- Email: [email protected]
331 SILODOSIN CONSISTENTLY IMPROVES NOCTURIA IN MEN WITH LUTS SUGGESTIVE OF BPH. ANALYSIS OF THREE PHASE III PLACEBO-CONTROLLED STUDIES
HOMA1
1,13±0,55 (0,31-2,39)
HOMA2
1,50±1,62 (0,2-8,7)
IPSS1
11,6±6,4 (3-28)
IPSS2
9,0±8,4 (0-33)
Qmax1 (ml/s)
16,1±9,3 (3-43)
0,916
4,79±3,21 (2,56-17,11)
0,015
3,0±1,84 (0,41-8,41) 0,040
10,4±6,4 (2-24)
0,116
7,5±6,8 (1-24) 0,008
18,0±9,4 (5-44)
0,477
Qmax2 17,8±9,1 (4-45) 18,8±9,3 (7-38) (ml/s) 1Pre-treatment, 2Post-treatment Conclusions: IR exerts a neutralizing effect on efficacy of doxazosin therapy for treatment of LUTS due to BPH. This may be because of the increased sympathetic tonus triggered by hyperinsulinemia which usually accompanies IR.IR should be kept in mind in evaluation of patients with LUTS refractory to alpha-blocker therapy.
329
Symptom, flow rate and quality of life improvements by prostate volume in the Combination of Avodart and Tamsulosin (CombAT) study of men with benign prostatic hyperplasia
Roehrborn C.1, Damião R.2, Morrill B.3, Castro R.4 1 UT Southwest Medical Center, Dept. of Urology, Dallas, United States of America, 2 State University of Rio de Janeiro, Dept. of Urology, Rio de Janeiro, Brazil, 3 GlaxoSmithKline, Statistics and Programming, Research Triangle Park, North Carolina, United States of America, 4GlaxoSmithKline, Oncology Research and Development, Collegeville, United States of America Introduction & Objectives: To assess the impact of baseline prostate volume (PV) on efficacy and safety of dutasteride/tamsulosin combination vs. each monotherapy in men with moderate to severe benign prostatic hyperplasia (BPH). Materials & Methods: In this 4-year, double-blind study, 4844 men age ≥50 years with BPH (International Prostate Symptom Score [IPSS] ≥12, PV ≥30 cc, PSA 1.5-10 ng/mL, Qmax 5-15 mL/s) were randomized to receive dutasteride 0.5 mg/ day, tamsulosin 0.4 mg/day, or the combination. Primary 4-year results have been reported: combination therapy was superior to either monotherapy in providing symptom, Qmax and quality of life (QoL) improvements. In this prespecified analysis, we report changes in IPSS, Qmax, BPH Impact Index (BII) and BPHrelated health status (IPSS question 8) by baseline PV within treatment groups. Pairwise comparisons of combination therapy vs. each monotherapy were based on t-tests from a general linear model. Results: Men were divided by baseline PV into tertiles, with 1609 men in tertile 1 (<42 cc), 1610 men in tertile 2 (42-58 cc) and 1608 men in tertile 3 (>58 cc). Mean baseline IPSS was 16.0-16.9 points across treatment groups and PV tertiles. In each tertile, combination therapy significantly (p≤0.003) improved IPSS, Qmax, BII and BPH-Related Health Status vs. tamsulosin at 4 years (Table). Compared with dutasteride, combination therapy significantly (p≤0.012) improved IPSS and BPH-Related Health Status in PV tertiles 1 and 2 and BII in tertile 1 (Table). The magnitude of benefit seen with combination was sustained across tertiles in all outcomes evaluated, with greater differences vs. tamsulosin and smaller differences vs. dutasteride observed as PV increased. The rate of drug-related adverse events (AEs) was higher with combination therapy across tertiles, however rates of overall AEs (69-75%) and withdrawal due to AEs (11-15%) were similar across treatment groups (Table). Table: Adjusted mean change from baseline after 4 years’ treatment Baseline PV
<42 cc D+T
D
T
D+T
42–58 cc D
T
D+T
>58 cc D
T
IPSS
-6.2
-5.0§
-4.7*
-6.6
-5.4§
-3.9*
-6.6
-6.2
-3.4*
Qmax (mL/s)
2.4
2.1
1.0*
2.1
1.8
0.8*
2.9
2.3
0.6*
BPHrelated health status
-1.5
-1.3†
-1.2*
-1.5
-1.2*
-1.0*
-1.6
-1.4
-1.0*
BII
-2.1
-1.7†
-1.6§
-2.2
-1.9
-1.2*
-2.3
-2.1
-1.0*
Any AE, %
73
74
72
74
69
70
74
75
74
Drugrelated AE, %
27
20†
21‡
31
22*
17*
28
21†
18*
Withdrawal 15 11 14 14 12 13 11 11 14 due to AE, % AE=adverse event: *p<0.001, §p≤0.003, †p≤0.012, ‡p=0.052 vs D+T based on t-tests from a general linear model Conclusions: In men with moderate to severe symptoms, dutasteride/
tamsulosin combination provides significantly superior symptom, QoL and Qmax improvements vs. tamsulosin regardless of baseline PV, and significantly superior symptom and QoL improvements vs. dutasteride in all men except those from the largest PV tertile.
