Abstract
Background
A variety of alpha‐blockers are used for treating lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Silodosin is a novel, more selective alpha‐blocker, which is specific to the lower urinary tract and may have fewer side effects than other alpha‐blockers.
Objectives
To assess the effects of silodosin for the treatment of LUTS in men with BPH.
Search methods
We performed a comprehensive search using multiple databases (Cochrane Library, MEDLINE, EMBASE, Scopus, Google Scholar, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up until 13 June 2017.
Selection criteria
We included all parallel, randomized controlled trials. We also included cross‐over designs.
Data collection and analysis
Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random‐effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence according to the GRADE approach.
Main results
We included 19 unique studies with 4295 randomized participants across four comparisons for short‐term follow‐up. The mean age, prostate volume, and International Prostate Symptom Score were 66.5 years, 38.2 mL, and 19.1, respectively.
Silodosin versus placebo
Based on four studies with a total of 1968 randomized participants, silodosin may reduce urologic symptom scores in an appreciable number of men (mean difference (MD) ‐2.65, 95% confidence interval (CI) ‐3.23 to ‐2.08; low‐quality evidence). Silodosin likely does not result in a clinically important reduction in quality of life (MD ‐0.42, 95% CI ‐0.71 to ‐0.13; moderate‐quality evidence). It may not increase rates of treatment withdrawal for any reason (relative risk (RR) 1.08, 95% CI 0.70 to 1.66; low‐quality evidence). We are uncertain about the effect of silodosin on cardiovascular adverse events (RR 1.28, 95% CI 0.67 to 2.45; very low‐quality evidence). Silodosin likely increases sexual adverse events (RR 26.07, 95% CI 12.36 to 54.97; moderate‐quality evidence); this would result in 180 more sexual adverse events per 1000 men (95% CI 82 more to 388 more).
Silodosin versus tamsulosin
Based on 13 studies with a total of 2129 randomized participants, silodosin may result in little to no difference in urologic symptom scores (MD ‐0.04, 95% CI ‐1.31 to 1.24; low‐quality evidence) and quality of life (MD ‐0.15, 95% CI ‐0.53 to 0.22; low‐quality evidence). We are uncertain about treatment withdrawals for any reason (RR 1.02, 95% CI 0.62 to 1.69; very low‐quality evidence). Silodosin may result in little to no difference in cardiovascular adverse events (RR 0.77, 95% CI 0.53 to 1.12; low‐quality evidence). Silodosin likely increases sexual adverse events (RR 6.05, 95% CI 3.55 to 10.31; moderate‐quality evidence); this would result in 141 more sexual adverse events per 1000 men (95% CI 71 more to 261 more).
Silodosin versus naftopidil
Based on five studies with a total of 763 randomized participants, silodosin may result in little to no differences in urologic symptom scores (MD ‐0.85, 95% CI ‐2.57 to 0.87; low‐quality evidence), quality of life (MD ‐0.17, 95% CI ‐0.60 to 0.27; low‐quality evidence), treatment withdrawal for any reason (RR 1.25, 95% CI 0.81 to 1.93; low‐quality evidence), and cardiovascular adverse events (RR 1.02, 95% CI 0.41 to 2.56; low‐quality evidence). Silodosin likely increases sexual adverse events (RR 5.93, 95% CI 2.16 to 16.29; moderate‐quality evidence); this would result in 74 more sexual adverse events per 1000 men (95% CI 17 more to 231 more).
Silodosin versus alfuzosin
Based on two studies with a total of 155 randomized participants, silodosin may or may not result in a clinically important increase in urologic symptom scores (MD 3.83, 95% CI 0.12 to 7.54; low‐quality evidence). Silodosin likely results in little to no difference in quality of life (MD 0.14, 95% CI ‐0.46 to 0.74; moderate‐quality evidence). We found no event of treatment withdrawal for any reason. Silodosin may not reduce cardiovascular adverse events (RR 0.67, 95% CI 0.36 to 1.24; low‐quality evidence) but likely increases sexual adverse events (RR 37.21, 95% CI 5.32 to 260.07; moderate‐quality evidence); this would result in 217 more sexual adverse events per 1000 men (95% CI 26 more to 1000 more).
Authors' conclusions
Silodosin may reduce urologic symptom scores in an appreciable number of men compared to placebo. Quality of life and treatment withdrawals for any reason appears similar. Its efficacy appears similar to that of other alpha blockers (tamsulosin, naftopidil and alfuzosin) but the rate of sexual side effects is likely higher. Our certainty in the estimates of effect was lowered due to study limitations, inconsistency and imprecision.
Plain language summary
Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia
Review question
Does silodosin improve bothersome urinary symptoms in men with an enlarged prostate?
Background
Prostate enlargement is common in men as they get older and may cause difficulties in urination such as a weak stream, having to get up at night and a feeling of not emptying the bladder completely. Silodosin is a newer medication that may help with these symptoms and may cause fewer unwanted drug effects. We did this review to compare silodosin to placebo (dummy drug) and other medications.
Study characteristics
We included 19 studies with 4295 men. Participants' average age was 66.5 years. All studies included men aged over 40 years and reported that on average these men had a moderate degree of bothersome urinary symptoms.
Key results
Silodosin may improve urinary symptoms compared to placebo. It may have comparable effects on urinary symptoms, quality of life, treatment discontinuation for any reason, and unwanted drug effects compared to other medications. However, silodosin likely increases unwanted sexual side effects compared to placebo and other medications.
Quality of the evidence
The quality of evidence for most outcomes was low. This means that the true effect may be substantially different from what this review shows.
