Safety and Efficacy of Tamsulosin, Alfuzosin Or Silodosin As

148 Central European Journal of Urology

O R I G I N A L P A P E R FUNCTIONAL UROLOGY Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH – a double-blind randomized trial Chikka Moga Siddaiah Manohar, Mahadevappa Nagabhushana, Vilvapathy Senguttuvan Karthikeyan, Ramachandra Pudakalkatti Sanjay, Ananth Janardhan Kamath, Ramaiah Keshavamurthy

Insititute of Nephro Urology, Bangalore, India

Citation: Manohar CS, Nagabhushana M, Karthikeyan VS, et al. Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH – a double blind randomized trial. Cent European J Urol. 2017; 70: 148-153.

Article history Introduction Currently alpha1-adrenoceptor blockers (AB) are widely used as first-line therapy to improve Submitted: Oct. 11, 2016 lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). We compared the Accepted: Feb. 5, 2017 efficacy and safety profile of tamsulosin, alfuzosin and silodosin in LUTS due to BPH. Published online: June 7, 2017 Material and methods Consecutive consenting male patients (N = 269) undergoing medical management of BPH with AB from February 2012 to October 2015 were enrolled. Patients were randomized to a 0.4 mg tamsulosin (group T), 10 mg alfuzosin (group A) or a 8 mg silodosin (group S) by double-blind randomization. All patients were assessed for improvements and post-void residual urine (PVR) and for adverse drug events (ADE). Results IPSS showed significant improvement in Group S at the first week (11.7 ±4.18, p = 0.027) and at 3 months (7.97 ±3.84, p = 0.020). QOL showed significant improvement at 1 (2.2 ±0.76, p = 0.020), 4 (1.47 ±0.63, p <0.001) and 12 (1.2 ±0.66, p <0.001) weeks in Group S. The mean Qmax improvement Corresponding author was the maximum (13.76 ±2.44, p = 0.028) in Group S at 1 week. Reduction in PVR was the maximum Vilvapathy Senguttuvan in Group S, but it was not statistically significant. Adverse drug events (ADE) were observed in 20.07% Karthikeyan (54/269) patients and distribution was similar in the three groups with decreasing incidence with progres- Insititute of Nephro Urology sion of time. Victoria Hospital Campus 560002 Bangalore, India Conclusions Silodosin is the most efficacious AB with rapid onset of action. Silodosin also improves the phone: +91 903 640 24 12 quality of life in patients with LUTS due to BPH and objectively improves maximum flow rate. However, [email protected] silodosin has more adverse events when compared to tamsulosin and alfuzosin.

Key Words: benign prostatic hyperplasia ‹› alpha 1-adrenoceptor blocker ‹› tamsulosin ‹› alfuzosin ‹› silodosin

INTRODUCTION Autopsy studies in Asian and Caucasian men showed an overall prevalence of BPH in 74.8% of men. Al- Benign prostatic hyperplasia (BPH) results in lower pha 1-adrenoceptor blockers (AB) are currently the urinary tract symptoms (LUTS) and is common in recommended first-line therapies for benign pros- 50% of men past the age of 60 years. BPH causes tatic hyperplasia (BPH) [2]. They have high effica- resistance to urinary flow due to the increase in cy, are less expensive and have fewer adverse events prostate capsule tone in prostates <30 cc [1]. LUTS (ADE) in the treatment of LUTS [1, 3, 4]. They act is caused by increased prostatic smooth muscle con- principally by blocking α1A-adrenoreceptors, which traction due to the sympathetic hyperactivity of al- is most prevalent in the prostatic smooth muscle pha 1-adrenoceptors. LUTS are bothersome and in- and produce relaxation in the smooth muscle terfere with quality of life (QoL) of aging males [2]. component of the prostate [4]. Multiple drugs are