330
Long-term efficacy of Silodosin on the lower urinary tract function in patients with benign prostatic hyperplasia according to prostate size: Prospective investigation using pressureflow study
Matsukawa Y., Hattori R., Yamamoto T., Oyabu M., Mizutani K., Gotoh M. Nagoya University Graduate School of Medicine, Dept. of Urology, Nagoya, Japan Introduction & Objectives: α1-adrenoceptor (AR) antagonists are widely used as the drug of first choice for LUTS with BPH. On the other hand, the efficacy of single use for patients with large prostate is debatable. We prospectively investigated the long-term effects of silodosin, a new α1-AR antagonist purely selective for the α1AAR subtype, on the lower urinary tract function in patients with BPH according to prostate size, using pressure-flow study (PFS). Materials & Methods: Silodosin was administered at 8 mg/day to patients with LUTS associated with BPH. The patients were classified into 2 groups according to prostate size; small prostate (SP) group (prostate volume <35ml) and large prostate (LP) group (>= 35 ml). Changes in parameters from baseline to 4 weeks and 1 year after administration were assessed in IPSS, IPSS-QOL, OABSS, and voiding and storage function as measured by PFS. Results: 102 patients were enrolled to the study. At baseline, no significant differences were detected in IPSS or QOL between LP group (50cases, mean prostate volume: 54.3ml) and SP group (52cases, 30.6ml), but LP group had a significantly higher OABSS. Comparison of the baseline data obtained by PFS revealed no significant differences in bladder capacity at first desire to void (FDV), maximum cystometric capacity (MCC), maximum flow rate (Qmax), or postvoid residual urine volume (PVR), while detrusor pressure at Qmax (pdetQmax) and bladder outlet obstruction index (BOOI) were significantly higher in LP group. The frequency of uninhibited detrusor contraction was also significantly higher in LP group at baseline. At 4 weeks after treatment, both groups showed significant improvement in IPSS-total, QOL, OABSS. For the long-term examination, SP group showed further improvement in both IPSS-total and QOL, while LP group reduced the effectiveness of improvement in both parameters. The improvement in OABSS at 4week was maintained at 1 year in both groups. In PFS, both groups showed a significant increase in FDV and MCC at 4 weeks and further improvement at 1 year. Uninhibited detrusor contraction observed before treatment disappeared in 50.0%, 44.1% in LP group and 45.0%, 50.0% in SP group (4weeks, 1year). PFS during the voiding phase at 4 weeks demonstrated a significant improvement in Qmax, PVR, pdetQmax and BOOI, regardless of prostate size. However, although the improvement in voiding parameters at 4 weeks was maintained to 1 year in SP group, these parameters changed for the worse compared with that of 4weeks in LP group. Conclusions: Silodosin quickly improves bladder storage function and relieves bladder outlet obstruction, regardless of prostate size. However, in long-term administration, an improvement of bladder outlet obstruction may be reversed in patients with large prostate, despite preservation of an improvement in storage function.
331
Silodosin consistently improves nocturia in men with LUTS suggestive of BPH. Analysis of three phase III placebo-controlled studies
Michel M.C.1, Casi M.2, Antonellini A.2 1 University of Amsterdam, Dept. of Pharmacology and Pharmacotherapy, Amsterdam, The Netherlands, 2Recordati S.p.A., Medical Dept., Milan, Italy Introduction & Objectives: Nocturia is a highly bothersome LUTS. In men with LUTS suggestive of BPH, α-blockers are the only drug class which has repeatedly shown some efficacy against nocturia. None of the α-blockers investigated to date has shown consistent nocturia reduction, in most cases with as many positive as negative studies. We have explored the effects of the novel, highly α1A-selective blocker silodosin on nocturia by analysing the results of the placebo-controlled studies conducted for its registration in Europe and the US. Materials & Methods: The analysis was performed on the responses to question 7 of the IPSS questionnaire given by 1,266 patients with ≥ 2 voids per night included in three phase III, randomized, double-blind, controlled studies with silodosin. Results: The baseline characteristics of the patients studied, and specifically the number of episodes of nocturia at baseline, were comparable in the two treatment groups overall and within each clinical study. Silodosin consistently induced a significantly greater reduction of nocturia within each study and within the overall patient cohort (see Table). While the reduction observed with silodosin was numerically small, it is likely to be clinically relevant since overall 35% of patients on silodosin had a reduction of ≥ 1 episode of nocturia from baseline, as compared to 23% in the placebo group (p < 0.0001).
