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Tamsulosin: Efficacy and Safety in Patients With Neurogenic Lower Urinary Tract Dysfunction Due to Suprasacral Spinal Cord Injury
0022-5347/03/1704-1242/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 170, 1242–1251, October 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000084623.65480.f8
TAMSULOSIN: EFFICACY AND SAFETY IN PATIENTS WITH NEUROGENIC LOWER URINARY TRACT DYSFUNCTION DUE TO SUPRASACRAL SPINAL CORD INJURY ´ SKI, PAUL ABRAMS,*,† GERARD AMARENCO, AUGUST BAKKE, ANDRZEJ BUCZYN DAVID CASTRO-DIAZ, SIMON HARRISON, GUUS KRAMER,‡ ROBERT MARSˇIK,§ ¨ HRER,§ PHILIP VAN KERREBROECK§ ANDRZEJ PRAJSNER,‡ MANFRED STO AND JEAN JACQUES WYNDAELE㛳 (THE EUROPEAN TAMSULOSIN NEUROGENIC LOWER URINARY TRACT DYSFUNCTION STUDY GROUP)
ABSTRACT
Purpose: We evaluated the efficacy and safety of tamsulosin in patients with neurogenic lower urinary tract dysfunction secondary to suprasacral spinal cord lesions in a 4-week randomized controlled trial (RCT) followed by a 1-year, open label, long-term study. Materials and Methods: A total of 263 patients were randomized to 4-week double-blind therapy with placebo, or 0.4 or 0.8 mg tamsulosin once daily. Of these, 244 patients completed the RCT, 186 continued long-term tamsulosin therapy (0.4 or 0.8 mg once daily) and 134 completed 1-year treatment. The primary efficacy parameter was maximum urethral pressure (MUP). Results: Although the mean decrease in MUP at 4 weeks in the RCT did not reach statistical significance over the placebo, it was more pronounced with 0.4 (⫺12.2 cm H2O or ⫺10%) and 0.8 mg (⫺9.6 cm H2O or ⫺9%) tamsulosin than placebo (⫺6.5 cm H2O or ⫺3%). In the long-term study there was a statistically significant mean decrease in MUP (⫺18.0 cm H2O, p ⬍0.001 or ⫺15%) from baseline to end point. In the long-term study tamsulosin also decreased maximum urethral closure pressure, improved several cystometry parameters related to bladder storage and emptying, and increased to a statistically significantly degree, from baseline to end point, mean voided volume based on the micturition diary. There was statistically significant improvement for the International Prostate Symptom Score Quality of Life, as well as several questions about symptoms related to urinary leakage, and 1 question on bladder emptying and frequency, bother and severity of symptoms of autonomic dysreflexia. Finally, 71% of patients improved according to investigators (44% slightly and 27% much improved). Both doses were effective and well tolerated. Conclusions: Long-term tamsulosin treatment (0.4 and 0.8 mg once daily) seems to be effective and well tolerated in patients with neurogenic lower urinary tract dysfunction. The results suggest that it improves bladder storage and emptying, and decreases symptoms of autonomic dysreflexia. KEY WORDS: receptors, adrenergic, alpha-1; bladder, neurogenic; reflex, abnormal; spinal cord injuries, autonomic dysreflexia
Spinal cord injury (SCI) is one of the causes of neurogenic lower urinary tract dysfunction (NLUTD). Patients with NLUTD due to sacral or suprasacral SCI often suffer from impaired bladder emptying with residual urine increasing the possibility of urinary tract infections and stones. Patients with suprasacral lesions can also suffer from involuntary detrusor contractions (IDCs)/neurogenic detrusor overactivity during the filling phase, inducing symptoms of frequency, urgency and urinary leakage. Increased filling and voiding pressure with or without vesicoureteral reflux may endanger the upper urinary tract, particularly the kidneys.1 Patients with a lesion above the level of sympathetic outflow, the 6th
thoracic (T6) level, may also experience bothersome symptoms of autonomic dysreflexia.2 The principal goals in the management of NLUTD are to preserve renal function and to maintain patient quality of life (QoL) by decreasing urological complications.3 Patients with NLUTD can be divided into 3 categories, those who cannot empty successfully, those who cannot store urine adequately, or a combination of these characteristics.4 Current treatment options are limited. For facilitating storage options include surgical procedures such as electrical stimulation or interruption of innervation (which are invasive and not always long lasting), other intravesical therapies such as resiniferatoxin, capsaicin and botulinum toxin type A (requiring catheterization and endoscopy), and antimuscarinic drug treatment (which has substantial side effects due to nonselectivity and the theoretical risk of acute urinary retention in patients with obstruction). Treatment options for facilitating voiding, include catheterization (which might cause bacteriuria with subsequent urinary tract infections) or surgical procedures such as sphincterotomy, urethral stents and neurostimulation (which are invasive). Studies with ␣-adrenoceptor (␣-AR)
Accepted for publication April 4, 2003. Supported by Yamanouchi Europe BV. * Corresponding author: Bristol Urological Institute, Southmead Hospital, Department of Urology, Westbury-on-Trym, Bristol BS10 5 NB, United Kingdom (telephone: 44-117-959-5145; FAX: 44-117-9502229; e-mail: [email protected]). † Financial interest and/or other relationship with Ethicon, Ferring, Glaxo, Genyx, Pfizer, Pharmacia, Synthelabo and Yamanouchi. ‡ Financial interest and/or other relationship with Yamanouchi and Pfizer. § Financial interest and/or other relationship with Yamanouchi. 㛳 Financial interest and/or other relationship with Pfizer. 1242
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
FIG. 1. Design of RCT and 1-year open label study, and number of patients (all randomized/enrolled). PLA, placebo. TAM, tamsulosin. w, week.
antagonists in NLUTD show a small but useful effect in facilitating bladder storage and emptying, and decreasing the symptoms of autonomic dysreflexia.1, 5–9 However, these trials were generally small, often uncontrolled, nonrandomized and of short duration. Therefore, the current trials evaluated the efficacy and safety of tamsulosin, a ␣1A/␣1D-AR antagonist, in patients with NLUTD secondary to suprasacral SCI in a 4-week, double-blind, randomized, placebo controlled trial followed by a long-term, 1-year, open label study. MATERIALS AND METHODS
Study inclusion/exclusion criteria. Patients (18 years old or older) with NLUTD secondary to suprasacral SCI were enrolled in the double-blind randomized controlled trial (RCT). They were out of spinal shock and in an established, stable phase. The patients had neurogenic detrusor overactivity (phasic wave 15 cm H2O or greater) or a voiding contraction (spontaneous or provoked through tapping). Patients could have other neurogenic voiding dysfunctions such as detrusor-sphincter dyssynergia. Maximum urethral pressure (MUP) during urethral pressure profilometry (UPP) had to be 60 cm H2O or greater. One or more urodynamic findings had also to be fulfilled during filling cystometry: detrusor pressure of 80 cm H2O or greater, bladder compliance of 15 ml/cm H2O or less (at filling rates of 20 ml per minute), or during voiding cystometry: maximum detrusor pressure during voiding 60 cm H2O or greater, residual volume greater than
30% of the maximum cystometric capacity or greater than 100 ml. The use of clean intermittent (self)catheterization was also allowed. Concomitant drugs which might influence the pharmacodynamic properties of tamsulosin (such as ␣-AR antagonists, ␣/-AR antagonists, ␣-AR agonists and cholinergic drugs) were not allowed for at least 1 month before, and until the end of the study. Medical treatment for NLUTD (anticholinergics in particular) was only allowed if the dose regimen remained stable from 1 month before the study until the end of study. Antihypertensive treatment should remain unchanged throughout the study. Patients who completed all visits of the RCT and wished to continue were able to participate in the 1-year, followup, open label study. All patients gave informed consent for both studies. Study design (fig. 1). In the short-term RCT patients were assessed at enrollment and within 2 weeks (the time required to complete a micturition diary and check all study inclusion and exclusion criteria). Subsequently eligible patients were randomized to 0.4 or 0.8 mg tamsulosin modified release capsules (after 2 weeks on 0.4 mg) or placebo once daily after breakfast. The randomized patients were assessed after 2 and 4 weeks of treatment. In the 1-year, open label, followup study, all patients started on 0.4 mg tamsulosin. In cases of insufficient response the dose could be increased to 0.8 mg at any subsequent visit, which was scheduled every 13 weeks, provided no adverse event (AE) possibly or probably related
TABLE 1. Baseline characteristics in medical history related to spinal cord lesion in RCT (all randomized patients) and 1-year open label study (safety population) Characteristics No. pts Mean lesion duration (mos) % Lesion location: Cervical Thoracic Lumbar % Lesion type: Complete Incomplete % Symptoms: Paraparesis Paraplegia Tetraparesis Tetraplegia % Intermittent catheterization % Intermittent self-catheterization
4-Wk RCT
1-Yr All Tamsulosin
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
92 97.9
88 103.9
83 85.0
178 88.5
31.5 52.2 15.2
30.7 54.5 13.6
42.2 47.0 10.8
30.9 53.9 14.6
51.1 48.9
64.8 34.1
59.0 41.0
54.5 45.5
21.7 45.7 9.8 21.7 48.9 30.8
20.5 51.1 8.0 19.3 40.9 35.2
10.8 45.8 16.9 26.5 44.6 34.9
19.7 51.1 11.2 17.4 42.7 35.4
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
TABLE 2. Primary efficacy results for MUP (UPP) and secondary efficacy results for UPP and cystometry parameters for patient groups in RCT and 1-year open label study RCT Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
1-Yr All Tamsulosin
Mean UPP MUP (cm H2O): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) % Change at end point p Value vs placebo MUCP (cm H2O): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Bladder vol 1st phasic detrusor contraction (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Bladder vol max cystometric capacity (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Voiding time (secs): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Voided (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo
83 88.3 (32.3) ⫺6.5 (2.8)* ⫺3
83 93.1 (35.1) ⫺12.2 (3.2)† ⫺10 0.184
76 87.3 (28.4) ⫺9.6 (2.9)‡ ⫺9 0.443
147 89.3 (31.5) ⫺18.0 (2.8)† ⫺15 Not applicable
83 79.9 (32.6) ⫺7.6 (2.7)‡
83 76 83.2 (33.6) 78.4 (28.0) ⫺11.8 (3.0)† ⫺8.9 (2.6)‡ 0.297 0.726 Mean cystometry (20 ml/min)
147 79.6 (30.8) ⫺15.7 (2.8)† Not applicable
77 203.3 (114.1) 6.7 (10.3)§
75 213.2 (111.2) 4.8 (11.4)§ 0.906
70 194.6 (106.4) 26.4 (13.7)§ 0.247
141 206.6 (112.8) 18.7 (9.3)* Not applicable
77 260.3 (135.4) 5.3 (11.2)§
75 254.6 (121.3) 7.3 (12.6)§ 0.905
70 256.8 (124.1) 17.3 (16.0)§ 0.533
140 255.3 (121.3) 29.9 (10.1)‡ Not applicable
53 85.6 (82.3) 5.9 (10.5)§
61 104.6 (114.8) ⫺17.6 (10.2)§ 0.112
47 87.7 (99.9) 16.5 (16.1)§ 0.575
94 94.5 (111.4) 33.0 (12.1)‡ Not applicable
72 64 117.0 (98.2) 111.1 (105.2) ⫺7.6 (11.1)§ 3.3 (13.2)§ 0.269 0.726 Cystometry (100 ml/min)
122 117.9 (99.6) 46.8 (9.9)† Not applicable
70 100.3 (95.3) 9.1 (10.0)§
Residual urine vol (ml): No. pts with baseline ⫹ end point data 46 41 41 78 Baseline (SD) 178.4 (147.1) 159.1 (136.8) 171.0 (155.7) 158.7 (145.2) Change at end point (SE) ⫺23.7 (13.7)§ ⫺5.6 (19.5)§ ⫺7.3 (19.7)§ ⫺30.1 (12.6)* p Value vs placebo 0.443 0.491 Not applicable Only variables with a statistically significant change from baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included. * p ⬍0.05. † p ⬍0.001. ‡ p ⬍0.01. § Not statistically significant vs baseline.
