Original Article. Introduction. Methods. Abstract

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1 Blackwell Science, LtdOxford, UKIJUInternational Journal of Urology Blackwell Publishing Asia Pty LtdNovember Original ArticleUsefulness of a1-blockers in BPHI Ikemoto et al. International Journal of Urology (2003) 10, Original Article Usefulness of tamsulosin hydrochloride and naftopidil in patients with urinary disturbances caused by benign prostatic hyperplasia: A comparative, randomized, two-drug crossover study ISAO IKEMOTO, HIROSHI KIYOTA, YUKIHIKO OHISHI, KAZUHIRO ABE, HIROKAZU GOTO, KOUICHI KISHIMOTO AND KENTA MIKI Department of Urology, Jikei University School of Medicine, Tokyo, Japan Abstract Key words Background: The aim of the study presented here was to stratify drug therapy for patients with benign prostatic hyperplasia (BPH) displaying various voiding symptoms. Methods: Two different a1-adrenoceptor antagonists; tamsulosin hydrochloride (Tam) and naftopidil (Naf ), were administered to 96 patients with BPH for 8 weeks in a crossover study. Results: With the administration of both drugs, the International Prostate Symptom Score (I-PSS) significantly decreased and the maximum urinary flow significantly increased. Whereas Naf monotherapy decreased the I-PSS for storage symptoms, Tam monotherapy decreased the I-PSS for voiding symptoms. In both the Naf-to-Tam and Tam-to-Naf groups, crossover was effective when the initial drug was judged subjectively and objectively to have been ineffective. Compliance was acceptable with both drugs. Conclusion: Our results show that either Naf or Tam can be used to treat patients on the basis of objective and subjective assessment of voiding symptoms. Our findings should be helpful for patient guidance and treatment of BPH. a1-adrenoceptor antagonist, benign prostatic hyperplasia, International Prostate Symptom Score. Introduction Benign prostatic hypertrophy (BPH) causes lower urinary tract symptoms and reduced urinary flow in 14% of 40- to 49-year-old men and 43% of 60- to 69-yearold men 1 and is, therefore, one of the most common conditions affecting middle-aged and elderly men. Although BPH rarely causes serious complications, it can cause persistent and troublesome voiding symptoms. Therefore, drug therapies that can treat symptoms associated with BPH are in great demand. Numerous drugs have been developed to treat diverse voiding symptoms associated with BPH, and a1-adrenoceptor Correspondence: Isao Ikemoto MD, Department of Urology, Jikei University School of Medicine, , Nishi- Shinbashi, Minatok-ku, Tokyo , Japan. isao@jikei.ac.jp Received 15 January 2003; accepted 16 June antagonists are widely used as drugs of first choice. 2 The present crossover study was conducted to compare and investigate the usefulness of two a1-adrenoceptor antagonists; naftopidil (Naf; Flivas, Asahi Kasei, Tokyo, Japan) and tamsulosin hydrochloride (Tam; Harnal, Yamanouchi Pharmaceutical, Tokyo, Japan), in treating urinary disturbance associated with BPH. Methods The subjects were 96 men with BPH diagnosed at the Tokyo Jikeikai University Hospital, the Tokyo Jikeikai University Aoto Hospital, or the Tokyo Jikeikai University Kashiwa Hospital from March 2000 through to April All subjects had an International Prostate Symptom Score (I-PSS) of 8 points or higher and maximum urinary flow less than 12 ml/s (greater than 150 ml in uroflowmetry). Patients who were receiving