Eur Urol Suppl 2011;10(2):121
Study
EU
US-1
US-2
Overall analysis
*p < 0.05
Parameter
Subgroup of patients with ≥ 2 nocturnal voids at baseline (ITT) Silodosin 8 mg/ day
Placebo
No. of patients
308
148
No. of episodes of nocturia at baseline (mean ± SD)
3.0 ± 0.93
2.9 ± 0.96
Adjusted change from baseline Difference (95%CI)
-0.9 -0.2* (-0.4, -0.1)
-0.7
No. of patients
201
197
No. of episodes of nocturia at baseline (mean ± SD)
3.1 ± 1.01
3.1 ± 1.04
Adjusted change from baseline Difference (95%CI)
-0.7 -0.2* (-0.4, 0.0)
-0.5
No. of patients
205
207
No. of episodes of nocturia at baseline (mean ± SD)
3.1 ± 1.01
3.0 ± 1.02
Adjusted change from baseline Difference (95%CI)
-0.8 -0.2* (-0.4, -0.0)
-0.6
No. of patients
714
552
No. of episodes of nocturia at baseline (mean ± SD)
3.0 ± 0.98
3.0 ± 1.02
Adjusted change from baseline Difference (95%CI)
-0.8 -0.2** (-0.3, -0.1)
-0.6
**p < 0.001
Conclusions: The results of this analysis suggest that the novel α1A-selective blocker silodosin consistently and significantly improves nocturia in men with LUTS suggestive of BPH. One possible explanation for this consistent effect, not previously reported for other α-blockers, relates to the unprecedented degree of α1A-selectivity of silodosin.
332
Comparison of the efficacy of tamsulosin and Naftopidil on the QOL specific to each symptom of the IPSS: A randomized controlled trial in elderly men with OAB
Naf were equally effective in improving voiding symptom. However, Naf is more likely to relieve bother in storage symptoms, especially in nocturia. Using the VAS questionnaire had a significant impact on identifying the chief patient complaint as well as defining the symptom most correlated with patient QOL.
333
Roehrborn C.G.1, Marberger M.2, Gomella L.G.3, Wilson T.4, Castro R.4 1 UT South-western Medical Center, Dept. of Urology, Dallas, United States of America, 2University of Vienna, Dept. of Urology, Vienna, Austria, 3Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, United States of America, 4Research Triangle Park, GlaxoSmithKline, Durham, United States of America Introduction & Objectives: REDUCE is a completed, 4-yr, randomized, placebocontrolled study of prostate cancer (PCa) risk reduction with dutasteride 0.5 mg. This analysis examines the initiation of alpha blocker therapy during the REDUCE study and the influence of alpha blocker use on efficacy parameters. Materials & Methods: Eligible men were aged 50–75 yrs, with serum PSA 2.5–10 ng/mL, prostate volume (PV) ≤80 cc, IPSS <25 (<20 if on an alpha blocker), and a single biopsy (6–12 cores) negative for PCa within 6 months prior to enrollment. Transrectal ultrasound guided biopsies (10 cores) were examined for PCa at 2 and 4 yrs. Efficacy parameters (IPSS, acute urinary retention [AUR], and BPH-related surgery) were assessed over the 4 yrs. Use of alpha blockers prior to and during the study was assessed for all randomized subjects (n=8231). This analysis includes 3 subgroups: subjects who did not use alpha blockers before or during the study (n=5677 [69%]); subjects who used alpha blockers prior to the study with or without continued use (n=1723 [21%]); and subjects who initiated alpha blockers during the study (n=831 [10%]). The proportion of subjects initiating alpha blocker therapy was compared between treatment groups. Outcomes of efficacy parameters were compared between treatment groups within each of the subgroups. Results: Alpha blockers were initiated during the study by 518 (12.6%) placebo subjects and 313 (7.6%) dutasteride subjects (p<0.001); of these, dutasteride subjects experienced a lower incidence of AUR or BPH-related surgery (p<0.001) and greater improvements in IPSS (p<0.001). AUR or BPH-related surgery rates were greater for placebo and dutasteride subjects who initiated alpha blockers during the study than for their counterparts in the other two subgroups. Relative risk reductions (RRR) in PCa and AUR/BPH-related surgery with dutasteride were similar regardless of subgroup. No alpha blocker use