to tamsulosin occurred. The group of all tamsulosin patients contained all patients who received tamsulosin (0.4 and/or 0.8 mg once daily) during the long-term study. Assessments. The major primary and secondary efficacy and safety parameters are presented in Appendix 1. The trial methodology was designed according to recommendations from the International Continence Society Standardization Committee10 and Steering Committee (Appendix 2). Furthermore, an expert urodynamicist performed a central review of urodynamic traces to achieve standardization of interpretation of the assessments. UPP was performed according to 1 of these methods with the patient in supine position: the Brown-Wickham technique with an 8 or 10CH water filled catheter, a perfusion rate of 3 ml per minute and a pulling speed of 1 mm per second, or a catheter mounted transducer with an 8 or 10CH microtip catheter, a pulling speed of 1 mm per second and 3 or 9 o’clock catheter orientation. We performed 3 assessments and the trace with the lowest MUP measurement (after central review) was used for analysis. Statistical methods and sample size. Efficacy analyses were performed on an intent to treat population. For the RCT sample size calculation was based on the results of a placebo controlled study with intravenous (iv) alfuzosin5 with an assumption of the primary efficacy end point variable MUP. For a difference in mean treatment effect between placebo and tamsulosin of 15 to 20 cm H2O, a standard deviation of 30 to 35 cm H2O, ␣ ⫽ 0.05 (2-sided) and a power of 80%, 240 evaluable patients were required. For the open label exten-
sion study we planned to have a minimum of 100 patients complete the 1-year visit. All statistical tests were performed at ␣ ⫽ 0.05, 2-sided. For the primary efficacy analysis in the RCT changes from baseline to end point were primarily subjected to an analysis of variance, and the global hypothesis (null hypothesis indicating no difference in mean change from baseline to end point visit among the different groups) was tested using the F test. The elementary hypotheses of 2 by 2 comparisons were tested using the t test. In the longterm study all data collected and changes from baseline were summarized for all patients on tamsulosin. The significance of the changes was tested in an explorative way using the paired t tests or the nonparametric Wilcoxon matched pairs signed rank test, as appropriate. In addition, the secondary efficacy variables were analyzed by descriptive statistics. At the request of the Steering Committee several post hoc analyses were performed to identify subgroups of patients who may benefit most from treatment (such as more symptomatic patients or patients needing certain types of bladder management) and responders. In addition, several questions from the urinary symptoms questionnaire (USQ) were clustered according to predefined subcategories and post hoc analyses were performed for these clusters. The questions relating to autonomic dysreflexia (AD) were analyzed in a subgroup of patients most likely to suffer from these symptoms (with lesion at T6 or higher). This report only presents clinically relevant results as judged by the Steering Committee. Extreme caution should be exercised in drawing conclu-
TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
sions given the large number of statistical tests performed. No correction for multiple testing was applied. Special caution is required in interpreting the results of the open label, uncontrolled, 1-year followup study. RESULTS
Baseline characteristics. In the RCT 263 patients were randomized and of these 244 (93%) completed the 4-week double-blind treatment. Subsequently, 186 (76%) continued in the open label, 1-year study, of whom 134 (72%) completed the 1-year treatment (fig. 1). Mean age for the group on placebo, and on 0.4 and 0.8 mg tamsulosin was 39, 35 and 36 years, respectively (range 17 to 73), and 29 (11%) of all randomized patients were female. There were no major differences between treatment groups in both studies for baseline characteristics in medical history related to SCI (table 1). In the open label, 1-year study more than half of the patients (54.5%) had a complete lesion, thoracic lesion (53.9%), paraplegia symptoms (51.1%) or were on intermittent catheterization (42.7%). Urodynamic and urinary symptom characteristics of the population are shown in tables 2 to 5 (baseline values). Discontinuations. A total of 19 patients (of 263) prematurely discontinued the RCT and 52 (of 186) discontinued during open label followup. In the open label study the 2 main reasons for discontinuation were AEs in 17 and insufficient therapeutic response in 16 with no increased incidence on tamsulosin compared to placebo during doubleblind treatment. Other reasons for discontinuation were no return for followup in 9, other in 8 and protocol violation in 2. The dose was increased to 0.8 mg in 69 patients (37.1%) at some stage during the long-term study. Primary efficacy results. In the RCT mean change in MUP with tamsulosin did not reach statistical significance compared to placebo at 4 weeks. However, the change was greater with 0.4 and 0.8 mg tamsulosin than with placebo. At the end point in the long-term study mean change in MUP was more pronounced in the all tamsulosin patient group than at 4 weeks (fig. 2, table 2). The group of patients originally treated with placebo during the RCT (64 patients) showed a further decrease in MUP of 15.6 cm H2O when switched to tamsulosin treatment in the followup study (fig. 3). In the RCT about 36% of patients in both tamsulosin
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groups had a decrease in MUP of 20 cm H2O or greater compared to 29% in the placebo group. In the long-term study at end point 50% of evaluable patients experienced this decrease. Secondary efficacy results. Other UPP Parameters: Mean change from baseline to end point in maximum urethral closure pressure (MUCP) followed the same pattern as MUP (table 2). No statistically significant difference in improvement with tamsulosin compared to placebo was seen during the RCT for cystometry parameters. However, during the 1-year open label study, several parameters related to bladder storage (increased bladder volume at first phasic detrusor contraction and at maximum cystometric capacity) and bladder emptying (voiding time, voided volume and residual urine) were statistically significantly improved from baseline to end point in the group of all tamsulosin patients (table 2). Patient Micturition Diary: In the RCT at end point 0.4 mg tamsulosin produced statistically significant improvements versus baseline for incontinence episode frequency and frequency of pads changed, as well as 0.8 mg tamsulosin for mean voided volume per micturition and urgency episode frequency. The difference versus placebo was statistically significant for frequency of pads changed with 0.4 mg (p ⫽ 0.009) and for mean voided volume with the 0.8 mg (p ⫽ 0.003) dose. In the 1-year, open label study, mean voided volume per micturition remained statistically significantly improved from baseline to end point in the group of all tamsulosin patients (table 3). USQ (Appendix 3): In the RCT with 0.8 mg tamsulosin several parameters relating to urinary leakage were statistically significantly improved from baseline to end point (severity of urinary leakage, bother due to leakage before reaching the toilet and wearing pads at night) or approached significance (changing underwear because of leakage, (table 4). This significance was sustained in the group of all tamsulosin patients in the long-term study for severity of leakage and changing underwear due to leakage. In addition, frequency of leakage, wearing pads during daytime, and leakage and associated bother during sexual intercourse were statistically improved from baseline to end point in the group of all tamsulosin patients in the long-term study. This significance was also the case for 1 question related to bladder emptying (table 4). Because 84% to 88% of patients in studies
TABLE 3. Secondary efficacy results from micturition diary RCT Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
1-Yr All Tamsulosin
Mean voided vol/micturition (ml): No. pts with baseline ⫹ end point data 53 50 43 101 Baseline (SD) 174.9 (92.1) 206.8 (122.7) 173.9 (138.3) 188.1 (112.8) Change at end point (SE) ⫺6.2 (11.9)* ⫺8.0 (9.3)* 28.2 (8.8)† 17.7 (8.4)† p Value vs placebo 0.744 0.003 Not applicable Mean frequency of incontinence episodes/24 hrs: No. pts with baseline ⫹ end point data 60 62 55 111 Baseline (SD) 1.0 (1.4) 1.0 (1.6) 1.0 (1.7) 0.9 (1.6) Change at end point (SE) ⫺0.2 (0.1)* ⫺0.3 (0.1)‡ ⫺0.0 (0.1)* ⫺0.1 (0.1)* p Value vs placebo 0.412 0.915 Not applicable Mean frequency of pads changed/24 hrs: No. pts with baseline ⫹ end point data 61 63 55 113 Baseline (SD) 2.0 (2.2) 3.2 (2.8) 2.4 (2.1) 2.5 (2.6) Change at end point (SE) 0.1 (0.1)* ⫺0.3 (0.2)§ 0.2 (0.1)* ⫺0.1 (0.2)* p Value vs placebo 0.009 0.823 Not applicable Mean frequency of urgency episodes/24 hrs: No. pts with baseline ⫹ end point data 65 69 62 131 Baseline (SD) 2.0 (3.0) 1.5 (2.6) 1.5 (2.5) 1.7 (2.8) Change at end point (SE) ⫺0.1 (0.2)* ⫺0.2 (0.1)* ⫺0.3 (0.2)† ⫺0.1 (0.1)* p Value vs placebo 0.688 0.230 Not applicable Only variables with statistically significant change from baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included. * Not statistically significant vs baseline. † p ⬍0.001. ‡ p ⬍0.01. § p ⬍0.05.
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 4. Secondary efficacy results from urinary symptoms questionnaire related to bladder emptying and urinary leakage Mean RCT Placebo
Score on incomplete bladder emptying (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency urinary leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on severity urinary leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency underwear change due to leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency pad usage during day (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on leakage during sexual intercourse (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on bother due to leakage during sexual intercourse (range 0–3): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on frequency of urinary leakage (total range 0–28): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on severity of urinary leakage (total range 0–20): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Total subscale score on frequency ⫹ severity urinary leakage (total range 0–48): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Only variables with a statistically significant change from * p ⬍0.01. † Not statistically significant vs baseline. ‡ p ⬍0.05.