Cent European J Urol. 2017; 70: 148-153 doi: 10.5173/ceju.2017.924 149 Central European Journal of Urology available and each drug has its own advantages Study population and disadvantages. Tamsulosin is the most widely used AB, alfuzosin is used in sexually active All consecutive consenting male patients with BPH males and silodosin is a newer agent with greater aged more than 50 years, LUTS with mild to moder- α-1A receptor selectivity. We compared the safety ate International Prostate Symptom Score (IPSS), and efficacy of the three drugs namely tamsulosin, Maximum flow rate (Qmax) <15 ml/sec on uroflow- alfuzosin and silodosin. metry (UFR), prostate size measuring 25–50 cm3 and post void residue (PVR) <100 ml on trans ab- MATERIAL AND METHODS dominal ultrasound (US) were eligible for the study after obtaining a written informed consent. The ex- This was a hospital-based, double-blind, random- clusion criteria were the following: use of AB within ized trial, performed in 269 patients undergoing 2 weeks/ 5-alpha reductase inhibitors (5ARI) within medical management of BPH in the Department 6 months or phytotherapy, active urinary tract in- of Urology, in a tertiary care institute, in South In- fection (UTI), bladder outlet obstruction due to any dia. After obtaining approval from the Institute Re- other cause like urethral stricture, bladder neck search Council and Ethics committee, the study was stenosis or diagnosed to have vesical calculus, ure- conducted from February 2012 to October 2015. thral or bladder diverticulum, neurogenic bladder,

Figure 1. Flow of study participants through the study. 150 Central European Journal of Urology prostatic or bladder cancer, significant orthostatic ables were summarized using mean, standard er- hypotension (OH), post-prostatectomy and renal ror, median, interquartile range, and percentages impairment (serum creatinine >2 mg/dl). based on the characteristics of the variable. One- way ANOVA and the Kruskal-Wallis test were used Randomization, allocation concealment as appropriate for the analysis of continuous vari- and blinding ables based on the normality of the distribution. Chi-Square test was used for categorical variables. Patients were randomized to receive oral tamsu- The P value of <0.05 was considered statistically losin 0.4 mg or alfuzosin 10 mg or silodosin 8 mg significant. by block randomization (block size of 10) performed using Microsoft Excel 2010. Allocation concealment RESULTS was performed using opaque sealed envelopes. Randomization and sealed envelopes were done For the purpose of tabulation and analysis, the by a person independent of the investigators. En- groups were denoted as: Group T receiving 0.4 mg velopes were opened in the outpatient department of oral tamsulosin, group A receiving 10 mg of al- by a nursing staff not involved in the research. The fuzosin and Group S receiving 8 mg of silodosin. drug was placed in a sealed envelope with the code. The baseline patient characteristics like age, dura- The patient and the investigators who assessed the tion of symptoms, prostate weight, Qmax, and PVR outcomes were also blinded. Hence, the study was were comparable (Table 1). double-blind. At the end of the study, the groups were decoded and analyzed (Figure 1). IPSS and QoL