Alpha blocker use prior to study (with or without continued use)
Alpha blockers initiated during study
Placebo n=2725
Dutasteride n=2952
Placebo n=883
Dutasteride n=840
Placebo n=518
Dutasteride n=313
Age, yrs*
62.4
62.4
63.9
64.2
62.5
63.0
IPSS
7.6
8.1
10.5
10.1
10.7
10.3
PSA, ng/ mL*
5.88
5.86
6.02
6.09
5.92
5.89
PV, cc*
43.8
44.8
50.8
48.9
47.3
45.9
Mean change in IPSS at 4 yrs
1.18
-0.42
1.56
-0.64
1.62
-0.01**
AUR or BPHrelated surgery, N (%)
106 (4.0%)
35 (1.2%)
144 (16.4%)
34 (4.1%)
116 (22.5%)
31 (10.0%) **
Fujihara A.1, Ukimura O.2, Iwata T.1, Hirahara N.1, Hayashi I.1, Miki T.1 1 Kyoto Prefectural University of Medicine, Dept. of Urology, Kyoto, Japan, 2 University of Southern California, Dept. of Urology, California, United States of America Introduction & Objectives: Lower urinary tract symptoms (LUTS) compatible with benign prostatic hyperplasia and concomitant overactive bladder (OAB) cause significant bother. α-adrenoceptor antagonists are the safe first-line treatment for men with LUTS, and the severity of LUTS is most commonly quantified using the 7 symptom questions of the International Prostate Symptom Score (IPSS). Although LUTS severity is well documented using IPSS, individual patient bother or satisfaction may not directly correlate with the severity of each IPSS symptom score. In order to compare the clinical efficacy of the 2 α-adrenoceptor antagonists of tamsulosin hydrochloride (Tam) and Naftopidil (Naf) on the bother/satisfaction specific to each symptom of LUTS, we performed a multi-center randomized controlled study with concomitant use of IPSS and visual analog scale (VAS) questionnaires in elderly men with OAB. Materials & Methods: 82 male patients complaining of LUTS with OAB symptom were randomized to receive either Tam or Naf for 12 weeks. Before and after treatment the patients were asked to complete the IPSS questionnaire with IPSSQOL score and VAS questionnaires to assess bother or satisfaction regarding patient QOL specific to each of the 7 items on the IPSS. Logistic regression analysis was used to identify the best predictor of pre- or post-treatment IPSS-QOL score, representing the patient’s pre- or post-treatment bother. Results: There were no significant differences in patient demographics between the Tam (n=43) and Naf (n=39) groups. There were significant improvements in total IPSS as well as voiding symptoms in both groups (P<0.001). However, Naf significantly improved the sum of IPSS storage symptoms (p<0.005) and the sum of VAS storage symptoms (p<0.001), while Tam did not improve the former or the latter. Before treatment, among the 14 items of the 7 IPSS scores and 7 VAS measures, multiple stepwise linear regression analysis identified that the best predictor of pre-treatment patient’s bother was VAS nocturia (F=14.0, p<0.001), followed by VAS incomplete emptying (F=12.0, p=0.001). After treatment, interestingly, multiple regression analysis to identify the VAS measure to impact most on patient’s post-treatment QOL revealed that, by the treatment with Naf, the post-treatment bother in nocturia and incomplete emptying were improved to be insignificant; on the other hand, by the treatment with Tam, the post-treatment bother in nocturia still remained as significant bother (p=0.000). Conclusions: In patients suffering from male LUTS with OAB, both Tam and
Eur Urol Suppl 2011;10(2):122
Alpha blocker initiation in the REDUCE study
*
RRR [95% CI] PCa, n (%) RRR [95% CI]
**
**
70.1% [56.2– 79.6%] 571 (25.9%)
486 (20.9%) **
**
**
77.2% [66.9– 84.3%] 177 (23.8%)
20.6% [11.2– 29.0%] * Values are means **p≤0.001 vs placebo
124 (17.5%) ** 30.2% [13.4– 43.8%]
57.4% [36.6– 71.3%] 110 (23.3%)
49 (18.1%) 23.6% [-4.7– 44.3%]
Conclusions: In a population at increased risk of developing PCa, alpha blocker therapy was initiated less frequently in subjects randomized to dutasteride. Dutasteride subjects benefited from improvements in IPSS and decreased AUR and BPH-related surgery regardless of alpha blocker use.