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
Mean 1-Yr All Tamsulosin
81 1.3 (1.3) ⫺0.3 (0.1)*
82 1.0 (1.3) 0 (0.1)†
76 1.0 (1.2) ⫺0.1 (0.1)†
145 1.2 (1.4) ⫺0.2 (0.1)‡
81 2.4 (1.5) ⫺0.2 (0.1)†
82 2.6 (1.6) ⫺0.2 (0.1)†
76 2.4 (1.5) 0 (0.1)†
145 2.3 (1.5) ⫺0.2 (0.1)‡
82 2.4 (1.6) ⫺0.1 (0.1)†
82 2.4 (1.6) ⫺0.1 (0.1)†
75 2.6 (1.5) ⫺0.2 (0.1)‡
144 2.3 (1.6) ⫺0.3 (0.1)*
82 1.2 (1.3) ⫺0.1 (0.1)†
81 0.9 (1.0) ⫺0.1 (0.1)†
74 1.4 (1.3) ⫺0.2 (0.1)†
143 1.2 (1.2) ⫺0.2 (0.1)‡
82 1.1 (1.6) ⫺0.1 (0.1)†
81 0.9 (1.6) 0.1 (0.1)†
76 1.3 (1.7) ⫺0.1 (0.1)†
145 1.1 (1.6) ⫺0.2 (0.1)‡
37 0.6 (0.8) ⫺0.2 (0.1)†
37 0.5 (0.9) ⫺0.1 (0.0)†
23 0.6 (0.8) ⫺0.1 (0.1)†
57 0.6 (0.8) ⫺0.2 (0.1)‡
32 0.7 (1.0) ⫺0.1 (0.1)†
33 0.5 (1.0) 0.0 (0.1)†
18 0.9 (1.2) ⫺0.2 (0.2)†
47 0.7 (1.1) ⫺0.3 (0.1)‡
82 10.3 (5.5) ⫺0.4 (0.5)†
82 11.4 (5.9) ⫺0.2 (0.4)†
76 10.5 (5.7) 0.1 (0.3)†
146 10.5 (5.7) ⫺0.6 (0.4)†
82 6.3 (4.8) ⫺0.4 (0.3)†
82 5.7 (4.4) ⫺0.1 (0.3)†
76 7.1 (4.8) ⫺0.7 (0.3)‡
145 6.2 (4.6) ⫺0.7 (0.2)*
82 82 76 146 16.6 (9.2) 17.1 (9.1) 17.6 (8.9) 16.7 (9.0) ⫺0.8 (0.7)† ⫺0.3 (0.5)† ⫺0.6 (0.5)† ⫺1.4 (0.6)‡ baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included.
suffered from incontinence and leakage, the results of the subscale on incontinence/leakage are presented in table 4. For the severity subscale a statistically significantly improvement from baseline to end point in the 0.8 mg tamsulosin group was observed in the RCT study. This improvement was sustained in the long-term study. For the frequency subscale a further improvement was observed in the long-term study compared to the RCT study. For the total (frequency and severity) subscale further improvement was observed in the long-term study compared to the RCT study, and this improvement became statistically significant from baseline to end point in the long-term study. In the RCT mean scores of frequency, severity and bother of autonomic dysreflexia were statistically significantly improved from baseline to end point in the 0.8 mg tamsulosin group, and for severity and bother on placebo (table 5). However, the magnitude of the effect was greater with 0.8 mg tamsulosin. The effect was sustained during long-term treatment. The results for the AD subscale were comparable to those for individual AD questions. An additional analysis in the subgroup of patients with a lesion at T6 or higher showed that the mean score of individual AD questions was statistically significantly improved from baseline to end point with 0.8 mg tamsulosin but not with placebo. The percentage of
patients in the RCT that had AD symptoms at baseline but became symptom-free at end point was greater with 0.8 mg tamsulosin (11 of 26 patients, 42%) than with placebo (6 of 19 patients, 32%). In the long-term study, 44% (16 out of 36) of such patients became symptom-free at end point. QoL Question: In the RCT no significant improvements from baseline to end point were observed in any treatment group for mean International Prostate Symptom Score Quality of Life. In the open label study the improvement at end point was statistically significant versus baseline in the all tamsulosin patients group. Investigator’s Global Assessment: In the RCT the percentage of patients who were slightly or much improved according to the investigator was 42% on placebo, and 51% and 58% on 0.4 mg and 0.8 mg tamsulosin, respectively. This assessment included 7.2%, 7.2% and 13.2% much improved patients on placebo, 0.4 and 0.8 mg tamsulosin, respectively. In the 1-year followup study 71% of patients were improved (44% slightly and 27% much improved) in the all tamsulosin patients group. Safety results. Tamsulosin was well tolerated in 0.4 and 0.8 mg doses and the risk of patients experiencing AEs related to the pharmacological mode of action of tamsulosin was low (table 6). No new or unexpected adverse events related to
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 5. Secondary efficacy results from the urinary symptoms questionnaire related to autonomic dysreflexia Mean RCT
Score on AD frequency (range 0–5): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on AD bother (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on AD severity (range 0–5): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on AD (range 0–14): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) * Not statistically significant vs baseline. † p ⬍0.01. ‡ p ⬍0.05.
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
Mean 1-Yr All Tamsulosin
79 0.6 (1.3) ⫺0.2 (0.1)*
80 0.9 (1.7) ⫺0.2 (0.1)*
71 0.8 (1.5) ⫺0.4 (0.1)†
141 0.6 (1.3) ⫺0.2 (0.1)‡
79 0.7 (1.4) ⫺0.2 (0.1)‡
80 0.7 (1.3) ⫺0.1 (0.1)*
71 0.8 (1.3) ⫺0.4 (0.1)†
141 0.7 (1.3) ⫺0.3 (0.1)†
79 0.7 (1.4) ⫺0.2 (0.1)‡
80 0.7 (1.4) ⫺0.1 (0.1)*
70 0.9 (1.4) ⫺0.5 (0.1)†
140 0.7 (1.4) ⫺0.2 (0.1)‡
79 2.0 (3.8) ⫺0.6 (0.3)‡
80 2.3 (4.0) ⫺0.4 (0.2)*
71 2.5 (3.9) ⫺1.3 (0.4)†
141 2.1 (3.7) ⫺0.7 (0.3)‡
tamsulosin were noted. Tamsulosin did not affect blood pressure or pulse rate, and there were no clinically significant changes over time in electrocardiogram or laboratory evaluations. DISCUSSION
Placebo controlled randomized studies with ␣1-AR antagonists had rarely been published when the current tamsulosin studies were designed. Most studies were small, open label and of short treatment duration without uniform methodology regarding urodynamic assessments,1, 6 – 8, 11–13 with the exception of a placebo controlled study by Perrigot et al5 with iv alfuzosin. Although the patient population in the Perrigot et al study was heterogeneous the effect on MUP was used (as primary efficacy parameter) for calculating the sample size of the tamsulosin RCT study since placebo controlled clinical data were not available. The minimum difference in MUP decrease to be detected in the tamsulosin RCT study was set at 15 to 20 cm H2O. However, the MUP was measured approximately 24 hours after oral tamsulosin dosing, whereas in the alfuzosin study MUP was measured 15 to 30 minutes after iv alfuzosin injection. In addition, mean alfuzosin plasma levels observed after iv administration were 4 times higher than peak plasma levels observed after oral administration of 2.5 mg alfuzosin 3 times daily.14 This difference may explain why none of the treatment groups in the RCT was able to achieve a mean decrease of 15 to 20 cm H2O or greater. However, the observed mean decrease from baseline to end point was statistically significant in all treatment groups with the mean decrease being largest in the tamsulosin groups. The percentage of patients achieving a decrease in MUP of 20 cm H2O or greater from baseline to end point was 29% on placebo and 36% on both tamsulosin doses in the RCT, and increased to 50% at end point in the long-term study. Furthermore, although for most secondary parameters the difference between tamsulosin and placebo did not reach statistical significance in the RCT, the results for some objective parameters, and the investigator global assessment and symptoms of autonomic dysreflexia (with [slightly] greater effects with 0.8 mg tamsulosin than 0.4) show a beneficial effect of tamsulosin compared to placebo. The fact that the frequency of incontinence episodes or pads changed was significantly decreased versus baseline and placebo (pads changed) with the 0.4 but not with the 0.8 mg dose may be because these were not primary parameters, the number of patients in each treatment group was small and there was perhaps some variation in bladder management among the groups. Finally, no inclusion criteria were set for the micturition diary (and the USQ). This lack of in-
formation may have led to inclusion of asymptomatic patients, high inter-patient variability and inconsistent results. The treatment duration of 4 weeks may have been too short to demonstrate a statistically significant difference for tamsulosin compared to placebo in patients with NLUTD. This treatment duration was based on results with tamsulosin in patients with symptomatic benign prostatic hyperplasia. However, the voiding pattern of patients with NLUTD may need more time to adjust since these patients are attached to normal habits and routine. It may take some time before they are convinced of a treatment effect and change their habits. In particular the treatment duration with 0.8 mg tamsulosin (2 weeks only) may have been too short to reveal additional effects compared to 0.4 mg tamsulosin. Furthermore, tamsulosin may have been under-dosed in this specific population. This observation may imply that 0.4 mg tamsulosin could be a good starting dose for patients with NLUTD but that increasing the dose to 0.8 mg may provide additional benefit. During the long-term study there was a tendency for several parameters to improve with time, eg mean decrease in MUP (18 cm H2O vs 12.6 cm H2O at 4 weeks) and the investigator global assessment (slightly or much improved in 71% vs 51% to 58% at 4 weeks). However, the results on investigator global assessment should be interpreted with some caution due to possible observer bias. The observed long-term improvements in several secondary efficacy parameters (such as MUCP, bladder volume at first phasic contraction and at maximum cystometric capacity, voided volume, voiding time, residual volume, mean voided volume per micturition, and several USQ items related to urinary leakage), especially with 0.8 mg tamsulosin, confirm the clinical improvements in bladder storage and emptying, and suggest positive effects of tamsulosin on the bladder and urethra. Although our study was hampered by the fact that no validated questionnaire existed for this patient population, the improvement in incontinence symptoms is potentially of clinical importance because these symptoms have a negative impact on patient QoL. The clinical benefits of long-term tamsulosin treatment are confirmed by the International Prostate Symptom Score Quality of Life and investigator global assessment. The positive effect on the urethra is probably related to ␣1A-AR blockade in the bladder neck and urethra (and prostate in males). The human detrusor predominantly expresses ␣1D (66%) and ␣1A-ARs (34%) subtypes and, in female rats, obstruction induces a shift in detrusor subtype expression (␣1A-AR mRNA was decreased from 70% to 5% and ␣1D-AR
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
FIG. 2. Mean change in MUP from baseline to end point in RCT and 1-year open label study (intent to treat population). PLA, placebo. TAM, tamsulosin.