Summary of findings
Summary of findings for the main comparison. Silodosin compared to placebo for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term).
| Silodosin compared to placebo for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term) | |||||
|
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: silodosin Comparator: placebo | |||||
| Outcomes | № of participants (studies) | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | |
| Risk with placebo | Risk difference with silodosin | ||||
| Urologic symptom scores Assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: mean 3 months | 1743 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of urologic symptom scores ranged from ‐5.30 to ‐3.50 | MD 2.65 lower (3.23 lower to 2.08 lower) |
| QoL Assessed with: IPSS‐QoL Scale from: 0 (best: delighted) to 6 (worst: terrible) Follow‐up: mean 3 months | 820 (2 RCTs) | ⊕⊕⊕⊝ Moderatea,c | ‐ | The mean change of QoL ranged from ‐1.10 to ‐0.80 | MD 0.42 lower (0.71 lower to 0.13 lower) |
| Treatment withdrawal due to any reason Follow‐up: mean 3 months | 1703 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | RR 1.08 (0.70 to 1.66) | Study population | |
| 83 per 1000 | 7 more per 1000 (25 fewer to 55 more) | ||||
| Cardiovascular adverse events Follow‐up: mean 3 months | 1967 (4 RCTs) | ⊕⊝⊝⊝ Very lowa,b,d | RR 1.28 (0.67 to 2.45) | Study population | |
| 42 per 1000 | 12 more per 1000 (14 fewer to 61 more) | ||||
| Assumed baseline riske | |||||
| 61 per 1000 | 17 more per 1000 (20 fewer to 88 more) | ||||
| Sexual adverse events Follow‐up: mean 3 months | 1967 (4 RCTs) | ⊕⊕⊝⊝ Moderatea | RR 26.07 (12.36 to 54.97) | Study population | |
| 7 per 1000 | 180 more per 1000 (82 more to 388 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCTs: randomized controlled trials; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
aDowngraded by one level for study limitations: unclear or high risk of bias for one or more domains among the included studies. bDowngraded by one level for imprecision: confidence interval crosses assumed threshold of clinically important difference. cNot downgraded for inconsistency despite moderate heterogeneity given that likely not clinically meaningful. dDowngraded by one level for inconsistency: substantial heterogeneity among the included studies. eEstimates for control event rates for cardiovascular adverse events come from Rosenzweig 1993.
Summary of findings 2. Silodosin compared to tamsulosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term).
| Silodosin compared to tamsulosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term) | |||||
|
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: silodosin Comparator: tamsulosin | |||||
| Outcomes | № of participants (studies) | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | |
| Risk with tamsulosin | Risk difference with silodosin | ||||
| Urologic symptom scores Assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: range 4 weeks to 12 months | 1708 (10 RCTs) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of urologic symptom scores ranged from ‐15.60 to ‐4.60 | MD 0.04 lower (1.31 lower to 1.24 higher) |
| QoL Assessed with: IPSS‐QoL Scale from: 0 (best: delighted) to 6 (worst: terrible) Follow‐up: range 4 weeks to 12 months | 1707 (10 RCTs) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of QoL ranged from ‐3.60 to ‐0.90 | MD 0.15 lower (0.53 lower to 0.22 higher) |
| Treatment withdrawal due to any reason Follow‐up: range 4 weeks to 12 months | 1573 (10 RCTs) | ⊕⊝⊝⊝ Very lowa,b,c | RR 1.02 (0.62 to 1.69) | Study population | |
| 121 per 1000 | 2 fewer per 1000 (46 fewer to 84 more) | ||||
| Cardiovascular adverse events Follow‐up: range 4 weeks to 3 months | 1955 (11 RCTs) | ⊕⊕⊝⊝ Lowa,c | RR 0.77 (0.53 to 1.12) | Study population | |
| 63 per 1000 | 14 fewer per 1000 (29 fewer to 8 more) | ||||
| Sexual adverse events Follow‐up: range 4 weeks to 3 months | 1849 (10 RCTs) | ⊕⊕⊕⊝ Moderatea | RR 6.05 (3.55 to 10.31) | Study population | |
| 28 per 1000 | 141 more per 1000 (71 more to 261 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCTs: randomized controlled trials; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
aDowngraded by one level for study limitations: unclear or high risk of bias for one or more domains among the included studies. bDowngraded by one level for inconsistency: considerable heterogeneity among the included studies. cDowngraded by one level for imprecision: confidence interval crosses assumed threshold of clinically important difference.
Summary of findings 3. Silodosin compared to naftopidil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term).
| Silodosin compared to naftopidil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term) | |||||
|
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: silodosin Comparator: naftopidil | |||||
| Outcomes | № of participants (studies) | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | |
| Risk with naftopidil | Risk difference with silodosin | ||||
| Urologic symptom scores Assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: range 6 weeks to 3 months | 652 (5 RCTs) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of urologic symptom scores ranged from ‐7.52 to ‐3.56 | MD 0.85 lower (2.57 lower to 0.87 higher) |
| QoL Assessed with: IPSS‐QoL Scale from: 0 (best: delighted) to 6 (worst: terrible) Follow‐up: range 6 weeks to 3 months | 652 (5 RCTs) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of QoL ranged from ‐1.60 to ‐0.95 | MD 0.17 lower (0.6 lower to 0.27 higher) |
| Treatment withdrawal due to any reason Follow‐up: range 2 months to 3 months | 659 (4 RCTs) | ⊕⊕⊝⊝ Lowa,c | RR 1.25 (0.81 to 1.93) | Study population | |
| 102 per 1000 | 25 more per 1000 (19 fewer to 94 more) | ||||
| Cardiovascular adverse events Follow‐up: range 6 weeks to 3 months | 808 (5 RCTs) | ⊕⊕⊝⊝ Lowa,c | RR 1.02 (0.41 to 2.56) | Study population | |
| 23 per 1000 | 0 more per 1000 (13 fewer to 35 more) | ||||
| Sexual adverse events Follow‐up: range 6 weeks to 3 months | 405 (4 RCTs) | ⊕⊕⊕⊝ Moderatea | RR 5.93 (2.16 to 16.29) | Study population | |
| 15 per 1000 | 74 more per 1000 (17 more to 231 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCTs: randomized controlled trials; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
aDowngraded by one level for study limitations: unclear or high risk of bias for one or more domains among the included studies. bDowngraded by one level for inconsistency: considerable heterogeneity among the included studies. cDowngraded by one level for imprecision: confidence interval crosses assumed threshold of clinically important difference.