2 588 I Ikemoto et al. drugs to treat BPH took no drugs at least 1 month before the start of the study. The 96 patients were randomly divided with the envelope method into two groups: Naf-to-Tam and Tam-to- Naf. Patients in the Naf-to-Tam group (n = 43) received 50 mg/day of Naf for 8 weeks (25 mg/day for the first 2 weeks) and then 0.2 mg/day of Tam for 8 weeks. Patients in the Tam-to-Naf group (n = 53) received 0.2 mg/day of Tam for 8 weeks and then 50 mg/day of Naf for 8 weeks (25 mg/day for the first 2 weeks; Fig. 1). In the Naf-to-Tam group, 12 patients were withdrawn from the study: nine patients failed to appear for reexamination, one had an adverse reaction to Naf, one had an adverse reaction to Tam, and one underwent elective surgery. Safety was therefore analyzed in 43 patients, and efficacy was analyzed in 31. In the Tam-to-Naf group, 18 patients were withdrawn from the study: 16 patients failed to appear for reexamination, one was transferred to another hospital, and one was found to have prostate cancer. One patient had an adverse reaction to Tam but continued to receive the drug; he then had a similar adverse reaction to Naf. Safety was therefore analyzed in 53 patients, and efficacy was analyzed in 34. Among the 65 patients in whom efficacy was analyzed, I-PSS, quality-of-life (QOL) score, urinary flow, and residual urine (as measured by transabdominal ultrasonography) were determined before the start of treatment, at the time of crossover, and at the end of treatment. No significant differences in variables, such as age, prostate volume (on transrectal ultrasonography), pretreatment total I-PSS, voided volume, maximum urinary flow rate (Q max ), were observed between the two groups, except for residual urine volume (Table 1). Urinary disturbance was also assessed on the basis of Guidelines for Clinical Analysis in Urination Disturbance. 3 The Wilcoxon test was used for statistical analysis of mean values, and Fisher s exact probability test was used for contingency table analysis. The study was reviewed and approved by our institutional ethics board for clinical study (#11 38[2738], 12 January 2000). Naf -to-tam Naftopidil Tamsulosin Results Tam-to-Naf I-PSS QOL Q max RUV Tamsulosin Naftopidil 8 w 8 w Fig. 1 Evaluation points and parameters. I-PSS, International Prostate Symptom Score; Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; Q max, maximum flow rate of urination; QOL, quality of life; RUV, residual urine volume; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. Efficacy analysis Before treatment was started, total I-PSS did not differ significantly between the Naf-to-Tam (17.0 ± 1.1) and Tam-to-Naf groups (17.5 ± 1.2, Fig. 2a). Most patients had moderate urinary disturbance, as defined by the Guidelines for Clinical Analysis in Urination Disturbance. 3 For both the Naf-to-Tam and Tam-to-Naf groups, total I-PSS at crossover was significantly lower than before treatment and remained significantly lower 8 weeks after crossover (Naf-to-Tam: 8.5 ± 1.1; Tam-to- Naf: 9.2 ± 0.9). Similar results were obtained when the Table 1 Characteristics of patients treated with tamsulosin followed by naftopidil and with naftopidil followed by tamsulosin Naf-to-Tam Tam-to-Naf t-test Age (years) 66.6 ± 7.6 (43) 63.8 ± 9.1 (53) NS (P = ) Prostate volume (cm 3 ) 38.9 ± 11.8 (43) 32.7 ± 9.4 (53) NS (P = ) I-PSS 17.4 ± 6.0 (43) 16.8 ± 7.2 (53) NS (P = ) QOL 4.6 ± 0.9 (43) 4.4 ± 0.9 (53) NS (P = ) Voided volume (ml) ± (39) ± (47) NS (P = ) Q max (ml/s) 9.3 ± 4.0 (39) 9.1 ± 6.0 (47) NS (P = ) RUV (ml) 86.8 ± 70.5 (39) 32.8 ± 41.3 (47) P = I-PSS, International Prostate Symptom Score; Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; NS, not significant; QOL, quality of life; RUV, residual urine volume; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. Values show mean ± SD.