FIG. 3. Mean change in MUP with time in 1-year open label study (intention to treat population). Single asterisk, p ⬍0.05. Double asterisk, p ⬍0.001 vs baseline. PLA, placebo. TAM, tamsulosin.
mRNA was increased from 16% to 91%).15 Assuming similar mechanisms would show in humans, this decrease may have contributed to observed changes in micturition behavior (increased frequency and decreased volume/micturition). In patients with obstruction, parasympathetic denervation or detrusor overactivity there may be a shift from a -adrenergic mediated relaxation to an ␣-adrenergic mediated contraction of the bladder during the storage phase or, in patients with a neurogenic overactive detrusor, an increase in ␣1-AR density.1, 9, 16 –18 These changes may be responsible for IDCs and related frequency, nocturia, urgency and urinary leakage in patients with NLUTD. Therefore, the positive effect of tamsulosin may be attributed to blockade of (upregulated) ␣1DARs in the detrusor, thereby decreasing detrusor overactivity and improving urine storage in the bladder. Alternatively, tamsulosin may block ␣1D-ARs in the spinal cord or prejunctional ␣1-ARs at peripheral ganglia and/or on cholinergic terminals in the bladder, thereby decreasing acetylcholine release and subsequent IDCs.15 In the RCT improvements were observed in the frequency, severity and bother of AD symptoms, especially in the subgroup of patients with lesions at T6 or higher. The main AD symptoms
are hypertension, headache, flushing, sweating and bradycardia, which can be bothersome. Moreover, paroxysmal hypertension is a serious symptom since it may lead to cerebral and retinal hemorrhages, seizures, coma and potentially death.2, 19 Although in the acute setting tamsulosin should not be considered appropriate treatment for an episode of AD, the observed improvements indicate a positive effect of tamsulosin in the prophylaxis of AD symptoms. Regarding subgroups of patients with certain types of bladder management, the available data do not provide a clear indication for tamsulosin being more beneficial in specific types of bladder management. However, it should be noted that the subgroups were too small to draw strong conclusions. CONCLUSIONS
Patients with NLUTD due to suprasacral SCI are difficult to treat due to a complex underlying etiology and medical history. Placebo controlled trials may need to last for at least 6 to 12 months to demonstrate superiority of active treatment over placebo. Since long-term therapy with 0.4 and 0.8 mg tamsulosin is safe and well tolerated,
1249
TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 6. Adverse events in RCT and 1-year long-term study (safety population) No. 4-Wk RCT (%)
Total Any adverse events Drug related adverse events* Discontinued due to any adverse events Most commonly reported drug related adverse events:* Dizziness Abnormal ejaculation Asthenia * Adverse events reported as possibly or probably drug related tamsulosin group in the long-term study.
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
No. 1-Yr (%) All Pts On Tamsulosin
90 38 (42.2) 13 (14.4) 4 (4.4)
86 31 (36.0) 14 (16.3) 2 (2.3)
81 26 (32.1) 12 (14.8) 2 (2.5)
178 129 (72.5) 48 (27.0) 17 (9.6)
5 (5.6) 1 (1.2) 6 (7.4) 12 (6.7) 0 (0) 3 (3.5) 2 (2.5) 8 (4.5) 1 (1.1) 2 (2.3) 1 (1.2) 7 (3.9) by at least 3% of patients in any of the tamsulosin groups in the 4-week RCT or in the all
even modest beneficial effects may justify long-term use. The 1-year open study suggests that tamsulosin, as a subtype selective ␣1A/␣1D-AR antagonist, affects the bladder and urethra, and improves bladder storage and emptying
in patients with NLUTD. Moreover, it may decrease symptoms of autonomic dysreflexia. Ismar Healthcare NV assisted in the editing of the manuscript.
APPENDIX 1: EFFICACY AND SAFETY ASSESSMENTS FOR RCT AND THE 1-YEAR OPEN LABEL STUDY
Primary efficacy parameter Y maximum urethral pressure Secondary efficacy parameters Urethral pressure profilometry Y maximum urethral closure pressure Y functional urethral profile length Cystometry (filling speed 20 ml per minute Y detrusor pressure (at first phasic contraction, at strong desire to and optional 100 ml per minute) void and at maximum cystometric capacity) Y maximum detrusor pressure (during filling and voiding) Y bladder volume (at first phasic contraction, at strong desire to void, at maximum cystometric capacity and at 25 cm H2O detrusor pressure) Y bladder compliance Y residual urine volume Y voiding time Y voided volume Patient urinary diary (completed in the week Y frequency of daytime and nighttime voiding prior to each visit) Y frequency of urgency and incontinence episodes Y frequency of pads changed Y frequency of intermittent catheterization Y mean voided volume/micturition Y mean catheterized volume/micturition Urinary Symptom Questionnaire (completed Y study-specific, adaptation of Bristol female lower urinary tract at each visit) symptoms questionnaire: 69 questions on frequency, severity and bother of urinary symptoms QoL (completed at each visit) Y International Prostate Symptom Score Global efficacy (completed at end visit in RCT Y investigator’s global assessment (worsened, unchanged, slightly and in followup study) improved, much improved) Safety parameters Adverse events (completed at each visit) Y number, severity, drug relationship, outcome, etc Vital signs (supine position) (measured at Y blood pressure each visit) Y pulse rate Laboratory (performed at screening and after Y hematology 2 and 4 weeks in RCT, and after 26 and Y biochemistry (including prolactin) 52 weeks in 1-year followup study) Y urinalysis Electrocardiogram (performed at screening Y 12-lead and end-visit of RCT, and after 26 and 52 weeks in 1-year followup study)
Urethral pressure profilometry
UPP and cystometry assessments could be obtained up to 12 months before enrollment or were otherwise performed at screening, and repeated at baseline and after 4 weeks of double-blind treatment. In the 1-year open label study they were performed at 26 and 52 weeks of tamsulosin treatment.
APPENDIX 2: THE NLUTD STUDY GROUP CONTRIBUTORS
Investigators Belgium Czech Republic Denmark Finland
J. H. Delannoy, K. Everaert, J. J. Wyndaele R. Fiala, R. Marsik, J. Zenisek P. Bagi P. Hellstro¨ m, S. Mustonen, M. Talja, T. Tammela
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
France
G. Amarenco, M. Barat, B. Brugerolle, A. Cormerais, P. Costa, A. Leriche, J. F. Mathe´ , J. M. Soler T. Boon, K. Delaere, E. Meuleman A. Bakke, H. Hedlund A. Buczynski, A. Prajsner A. Borau, D. Castro-Dı´az, J. Conejero B. Bergman I. Conn, S. Harrison, J. Shah
Netherlands Norway Poland Spain Sweden United Kingdom Steering Committee Provided input on the development of the study protocol, symptoms questionnaire (adapted from the Bristol female lower urinary tract symptoms questionnaire), urodynamic review procedures and discussion of the obtained study results, and reviewed the study reports. Belgium J. J. Wyndaele France G. Amarenco Germany G. Kramer, M. Sto¨ hrer Netherlands P. Van Kerrebroeck Norway A. Bakke Poland A. Buczynski Spain D. Castro-Dı´az UK P. Abrams (chairman), S. Harrison Guarantors Participated in the writing and reviewing of this manuscript. Consisted of Steering Committee members with A. Prajsner and R. Marsik as best enrolling investigators. Data management and statistical analyses R. Sieders (Data Manager) and J. N. Visser (Biostatistician) of Yamanouchi Europe BV, The Netherlands. Central review of urodynamic traces was performed by G. Kramer of the Unfallklinik Murnau, Germany and coordinated by M. Callaert of Yamanouchi Pharma BV, Belgium. Overall management I. C. M. Van der Putten-Slob (Clinical Research Manager, Chairman of the Study Team) of Yamanouchi Europe BV, The Netherlands APPENDIX 3: FREQUENCY AND SEVERITY SUBSCALES
Subscale on frequency of urinary leakage consisted of the following questions: - How often does your bladder empty without your having control over it? (never, occasionally, sometimes, most of the time, all of the time) - Does urine leak before you can get to the toilet? (from ‘never’ to ‘all of the time’) - How often do you leak urine? (never, ⱕ1 ⫻/week, 2–3⫻/week, 1⫻/day, several times per day) - Does urine leak when you are physically active, transfer, exert yourself, cough or sneeze? (from ‘never’ to ‘all of the time’) - Do you ever leak urine without feeling that you want to go? (from ‘never’ to ‘all of the time’) - Do you leak urine when you are asleep? (from ‘never’ to ‘all of the time’) - Do you leak urine when you have sexual intercourse? (not at all, slightly, moderately, quite a bit, extremely) Subscale on severity of urinary leakage consisted of the following questions: - How much urinary leakage occurs? (no leakage, slight leakage, drops/pants damp, dribble/pants wet, floods) - How often do you have to change your underwear because of leakage? (never, 1⫻/week, several times/week, about 1⫻/day, ⬎1⫻/day) - How often do you have to change your outer clothing because of urine leakage? (never, 1⫻/week, several times/ week, about 1⫻/day, ⬎1⫻/day) - Do you wear pads during the day? (from ‘never’ to ‘all of the time’) - Do you wear pads during the night? (from ‘never’ to ‘all of the time’) REFERENCES
1. Sullivan, J. and Abrams, P.: Alpha-adrenoceptor antagonists in neurogenic lower urinary tract dysfunction. Urology, 53: 21, 1999 2. Selzman, A. A. and Hampel, N.: Urologic complications of spinal cord injury. Urol Clin North Am, 20: 453, 1993 3. Kakizaki, H. and Koyanagi, T.: Current view and status of the treatment of lower urinary tract symptoms and neurogenic lower urinary tract dysfunction. BJU Int, 85: 25, 2000 4. Elliott, D. S. and Boone, T. B.: Recent advances in the management of the neurogenic bladder. Urology, 56: 76, 2000 5. Perrigot, M., Delauche-Cavallier, M. C., Amarenco, G., Geffriaud, C., Stalla-Bourdillon, A. and Costa, P.: Effect of intravenous alfuzosin on urethral pressure in patients with neurogenic bladder dysfunction. DORALI Study Group. Neurourol Urodyn, 15: 119, 1996 6. Krane, R. J. and Olsson, C. A.: Phenoxybenzamine in neurogenic bladder dysfunction. II. Clinical considerations. J Urol, 110: 653, 1973 7. Yasuda, K., Yamanishi, T., Kawabe, K., Ohshima, H. and
8.
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12. 13.