Summary of findings 4. Silodosin compared to alfuzosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term).
| Silodosin compared to alfuzosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term) | |||||
|
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: silodosin Comparator: alfuzosin | |||||
| Outcomes | № of participants (studies) | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | |
| Risk with alfuzosin | Risk difference with silodosin | ||||
| Urologic symptom scores Assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: mean 3 months | 60 (1 RCT) | ⊕⊕⊝⊝ Lowa,b | ‐ | The mean change of urologic symptom scores was ‐16.93 | MD 3.83 higher (0.12 higher to 7.54 higher) |
| QoL Assessed with: IPSS‐QoL Scale from: 0 (best: delighted) to 6 (worst: terrible) Follow‐up: mean 3 months | 60 (1 RCT) | ⊕⊕⊕⊝ Moderatea | ‐ | The mean change of QoL was ‐4.27 | MD 0.14 higher (0.46 lower to 0.74 higher) |
| Treatment withdrawal due to any reason Follow‐up: mean 3 months | 60 (1 RCT) | ⊕⊕⊝⊝ Lowa,c | Not estimable | Study population | |
| ‐ | ‐ | ||||
| Cardiovascular adverse events Follow‐up: mean 3 months | 60 (1 RCT) | ⊕⊕⊝⊝ Lowa,b | RR 0.67 (0.36 to 1.24) | Study population | |
| 500 per 1000 | 165 fewer per 1000 (320 fewer to 120 more) | ||||
| Assumed baseline riskd | |||||
| 44 per 1000 | 15 fewer per 1000 (11 fewer to 28 more) | ||||
| Sexual adverse events Follow‐up: mean 3 months | 95 (1 RCT) | ⊕⊕⊝⊝ Moderatea | RR 37.21 (5.32 to 260.07) | Study population | |
| 21 per 1000 | 770 more per 1000 (92 more to 5,512 more) | ||||
| Assumed baseline riskd | |||||
| 6 per 1000 | 217 more per 1000 (26 more to 1000 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCTs: randomized controlled trials; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
aDowngraded by one level for study limitations: unclear or high risk of bias for one or more domains in the included study. bDowngraded by one level for imprecision: confidence interval crosses assumed threshold of clinically important difference. cDowngraded by one level for imprecision: no event (very rare event). dEstimates for control event rates for cardiovascular and sexual adverse events come from Van Kerrebroec 2002.
Background
Description of the condition
Benign prostatic hyperplasia (BPH) is characterized by an unregulated proliferative process of connective tissue, smooth muscle and glandular epithelium within the prostate, and is one of the most common conditions in elderly men (Roehrborn 2008). The prevalence of BPH rises significantly with increased age. Autopsy studies have observed a histological prevalence of 40% and 70% in the sixth and eighth decades of life, respectively (Barry 1997; Egan 2016; Roehrborn 2008). BPH can lead to troublesome lower urinary tract symptoms (LUTS), including storage disturbances (such as daytime urinary urgency and nocturia) or voiding disturbances (such as urinary hesitancy, weak urinary stream, straining to void, and prolonged voiding), or both (AUA Practice Guidelines Committee 2003; EAU 2017; McVary 2011). LUTS secondary to BPH (LUTS/BPH) may negatively impact on public health and reduce quality of life because BPH can progress over time and cause serious consequences, such as acute urinary retention (AUR), urinary tract infection, and upper urinary tract deterioration (Crawford 2006; Kozminski 2015; Martin 2014). In 2000, the direct treatment cost for LUTS/BPH in the USA was more than USD 1 billion. Based on the Hospital Episode Statistics data from the UK, LUTS/BPH is the fifth most expensive disease and costs GBP 1.16 billion each year (Cornu 2010).
Diagnosis
Initial assessment of LUTS/BPH includes patient history, review of current medications, physical exam including a digital rectal examination, urinalysis, a frequency/volume chart, and validated symptom questionnaires such as the International Prostate Symptom Score (IPSS) and BPH Impact Index (BII) (EAU 2017; Juliao 2012; McVary 2011). The IPSS questionnaire is composed of three domains related to storage symptoms (frequency, urgency, and nocturia); four domains related to voiding symptoms (hesitancy, weak stream, intermittence, and incomplete emptying); and one quality of life domain (AUA Practice Guidelines Committee 2003; Barry 1992). Seven symptom domains use a six‐point scale ranging from 0 (none) to 5 (5 or more) (Barry 1992). The quality of life domain is assigned a score from 1 to 6 (ordinal and range from 0 to 6: 0 = delighted, 1 = pleased, 2 = mostly satisfied, 3 = mixed, 4 = mostly dissatisfied, 5 = unhappy, 6 = terrible) (AUA Practice Guidelines Committee 2003; Barry 1992).
Simultaneous with the development of the IPSS, the BII was developed to assess the effect of LUTS/BPH on the men's health. The BII questionnaire is composed of four items: physical discomfort (0 = none, 1 = only a little, 2 = some, 3 = a lot); worry item (0 = none, 1 = only a little, 2 = some, 3 = a lot); bother item (0 = not at all bothersome, 1 = bothers me a little, 2 = bothers me some, 3 = bothers me a lot); the interference with usual activities item (0 = none of the time, 1 = a little of the time, 2 = some of the time, 3 = most of the time, 4 = all of the time) (Barry 1995). In addition, measurement of the maximum flow rate (Qmax) and postvoid residual (PVR) are widely used, noninvasive tests to evaluate joint functioning between bladder and prostate (EAU 2017; McVary 2011). Although diagnostic thresholds of Qmax and PVR have not been determined, low Qmax and large PVR have been associated with an increased risk of symptom deterioration (Crawford 2006; Kozminski 2015). Other optional tests include imaging of the urinary tract and prostate, urodynamic evaluation of bladder function, and cystoscopy to predict the response to medical therapy or determine the need for invasive therapy and therefore, the best approach (EAU 2017; McVary 2011).
Treatment
Treatment decisions are based on symptoms and degree of bother (EAU 2017; McVary 2011). Watchful waiting is a reasonable treatment strategy for men with mild LUTS (IPSS: 0 to 7) or those who do not perceive their symptoms to be particularly bothersome (Netto 1999). Lifestyle interventions such as modifying fluid intake or toileting behavior can be used as conservative treatments in men with mild LUTS (Yap 2009). In men with bothersome, moderate (IPSS: 8 to 19) to severe LUTS (IPSS: 20 to 35), surgical and medical therapies are the treatment options, and the choice of treatment depends on a number of factors such as the severity of disease, risk of progression, patient preference, and morbidity (EAU 2017; McVary 2011).