Intervention The mean IPSS scores at baseline were comparable between the three groups (Table 1; p = 0.337). A standard protocol was used for all our patients. At follow-up at first week (11.7 ±4.18, p = 0.027 Patients were evaluated with detailed history re- and at 3 months (7.97 ± 3.84, p = 0.020) the maxi- garding LUTS. Clinical and digital rectal examina- mum improvement was observed in Group S and tion was done. LUTS was assessed using the IPSS this was statistically significant. At end of the questionnaire (English and native language Kanna- first month, the maximum improvement was seen da) including QoL. UFR, ultrasound of the kidney, in Group S; however, it did not reach statistical sig- ureters, bladder (KUB) and prostate, with PVR, nificance (9.43 ±3.89, p = 0.077). The mean QoL serum prostate specific antigen (PSA), blood urea, serum creatinine, blood pressure (BP) in supine and standing position and electrocardiogram were Table 1. Baseline characteristics done in all patients at the beginning of the study. Group T Group A Group S Parameter P value Follow-up was done at 1,4 and 12 weeks with LUTS N = 89 N = 87 N = 93 assessment using IPSS, QoL, Qmax using UFR and Age, years 58.47 56.90 59.10 0.451 US for PVR and side effects of each drug and BP Mean ±SD ±6.16 ±10.26 ±8.79 in supine and standing positions. Eight patients IPSS 16.27 16.23 14.27 0.337 each in groups T and A and five patients in group S Mean ±SD ±6.07 ±6.48 ±5.33 opted out due to side effects. Mild: Moderate IPSS, N 18:71 14:73 21:72 0.544 QoL 2.40 2.37 2.47 0.465 Study endpoints Mean ±SD ±0.86 ±0.89 ±0.82 Prostate weight, cc 33.82 37.76 35.18 0.342 The primary endpoints were improvement in IPSS Mean ±SD ±11.38 ±12.10 ±11.20 LUTS scores, QoL, Qmax and PVR from baseline Voided volume, cc 162.36 165.67 159.78 0.654 at 1,4 and 12 weeks. The secondary endpoints were Mean ±SD ±45.46 ±39.51 ±43.41 ADE to the drugs. Qmax, ml/sec 11.75 12.69 12.13 0.381 Mean ±SD ±2.64 ±2.58 ±2.62 PVR, cc 44.74 41.88 53.61 Statistical analysis 0.218 Mean ±SD ±27.14 ±19.33 ±29.00 Serum creatinine, mg/dl 1.45 1.56 1.39 Statistical analysis was performed using SPSS ver- 0.260 sion 19 for Windows (IBM Corporation, Armonk, Mean ±SD ±0.89 ±0.24 ±0.78 PSA ng/ml 2.8 3.1 2.7 New York). The normality of the data was initially 0.129 assessed using a Box and Whisker plot. The vari- Mean ±SD ±1.54 ±1.72 ±0.61 151 Central European Journal of Urology scores at baseline were comparable between the Table 2. IPSS and QoL in tamsulosin, alfuzosin and silodosin three groups (Table 1; p = 0.465). At follow-up at 1 at 1, 4 and 12 weeks (2.2 ±0.76, p = 0.020), 4 (1.47 ±0.64, p <0.001) and Group T Group A Group S Time Parameter P value 12 (1.2 ±0.66, p <0.001) weeks after starting AB, Mean ±SD Mean ±SD Mean ±SD improvement in QoL was the maximum in Group S 15.23 ± 15.4 11.7 IPSS 0.027 and this was statistically significant (Table 2). 6.67 ±6.52 ±4.18 1 week 2.77 2.3 2.2 QoL 0.020 Qmax and PVR ±0.9 ±0.79 ±0.76