Morita, T.: The effect of urapidil on neurogenic bladder: a placebo controlled double-blind study. J Urol, 156: 1125, 1996 Swierzewski, S. J., III, Gormely, E. A., Belville, W. D., Sweetser, P. M., Wan, J. and McGuire, E. J.: The effect of terazosin on bladder function in the spinal cord injured patient. J Urol, 151: 951, 1994 Sundin, T., Dahlstrom, A., Norlen, L. and Svedmyr, N.: The sympathetic innervation and adrenoreceptor function of the human lower urinary tract in the normal state and after parasympathetic denervation. Invest Urol, 14: 322, 1977 Stohrer, M., Goepel, M., Kondo, A., Kramer, G., Madersbacher, H., Miljard, R. et al: The standardization of terminology in neurogenic lower urinary tract dysfunction: with suggestions for diagnostic procedures. Neurourol Urodyn, 18: 139, 1999 Hachen, H. J.: Clinical and urodynamic assessment of alphaadrenolytic therapy in patients with neurogenic bladder function. Paraplegia, 18: 229, 1980 Jensen, D., Jr.: Uninhibited neurogenic bladder treated with Prazosin. Scand J Urol Nephrol, 15: 229, 1981 Vereecken, R. L., Van Poppel, H., Boeckx, G. and Leruitte, A.:
TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION Long-term alpha-adrenergic-blocking therapy in detrusorurethra dyssynergia. Eur Urol, 9: 167, 1983 14. Rauch-Desanti, C., Fraisse, J., Dubruc, C. et al: Pharmacokinetic and metabolic profiles of alfuzosin. In: Benign Prostatic Hyperplasia— the Place of Alfuzosin. Edited by F. M. J. Debruyne, A. Jardin, C. G. Roehrborn et al. Auckland: Adis International, p. 63, 1998 15. Price, D.: Potential mechanism of action of superselective alpha(1)-adrenoceptor antagonists. Eur Urol, 40: 5, 2001 16. Andersson, K.: Alpha1-adrenoceptors and bladder function. Eur
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Urol, 36: 96, 1999 17. Perlberg, S. and Caine, M.: Adrenergic response of bladder muscle in prostatic obstruction. Its relation to detrusor instability. Urology, 20: 524, 1982 18. Restorick, J. M. and Mundy, A. R.: The density of cholinergic and alpha and beta receptors in the normal and hyper-reflexic human detrusor. Br J Urol, 63: 32, 1989 19. Karlsson, A. K.: Autonomic dysreflexia. Spinal Cord, 37: 383, 1999
Vol. 170, 1242–1251, October 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000084623.65480.f8
TAMSULOSIN: EFFICACY AND SAFETY IN PATIENTS WITH NEUROGENIC LOWER URINARY TRACT DYSFUNCTION DUE TO SUPRASACRAL SPINAL CORD INJURY ´ SKI, PAUL ABRAMS,*,† GERARD AMARENCO, AUGUST BAKKE, ANDRZEJ BUCZYN DAVID CASTRO-DIAZ, SIMON HARRISON, GUUS KRAMER,‡ ROBERT MARSˇIK,§ ¨ HRER,§ PHILIP VAN KERREBROECK§ ANDRZEJ PRAJSNER,‡ MANFRED STO AND JEAN JACQUES WYNDAELE㛳 (THE EUROPEAN TAMSULOSIN NEUROGENIC LOWER URINARY TRACT DYSFUNCTION STUDY GROUP)
ABSTRACT
Purpose: We evaluated the efficacy and safety of tamsulosin in patients with neurogenic lower urinary tract dysfunction secondary to suprasacral spinal cord lesions in a 4-week randomized controlled trial (RCT) followed by a 1-year, open label, long-term study. Materials and Methods: A total of 263 patients were randomized to 4-week double-blind therapy with placebo, or 0.4 or 0.8 mg tamsulosin once daily. Of these, 244 patients completed the RCT, 186 continued long-term tamsulosin therapy (0.4 or 0.8 mg once daily) and 134 completed 1-year treatment. The primary efficacy parameter was maximum urethral pressure (MUP). Results: Although the mean decrease in MUP at 4 weeks in the RCT did not reach statistical significance over the placebo, it was more pronounced with 0.4 (⫺12.2 cm H2O or ⫺10%) and 0.8 mg (⫺9.6 cm H2O or ⫺9%) tamsulosin than placebo (⫺6.5 cm H2O or ⫺3%). In the long-term study there was a statistically significant mean decrease in MUP (⫺18.0 cm H2O, p ⬍0.001 or ⫺15%) from baseline to end point. In the long-term study tamsulosin also decreased maximum urethral closure pressure, improved several cystometry parameters related to bladder storage and emptying, and increased to a statistically significantly degree, from baseline to end point, mean voided volume based on the micturition diary. There was statistically significant improvement for the International Prostate Symptom Score Quality of Life, as well as several questions about symptoms related to urinary leakage, and 1 question on bladder emptying and frequency, bother and severity of symptoms of autonomic dysreflexia. Finally, 71% of patients improved according to investigators (44% slightly and 27% much improved). Both doses were effective and well tolerated. Conclusions: Long-term tamsulosin treatment (0.4 and 0.8 mg once daily) seems to be effective and well tolerated in patients with neurogenic lower urinary tract dysfunction. The results suggest that it improves bladder storage and emptying, and decreases symptoms of autonomic dysreflexia. KEY WORDS: receptors, adrenergic, alpha-1; bladder, neurogenic; reflex, abnormal; spinal cord injuries, autonomic dysreflexia
Spinal cord injury (SCI) is one of the causes of neurogenic lower urinary tract dysfunction (NLUTD). Patients with NLUTD due to sacral or suprasacral SCI often suffer from impaired bladder emptying with residual urine increasing the possibility of urinary tract infections and stones. Patients with suprasacral lesions can also suffer from involuntary detrusor contractions (IDCs)/neurogenic detrusor overactivity during the filling phase, inducing symptoms of frequency, urgency and urinary leakage. Increased filling and voiding pressure with or without vesicoureteral reflux may endanger the upper urinary tract, particularly the kidneys.1 Patients with a lesion above the level of sympathetic outflow, the 6th
thoracic (T6) level, may also experience bothersome symptoms of autonomic dysreflexia.2 The principal goals in the management of NLUTD are to preserve renal function and to maintain patient quality of life (QoL) by decreasing urological complications.3 Patients with NLUTD can be divided into 3 categories, those who cannot empty successfully, those who cannot store urine adequately, or a combination of these characteristics.4 Current treatment options are limited. For facilitating storage options include surgical procedures such as electrical stimulation or interruption of innervation (which are invasive and not always long lasting), other intravesical therapies such as resiniferatoxin, capsaicin and botulinum toxin type A (requiring catheterization and endoscopy), and antimuscarinic drug treatment (which has substantial side effects due to nonselectivity and the theoretical risk of acute urinary retention in patients with obstruction). Treatment options for facilitating voiding, include catheterization (which might cause bacteriuria with subsequent urinary tract infections) or surgical procedures such as sphincterotomy, urethral stents and neurostimulation (which are invasive). Studies with ␣-adrenoceptor (␣-AR)
Accepted for publication April 4, 2003. Supported by Yamanouchi Europe BV. * Corresponding author: Bristol Urological Institute, Southmead Hospital, Department of Urology, Westbury-on-Trym, Bristol BS10 5 NB, United Kingdom (telephone: 44-117-959-5145; FAX: 44-117-9502229; e-mail: [email protected]). † Financial interest and/or other relationship with Ethicon, Ferring, Glaxo, Genyx, Pfizer, Pharmacia, Synthelabo and Yamanouchi. ‡ Financial interest and/or other relationship with Yamanouchi and Pfizer. § Financial interest and/or other relationship with Yamanouchi. 㛳 Financial interest and/or other relationship with Pfizer. 1242
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
FIG. 1. Design of RCT and 1-year open label study, and number of patients (all randomized/enrolled). PLA, placebo. TAM, tamsulosin. w, week.
antagonists in NLUTD show a small but useful effect in facilitating bladder storage and emptying, and decreasing the symptoms of autonomic dysreflexia.1, 5–9 However, these trials were generally small, often uncontrolled, nonrandomized and of short duration. Therefore, the current trials evaluated the efficacy and safety of tamsulosin, a ␣1A/␣1D-AR antagonist, in patients with NLUTD secondary to suprasacral SCI in a 4-week, double-blind, randomized, placebo controlled trial followed by a long-term, 1-year, open label study. MATERIALS AND METHODS
Study inclusion/exclusion criteria. Patients (18 years old or older) with NLUTD secondary to suprasacral SCI were enrolled in the double-blind randomized controlled trial (RCT). They were out of spinal shock and in an established, stable phase. The patients had neurogenic detrusor overactivity (phasic wave 15 cm H2O or greater) or a voiding contraction (spontaneous or provoked through tapping). Patients could have other neurogenic voiding dysfunctions such as detrusor-sphincter dyssynergia. Maximum urethral pressure (MUP) during urethral pressure profilometry (UPP) had to be 60 cm H2O or greater. One or more urodynamic findings had also to be fulfilled during filling cystometry: detrusor pressure of 80 cm H2O or greater, bladder compliance of 15 ml/cm H2O or less (at filling rates of 20 ml per minute), or during voiding cystometry: maximum detrusor pressure during voiding 60 cm H2O or greater, residual volume greater than
30% of the maximum cystometric capacity or greater than 100 ml. The use of clean intermittent (self)catheterization was also allowed. Concomitant drugs which might influence the pharmacodynamic properties of tamsulosin (such as ␣-AR antagonists, ␣/-AR antagonists, ␣-AR agonists and cholinergic drugs) were not allowed for at least 1 month before, and until the end of the study. Medical treatment for NLUTD (anticholinergics in particular) was only allowed if the dose regimen remained stable from 1 month before the study until the end of study. Antihypertensive treatment should remain unchanged throughout the study. Patients who completed all visits of the RCT and wished to continue were able to participate in the 1-year, followup, open label study. All patients gave informed consent for both studies. Study design (fig. 1). In the short-term RCT patients were assessed at enrollment and within 2 weeks (the time required to complete a micturition diary and check all study inclusion and exclusion criteria). Subsequently eligible patients were randomized to 0.4 or 0.8 mg tamsulosin modified release capsules (after 2 weeks on 0.4 mg) or placebo once daily after breakfast. The randomized patients were assessed after 2 and 4 weeks of treatment. In the 1-year, open label, followup study, all patients started on 0.4 mg tamsulosin. In cases of insufficient response the dose could be increased to 0.8 mg at any subsequent visit, which was scheduled every 13 weeks, provided no adverse event (AE) possibly or probably related
TABLE 1. Baseline characteristics in medical history related to spinal cord lesion in RCT (all randomized patients) and 1-year open label study (safety population) Characteristics No. pts Mean lesion duration (mos) % Lesion location: Cervical Thoracic Lumbar % Lesion type: Complete Incomplete % Symptoms: Paraparesis Paraplegia Tetraparesis Tetraplegia % Intermittent catheterization % Intermittent self-catheterization
4-Wk RCT
1-Yr All Tamsulosin
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
92 97.9
88 103.9
83 85.0
178 88.5
31.5 52.2 15.2
30.7 54.5 13.6
42.2 47.0 10.8
30.9 53.9 14.6
51.1 48.9
64.8 34.1
59.0 41.0
54.5 45.5
21.7 45.7 9.8 21.7 48.9 30.8
20.5 51.1 8.0 19.3 40.9 35.2
10.8 45.8 16.9 26.5 44.6 34.9
19.7 51.1 11.2 17.4 42.7 35.4
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
TABLE 2. Primary efficacy results for MUP (UPP) and secondary efficacy results for UPP and cystometry parameters for patient groups in RCT and 1-year open label study RCT Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
1-Yr All Tamsulosin
Mean UPP MUP (cm H2O): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) % Change at end point p Value vs placebo MUCP (cm H2O): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Bladder vol 1st phasic detrusor contraction (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Bladder vol max cystometric capacity (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Voiding time (secs): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo Voided (ml): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) p Value vs placebo
83 88.3 (32.3) ⫺6.5 (2.8)* ⫺3
83 93.1 (35.1) ⫺12.2 (3.2)† ⫺10 0.184
76 87.3 (28.4) ⫺9.6 (2.9)‡ ⫺9 0.443
147 89.3 (31.5) ⫺18.0 (2.8)† ⫺15 Not applicable
83 79.9 (32.6) ⫺7.6 (2.7)‡
83 76 83.2 (33.6) 78.4 (28.0) ⫺11.8 (3.0)† ⫺8.9 (2.6)‡ 0.297 0.726 Mean cystometry (20 ml/min)
147 79.6 (30.8) ⫺15.7 (2.8)† Not applicable
77 203.3 (114.1) 6.7 (10.3)§
75 213.2 (111.2) 4.8 (11.4)§ 0.906
70 194.6 (106.4) 26.4 (13.7)§ 0.247
141 206.6 (112.8) 18.7 (9.3)* Not applicable
77 260.3 (135.4) 5.3 (11.2)§
75 254.6 (121.3) 7.3 (12.6)§ 0.905
70 256.8 (124.1) 17.3 (16.0)§ 0.533
140 255.3 (121.3) 29.9 (10.1)‡ Not applicable
53 85.6 (82.3) 5.9 (10.5)§
61 104.6 (114.8) ⫺17.6 (10.2)§ 0.112
47 87.7 (99.9) 16.5 (16.1)§ 0.575
94 94.5 (111.4) 33.0 (12.1)‡ Not applicable
72 64 117.0 (98.2) 111.1 (105.2) ⫺7.6 (11.1)§ 3.3 (13.2)§ 0.269 0.726 Cystometry (100 ml/min)
122 117.9 (99.6) 46.8 (9.9)† Not applicable
70 100.3 (95.3) 9.1 (10.0)§
Residual urine vol (ml): No. pts with baseline ⫹ end point data 46 41 41 78 Baseline (SD) 178.4 (147.1) 159.1 (136.8) 171.0 (155.7) 158.7 (145.2) Change at end point (SE) ⫺23.7 (13.7)§ ⫺5.6 (19.5)§ ⫺7.3 (19.7)§ ⫺30.1 (12.6)* p Value vs placebo 0.443 0.491 Not applicable Only variables with a statistically significant change from baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included. * p ⬍0.05. † p ⬍0.001. ‡ p ⬍0.01. § Not statistically significant vs baseline.