Recently, the dynamic component of BPH has been elucidated, with a focus on symptoms rather than prostate enlargement, which has led to a shift from surgery to medical treatment (Yoo 2012). Alpha‐adrenergic receptor blockers (ABs), which reduce smooth‐muscle tone in the prostate and bladder neck with/without 5‐alpha reductase inhibitors (5‐ARIs), which reduce prostate volume by inducing epithelial atrophy, are an established treatment in LUTS/BPH and have been widely used as first‐line therapy for decades (McConnell 2003; Milani 2005; Yoo 2012). In particular, ABs that can decrease smooth muscle tone in the prostate and bladder neck have been considered as fundamental pharmacotherapy for men with BPH (Cornu 2010; Milani 2005; Yoo 2012). Prior systematic reviews have shown that ABs can typically reduce the IPSS by 20% to 50% and increase the Qmax by 15% to 45% (MacDonald 2005; Wilt 2006). ABs are the most commonly prescribed category of drug, accounting for about 70% of all medications prescribed in 2008 (Cornu 2010). Adverse effects of ABs include postural hypotension, dizziness, headache, asthenia, syncope, peripheral edema, and retrograde ejaculation, which cause approximately 4% to 10% of men to withdraw from AB treatment (Djavan 1999; Gacci 2014; MacDonald 2005; Schulman 2003; Wilt 2006).
Other medical therapies, such as anticholinergics and desmopressin, have been used with ABs, depending on the main symptoms of patients (Brasure 2016; Dahm 2016; EAU 2017). Alternatively, a phosphodiesterase type 5 inhibitor, tadalafil (5 mg once daily), has been licensed for the treatment of male LUTS in the last few years, and various plant extracts have been proposed for the treatment of male LUTS (EAU 2017; Keehn 2016; Oelke 2012). In men with LUTS/BPH refractory to conservative/medical treatment or in cases of absolute clinical indications (e.g. AUR, recurrent urinary tract infection, bladder stones or diverticula, hematuria, or renal insufficiency), surgical techniques should be considered (EAU 2017; McVary 2011). Transurethral resection of the prostate (TURP) is regarded as the standard surgical procedure for the treatment of LUTS/BPH (EAU 2017; Juliao 2012; McVary 2011). Recently, minimal invasive laser therapies such as holmium laser enucleation of the prostate and photoselective vaporization were introduced as treatment alternatives to TURP (Nair 2016).
Description of the intervention
Silodosin is a new subtype selective AB that was approved in Japan in 2006, and more recently has received approval in the USA and Europe (Kawabe 2006a; Yoshida 2007). An initial randomized, placebo‐controlled trial, which was conducted in Japan showed a greater reduction in IPSS after 12 weeks' treatment compared to both tamsulosin – which is a well established AB for LUTS – and placebo. Furthermore, a clinical benefit in IPSS in the silodosin group over placebo was found from one week onwards (Kawabe 2006a). There were no significant differences in the incidence of cardiovascular adverse events between the silodosin and tamsulosin groups. Abnormal ejaculation was more frequent in the silodosin group than in the tamsulosin group (22.3% versus 1.6%), but only five men (2.9%) discontinued treatment due to abnormal ejaculation (Kawabe 2006a).
How the intervention might work
The A1a adrenergic receptors are a class of G protein‐coupled receptors that consists of three homologous subtypes, including A1a, A1b, and A1d receptors. The A1a receptor subtype predominates in the human prostate, bladder neck, and urethra (Minneman 1994; Schilit 2009). On the other hand, A1b receptor subtypes are mainly expressed in the peripheral vasculature and are important in the regulation of blood pressure. A1d receptor is expressed in the detrusor muscle of the bladder and the sacral region of the spinal cord (Minneman 1994; Schilit 2009). In the initial in vitro study, it was shown that silodosin had a high binding ratio (162:1) for A1a versus A1b receptors, which can be more specific to the lower urinary tract, and may therefore induce a therapeutic effect without cardiovascular side effects, such as dizziness, headache, and orthostatic hypotension related to vasodilation, compared with the other ABs, which have either no specific selectivity for the different adrenergic receptor subtypes (alfuzosin, doxazosin, terazosin) or a limited selectivity for the A1a receptor (tamsulosin) (Osman 2012; Schilit 2009; Yoshida 2007).
Why it is important to do this review
It is unclear whether the high affinity of silodosin to A1a adrenergic receptor actually translates into more clinical benefits and fewer adverse effects in clinical practice (Cui 2012; Novara 2013). While there are existing systematic reviews that compare silodosin to other agents used to treat men with LUTS/BPH, none so far has used the same rigorous methodology as Cochrane Reviews, which include the GRADE approach (Cui 2012; Fusco 2016; Novara 2013). In this era, with the availability of numerous ABs to treat LUTS/BPH, the findings of this Cochrane Review will be relevant to policymakers, healthcare providers and patients.
Objectives
To assess the effects of silodosin for the treatment of LUTS in men with BPH.
Methods
Criteria for considering studies for this review
Types of studies
We included parallel, randomized controlled trials regardless of their publication status or language of publication. We also included cross‐over designs.
Types of participants
We included adult men (aged 40 years and over) with LUTS/BPH. The age limitation was based on the observation that the prevalence of BPH increases in middle‐aged and older men (Barry 1997; Egan 2016), and is infrequent in younger men.
We excluded trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease, and men who have been treated with surgery for BPH already. We included studies in which only a subset of participants were relevant to this review.
Types of interventions
We planned to investigate the following comparisons of experimental intervention versus comparator intervention. Concomitant interventions had to be the same in the experimental and comparator groups to establish fair comparisons.
Experimental interventions
Silodosin
Silodosin + any 5‐ARIs (if available)
Silodosin at 8 mg/day is the clinically recommended dosage in Japan, Europe, and the USA (Chapple 2011; Kawabe 2006a; Marks 2009). A recent study reported that silodosin at 4 mg/day was also useful for Japanese men with BPH, in order to improve treatment compliance (Seki 2015). We included trials with a dosage of silodosin at 8 mg/day (4 mg twice daily or 8 mg once daily) and 4 mg/day.