1,13±0,55 (0,31-2,39)
HOMA2
1,50±1,62 (0,2-8,7)
IPSS1
11,6±6,4 (3-28)
IPSS2
9,0±8,4 (0-33)
Qmax1 (ml/s)
16,1±9,3 (3-43)
0,916
4,79±3,21 (2,56-17,11)
0,015
3,0±1,84 (0,41-8,41) 0,040
10,4±6,4 (2-24)
0,116
7,5±6,8 (1-24) 0,008
18,0±9,4 (5-44)
0,477
Qmax2 17,8±9,1 (4-45) 18,8±9,3 (7-38) (ml/s) 1Pre-treatment, 2Post-treatment Conclusions: IR exerts a neutralizing effect on efficacy of doxazosin therapy for treatment of LUTS due to BPH. This may be because of the increased sympathetic tonus triggered by hyperinsulinemia which usually accompanies IR.IR should be kept in mind in evaluation of patients with LUTS refractory to alpha-blocker therapy.
329
Symptom, flow rate and quality of life improvements by prostate volume in the Combination of Avodart and Tamsulosin (CombAT) study of men with benign prostatic hyperplasia
Roehrborn C.1, Damião R.2, Morrill B.3, Castro R.4 1 UT Southwest Medical Center, Dept. of Urology, Dallas, United States of America, 2 State University of Rio de Janeiro, Dept. of Urology, Rio de Janeiro, Brazil, 3 GlaxoSmithKline, Statistics and Programming, Research Triangle Park, North Carolina, United States of America, 4GlaxoSmithKline, Oncology Research and Development, Collegeville, United States of America Introduction & Objectives: To assess the impact of baseline prostate volume (PV) on efficacy and safety of dutasteride/tamsulosin combination vs. each monotherapy in men with moderate to severe benign prostatic hyperplasia (BPH). Materials & Methods: In this 4-year, double-blind study, 4844 men age ≥50 years with BPH (International Prostate Symptom Score [IPSS] ≥12, PV ≥30 cc, PSA 1.5-10 ng/mL, Qmax 5-15 mL/s) were randomized to receive dutasteride 0.5 mg/ day, tamsulosin 0.4 mg/day, or the combination. Primary 4-year results have been reported: combination therapy was superior to either monotherapy in providing symptom, Qmax and quality of life (QoL) improvements. In this prespecified analysis, we report changes in IPSS, Qmax, BPH Impact Index (BII) and BPHrelated health status (IPSS question 8) by baseline PV within treatment groups. Pairwise comparisons of combination therapy vs. each monotherapy were based on t-tests from a general linear model. Results: Men were divided by baseline PV into tertiles, with 1609 men in tertile 1 (<42 cc), 1610 men in tertile 2 (42-58 cc) and 1608 men in tertile 3 (>58 cc). Mean baseline IPSS was 16.0-16.9 points across treatment groups and PV tertiles. In each tertile, combination therapy significantly (p≤0.003) improved IPSS, Qmax, BII and BPH-Related Health Status vs. tamsulosin at 4 years (Table). Compared with dutasteride, combination therapy significantly (p≤0.012) improved IPSS and BPH-Related Health Status in PV tertiles 1 and 2 and BII in tertile 1 (Table). The magnitude of benefit seen with combination was sustained across tertiles in all outcomes evaluated, with greater differences vs. tamsulosin and smaller differences vs. dutasteride observed as PV increased. The rate of drug-related adverse events (AEs) was higher with combination therapy across tertiles, however rates of overall AEs (69-75%) and withdrawal due to AEs (11-15%) were similar across treatment groups (Table). Table: Adjusted mean change from baseline after 4 years’ treatment Baseline PV
<42 cc D+T
D
T
D+T
42–58 cc D
T
D+T
>58 cc D
T
IPSS
-6.2
-5.0§
-4.7*
-6.6
-5.4§
-3.9*
-6.6
-6.2
-3.4*
Qmax (mL/s)
2.4
2.1
1.0*
2.1
1.8
0.8*
2.9
2.3
0.6*
BPHrelated health status
-1.5
-1.3†
-1.2*
-1.5
-1.2*
-1.0*
-1.6
-1.4
-1.0*
BII
-2.1
-1.7†
-1.6§
-2.2
-1.9
-1.2*
-2.3
-2.1
-1.0*
Any AE, %
73
74
72
74
69
70
74
75
74
Drugrelated AE, %
27
20†
21‡
31
22*
17*
28
21†
18*
Withdrawal 15 11 14 14 12 13 11 11 14 due to AE, % AE=adverse event: *p<0.001, §p≤0.003, †p≤0.012, ‡p=0.052 vs D+T based on t-tests from a general linear model Conclusions: In men with moderate to severe symptoms, dutasteride/
tamsulosin combination provides significantly superior symptom, QoL and Qmax improvements vs. tamsulosin regardless of baseline PV, and significantly superior symptom and QoL improvements vs. dutasteride in all men except those from the largest PV tertile.