to tamsulosin occurred. The group of all tamsulosin patients contained all patients who received tamsulosin (0.4 and/or 0.8 mg once daily) during the long-term study. Assessments. The major primary and secondary efficacy and safety parameters are presented in Appendix 1. The trial methodology was designed according to recommendations from the International Continence Society Standardization Committee10 and Steering Committee (Appendix 2). Furthermore, an expert urodynamicist performed a central review of urodynamic traces to achieve standardization of interpretation of the assessments. UPP was performed according to 1 of these methods with the patient in supine position: the Brown-Wickham technique with an 8 or 10CH water filled catheter, a perfusion rate of 3 ml per minute and a pulling speed of 1 mm per second, or a catheter mounted transducer with an 8 or 10CH microtip catheter, a pulling speed of 1 mm per second and 3 or 9 o’clock catheter orientation. We performed 3 assessments and the trace with the lowest MUP measurement (after central review) was used for analysis. Statistical methods and sample size. Efficacy analyses were performed on an intent to treat population. For the RCT sample size calculation was based on the results of a placebo controlled study with intravenous (iv) alfuzosin5 with an assumption of the primary efficacy end point variable MUP. For a difference in mean treatment effect between placebo and tamsulosin of 15 to 20 cm H2O, a standard deviation of 30 to 35 cm H2O, ␣ ⫽ 0.05 (2-sided) and a power of 80%, 240 evaluable patients were required. For the open label exten-
sion study we planned to have a minimum of 100 patients complete the 1-year visit. All statistical tests were performed at ␣ ⫽ 0.05, 2-sided. For the primary efficacy analysis in the RCT changes from baseline to end point were primarily subjected to an analysis of variance, and the global hypothesis (null hypothesis indicating no difference in mean change from baseline to end point visit among the different groups) was tested using the F test. The elementary hypotheses of 2 by 2 comparisons were tested using the t test. In the longterm study all data collected and changes from baseline were summarized for all patients on tamsulosin. The significance of the changes was tested in an explorative way using the paired t tests or the nonparametric Wilcoxon matched pairs signed rank test, as appropriate. In addition, the secondary efficacy variables were analyzed by descriptive statistics. At the request of the Steering Committee several post hoc analyses were performed to identify subgroups of patients who may benefit most from treatment (such as more symptomatic patients or patients needing certain types of bladder management) and responders. In addition, several questions from the urinary symptoms questionnaire (USQ) were clustered according to predefined subcategories and post hoc analyses were performed for these clusters. The questions relating to autonomic dysreflexia (AD) were analyzed in a subgroup of patients most likely to suffer from these symptoms (with lesion at T6 or higher). This report only presents clinically relevant results as judged by the Steering Committee. Extreme caution should be exercised in drawing conclu-
TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
sions given the large number of statistical tests performed. No correction for multiple testing was applied. Special caution is required in interpreting the results of the open label, uncontrolled, 1-year followup study. RESULTS
Baseline characteristics. In the RCT 263 patients were randomized and of these 244 (93%) completed the 4-week double-blind treatment. Subsequently, 186 (76%) continued in the open label, 1-year study, of whom 134 (72%) completed the 1-year treatment (fig. 1). Mean age for the group on placebo, and on 0.4 and 0.8 mg tamsulosin was 39, 35 and 36 years, respectively (range 17 to 73), and 29 (11%) of all randomized patients were female. There were no major differences between treatment groups in both studies for baseline characteristics in medical history related to SCI (table 1). In the open label, 1-year study more than half of the patients (54.5%) had a complete lesion, thoracic lesion (53.9%), paraplegia symptoms (51.1%) or were on intermittent catheterization (42.7%). Urodynamic and urinary symptom characteristics of the population are shown in tables 2 to 5 (baseline values). Discontinuations. A total of 19 patients (of 263) prematurely discontinued the RCT and 52 (of 186) discontinued during open label followup. In the open label study the 2 main reasons for discontinuation were AEs in 17 and insufficient therapeutic response in 16 with no increased incidence on tamsulosin compared to placebo during doubleblind treatment. Other reasons for discontinuation were no return for followup in 9, other in 8 and protocol violation in 2. The dose was increased to 0.8 mg in 69 patients (37.1%) at some stage during the long-term study. Primary efficacy results. In the RCT mean change in MUP with tamsulosin did not reach statistical significance compared to placebo at 4 weeks. However, the change was greater with 0.4 and 0.8 mg tamsulosin than with placebo. At the end point in the long-term study mean change in MUP was more pronounced in the all tamsulosin patient group than at 4 weeks (fig. 2, table 2). The group of patients originally treated with placebo during the RCT (64 patients) showed a further decrease in MUP of 15.6 cm H2O when switched to tamsulosin treatment in the followup study (fig. 3). In the RCT about 36% of patients in both tamsulosin
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groups had a decrease in MUP of 20 cm H2O or greater compared to 29% in the placebo group. In the long-term study at end point 50% of evaluable patients experienced this decrease. Secondary efficacy results. Other UPP Parameters: Mean change from baseline to end point in maximum urethral closure pressure (MUCP) followed the same pattern as MUP (table 2). No statistically significant difference in improvement with tamsulosin compared to placebo was seen during the RCT for cystometry parameters. However, during the 1-year open label study, several parameters related to bladder storage (increased bladder volume at first phasic detrusor contraction and at maximum cystometric capacity) and bladder emptying (voiding time, voided volume and residual urine) were statistically significantly improved from baseline to end point in the group of all tamsulosin patients (table 2). Patient Micturition Diary: In the RCT at end point 0.4 mg tamsulosin produced statistically significant improvements versus baseline for incontinence episode frequency and frequency of pads changed, as well as 0.8 mg tamsulosin for mean voided volume per micturition and urgency episode frequency. The difference versus placebo was statistically significant for frequency of pads changed with 0.4 mg (p ⫽ 0.009) and for mean voided volume with the 0.8 mg (p ⫽ 0.003) dose. In the 1-year, open label study, mean voided volume per micturition remained statistically significantly improved from baseline to end point in the group of all tamsulosin patients (table 3). USQ (Appendix 3): In the RCT with 0.8 mg tamsulosin several parameters relating to urinary leakage were statistically significantly improved from baseline to end point (severity of urinary leakage, bother due to leakage before reaching the toilet and wearing pads at night) or approached significance (changing underwear because of leakage, (table 4). This significance was sustained in the group of all tamsulosin patients in the long-term study for severity of leakage and changing underwear due to leakage. In addition, frequency of leakage, wearing pads during daytime, and leakage and associated bother during sexual intercourse were statistically improved from baseline to end point in the group of all tamsulosin patients in the long-term study. This significance was also the case for 1 question related to bladder emptying (table 4). Because 84% to 88% of patients in studies
TABLE 3. Secondary efficacy results from micturition diary RCT Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
1-Yr All Tamsulosin
Mean voided vol/micturition (ml): No. pts with baseline ⫹ end point data 53 50 43 101 Baseline (SD) 174.9 (92.1) 206.8 (122.7) 173.9 (138.3) 188.1 (112.8) Change at end point (SE) ⫺6.2 (11.9)* ⫺8.0 (9.3)* 28.2 (8.8)† 17.7 (8.4)† p Value vs placebo 0.744 0.003 Not applicable Mean frequency of incontinence episodes/24 hrs: No. pts with baseline ⫹ end point data 60 62 55 111 Baseline (SD) 1.0 (1.4) 1.0 (1.6) 1.0 (1.7) 0.9 (1.6) Change at end point (SE) ⫺0.2 (0.1)* ⫺0.3 (0.1)‡ ⫺0.0 (0.1)* ⫺0.1 (0.1)* p Value vs placebo 0.412 0.915 Not applicable Mean frequency of pads changed/24 hrs: No. pts with baseline ⫹ end point data 61 63 55 113 Baseline (SD) 2.0 (2.2) 3.2 (2.8) 2.4 (2.1) 2.5 (2.6) Change at end point (SE) 0.1 (0.1)* ⫺0.3 (0.2)§ 0.2 (0.1)* ⫺0.1 (0.2)* p Value vs placebo 0.009 0.823 Not applicable Mean frequency of urgency episodes/24 hrs: No. pts with baseline ⫹ end point data 65 69 62 131 Baseline (SD) 2.0 (3.0) 1.5 (2.6) 1.5 (2.5) 1.7 (2.8) Change at end point (SE) ⫺0.1 (0.2)* ⫺0.2 (0.1)* ⫺0.3 (0.2)† ⫺0.1 (0.1)* p Value vs placebo 0.688 0.230 Not applicable Only variables with statistically significant change from baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included. * Not statistically significant vs baseline. † p ⬍0.001. ‡ p ⬍0.01. § p ⬍0.05.