Comparator interventions
Placebo
Other ABs
Other ABs + any 5‐ARIs (if available)
Comparisons
Silodosin versus placebo
Silodosin versus other ABs
Silodosin + any 5‐ARIs versus other ABs + any 5‐ARIs (if available)
Types of outcome measures
We did not use the measurement of the outcomes assessed in this review as an eligibility criterion.
Primary outcomes
Urologic symptom scores
Quality of life
Treatment withdrawals for any reason
Secondary outcomes
Treatment withdrawals due to adverse events
AUR
Surgical intervention for LUTS/BPH
Cardiovascular adverse events
Sexual adverse events
Method and timing of outcome measurement
Urologic symptom scores: final value or change from baseline assessed with a validated scale (such as IPSS)
Quality of life: final value or change from baseline assessed with a validated scale (such as IPSS‐quality of life or BII scores)
Treatment withdrawals for any reason: defined as treatment discontinuation from any cause at any time after participants were randomized to intervention/comparator groups
Treatment withdrawals due to adverse events: defined as treatment discontinuation from adverse event at any time after participants were randomized to intervention/comparator groups
AUR: events requiring catheterization after intervention
Surgical intervention for LUTS/BPH: events requiring other surgical treatment modalities (e.g. TURP) after intervention
Cardiovascular adverse events: such as dizziness, headache, orthostatic hypotension, and syncope
Sexual adverse events: such as retrograde ejaculation, anejaculation, and decreased libido
We used the clinically important difference for the review outcomes to rate the quality of the evidence in the 'Summary of finding' tables (Jaeschke 1989; Johnston 2013). When the mean difference (MD) or risk ratio (RR) is equal to or larger than the minimal clinically important difference (MCID), we would assume that many participants may have gained a clinically meaningful improvement from treatment; when the MD is at least half of the MCID but less than the MCID, an appreciable number of participants have likely achieved a clinically meaningful improvement; and when the MD is less than one‐half of the MCID, it is unlikely that an appreciable number of participants have achieved a clinically meaningful improvement (Johnston 2010). We considered MCID in the IPSS and BII score to be 3 and 0.5 points, respectively (Barry 1995). We did not find any published information on a MCID for the IPSS‐quality of life question. We used a MCID of 1 to assess efficacy and comparative effectiveness (Brasure 2016). We did not establish thresholds for treatment withdrawals due to adverse events, AUR, surgical intervention for LUTS/BPH, cardiovascular adverse events, and sexual adverse events. We considered the clinically important differences of all listed outcomes above as a relative risk increase of at least 25% (Guyatt 2011a).
We considered outcomes measured up to and including 12 months after randomization as short term, and later than 12 months as long term.
Up to 12 months (short term)
More than 12 months (long term)
Main outcomes for 'Summary of findings' tables
We present 'Summary of findings' tables, reporting the following outcomes listed according to priority.
Urologic symptom scores
Quality of life
Treatment withdrawals for any reason
Cardiovascular adverse events
Sexual adverse events
Search methods for identification of studies
We performed a comprehensive search with no restrictions on the language of publication or publication status. We updated searches within three months prior to the anticipated publication of the review.
Electronic searches
We initially searched the following sources from inception of each database to 1 September 2016. The date of last search of all databases was 13 June 2017. See Appendix 1.
-
Cochrane Library (via Wiley)
Cochrane Database of Systematic Reviews
Cochrane Central Register of Controlled Trials (CENTRAL)
Database of Abstracts of Reviews of Effects
Health Technology Assessment Database
MEDLINE (via Pubmed)
EMBASE (via Ovid)
Scopus
Google Scholar
Web of Science
We also searched the following trials registers on 1 September 2016 and again on 13 June 2017.
ClinicalTrials.gov (clinicaltrials.gov/)
World Health Organization International Clinical Trials Registry Platform search portal (apps.who.int/trialsearch/)
Grey Literature Report (www.greylit.org/)
Searching other resources
We tried to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, reviews, meta‐analyses and health technology assessment reports. We also contacted study authors of included trials to identify any further studies that we might have missed. We contacted drug/device manufacturers for ongoing or unpublished trials. We searched for unpublished studies by handsearching the abstract proceedings of the annual meetings of the American Urological Association, European Association of Urology, and International Continence Society for the last three years (2014 to 2016) and then updated the search for the most recent year (2017).
Data collection and analysis
Selection of studies
We used reference management software to identify and remove potential duplicate records (EndNote). Two review authors (JHJ, JK) independently scanned the abstract, title, or both, of remaining records retrieved, to determine which studies should be assessed further. Two review authors (JHJ, JK) investigated all potentially relevant records as full text, mapped records to studies, and classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies, in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We used Covidence for title/abstract, and full‐text screening. We resolved any discrepancies through consensus or recourse to a third review author (PD). If resolution of a disagreement was not possible, we planned to designate the study as 'awaiting classification' and contact study authors for clarification. We documented reasons for exclusion of studies that may have reasonably been expected to be included in the review in a Characteristics of excluded studies table. We present an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).
Data extraction and management
We developed a dedicated data abstraction form that we pilot tested ahead of time.
For studies that fulfilled the inclusion criteria, two review authors (JHJ, JK) independently abstracted the following information, which we provided in the Characteristics of included studies table.
Study design
Study dates
Study settings and country
Participant inclusion and exclusion criteria (e.g. age, baseline IPSS)
Participant details, baseline demographics (e.g. age, ethnic background, IPSS)
The number of participants by study and by study arm
Details of relevant experimental and comparator interventions such as such as frequency (e.g. once a day or twice a day) and treatment duration (in weeks or months)
Definitions of relevant outcomes, and method (e.g. type of instrument such as IPSS) and timing of outcome measurement (e.g. in weeks or months) as well as any relevant subgroups (e.g. based on age)
Study funding sources
Declarations of interest by primary investigators
We extracted outcome data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we obtained numbers of events and totals for population of a 2 x 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we obtained means and standard deviations or data necessary to calculate this information.