11.83 12.33 The mean Qmax at baseline was comparable be- IPSS 9.43 ±3.89 0.077 ±5.31 ±6.22 tween the three groups (Table 1; p = 0.381). 4 weeks 2.17 1.67 1.47 At follow-up, the improvement was the maximum QoL <0.001 in Group S and it was statistically significant ±0.7 ±0.61 ±0.63 at 1 week (13.76 ±2.44, p = 0.028). At 4 and 11.03 11.43 7.97 IPSS 0.020 12 weeks after starting the drug, the improvement ±5.07 ±6.19 ±3.84 12 weeks was the maximum in Group S; however, it was 2.03 1.53 1.2 <0.001 not statistically significant. The PVR was similar ±0.61 ±0.63 ±0.66 in the three groups at baseline. Though the PVR was reduced in Group S at all three intervals, it was not significant (Table 3). Table 3. Qmax and PVR in tamsulosin, alfuzosin and silodosin at 1, 4 and 12 weeks Adverse drug events (ADE) Group T Group A Group S Time Parameter P value Mean ±SD Mean ±SD Mean ±SD ADE were observed in 54 out of 269 patients 156.12 155.17 151.29 Vvol 0.572 (20.07%). At 1,4 and 12 weeks, the proportion ±39.12 ±16.28 ±37.11 of patients developing side effects was least promi- 11.90 13.11 13.76 1 week Qmax 0.028 nent in group S. Dizziness was the most common ±2.95 ±2.63 ±2.44 side effects in all of the 3 groups. Abnormal ejac- 38.64 35.27 43.31 PVR 0.435 ulation (AE) was most common in group S (6.5% ±24.78 ±19.33 ±22.93 at 4 weeks and 9.7% at 12 weeks) and insomnia 153.21 159.19 154.13 Vvol 0.440 (3/93; 3.2% at 1 and 12 weeks) and syncope (6/93; ±31.11 ±43.12 ±23.18 6.45% at 1 week) were observed only in group S. 13.87 15.00 15.77 4 weeks Qmax 0.097 Fatigue was observed in groups T and A. Headache ±2.33 ±2.18 ±4.91 was observed only in 6 (6.9) patients in group A 27.96 30.18 29.25 PVR 0.910 at 1 and 12 weeks. The incidence of ADE reduced ±17.36 ±17.24 ±17.86 with progression of time. However, there was 161.23 157.32 159.14 Vvol 0.683 no statistically significant difference at any point ±27.34 ±28.98 ±32.45 of time between the three groups (Table 4). 14.33 15.76 16.15 12 weeks Qmax 0.083 ±2.15 ±2.08 ±4.81 DISCUSSION 24.42 25.80 25.74 PVR 0.949 ±14.73 ±17.99 ±15.9 There are no studies in literature comparing the Vvol – voided volume (ml); Qmax – maximum flow rate (ml/second); PVR – post void following three drugs: tamsulosin, alfuzosin and residual urine (ml) silodosin in the medical management of LUTS due to BPH. We administered these three drugs as monotherapy in symptomatic LUTS due to BPH in 269 pa- on 29,384 patients [6]. Yuan et al. assessed the ef- tients and observed for improvements in IPSS, QoL, fect of AB, 5ARI, muscarinic receptor antagonists Qmax, PVR and also for ADE. Robert et al. recom- (MRA) and PDE5I in 58548 patients. They found mended newer drugs like PDE5I and combination that AB, 5ARI and PDE5I were the most effective therapies like AB with 5-alpha- reductase inhibi- agents. Among alpha1-adrenoceptor blockers, doxa- tors (5ARI). They however suggested that selection zosin and terazosin were most effective. They also of therapy is to be individualized [5]. Wang et al. as- concluded that medical therapy in BPH is safe and sessed the effect of alpha adrenoceptor antagonists, drugs have a comparable ADE profile [3]. Novara 5-alpha reductase inhibitors, PDE-5 inhibitors and et al. analyzed the effect of silodosin over placebo muscarinic receptor antagonists in a meta-analysis in a pooled analysis [7]. 152 Central European Journal of Urology

IPSS and QoL sulosin in improving IPSS. They also observed that nocturia was exclusively improved by silodosin [11]. Wang et al. showed that IPSS score reduction with all drug groups when compared with the placebo. Maximum flow rate They also observed that there was no significant difference between AB and ARI or PDE5I. AB Wang et al. observed Qmax improvement with AB with PDE5I had the best symptom score improve- which was similar to the placebo. However, AB with ment [2, 6]. However, they did not find which 5ARI combination had the maximum improvement. of the three alpha1-adrenoceptor blockers is bet- PDE5I showed improvement in IPSS scores, but ter [6]. Improvement in IPSS was comparable not in Qmax [6]. Novara et al. identified that doxazo- among tamsulosin, alfuzosin, silodosin, naftopidil, sin and dutasteride showed the maximum improve- dutasteride, vardenafil, sildenafil, and tadalafil [3]. ment in Qmax. With placebo, doxazosin, dutasteride, We observed that all three drugs had improvement terazosin, alfuzosin, tamsulosin, naftopidil, and silo- in IPSS scores and it was the maximum with silodosin all had significantly higher Qmax post-treat- dosin. Pande et al. observed that tamsulosin and ment [3, 7]. Silodosin objectively improved Qmax, silodosin were comparable for efficacy [8]. Zhang while tamsulosin did not improve Qmax in a recent et al. observed alfuzosin 10 mg to be effective and study [11]. In our study, Qmax improvement was well tolerated in LUTS due to BPH with or with- the maximum at first week with silodosin. In the out antihypertensive medications [9]. Oelke et al. following weeks, similar Qmax improvement was observed that the overall satisfaction and satisfac- observed with all three drugs. We observed that al- tion with efficacy was greater with tadalafil when though the baseline IPSS scores were comparable compared with the placebo, than tamsulosin when among the three groups, it was lower among pa- compared with the placebo [10]. In our study, the tients of the silodosin arm. However, the distribution maximum improvement in QoL was with silodosin. of mild and moderate IPSS categories was similar Novara et al. observed that silodosin significantly across the three arms. Also, baseline Qmax, a more improved IPSS and QoL compared to placebo [7]. objective measurement was comparable among the In a recent study, Takeshita et al. proved that 4 mg three arms (Table 1). of silodosin has a similar efficacy to 0.4 mg of tam- Adverse drug events (ADE)