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 4. Secondary efficacy results from urinary symptoms questionnaire related to bladder emptying and urinary leakage Mean RCT Placebo
Score on incomplete bladder emptying (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency urinary leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on severity urinary leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency underwear change due to leakage (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on frequency pad usage during day (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on leakage during sexual intercourse (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on bother due to leakage during sexual intercourse (range 0–3): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on frequency of urinary leakage (total range 0–28): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on severity of urinary leakage (total range 0–20): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Total subscale score on frequency ⫹ severity urinary leakage (total range 0–48): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Only variables with a statistically significant change from * p ⬍0.01. † Not statistically significant vs baseline. ‡ p ⬍0.05.
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
Mean 1-Yr All Tamsulosin
81 1.3 (1.3) ⫺0.3 (0.1)*
82 1.0 (1.3) 0 (0.1)†
76 1.0 (1.2) ⫺0.1 (0.1)†
145 1.2 (1.4) ⫺0.2 (0.1)‡
81 2.4 (1.5) ⫺0.2 (0.1)†
82 2.6 (1.6) ⫺0.2 (0.1)†
76 2.4 (1.5) 0 (0.1)†
145 2.3 (1.5) ⫺0.2 (0.1)‡
82 2.4 (1.6) ⫺0.1 (0.1)†
82 2.4 (1.6) ⫺0.1 (0.1)†
75 2.6 (1.5) ⫺0.2 (0.1)‡
144 2.3 (1.6) ⫺0.3 (0.1)*
82 1.2 (1.3) ⫺0.1 (0.1)†
81 0.9 (1.0) ⫺0.1 (0.1)†
74 1.4 (1.3) ⫺0.2 (0.1)†
143 1.2 (1.2) ⫺0.2 (0.1)‡
82 1.1 (1.6) ⫺0.1 (0.1)†
81 0.9 (1.6) 0.1 (0.1)†
76 1.3 (1.7) ⫺0.1 (0.1)†
145 1.1 (1.6) ⫺0.2 (0.1)‡
37 0.6 (0.8) ⫺0.2 (0.1)†
37 0.5 (0.9) ⫺0.1 (0.0)†
23 0.6 (0.8) ⫺0.1 (0.1)†
57 0.6 (0.8) ⫺0.2 (0.1)‡
32 0.7 (1.0) ⫺0.1 (0.1)†
33 0.5 (1.0) 0.0 (0.1)†
18 0.9 (1.2) ⫺0.2 (0.2)†
47 0.7 (1.1) ⫺0.3 (0.1)‡
82 10.3 (5.5) ⫺0.4 (0.5)†
82 11.4 (5.9) ⫺0.2 (0.4)†
76 10.5 (5.7) 0.1 (0.3)†
146 10.5 (5.7) ⫺0.6 (0.4)†
82 6.3 (4.8) ⫺0.4 (0.3)†
82 5.7 (4.4) ⫺0.1 (0.3)†
76 7.1 (4.8) ⫺0.7 (0.3)‡
145 6.2 (4.6) ⫺0.7 (0.2)*
82 82 76 146 16.6 (9.2) 17.1 (9.1) 17.6 (8.9) 16.7 (9.0) ⫺0.8 (0.7)† ⫺0.3 (0.5)† ⫺0.6 (0.5)† ⫺1.4 (0.6)‡ baseline to end point in at least 1 group of patients in the RCT and/or 1-year study are included.
suffered from incontinence and leakage, the results of the subscale on incontinence/leakage are presented in table 4. For the severity subscale a statistically significantly improvement from baseline to end point in the 0.8 mg tamsulosin group was observed in the RCT study. This improvement was sustained in the long-term study. For the frequency subscale a further improvement was observed in the long-term study compared to the RCT study. For the total (frequency and severity) subscale further improvement was observed in the long-term study compared to the RCT study, and this improvement became statistically significant from baseline to end point in the long-term study. In the RCT mean scores of frequency, severity and bother of autonomic dysreflexia were statistically significantly improved from baseline to end point in the 0.8 mg tamsulosin group, and for severity and bother on placebo (table 5). However, the magnitude of the effect was greater with 0.8 mg tamsulosin. The effect was sustained during long-term treatment. The results for the AD subscale were comparable to those for individual AD questions. An additional analysis in the subgroup of patients with a lesion at T6 or higher showed that the mean score of individual AD questions was statistically significantly improved from baseline to end point with 0.8 mg tamsulosin but not with placebo. The percentage of
patients in the RCT that had AD symptoms at baseline but became symptom-free at end point was greater with 0.8 mg tamsulosin (11 of 26 patients, 42%) than with placebo (6 of 19 patients, 32%). In the long-term study, 44% (16 out of 36) of such patients became symptom-free at end point. QoL Question: In the RCT no significant improvements from baseline to end point were observed in any treatment group for mean International Prostate Symptom Score Quality of Life. In the open label study the improvement at end point was statistically significant versus baseline in the all tamsulosin patients group. Investigator’s Global Assessment: In the RCT the percentage of patients who were slightly or much improved according to the investigator was 42% on placebo, and 51% and 58% on 0.4 mg and 0.8 mg tamsulosin, respectively. This assessment included 7.2%, 7.2% and 13.2% much improved patients on placebo, 0.4 and 0.8 mg tamsulosin, respectively. In the 1-year followup study 71% of patients were improved (44% slightly and 27% much improved) in the all tamsulosin patients group. Safety results. Tamsulosin was well tolerated in 0.4 and 0.8 mg doses and the risk of patients experiencing AEs related to the pharmacological mode of action of tamsulosin was low (table 6). No new or unexpected adverse events related to
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 5. Secondary efficacy results from the urinary symptoms questionnaire related to autonomic dysreflexia Mean RCT
Score on AD frequency (range 0–5): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on AD bother (range 0–4): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Score on AD severity (range 0–5): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) Subscale score on AD (range 0–14): No. pts with baseline ⫹ end point data Baseline (SD) Change at end point (SE) * Not statistically significant vs baseline. † p ⬍0.01. ‡ p ⬍0.05.
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
Mean 1-Yr All Tamsulosin
79 0.6 (1.3) ⫺0.2 (0.1)*
80 0.9 (1.7) ⫺0.2 (0.1)*
71 0.8 (1.5) ⫺0.4 (0.1)†
141 0.6 (1.3) ⫺0.2 (0.1)‡
79 0.7 (1.4) ⫺0.2 (0.1)‡
80 0.7 (1.3) ⫺0.1 (0.1)*
71 0.8 (1.3) ⫺0.4 (0.1)†
141 0.7 (1.3) ⫺0.3 (0.1)†
79 0.7 (1.4) ⫺0.2 (0.1)‡
80 0.7 (1.4) ⫺0.1 (0.1)*
70 0.9 (1.4) ⫺0.5 (0.1)†
140 0.7 (1.4) ⫺0.2 (0.1)‡
79 2.0 (3.8) ⫺0.6 (0.3)‡
80 2.3 (4.0) ⫺0.4 (0.2)*
71 2.5 (3.9) ⫺1.3 (0.4)†
141 2.1 (3.7) ⫺0.7 (0.3)‡
tamsulosin were noted. Tamsulosin did not affect blood pressure or pulse rate, and there were no clinically significant changes over time in electrocardiogram or laboratory evaluations. DISCUSSION
Placebo controlled randomized studies with ␣1-AR antagonists had rarely been published when the current tamsulosin studies were designed. Most studies were small, open label and of short treatment duration without uniform methodology regarding urodynamic assessments,1, 6 – 8, 11–13 with the exception of a placebo controlled study by Perrigot et al5 with iv alfuzosin. Although the patient population in the Perrigot et al study was heterogeneous the effect on MUP was used (as primary efficacy parameter) for calculating the sample size of the tamsulosin RCT study since placebo controlled clinical data were not available. The minimum difference in MUP decrease to be detected in the tamsulosin RCT study was set at 15 to 20 cm H2O. However, the MUP was measured approximately 24 hours after oral tamsulosin dosing, whereas in the alfuzosin study MUP was measured 15 to 30 minutes after iv alfuzosin injection. In addition, mean alfuzosin plasma levels observed after iv administration were 4 times higher than peak plasma levels observed after oral administration of 2.5 mg alfuzosin 3 times daily.14 This difference may explain why none of the treatment groups in the RCT was able to achieve a mean decrease of 15 to 20 cm H2O or greater. However, the observed mean decrease from baseline to end point was statistically significant in all treatment groups with the mean decrease being largest in the tamsulosin groups. The percentage of patients achieving a decrease in MUP of 20 cm H2O or greater from baseline to end point was 29% on placebo and 36% on both tamsulosin doses in the RCT, and increased to 50% at end point in the long-term study. Furthermore, although for most secondary parameters the difference between tamsulosin and placebo did not reach statistical significance in the RCT, the results for some objective parameters, and the investigator global assessment and symptoms of autonomic dysreflexia (with [slightly] greater effects with 0.8 mg tamsulosin than 0.4) show a beneficial effect of tamsulosin compared to placebo. The fact that the frequency of incontinence episodes or pads changed was significantly decreased versus baseline and placebo (pads changed) with the 0.4 but not with the 0.8 mg dose may be because these were not primary parameters, the number of patients in each treatment group was small and there was perhaps some variation in bladder management among the groups. Finally, no inclusion criteria were set for the micturition diary (and the USQ). This lack of in-
formation may have led to inclusion of asymptomatic patients, high inter-patient variability and inconsistent results. The treatment duration of 4 weeks may have been too short to demonstrate a statistically significant difference for tamsulosin compared to placebo in patients with NLUTD. This treatment duration was based on results with tamsulosin in patients with symptomatic benign prostatic hyperplasia. However, the voiding pattern of patients with NLUTD may need more time to adjust since these patients are attached to normal habits and routine. It may take some time before they are convinced of a treatment effect and change their habits. In particular the treatment duration with 0.8 mg tamsulosin (2 weeks only) may have been too short to reveal additional effects compared to 0.4 mg tamsulosin. Furthermore, tamsulosin may have been under-dosed in this specific population. This observation may imply that 0.4 mg tamsulosin could be a good starting dose for patients with NLUTD but that increasing the dose to 0.8 mg may provide additional benefit. During the long-term study there was a tendency for several parameters to improve with time, eg mean decrease in MUP (18 cm H2O vs 12.6 cm H2O at 4 weeks) and the investigator global assessment (slightly or much improved in 71% vs 51% to 58% at 4 weeks). However, the results on investigator global assessment should be interpreted with some caution due to possible observer bias. The observed long-term improvements in several secondary efficacy parameters (such as MUCP, bladder volume at first phasic contraction and at maximum cystometric capacity, voided volume, voiding time, residual volume, mean voided volume per micturition, and several USQ items related to urinary leakage), especially with 0.8 mg tamsulosin, confirm the clinical improvements in bladder storage and emptying, and suggest positive effects of tamsulosin on the bladder and urethra. Although our study was hampered by the fact that no validated questionnaire existed for this patient population, the improvement in incontinence symptoms is potentially of clinical importance because these symptoms have a negative impact on patient QoL. The clinical benefits of long-term tamsulosin treatment are confirmed by the International Prostate Symptom Score Quality of Life and investigator global assessment. The positive effect on the urethra is probably related to ␣1A-AR blockade in the bladder neck and urethra (and prostate in males). The human detrusor predominantly expresses ␣1D (66%) and ␣1A-ARs (34%) subtypes and, in female rats, obstruction induces a shift in detrusor subtype expression (␣1A-AR mRNA was decreased from 70% to 5% and ␣1D-AR
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
FIG. 2. Mean change in MUP from baseline to end point in RCT and 1-year open label study (intent to treat population). PLA, placebo. TAM, tamsulosin.