We resolved any disagreements by discussion, or, if required, by consultation with a third review author (PD).
We provided information (including trial identifier), about potentially relevant, ongoing studies in the table Characteristics of ongoing studies.
We attempted to contact authors of included studies to obtain key missing data as needed.
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents or multiple reports of a primary study, we maximized yield of information by mapping all publications to unique studies and collating all available data. We used the most complete data‐set aggregated across all known publications. In case of doubt, we gave priority to the publication reporting the longest follow‐up associated with our primary or secondary outcomes.
Assessment of risk of bias in included studies
Two review authors (JHJ, JK) assessed the risk of bias of each included study independently. We resolved disagreements by consensus, or by consultation with a third review author (PD).
We assessed risk of bias using Cochrane's 'Risk of bias' assessment tool (Higgins 2011b) for the following domains.
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other sources of bias
We judged risk of bias domains as 'low risk', 'high risk', or 'unclear risk' and evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We presented a 'Risk of bias' summary figure to illustrate these findings.
For selection bias (random sequence generation and allocation concealment), we evaluated risk of bias at a trial level.
For performance bias (blinding of participants and personnel), we considered that all outcomes were susceptible to performance bias and assessed in one group.
For detection bias (blinding of outcome assessment), we grouped outcomes as susceptible to detection bias (subjective) or not susceptible to detection bias (objective) outcomes.
We defined the following outcomes as subjective outcomes:
Urologic symptom scores
Quality of life
Treatment withdrawals for any reason
Treatment withdrawals due to adverse events
Cardiovascular adverse events
Sexual adverse events
We defined the following outcomes as objective outcomes:
AUR
Surgical intervention for LUTS/BPH
We initially assessed attrition bias (incomplete outcome data) on a per‐outcome basis but created groups of outcomes based on similar reporting characteristic.
For reporting bias (selective reporting), we evaluated risk of bias on a trial level.
We further summarized the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome, in accordance with the approach for summary assessments of the risk of bias presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).
Measures of treatment effect
We expressed dichotomous data as RRs with 95% confidence intervals (CIs). We expressed continuous data as MDs with 95% CIs unless different studies used different measures to assess the same outcome, in which case we expressed data as standardized MDs with 95% CIs.
Unit of analysis issues
The unit of analysis was the individual participant. For cross‐over trials or trials with more than two intervention groups, we planned to incorporate these study designs in meta‐analysis in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c)
Dealing with missing data
We obtained missing data from study authors and performed intention‐to‐treat analyses if data were available; we otherwise performed available case analyses. We investigated attrition rates, for example, dropouts, losses to follow‐up and withdrawals, and critically appraised issues of missing data. We did not impute missing data.
Assessment of heterogeneity
We identified heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs, and the I2 statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity in the meta‐analysis (Higgins 2002; Higgins 2003); we interpreted the I2 statistic as follows (Deeks 2011).
0% to 40%: may not be important
30% to 60%: may indicate moderate heterogeneity
50% to 90%: may indicate substantial heterogeneity
75% to 100%: considerable heterogeneity
When we found heterogeneity, we attempted to determine possible reasons for it by examining individual study and subgroup characteristics.
Assessment of reporting biases
We attempted to obtain study protocols to assess for selective outcome reporting.
If we included 10 studies or more investigating a particular outcome, we planned to use funnel plots to assess small study effects (Sterne 2011). Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials), and publication bias. We therefore interpreted results carefully. However, there were fewer than 10 studies for each comparison.
Data synthesis
We summarized data using a random‐effects model. We interpreted random‐effects meta‐analyses with due consideration of the whole distribution of effects. In addition, we performed statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). For dichotomous outcomes, we used the Mantel‐Haenszel method; for continuous outcomes, we used the inverse variance method. We used Review Manager 5 software to perform analyses (RevMan 2014).
Subgroup analysis and investigation of heterogeneity
We expected the following characteristics to introduce clinical heterogeneity, and planned to carry out subgroup analyses with investigation of interactions.
Severity of baseline symptoms based on IPSS (0 to 7 = mildly symptomatic; 8 to 19 = moderately symptomatic; 20 to 35 = severely symptomatic)
Participant age (less than 65 years versus 65 years and older)
These subgroup analyses are based on the following observations.
The relationship between changes in IPSS scores and patient global ratings of improvement is influenced by the baseline scores (Barry 1995).
Tolerability of other ABs (as the main comparator) may differ by patient age but that this may be less the case for silodosin, which would represent a potential benefit of this agent (Kozminski 2015; Lepor 2007; Schilit 2009).
We planned to perform subgroup analyses limited to the primary outcomes.
Sensitivity analysis
We planned to perform sensitivity analyses limited to the primary outcomes in order to explore the influence of the following factors (when applicable) on effect sizes.
Restricting the analysis by taking into account risk of bias, by excluding studies at 'high risk' or 'unclear risk' of bias
'Summary of findings' tables
We presented the quality of the evidence for each outcome according to the GRADE approach, which takes into account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias), but also to external validity, such as directness of results (Guyatt 2008). For each comparison, two review authors (JHJ, JK, or RM) independently rated the quality of evidence for each outcome as 'high', 'moderate', 'low', or 'very low' using GRADEpro GDT 2015. We resolved any discrepancies by consensus, or, if needed, by arbitration by a third review author (PD). For each comparison, we presented a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011b; Schünemann 2011).
Results
Description of studies
Results of the search
We identified 645 records through electronic database searching, including 52 records in trials registers. We found no records in the grey literature repository nor through handsearching abstract proceedings of relevant meetings from the last three years. We identified further six records through other sources by searching the reference lists of reviews (Alcántara Montero 2016; Brasure 2016) and one additional protocol for Takeshita 2016. After removal of duplicates, we screened the titles and abstracts of 458 records, and excluded 378 records. We screened 80 full‐text articles, and excluded 23 studies (24 records) that did not meet the inclusion criteria or were not relevant to the question under trial. Two studies are ongoing and 12 studies are awaiting classification. We included a total of 19 studies (42 records) in the review. The flow of literature through the assessment process is shown in the PRISMA flowchart (Figure 1).