Table 4. Adverse effects to tamsulosin, alfuzosin and silodosin When compared to placebo, doxazosin, terazosin, si- at 1, 4 and 12 weeks lodosin and tadalafil had a significantly higher incidence of adverse drug events [3]. The primary specif- Group T Group A Group S Side effect Time N = 89 N = 87 N = 93 P value ic ADE reported for AB was dizziness, headache and N (%) N (%) N (%) asthenia. Pande et al. observed abnormal ejaculation only with silodosin and orthostatic hypotension 1 week 81 (91.1) 72 (82.8) 64 (68.9) only with tamsulosin. They reported silodosin to be Nil 4 weeks 75 (84.3) 84 (94.4) 73 (78.5) 0.199 useful for elderly patients and alfuzosin for young- 12 weeks 73 (82.1) 76 (87.4) 68 (73.1) er sexually active men. However, we observed that 1 week 0 0 0 ADE was the maximum with silodosin and least with Abnormal tamsulosin and alfuzosin. Zhang et al. observed that 4 weeks 0 0 6 (6.5) 0.223 ejaculation alfuzosin with antihypertensive medication decreas- 12 weeks 3 (3.4) 0 9 (9.7) es systolic and diastolic blood pressure. Orthostatic 1 week 3 (3.4) 3 (3.5) 11 (11.8) hypotension was observed only with tamsulosin in 3% patients, but not with alfuzosin and silodo- Dizziness 4 weeks 8 (9) 0 13 (14) 0.189 sin [9]. In a study on silodosin, the most common 12 weeks 3 (10) 3 (3.4) 4 (13.3) ADE was abnormal ejaculation in 22% patients. 1 week 4 (4.6) 9 (10.3) 0 The incidence of dizziness, orthostatic hypoten- Fatigue 4 weeks 3 (3.4) 5 (5.7) 0 0.254 sion and cardiovascular ADE was similar to placebo [7]. Takeshita et al. identified that patients did not 12 weeks 3 (3.4) 6 (6.9) 0 have preference to either tamsulosin or silodosin 1 week 3 (3.4) 0 7 (7.5) in their crossover open label randomized trial [11]. Orthostatic hypoten- 4 weeks 2 (2.3) 0 0 0.278 Lower dose of silodosin can be more cost efficacious sion and reduce the incidence of side effects like abnor- 12 weeks 3 (3.4) 1 (1.2) 0 mal ejaculation and orthostatic hypotension [11]. 153 Central European Journal of Urology

We observed that silodosin was the efficacious al- dian men. Silodosin also improves the quality of life pha1-adrenoceptor blocker and also had the highest of patient with LUTS due to BPH and objectively incidence of abnormal ejaculation. improves maximum flow rate. However, silodosin has more adverse events in the form of abnormal CONCLUSIONS ejaculation and dizziness when compared to tamsulosin and alfuzosin. Silodosin is the most efficacious alpha-1 adrenoceptor blocker with a rapid onset of action and had Conflicts of interest consistent improvement in LUTS at 3 months in In- The authors declare no conflicts of interest.

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