330
Long-term efficacy of Silodosin on the lower urinary tract function in patients with benign prostatic hyperplasia according to prostate size: Prospective investigation using pressureflow study
Matsukawa Y., Hattori R., Yamamoto T., Oyabu M., Mizutani K., Gotoh M. Nagoya University Graduate School of Medicine, Dept. of Urology, Nagoya, Japan Introduction & Objectives: α1-adrenoceptor (AR) antagonists are widely used as the drug of first choice for LUTS with BPH. On the other hand, the efficacy of single use for patients with large prostate is debatable. We prospectively investigated the long-term effects of silodosin, a new α1-AR antagonist purely selective for the α1AAR subtype, on the lower urinary tract function in patients with BPH according to prostate size, using pressure-flow study (PFS). Materials & Methods: Silodosin was administered at 8 mg/day to patients with LUTS associated with BPH. The patients were classified into 2 groups according to prostate size; small prostate (SP) group (prostate volume <35ml) and large prostate (LP) group (>= 35 ml). Changes in parameters from baseline to 4 weeks and 1 year after administration were assessed in IPSS, IPSS-QOL, OABSS, and voiding and storage function as measured by PFS. Results: 102 patients were enrolled to the study. At baseline, no significant differences were detected in IPSS or QOL between LP group (50cases, mean prostate volume: 54.3ml) and SP group (52cases, 30.6ml), but LP group had a significantly higher OABSS. Comparison of the baseline data obtained by PFS revealed no significant differences in bladder capacity at first desire to void (FDV), maximum cystometric capacity (MCC), maximum flow rate (Qmax), or postvoid residual urine volume (PVR), while detrusor pressure at Qmax (pdetQmax) and bladder outlet obstruction index (BOOI) were significantly higher in LP group. The frequency of uninhibited detrusor contraction was also significantly higher in LP group at baseline. At 4 weeks after treatment, both groups showed significant improvement in IPSS-total, QOL, OABSS. For the long-term examination, SP group showed further improvement in both IPSS-total and QOL, while LP group reduced the effectiveness of improvement in both parameters. The improvement in OABSS at 4week was maintained at 1 year in both groups. In PFS, both groups showed a significant increase in FDV and MCC at 4 weeks and further improvement at 1 year. Uninhibited detrusor contraction observed before treatment disappeared in 50.0%, 44.1% in LP group and 45.0%, 50.0% in SP group (4weeks, 1year). PFS during the voiding phase at 4 weeks demonstrated a significant improvement in Qmax, PVR, pdetQmax and BOOI, regardless of prostate size. However, although the improvement in voiding parameters at 4 weeks was maintained to 1 year in SP group, these parameters changed for the worse compared with that of 4weeks in LP group. Conclusions: Silodosin quickly improves bladder storage function and relieves bladder outlet obstruction, regardless of prostate size. However, in long-term administration, an improvement of bladder outlet obstruction may be reversed in patients with large prostate, despite preservation of an improvement in storage function.
331
Silodosin consistently improves nocturia in men with LUTS suggestive of BPH. Analysis of three phase III placebo-controlled studies
Michel M.C.1, Casi M.2, Antonellini A.2 1 University of Amsterdam, Dept. of Pharmacology and Pharmacotherapy, Amsterdam, The Netherlands, 2Recordati S.p.A., Medical Dept., Milan, Italy Introduction & Objectives: Nocturia is a highly bothersome LUTS. In men with LUTS suggestive of BPH, α-blockers are the only drug class which has repeatedly shown some efficacy against nocturia. None of the α-blockers investigated to date has shown consistent nocturia reduction, in most cases with as many positive as negative studies. We have explored the effects of the novel, highly α1A-selective blocker silodosin on nocturia by analysing the results of the placebo-controlled studies conducted for its registration in Europe and the US. Materials & Methods: The analysis was performed on the responses to question 7 of the IPSS questionnaire given by 1,266 patients with ≥ 2 voids per night included in three phase III, randomized, double-blind, controlled studies with silodosin. Results: The baseline characteristics of the patients studied, and specifically the number of episodes of nocturia at baseline, were comparable in the two treatment groups overall and within each clinical study. Silodosin consistently induced a significantly greater reduction of nocturia within each study and within the overall patient cohort (see Table). While the reduction observed with silodosin was numerically small, it is likely to be clinically relevant since overall 35% of patients on silodosin had a reduction of ≥ 1 episode of nocturia from baseline, as compared to 23% in the placebo group (p < 0.0001).
