 6.84 χ²r = final outcome p = p =

5 Table 4 - Changes in Qmax of the alfuzosin and placebo groups after 3 months of treatment. Qmax Alfuzosin Group Placebo Group Comparison Mean ± SD Mean ± SD Between Groups Median Median Minimum / Maximum Minimum / Maximum Baseline 9.8 ± 2 12 ± 2.9 U = p = / 15 5 / 15 Final 14.5 ± ± 4.4 U = p = / 25 7 / 23 % 50.4 ± ± U = p = / / Comparison - baseline vs. Z = 2.98 Z = 0.09 final outcome p = p = Qmax = peak urinary flow rate; SD = standard deviation; U = Mann-Whitney test; Z = Wilcoxon test Hansen et al. (10) treated 205 patients with alfuzosin or placebo during 12 weeks and obtained a statistically significant difference between the AG, with a decrease of 29% in the Madsen-Iversen score, and a decrease of 14% in the PG (p < 0.01). In a multicentric, randomized and placebo-controlled study, Jardin et al. (9) evaluated 518 patients using the Boyarsky score, and observed statistically significant decrease (p = ) after the alfuzosin 7.5 mg or 10 mg use during 6 months compared to placebo, with a clinical improvement rate of 42% and 32%, respectively. More recently, Buzelin et al. (11) reported a statistically significant decrease in the IPSS of 194 patients after a 12-week treatment with 10 mg of alfuzosin when compared to the PG (p = 0.007), with a clinical improvement rate of 31% in the AG and 18% in the PG. Table 5 - Clinically significant response of the alfuzosin and placebo groups after 3 months of treatment. Decrease of the % in IPSS Alfuzosin Group Placebo Group Comparison n % n % between groups 30% 3 months p = % p = 1 Decrease of the % in QLI Alfuzosin Group Placebo Group Comparison n % n % between groups 30% 3 months p = % p = 1 Increase of the % in Qmax Alfuzosin Group Placebo Group Comparison n % n % between groups 30% p = % p =

6 Table 6 - Changes of the cardiovascular parameters of the alfuzosin and placebo groups after 3 months of treatment. Alfuzosin Group p Value Placebo Group p Value Baseline Final Baseline Final SSBP ± ± ± ± SUSBP ± ± ± ± SDBP 86.9 ± ± ± ± SUDBP 86.9 ± ± ± ± SHR 80.2 ± ± ± ± SUHR 75 ± ± ± ± SSBP = sitting systolic blood pressure; SUSBP = supine systolic blood pressure; SDBP = sitting diastolic blood pressure; SUDBP = supine diastolic blood pressure; SHR = sitting heart rate; SUHR = supine heart rate In this study, we observed a statistically significant IPSS decrease both in the AG (p = 0.011) and the PG (p = 0.001) after a 12-week treatment. However, when we compare the mean percentage of IPSS decrease in the AG (37% or a mean reduction of 7.4 points) with the PG (29% or a mean reduction of 6.8 points), there was no significant difference (p = 0.446), indicating that the clinical improvement caused by the alfuzosin was not better than the placebo effect. Also, we did not find a QLI difference after the end of the treatment. While the QLI mean improvement in the AG was of 15% or a mean reduction of 0.8 points, the QLI mean drop in the placebo was of 21% or a mean reduction of 0.9 points, again without significant difference between both groups (p = 0.470). The results of our study should obviously be interpreted cautiously due to the small sample size. However, there are many aspects to be considered. If on one hand there is insufficient number of patients to draw consistent conclusions, on the other we cannot forget that this study was conducted following the strictness of a prospective, randomized, double-blind, placebo-controlled protocol, in an attempt to avoid possible intentional influences. The improvement in IPSS observed in our patients using alfuzosin (37%) is comparable to the studies described above (29 to 42%), and the difference in response between the active drug and the placebo of 8% is also close to the variations of those same studies, which reported a 10% to 15% difference. However, these differences in response intensity between the active drug and the Table 7 - Incidence of side effects throughout the study. Side Effect Alfuzosin Group Placebo Group Total n % n % n % Dizziness Dyspepsia Digestive bleeding Visual opacity Buzz Myocardial infarction Shaking in extremities