1.
Flow diagram
Included studies
Details of included studies are presented elsewhere (see Characteristics of included studies; Table 5; Table 6).
1. Baseline characteristics of included studies.
| Study name | Trial period (year to year) | Country | Setting | Description of participants | Intervention(s) and comparator(s) | Duration of intervention (duration of follow‐up) | Age | Prostate volume | IPSS |
| Chapple 2011 | 2006‐2007 | Europe | 72 hospital clinics and inpatient units in 11 countries | Men ≥ 50 years with LUTS (defined by a stable IPSS total score ≥ 13 points), bladder outlet obstruction (defined by a Qmax between 4 and 15 mL/s, with a minimum voided volume of ≥ 125 mL) | Silodosin 8 mg once daily | 12 weeks | 65.8 ± 7.70 | NR | 19.1 ± 4.2 |
| Tamsulosin 0.4 mg once daily | 65.9 ± 7.41 | 18.9 ± 4.3 | |||||||
| Placebo once daily | 66.0 ± 7.37 | 19.3 ± 4.3 | |||||||
| Jung 2012 | NR | South Korea | NR | Sexually active men with BPH | Silodosin 8 mg once daily | 4 weeks | NR | NR | NR |
| Tamsulosin 0.2 mg once daily | |||||||||
| Alfuzosin 10 mg once daily | |||||||||
| Kawabe 2006a | NR | Japan | 88 centers/outpatient | Men ≥ 50 years with LUTS (IPSS of ≥ 8, an associated QoL score of ≥ 3) and prostate volume of ≥ 20 mL | Silodosin 4 mg twice daily | 12 weeks | 65.4 ± 7.0 | 36.0 ± 16.9 | 17.1 ± 5.7 |
| Tamsulosin 0.2 mg once daily | 65.6 ± 7.0 | 35.7 ± 14.4 | 17.0 ± 5.7 | ||||||
| Placebo twice daily | 65.0 ± 6.9 | 35.2 ± 16.0 | 17.1 ± 6.1 | ||||||
| Manjunatha 2016a | 2013‐2014 | India | Tertiary care hospital | Men ≥ 45 years with symptomatic BPH with LUTS (IPSS of ≥ 8, QoL of ≥ 3, and Qmax of < 15 mL/s, but > 4 mL/s with a voided volume of > 100 mL) | Silodosin 8 mg once daily | 12 weeks | 64.00 ± 11.14 | 40.57 ± 16.45 | 15.93 ± 6.03 |
| Tamsulosin 0.4 mg once daily | 63.60 ± 9.05 | 40.33 ± 21.55 | 21.63 ± 7.63 | ||||||
| Alfuzosin 10 mg once daily | 63.43 ± 8.91 | 44.43 ± 27.72 | 19.2 ± 9.6 | ||||||
| Marks 2009 | 2005‐2006 | USA | Multicenter | Men ≥ 50 years with IPSS ≥ 13, Qmax 4 mL/s‐15 mL/s and a PVR < 250 mL | Silodosin 8 mg once daily | 12 weeks | 64.6 ± 8.1 | NR | 21.3 ± 5.1 |
| Placebo once daily | 64.7 ± 8.1 | 21.3 ± 4.9 | |||||||
| Masuda 2012 | 2009‐2011 | Japan | NR | Men ≥ 50 years with prostate estimated volume of > 20 mL, IPSS ≥ 8, QoL score ≥ 3 points | Silodosin 2 mg‐4 mg twice/d for 2 weeks, followed by 4 mg twice/d for 4 weeks | 6 weeks (before cross‐over)/total 12 weeks | 66.5 ± 5.6 | 38.8 ± 13.1 | 18.6 ± 5.5 |
| Naftopidil 50 mg‐75 mg once/d for 2 weeks, followed by 75 mg once/d for 4 weeks | 68.5 ± 5.7 | 45.7 ± 17.8 | 17.6 ± 5.0 | ||||||
| Matsukawa 2016 | 2012‐2013 | Japan | 52 urologists participated at a total of 44 investigational sites/outpatients | Men with LUTS (IPSS ≥ 8, IPSS QoL score 3) and prostate volume ≥ 20 mL | Silodosin 4 mg/d for 4 weeks, followed by 8 mg/d for 8 weeks | 12 weeks | 70.6 ± 7.8 | 39.6 ± 16.7 | 18.8 ± 6.2 |
| Naftopidil 50 mg/d for 4 weeks, followed by 75 mg/d for 8 weeks | 70.3 ± 7.8 | 38.6 ± 14.8 | 18.9 ± 6.1 | ||||||
| Miyakita 2010 | 2006‐2007 | Japan | Multicenter | Men with IPSS ≥ 8 points; QoL score ≥ 3 points; prostate volume measured by ultrasonographic method ≥ 20 mL; void volume ≥ 100 mL; and maximal urinary flow rate (Qmax) < 15 mL/s | Silodosin 4 mg twice daily | 4 weeks (before cross‐over)/total 8 weeks | 68.2 ± 8.6 | 41.3 ± 25.3 | 16.6 ± 5.2 |
| Tamsulosin 0.2 mg once daily | 70.1 ± 8.9 | 37.8 ± 16.3 | 18.2 ± 5.8 | ||||||
| Natarajan 2015 | 2013‐2015 | India | Tertiary hospital | Men > 50 years with bothersome LUTS from BPH and IPSS > 7 | Silodosin 8 mg once daily | 12 weeks | 61 ‐ 62 | NR | NR |
| Tamsulosin 0.4 mg once daily | |||||||||
| NCT00793819 | 2009 | NR | NR | Men ≥ 50 years, with symptoms of moderate‐severe BPH and nocturia (≥ 2 episodes/night) | Silodosin 8 mg daily | 12 weeks | 64.6 ± 8.03 | NR | NR |
| Placebo once daily | 64.2 ± 8.92 | ||||||||