Eur Urol Suppl 2011;10(2):121
Study
EU
US-1
US-2
Overall analysis
*p < 0.05
Parameter
Subgroup of patients with ≥ 2 nocturnal voids at baseline (ITT) Silodosin 8 mg/ day
Placebo
No. of patients
308
148
No. of episodes of nocturia at baseline (mean ± SD)
3.0 ± 0.93
2.9 ± 0.96
Adjusted change from baseline Difference (95%CI)
-0.9 -0.2* (-0.4, -0.1)
-0.7
No. of patients
201
197
No. of episodes of nocturia at baseline (mean ± SD)
3.1 ± 1.01
3.1 ± 1.04
Adjusted change from baseline Difference (95%CI)
-0.7 -0.2* (-0.4, 0.0)
-0.5
No. of patients
205
207
No. of episodes of nocturia at baseline (mean ± SD)
3.1 ± 1.01
3.0 ± 1.02
Adjusted change from baseline Difference (95%CI)
-0.8 -0.2* (-0.4, -0.0)
-0.6
No. of patients
714
552
No. of episodes of nocturia at baseline (mean ± SD)
3.0 ± 0.98
3.0 ± 1.02
Adjusted change from baseline Difference (95%CI)
-0.8 -0.2** (-0.3, -0.1)
-0.6
**p < 0.001
Conclusions: The results of this analysis suggest that the novel α1A-selective blocker silodosin consistently and significantly improves nocturia in men with LUTS suggestive of BPH. One possible explanation for this consistent effect, not previously reported for other α-blockers, relates to the unprecedented degree of α1A-selectivity of silodosin.
332
Comparison of the efficacy of tamsulosin and Naftopidil on the QOL specific to each symptom of the IPSS: A randomized controlled trial in elderly men with OAB
Naf were equally effective in improving voiding symptom. However, Naf is more likely to relieve bother in storage symptoms, especially in nocturia. Using the VAS questionnaire had a significant impact on identifying the chief patient complaint as well as defining the symptom most correlated with patient QOL.
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Roehrborn C.G.1, Marberger M.2, Gomella L.G.3, Wilson T.4, Castro R.4 1 UT South-western Medical Center, Dept. of Urology, Dallas, United States of America, 2University of Vienna, Dept. of Urology, Vienna, Austria, 3Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, United States of America, 4Research Triangle Park, GlaxoSmithKline, Durham, United States of America Introduction & Objectives: REDUCE is a completed, 4-yr, randomized, placebocontrolled study of prostate cancer (PCa) risk reduction with dutasteride 0.5 mg. This analysis examines the initiation of alpha blocker therapy during the REDUCE study and the influence of alpha blocker use on efficacy parameters. Materials & Methods: Eligible men were aged 50–75 yrs, with serum PSA 2.5–10 ng/mL, prostate volume (PV) ≤80 cc, IPSS <25 (<20 if on an alpha blocker), and a single biopsy (6–12 cores) negative for PCa within 6 months prior to enrollment. Transrectal ultrasound guided biopsies (10 cores) were examined for PCa at 2 and 4 yrs. Efficacy parameters (IPSS, acute urinary retention [AUR], and BPH-related surgery) were assessed over the 4 yrs. Use of alpha blockers prior to and during the study was assessed for all randomized subjects (n=8231). This analysis includes 3 subgroups: subjects who did not use alpha blockers before or during the study (n=5677 [69%]); subjects who used alpha blockers prior to the study with or without continued use (n=1723 [21%]); and subjects who initiated alpha blockers during the study (n=831 [10%]). The proportion of subjects initiating alpha blocker therapy was compared between treatment groups. Outcomes of efficacy parameters were compared between treatment groups within each of the subgroups. Results: Alpha blockers were initiated during the study by 518 (12.6%) placebo subjects and 313 (7.6%) dutasteride subjects (p<0.001); of these, dutasteride subjects experienced a lower incidence of AUR or BPH-related surgery (p<0.001) and greater improvements in IPSS (p<0.001). AUR or BPH-related surgery rates were greater for placebo and dutasteride subjects who initiated alpha blockers during the study than for their counterparts in the other two subgroups. Relative risk reductions (RRR) in PCa and AUR/BPH-related surgery with dutasteride were similar regardless of subgroup. No alpha blocker use