3 Usefulness of a1-blockers in BPH 589 Fig. 2 Changes in International Prostate Symptom Score (I-PSS). (a) I-PSS total score. (b) Storage symptom score. (c) Voiding symptom score. Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. ( ) Naf-to-Tam (n = 31); ( ) Tam-to-Naf (n = 34). Mean ± SEM. *P < 0.05; **P < I-PSS was divided into storage symptoms (incomplete emptying, frequency, urgency, and nocturia) and voiding symptoms (straining, weak stream, and intermittency; Figs 2b,c). Eight weeks after the start of treatment the severity of storage and voiding symptoms were significantly less than before treatment and showed further decreases 16 weeks after the start of treatment (Fig. 2b). Table 2 shows the I-PSS for each storage and voiding symptom. Naf was administered first in the Naf-to-Tam group (n = 31) and second in the Tam-to-Naf group (n = 34); these 65 patients comprised group N. Tam was administered first in the Tam-to-Naf group (n = 34) and second in the Naf-to-Tam group (n = 31); these 65 patients comprised group T. The I-PPS for each symptom was lower 8 weeks after treatment was started. Scores for incomplete emptying decreased significantly for both groups N and T, whereas scores for frequency, urgency, and nocturia decreased significantly for the group N, but not for group T (Table 2). With regard to the three voiding symptoms, scores for weak stream decreased significantly for both groups, whereas scores for intermittency and straining decreased significantly for group T, but not for group N (Table 2). The QOL scores in both the Naf-to-Tam group and the Tam-to-Naf group were significantly lower 8 weeks after the start of treatment (Fig. 3). However, little change was seen between 8 and 16 weeks after the start of treatment in either group, confirming that the initial drug was effective in most patients of both groups (Fig. 3). The Q max for both the Naf-to-Tam group and the Tamto-Naf group was approximately 10 ml/s in many patients before the start of treatment but had increased by 8 and 16 weeks after treatment was started (Fig. 4). After 16 weeks of treatment, the Q max had increased significantly to 12 ml/s in both groups. Residual urine volume differed significantly between the groups before the start of treatment, but no drug-induced changes were observed after 8 or 16 weeks of treatment (Fig. 5). To investigate the effects of crossover, the I-PSS was compared before and after crossover in the Naf-to-Tam group (Fig. 6a) and the Tam-to-Naf group (Fig. 6b). In the Naf-to-Tam group, crossover decreased the I-PSS in 10 of the 12 patients for whom symptoms had either remained unchanged or been exacerbated by Naf but increased the I-PSS in 12 of the 14 patients in whom

4 590 I Ikemoto et al. Table 2 Changes in International Prostate Storage Symptom Score (n = 65) Voiding Before Tx After Tx Comparison between pre-tx and post-tx Difference between pre-tx and post-tx Incomplete emptying Group N 1.86 ± ± 0.14 P < ± 0.20 Group T 1.78 ± ± 0.17 P < ± 0.21 Comparison NS NS NS Urgency Group N 1.23 ± ± 0.15 P < ± 0.12 Group T 1.26 ± ± 0.15 NS 0.32 ± 0.19 Comparison NS NS NS Frequency Group N 2.43 ± ± 0.17 P < ± 0.20 Group T 2.15 ± ± 0.20 NS 0.31 ± 0.21 Comparison NS NS P < Nocturia Group N 2.09 ± ± 0.11 P < ± 0.14 Group T 1.98 ± ± 0.14 NS 0.26 ± 0.14 Comparison NS NS NS Intermittency Group N 1.72 ± ± 0.17 NS 0.25 ± 0.23 Group T 2.02 ± ± 0.18 P < ± 0.18 Comparison NS NS P < Weak stream Group N 3.23 ± ± 0.22 P < ± 0.22 Group T 3.29 ± ± 0.22 P < ± 0.25 Comparison NS NS NS Straining Group N 1.52 ± ± 0.19 NS 0.22 ± 0.22 Group T 1.88 ± ± 0.17 P < ± 0.23 Comparison NS NS NS Comparison between the two treatment groups. Group N, 65 patients administered naftopidil first in the Naf-to-Tam group (n = 31); Group T, 65 patients administered first in the Tam-to-Naf group (n = 34) and second in the Naf-to-Tam group (n = 31); Tx, treatment. Values show mean ± SD. Fig. 3 Changes in quality of life (QOL) score in both crossover groups. Significant improvement in QOL was identified in both groups after 4 and 8 weeks of treatment with an a1-adrenoreceptor blocker. Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. ( ) Naf-to-Tam; ( ) Tam-to-Naf. Mean ± SEM. *P < 0.05; **P < symptoms had either improved or improved markedly by Naf assessed on the basis of Guidelines for Clinical Analysis in Urination Disturbance. 3 Similar results were obtained in the Tam-to-Naf group: although crossover decreased I-PSS in all 16 patients in whom symptoms had either shown no change or been exacerbated by Tam, I-PSS increased in 11 of the 13 patients in whom symptoms had been either improved or improved markedly by Tam. Overall efficacy was assessed on the basis of Guidelines for Clinical Analysis in Urination Disturbance. Overall efficacy of the first and second drugs was compared in the Naf-to-Tam and Tam-to-Naf groups (Tables 3, 4). When the first drug had been judged effective, the second drug showed no change in efficacy in 10 of 10 patients (100%). However, when the first drug had no effect on symptoms, the second drug was judged at least slightly effective in 11 of the 23 patients (47.8%). Contingency table analysis revealed significant differences (P < )

5 Usefulness of a1-blockers in BPH Q max Initiation point Crossing point Endpoint Fig. 4 Changes in maximum flow rate (Q max ) in both treatment groups. Significant increases in Q max were identified in both groups after treatment. Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. ( ) Naf-to-Tam; ( ) Tam-to-Naf. Mean ± SEM. *P < 0.05; **P < Residual urine volume (ml) Initiation point Crossing point Endpoint Fig. 5 Changes in residual urine volume in both treatment groups. Naf-to-Tam, group treated initially with naftopidil followed by tamsulosin; Tam-to-Naf, group treated initially with tamsulosin followed by naftopidil. ( ) Nafto-Tam; ( ) Tam-to-Naf. Mean ± SEM. *P < 0.05; **P < International Prostate Symptom Score International Prostate Symptom Score Initiation point Crossing point Endpoint Fig. 6 (a) Changes in International Prostate Symptom Score (I-PSS) in the group treated initially with naftopidil followed by tamsulosin (n = 31). (b) Changes I-PSS in the group treated initially with tamsulosin followed by naftopidil (n = 34). ( ) Patients judged improved or improved markedly with initial treatment (n = 14); ( ) Patients judged not effective or worse with initial treatment (n = 12).