FIG. 3. Mean change in MUP with time in 1-year open label study (intention to treat population). Single asterisk, p ⬍0.05. Double asterisk, p ⬍0.001 vs baseline. PLA, placebo. TAM, tamsulosin.
mRNA was increased from 16% to 91%).15 Assuming similar mechanisms would show in humans, this decrease may have contributed to observed changes in micturition behavior (increased frequency and decreased volume/micturition). In patients with obstruction, parasympathetic denervation or detrusor overactivity there may be a shift from a -adrenergic mediated relaxation to an ␣-adrenergic mediated contraction of the bladder during the storage phase or, in patients with a neurogenic overactive detrusor, an increase in ␣1-AR density.1, 9, 16 –18 These changes may be responsible for IDCs and related frequency, nocturia, urgency and urinary leakage in patients with NLUTD. Therefore, the positive effect of tamsulosin may be attributed to blockade of (upregulated) ␣1DARs in the detrusor, thereby decreasing detrusor overactivity and improving urine storage in the bladder. Alternatively, tamsulosin may block ␣1D-ARs in the spinal cord or prejunctional ␣1-ARs at peripheral ganglia and/or on cholinergic terminals in the bladder, thereby decreasing acetylcholine release and subsequent IDCs.15 In the RCT improvements were observed in the frequency, severity and bother of AD symptoms, especially in the subgroup of patients with lesions at T6 or higher. The main AD symptoms
are hypertension, headache, flushing, sweating and bradycardia, which can be bothersome. Moreover, paroxysmal hypertension is a serious symptom since it may lead to cerebral and retinal hemorrhages, seizures, coma and potentially death.2, 19 Although in the acute setting tamsulosin should not be considered appropriate treatment for an episode of AD, the observed improvements indicate a positive effect of tamsulosin in the prophylaxis of AD symptoms. Regarding subgroups of patients with certain types of bladder management, the available data do not provide a clear indication for tamsulosin being more beneficial in specific types of bladder management. However, it should be noted that the subgroups were too small to draw strong conclusions. CONCLUSIONS
Patients with NLUTD due to suprasacral SCI are difficult to treat due to a complex underlying etiology and medical history. Placebo controlled trials may need to last for at least 6 to 12 months to demonstrate superiority of active treatment over placebo. Since long-term therapy with 0.4 and 0.8 mg tamsulosin is safe and well tolerated,
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION TABLE 6. Adverse events in RCT and 1-year long-term study (safety population) No. 4-Wk RCT (%)
Total Any adverse events Drug related adverse events* Discontinued due to any adverse events Most commonly reported drug related adverse events:* Dizziness Abnormal ejaculation Asthenia * Adverse events reported as possibly or probably drug related tamsulosin group in the long-term study.
Placebo
0.4 Mg Tamsulosin
0.8 Mg Tamsulosin
No. 1-Yr (%) All Pts On Tamsulosin
90 38 (42.2) 13 (14.4) 4 (4.4)
86 31 (36.0) 14 (16.3) 2 (2.3)
81 26 (32.1) 12 (14.8) 2 (2.5)
178 129 (72.5) 48 (27.0) 17 (9.6)
5 (5.6) 1 (1.2) 6 (7.4) 12 (6.7) 0 (0) 3 (3.5) 2 (2.5) 8 (4.5) 1 (1.1) 2 (2.3) 1 (1.2) 7 (3.9) by at least 3% of patients in any of the tamsulosin groups in the 4-week RCT or in the all
even modest beneficial effects may justify long-term use. The 1-year open study suggests that tamsulosin, as a subtype selective ␣1A/␣1D-AR antagonist, affects the bladder and urethra, and improves bladder storage and emptying
in patients with NLUTD. Moreover, it may decrease symptoms of autonomic dysreflexia. Ismar Healthcare NV assisted in the editing of the manuscript.
APPENDIX 1: EFFICACY AND SAFETY ASSESSMENTS FOR RCT AND THE 1-YEAR OPEN LABEL STUDY
Primary efficacy parameter Y maximum urethral pressure Secondary efficacy parameters Urethral pressure profilometry Y maximum urethral closure pressure Y functional urethral profile length Cystometry (filling speed 20 ml per minute Y detrusor pressure (at first phasic contraction, at strong desire to and optional 100 ml per minute) void and at maximum cystometric capacity) Y maximum detrusor pressure (during filling and voiding) Y bladder volume (at first phasic contraction, at strong desire to void, at maximum cystometric capacity and at 25 cm H2O detrusor pressure) Y bladder compliance Y residual urine volume Y voiding time Y voided volume Patient urinary diary (completed in the week Y frequency of daytime and nighttime voiding prior to each visit) Y frequency of urgency and incontinence episodes Y frequency of pads changed Y frequency of intermittent catheterization Y mean voided volume/micturition Y mean catheterized volume/micturition Urinary Symptom Questionnaire (completed Y study-specific, adaptation of Bristol female lower urinary tract at each visit) symptoms questionnaire: 69 questions on frequency, severity and bother of urinary symptoms QoL (completed at each visit) Y International Prostate Symptom Score Global efficacy (completed at end visit in RCT Y investigator’s global assessment (worsened, unchanged, slightly and in followup study) improved, much improved) Safety parameters Adverse events (completed at each visit) Y number, severity, drug relationship, outcome, etc Vital signs (supine position) (measured at Y blood pressure each visit) Y pulse rate Laboratory (performed at screening and after Y hematology 2 and 4 weeks in RCT, and after 26 and Y biochemistry (including prolactin) 52 weeks in 1-year followup study) Y urinalysis Electrocardiogram (performed at screening Y 12-lead and end-visit of RCT, and after 26 and 52 weeks in 1-year followup study)
Urethral pressure profilometry
UPP and cystometry assessments could be obtained up to 12 months before enrollment or were otherwise performed at screening, and repeated at baseline and after 4 weeks of double-blind treatment. In the 1-year open label study they were performed at 26 and 52 weeks of tamsulosin treatment.
APPENDIX 2: THE NLUTD STUDY GROUP CONTRIBUTORS
Investigators Belgium Czech Republic Denmark Finland
J. H. Delannoy, K. Everaert, J. J. Wyndaele R. Fiala, R. Marsik, J. Zenisek P. Bagi P. Hellstro¨ m, S. Mustonen, M. Talja, T. Tammela
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TAMSULOSIN FOR NEUROGENIC LOWER URINARY TRACT DYSFUNCTION
France
G. Amarenco, M. Barat, B. Brugerolle, A. Cormerais, P. Costa, A. Leriche, J. F. Mathe´ , J. M. Soler T. Boon, K. Delaere, E. Meuleman A. Bakke, H. Hedlund A. Buczynski, A. Prajsner A. Borau, D. Castro-Dı´az, J. Conejero B. Bergman I. Conn, S. Harrison, J. Shah
Netherlands Norway Poland Spain Sweden United Kingdom Steering Committee Provided input on the development of the study protocol, symptoms questionnaire (adapted from the Bristol female lower urinary tract symptoms questionnaire), urodynamic review procedures and discussion of the obtained study results, and reviewed the study reports. Belgium J. J. Wyndaele France G. Amarenco Germany G. Kramer, M. Sto¨ hrer Netherlands P. Van Kerrebroeck Norway A. Bakke Poland A. Buczynski Spain D. Castro-Dı´az UK P. Abrams (chairman), S. Harrison Guarantors Participated in the writing and reviewing of this manuscript. Consisted of Steering Committee members with A. Prajsner and R. Marsik as best enrolling investigators. Data management and statistical analyses R. Sieders (Data Manager) and J. N. Visser (Biostatistician) of Yamanouchi Europe BV, The Netherlands. Central review of urodynamic traces was performed by G. Kramer of the Unfallklinik Murnau, Germany and coordinated by M. Callaert of Yamanouchi Pharma BV, Belgium. Overall management I. C. M. Van der Putten-Slob (Clinical Research Manager, Chairman of the Study Team) of Yamanouchi Europe BV, The Netherlands APPENDIX 3: FREQUENCY AND SEVERITY SUBSCALES
Subscale on frequency of urinary leakage consisted of the following questions: - How often does your bladder empty without your having control over it? (never, occasionally, sometimes, most of the time, all of the time) - Does urine leak before you can get to the toilet? (from ‘never’ to ‘all of the time’) - How often do you leak urine? (never, ⱕ1 ⫻/week, 2–3⫻/week, 1⫻/day, several times per day) - Does urine leak when you are physically active, transfer, exert yourself, cough or sneeze? (from ‘never’ to ‘all of the time’) - Do you ever leak urine without feeling that you want to go? (from ‘never’ to ‘all of the time’) - Do you leak urine when you are asleep? (from ‘never’ to ‘all of the time’) - Do you leak urine when you have sexual intercourse? (not at all, slightly, moderately, quite a bit, extremely) Subscale on severity of urinary leakage consisted of the following questions: - How much urinary leakage occurs? (no leakage, slight leakage, drops/pants damp, dribble/pants wet, floods) - How often do you have to change your underwear because of leakage? (never, 1⫻/week, several times/week, about 1⫻/day, ⬎1⫻/day) - How often do you have to change your outer clothing because of urine leakage? (never, 1⫻/week, several times/ week, about 1⫻/day, ⬎1⫻/day) - Do you wear pads during the day? (from ‘never’ to ‘all of the time’) - Do you wear pads during the night? (from ‘never’ to ‘all of the time’) REFERENCES
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