Alpha blocker use prior to study (with or without continued use)
Alpha blockers initiated during study
Placebo n=2725
Dutasteride n=2952
Placebo n=883
Dutasteride n=840
Placebo n=518
Dutasteride n=313
Age, yrs*
62.4
62.4
63.9
64.2
62.5
63.0
IPSS
7.6
8.1
10.5
10.1
10.7
10.3
PSA, ng/ mL*
5.88
5.86
6.02
6.09
5.92
5.89
PV, cc*
43.8
44.8
50.8
48.9
47.3
45.9
Mean change in IPSS at 4 yrs
1.18
-0.42
1.56
-0.64
1.62
-0.01**
AUR or BPHrelated surgery, N (%)
106 (4.0%)
35 (1.2%)
144 (16.4%)
34 (4.1%)
116 (22.5%)
31 (10.0%) **
Fujihara A.1, Ukimura O.2, Iwata T.1, Hirahara N.1, Hayashi I.1, Miki T.1 1 Kyoto Prefectural University of Medicine, Dept. of Urology, Kyoto, Japan, 2 University of Southern California, Dept. of Urology, California, United States of America Introduction & Objectives: Lower urinary tract symptoms (LUTS) compatible with benign prostatic hyperplasia and concomitant overactive bladder (OAB) cause significant bother. α-adrenoceptor antagonists are the safe first-line treatment for men with LUTS, and the severity of LUTS is most commonly quantified using the 7 symptom questions of the International Prostate Symptom Score (IPSS). Although LUTS severity is well documented using IPSS, individual patient bother or satisfaction may not directly correlate with the severity of each IPSS symptom score. In order to compare the clinical efficacy of the 2 α-adrenoceptor antagonists of tamsulosin hydrochloride (Tam) and Naftopidil (Naf) on the bother/satisfaction specific to each symptom of LUTS, we performed a multi-center randomized controlled study with concomitant use of IPSS and visual analog scale (VAS) questionnaires in elderly men with OAB. Materials & Methods: 82 male patients complaining of LUTS with OAB symptom were randomized to receive either Tam or Naf for 12 weeks. Before and after treatment the patients were asked to complete the IPSS questionnaire with IPSSQOL score and VAS questionnaires to assess bother or satisfaction regarding patient QOL specific to each of the 7 items on the IPSS. Logistic regression analysis was used to identify the best predictor of pre- or post-treatment IPSS-QOL score, representing the patient’s pre- or post-treatment bother. Results: There were no significant differences in patient demographics between the Tam (n=43) and Naf (n=39) groups. There were significant improvements in total IPSS as well as voiding symptoms in both groups (P<0.001). However, Naf significantly improved the sum of IPSS storage symptoms (p<0.005) and the sum of VAS storage symptoms (p<0.001), while Tam did not improve the former or the latter. Before treatment, among the 14 items of the 7 IPSS scores and 7 VAS measures, multiple stepwise linear regression analysis identified that the best predictor of pre-treatment patient’s bother was VAS nocturia (F=14.0, p<0.001), followed by VAS incomplete emptying (F=12.0, p=0.001). After treatment, interestingly, multiple regression analysis to identify the VAS measure to impact most on patient’s post-treatment QOL revealed that, by the treatment with Naf, the post-treatment bother in nocturia and incomplete emptying were improved to be insignificant; on the other hand, by the treatment with Tam, the post-treatment bother in nocturia still remained as significant bother (p=0.000). Conclusions: In patients suffering from male LUTS with OAB, both Tam and
Eur Urol Suppl 2011;10(2):122
Alpha blocker initiation in the REDUCE study
*
RRR [95% CI] PCa, n (%) RRR [95% CI]
**
**
70.1% [56.2– 79.6%] 571 (25.9%)
486 (20.9%) **
**
**
77.2% [66.9– 84.3%] 177 (23.8%)
20.6% [11.2– 29.0%] * Values are means **p≤0.001 vs placebo
124 (17.5%) ** 30.2% [13.4– 43.8%]
57.4% [36.6– 71.3%] 110 (23.3%)
49 (18.1%) 23.6% [-4.7– 44.3%]
Conclusions: In a population at increased risk of developing PCa, alpha blocker therapy was initiated less frequently in subjects randomized to dutasteride. Dutasteride subjects benefited from improvements in IPSS and decreased AUR and BPH-related surgery regardless of alpha blocker use.