7 placebo cannot be interpreted as clinically significant responses to a particular individual, mainly if there is other more efficient treatment options, and even though they reach statistically significant values with bigger samples. Recently, Djavan & Marberger (12) published the result of a meta-analysis study involving more than 6000 patients using different a-blockers, including the alfuzosin, and concluded that the improvement in the symptoms score varies from 30% to 40%, reinforcing the favorable comparison between our data and the literature. Besides that, the result of the PG of our study also showed an improvement (29%) which approximates to the improvement observed after the use of alfuzosin in some of the studies mentioned above. Indeed, placebo effect influence may be translated in an improvement of up to 40% in the symptoms score (13). This way, it seems to be clear that any BPH clinical treatment which results in IPSS improvement around 30% to 40% could be interpreted simply as the placebo effect. Curiously, 30% to 40% corresponds to the exact symptoms score mean improvement induced by the α-blockers. Even though alfuzosin has not caused a better clinical improvement when compared to placebo, there was a statistically significant Qmax increase induced by the α-blocker. While in the placebo group the Qmax did not change (mean increase of 0.3 ml/ s or 5.5%), there was a mean increase of 4.7 ml/s in alfuzosin patients (p = 0.03). This represented a Qmax increase of 50.4% on the baseline parameters, which is really above the increase of 16% to 25% reported in the meta-analysis studies (12). These discrepancies between clinical and urodynamic data have already been shown in the general urologic literature (14), and once again in this study in particular. However, it is important to emphasize that the Qmax increase described in our study may have not been enough to completely unblock most of our patients, which could be another justification for the lack of clinical superiority of alfuzosin when compared to placebo. In order to prove this affirmative, Bosch (15) analyzed many studies focusing on prostate obstruction evaluated by urodynamics, and concluded that despite the fact that some studies have shown decrease in the prostatic obstructive process after the use of a- blockers, the only treatment which effectively unblocks the patient is surgery. Rossi et al. (16) recently reported that a-blockers, including the alfuzosin, improve the symptoms secondary to the prostate obstruction, but are not able to completely alleviate it. Therefore, the treatment with α-blockers can be seen as clinical improvement and Qmax increase, but the effects on the obstructive process are limited, hardly reaching total unblockage of the patients. For many reasons, this was in a way already expected. First, on a physiopathologic point of view, the α-blockers only act on the dynamic component of prostate obstruction. Second, only 50% of the urethral pressure in the BPH are mediated by the α- adrenergic receptors, indicating the existence of other elements involved in the contractile properties of the prostate smooth muscle (17). Finally, the α 1 adrenergic receptors are neither specific nor exclusive to the prostate (18). The absence of significant difference between the alfuzosin and the placebo becomes even clearer when we analyze the clinical response to symptoms. We did not find significant difference between the AG and the PG, considering the improvement 30% and 50% in the IPSS or in the QLI (table 5). The Qmax improvement of 30% was marginally significant in the AG when compared to the PG (p = 0.083); however, when we consider the increase 50%, there was no difference between the groups (p = 0.183). Finally, the alfuzosin demonstrated a tolerability profile extremely acceptable, with side effects incidence similar to the PG patients.the main side effects are related to the cardiovascular system, especially arterial hypotension. We conclude that the α-blocker alfuzosin is not a panacea, and part of its clinical benefit may be due to the placebo effect, which, in this study, reached approximately 30% of IPSS improvement (p = 0.001), 21% of QLI improvement (p = 0.017) and Qmax increase 50% in 26.5% of the patients. However, we recognize that alfuzosin plays an important role in the BPH clinical approach, because it really alleviates the prostate obstruction dynamic component. 31

8 REFERENCES 1. Caine M, Raz S, Ziegler M: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol, 47: , Caine M, Perlberg S, Meretyk S: A placebocontroled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Br J Urol, 50: , Caine M, Pfau A, Perlberg S: The use of alphablockers in benign prostatic obstruction. Br J Urol, 48: , Caine M, Perlberg S, Shapiro A: Phenoxybenzamine for benign prostatic obstruction. Review of 200 cases. Urology, 17: , Abrams PH, Shah PJ, Stone R, Choah RG: Bladder outlet obstruction treated with phenoxybenzamine. Br J Urol, 54: , Lepor H: Alpha blockade for the treatmnet of benign prostatic hyperplasia: Urol Clin North Am, 22: , Gee WF, Holtgrewe HL, Albertsen PC, Litwin MS, Manyak MJ, O Leary MP, Painter MR: Practice trends in the diagnosis and management of benign prostatic hyperplasia in the United States. J Urol, 154: Jardim A: Alfuzosin. In: Kirb R, McConnell JD, Fitzpatrick JM, Roehrborn CG, Boyle (eds.). Textbook of Benign Prostatic Hyperplasia. Oxford, ISIS Medical Media, pp , Jardin A, Bensadoun H, Delauche-Cavallier MC, Attali P: Alfuzosin for treatment of benign prostatic hypertrophy. Lancet, 15, 337: , Hansen BJ, Meyhoff HH, Nordling J, Mensink HJ, Mogensen P, Larsen EH: Placebo effects in the pharmacological treatment of uncomplicated benign prostatic hyperplasia. Scand J Urol Nephrol, 30: , Buzelin JM, Roth S, Geffriaud-Ricouard C, Delauche-Cavallier MC: Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. Eur Urol, 31: , Djavan B, Marberger M: A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol, 36: 1-13, Hansen BJ, Meyhoff HH, Nordling J, Mensink HJ, Mogensen P, Larsen EH: Placebo effects in the pharmacological treatment of uncomplicated benign prostatic hyperplasia. Scand J Urol Nephrol, 30: , Barry MJ, Cockett ATK, Holtgrewe L, McConnell JD, Sihelnik AS, Winfield HN: Relationship of symptoms of prostatism to commonly used physiologic and anatomic measures of the severity of benign prostatic hyperplasia. J Urol, 150: , Bosch JL: Urodynamic effects of various treatment modalities for benign prostatic hyperplasia. J Urol, 158: , Rossi C, Kortmann BBM, Sonke GS, Floratos DL, Kiemeney LALM, Wijkstra H, De la rosette JJMCH: α-blockade improves symptoms suggestive of bladder outlet obstruction but fails to relieve it. J Urol, 165: 38-41, Furuya S, Kumamoto Y, Yokoyama E, Tsukamoto T, Izumi T, Abiko Y: Alpha-Adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol, 128: , Price DT, Lefkowitz RJ, Caron MG: Localization of mrna for three distinct apha 1-adrenergic receptor subtypes in human tissue: implications for human alpha-adrenergic physiology. Mol Pharmacol, 45: , Received: July 26, 2001 Accepted after revision: November 30, 2001 Correspondence address: Dr. Ézer Amoras Melo Av. Ricardo Jafet, 148 São Paulo, SP, , Brazil Fax: + + (55) (11) ezeramelo@uol.com.br 32