6 592 I Ikemoto et al. Table 3 Correlation of estimation of initial drug with following drug Estimation for initial treatment Estimation for following treatment Very effective Effective Slightly effective No change Total Very effective Effective Slightly effective No change Total Initial treatment tended to display higher estimation, while following treatment tended to display lower estimation. Table 4 Crossover effect of the two drugs on total estimation of urination parameters Tam-to-Naf/Naf-to-Tam Patients estimated greater than one rank for following drug compared to initial estimation Patients estimated no improvement for following drug to initial estimation Patients estimated better than 1 (2.9%) 34 (97.1%) slightly effective after initial treatment (n = 35) Patients estimated no change 11 (47.8%) 12 (52.2%) after initial treatment (n = 23) If initial estimation was greater than slightly effective, the likelihood of following treatment being estimated as not effective was significantly increased (P < , Fisher s exact probability test). in the degree of improvement after crossover ( 1 and <1) when the patients were divided into two groups on the basis of the efficacy of the first drug ( slightly effective vs. no change ). Safety analysis In the Naf-to-Tam group dizziness and postural hypotension each developed in one of the 43 patients during treatment with Naf but resolved when treatment was ended. Dizziness was also reported by one patient while receiving Tam but also resolved when treatment ended. In the Tam-to-Naf group, dull headache developed in one of the 53 patients while receiving Tam, but treatment was continued. Because headache persisted after crossover to Naf, treatment was discontinued, which caused the headache to resolve. In total, three adverse reactions occurred during treatment with Naf (3.12%) and two adverse reactions occurred during treatment with Tam (2.08%); however, each resolved after treatment ended. Hence, safety did not differ between the two groups. Discussion First-generation a1-adrenoceptor antagonists, such as prazosin, terazosin, and urapidil, have been used to treat urinary disturbances associated with BPH. However, second-generation a1-adrenoceptor antagonists, such as Tam and Naf, are now widely used as drugs of first choice. 4 Whereas first-generation a1-adrenoceptor antagonists block a wide variety of a1-adrenoceptor subtypes, Tam and Naf show extremely higher affinity for a1-adrenoceptor subtypes found in the prostate and the bladder neck but lower affinity for a1-adrenoceptors found in peripheral vessels. 4 This selective affinity is one reason why Tam and Naf are highly regarded. Furthermore, Tam and Naf affect BPH differently. Whereas Tam exhibits high affinity for a1-adrenoceptors, Naf has high affinity for a1-adrenoceptors. 5 Both a1a and a1d adrenoceptors are thus believed to be involved in BPH. Naturally, differences in efficacy attributable to pharmacological differences in affinity for adrenoceptor subtypes have been the subject of numerous investigations. 6,7 Because Naf is available only in Japan, studies comparing Naf and Tam have similarly been performed only in Japan and have included those of Ohoka et al. 8 Torimoto et al. 9 Nishino et al. 10 and Hayashi et al. 11 Most of these studies have found that Tam decreases voiding symptoms and that Naf decreases storage symptoms (particularly nocturia). However, only Ohoka et al. 8 and Hayashi et al. 11 have provided such information as inclusion criteria and actual values of clinical variables. Although the study of Ohoka et al. 8 involved only 12

7 Usefulness of a1-blockers in BPH 593 patients, significant improvements in I-PSS, QOL, nocturia, and bladder compliance were observed 6 weeks after switching to Naf after Tam had been ineffective. Hayashi et al. 11 have reported that Tam is more effective for treating urinary urgency and reduced urinary flow and for improving maximum urinary flow and urinary output; in contrast, they have also reported that Naf is more effective for treating nocturia. This improvement in nocturia was maintained after the switch to Tam, and even when one drug had been ineffective, the other drug was effective. However, Hayashi et al. 11 did not provide inclusion criteria and did not randomly assign patients; therefore, bias may have been introduced. Furthermore, the study had no crossover component, because the second drug was used only after the first drug had been judged ineffective (i.e. administration periods varied). Because of the shortcomings of previous studies, we conducted this randomized, prospective, crossover study comparing Naf and Tam to assess their usefulness by administering them for a set period of time to patients with BPH who had various voiding symptoms. As did Hayashi et al. 11 we found significant improvements in nocturia within the first 8 weeks in the Naf-to-Tam group but only after Naf administration in the Tam-to- Naf group. In addition, we confirmed that I-PSS worsened after crossover in patients for whom the first drug had been effective but that I-PSS improved after crossover in patients in whom the first drug had been ineffective. Similar results were obtained when overall efficacy was assessed on the basis of the Guidelines for Clinical Analysis of Urinary Disturbance. In other words, the effects of crossover were verified both subjectively (I-PSS) and objectively (Q max ). Therefore, although our study was not blinded, our results suggest that when a first drug is ineffective, the second drug is likely to prove effective. Conversely, when the first drug is effective, the second drug is likely to prove ineffective. The present study therefore provides important evidence for appropriate use of a1-adrenoceptor antagonists in the treatment of urinary disturbances associated with BPH. Conclusion We conducted a crossover study to compare and investigate the effects of Tam and Naf in patients with BPH who had diverse voiding symptoms. Results were as follows: 1Total I-PSS decreased significantly and Q max increased significantly in both the Naf-to-Tam and Tam-to-Naf groups. 2 The I-PSS for storage symptoms, such as increased urinary frequency, urinary urgency, and nocturia, decreased significantly with Naf monotherapy, whereas the I-PSS for voiding symptoms decreased significantly with Tam monotherapy. 3For both the Naf-to-Tam and Tam-to-Naf groups, crossover was effective, as assessed with both subjective and objective criteria, when the first drug had been ineffective. 4 Compliance was acceptable for both drugs. To our knowledge, our prospective study is the first to clarify that proper use of Naf and Tam is effective. Such results are important for more effective patient guidance and treatment of urinary disturbances associated with BPH. References 1 Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338: Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of a1-adrenoreceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur. Urol. 1991; 36: The Preparing Committee of the Guideline for Clinical Analysis in Urination Disturbance. The Guideline for Clinical Analysis in Urination Disturbance. Igakutosho, Tokyo, Wilt TJ, Howe W, MacDonald R. Terazosin for treating symptomatic benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int. 2002; 89: Takei R, Ikegami I, Shibata K et al. Naftopidil, a novel a1-adrenorecetpor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human a1-adrenoreceptors. Jpn J. Pharmacol. 1999; 79: Hampel CH, Dolber PC, Smith MP et al. Modulation of bladder a1-adrenergic receptor subtype expression by bladder outlet obstruction. J. Urol. 2002; 167: Sugaya K, Nishigima S, Miyazato M et al. Effect of intrathecal injection of tamsulosin and naftopidil, alpha-1a and -1D adrenergic receptor antagonists, on bladder activity in rats. Neuroscience Lett. 2002; 328: Ohoka H, Katada A, Arakawa S, Kamidono S. Clinical efficacy of naftopidil for benign prostatic hyperplasia. Jpn. J. Neurogenic Bladder Society 2001; 12: Torimoto K, Kishino T, Ono T, Ueko M, Momose H. A comparative study for clinical outcome of tamsulosin and naftopidil for benign prostatic hyperplasia. Jpn J. Urol. 2001; 92: 362.

8 594 I Ikemoto et al. 10 Nishino Y, Moriyama Y, Hagiwara N, Miwa Y, Deguchi T. A comparative crossover study for effectiveness of naftopidil and tamsulosin in patients with benign prostatic hyperplasia. Jpn J. Neurogenic Bladder Society 2001; 12: Hayashi T, Sakai Y, Saito K et al. A comparative study assessing clinical effects of naftopidil and tamsulosin hydrochloride on benign prostatic hyperplasia. Acta Urol. Jpn 2002; 48: 7 11.