| Pande 2014 | 2012‐2013 | India | Tertiary care hospital/ outpatient | Men > 50 years with bothersome LUTS from BPH and IPSS > 7 | Silodosin 8 mg once daily | 12 weeks | 61.4 ± 7.88 | 42.0 ± 19.96 | 18.4 ± 3.32 |
| Tamsulosin 0.4 mg once daily | 62.6 ± 7.55 | 35.6 ± 9.56 | 18.4 ± 3.94 | ||||||
| Shirakawa 2013 | 2007‐2011 | Japan | Kobe University School or other collaborating institutions | Men with LUTS (total IPSS ≥ 8, QoL index ≥ 3) and prostate volume ≥ 20 mL | Silodosin 4 mg twice daily | 8 weeks | 70.98 ± 6.69 | 38.24 ± 12.94 | 17.53 ± 5.4 |
| Naftopidil 50 mg once daily | 70.50 ± 6.58 | 39.39 ± 25.96 | 17.56 ± 6.7 | ||||||
| Takeshita 2016 | 2011‐2014 | Japan | Four community‐based hospitals | Men aged ≥ 50 years with LUTS/BPH, an IPSS of ≥ 8, QoL score of ≥ 3, and ultrasound‐estimated prostatic volume of ≥ 20 mL | Silodosin 4 mg once daily | 4 weeks (before cross‐over)/total 8 weeks | 69.6 ± 5.4 | 38.7 ± 11.6 | 17.1 ± 7.3 |
| Tamsulosin 0.2 mg once daily | 69.4 ± 7.0 | 47.3 ± 30.4 | 15.2 ± 7.0 | ||||||
| Watanabe 2011 | 2008‐2009 | Japan | Three institutions | Men with LUTS associated with BPH and had an IPSS ≥ 8 and an IPSS‐QoL score ≥ 2 | Silodosin 4 mg twice daily | 4 weeks (before cross‐over)/total 8 weeks | 69.3 ± 8.3 | 36.6 ± 18.3 | 16.4 ± 5.0 |
| Tamsulosin 0.2 mg once daily | 69.9 ± 8.4 | 35.1 ± 13.0 | 18.1 ± 6.2 | ||||||
| Yamaguchi 2013 | 2007‐2010 | Japan | Nihon University School of Medicine | Men with BPH, ≥ 50 years with significant LUTS (IPSS ≥ 8, QoL score ≥ 3) | Silodosin 8 mg/ day | 12 weeks | 69.3 ± 7.8 | 33.2 ± 21.2 | 16.9 ± 5.5 |
| Naftopidil 75 mg/ day | 70.0 ± 7.0 | 39.5 ± 18.0 | 18.9 ± 7.0 | ||||||
| Yamanishi 2011 | NR | NR | NR | Men with LUTS (IPSS total score ≥ 8, Qmax < 15 mL/s) and prostate volume > 20 mL | Silodosin 4 mg twice daily | 12 months | 71.3 ± 8.2 | 42.0 ± 23.7 | 18.8 ± 7.3 |
| Tamsulosin 0.2 ‐ 0.4 mg daily | 72.2 ± 7.6 | 41.2 ± 23.0 | 17.8 ± 6.4 | ||||||
| Yokoyama 2011 | NR | Japan | Kawasaki Medical School | Men aged 50–‐80 years and with IPSS ≥ 8 | Silodosin 4 mg twice daily | 12 weeks | 70.2 ± 0.9 | 33.3 ± 2.3 | 18.7 ± 0.7 |
| Tamsulosin 0.2 mg once daily | 71.5 ± 1.1 | 32.5 ± 2.0 | 18.0 ± 1.1 | ||||||
| Naftopidil 50 mg once daily | 69.1 ± 1.2 | 35.0 ± 3.1 | 17.4 ± 0.8 | ||||||
| Yokoyama 2012 | 2008‐2010 | Japan | Single center | Men aged 50 years who had a total IPSS ≥ 8 and a QoL index ≥ 3 | Silodosin 4 mg twice daily | 3 months (before cross‐over)/1 month wash‐out/3 months (after cross‐over)/total 7 months | 68.9 ± 5.6 | 35.0 ± 18.4 | 19.3 ± 4.9 |
| Tamsulosin 0.2 mg once daily | 70.0 ± 6.8 | 36.1 ± 15.5 | 21.1 ± 6.8 | ||||||
| Yu 2011 | 2007‐2008 | Taiwan | Nine medical centers | Men aged ≥ 40 years with an IPSS of ≥ 13 and prostate volume of ≥ 20 mL | Silodosin 4 mg twice daily | 12 weeks | 67.5 ± 9.3 | 44.8 ± 24.2 | 19.3 ± 4.5 |
| Tamsulosin 0.2 mg and one placebo | 65.0 ± 8.8 | 38.2 ± 16.7 | 19.8 ± 4.5 |
BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; NR: not reported; PVR: postvoid residual; Qmax: maximum flow rate; QoL: quality of life
2. Participants in included studies.
| Study name | Intervention(s) and comparator(s) | Screened/eligible (N) | randomized (N) | Analysed (N) | Finishing trial (N (%)) |
| Chapple 2011 | Silodosin 8 mg | 1228/955 | 381 | 346 | 356 (93.4) |
| Tamsulosin 0.4 mg | 384 | 347 | 364 (94.7) | ||
| Placebo | 190 | 168 | 172 (90.5) | ||
| Total | 955 | 861 | 892 (93.4) | ||
| Jung 2012 | Silodosin 8 mg | NR/138 | 48 | 48 | 48 (100.0) |
| Tamsulosin 0.2 mg | 43 | 43 | 43 (100.0) | ||
| Alfuzosin 10 mg | 47 | 47 | 47 (100.0) | ||
| Total | 138 | 138 | 138 (100.0) | ||
| Kawabe 2006a | Silodosin 8 mg | NR/457 | 176 | 175 | 175 (99.4) |
| Tamsulosin 0.2 mg | 192 | 192 | 192 (100.0) | ||
| Placebo | 89 | 89 | 89 (100.0) | ||
| Total | 457 | 456 | 456 (99.7) | ||
| Manjunatha 2016a | Silodosin 8 mg | NR/90 | 30 | 30 | 30 (100.0) |
| Tamsulosin 0.4 mg | 30 | 30 | 30 (100.0) | ||
| Alfuzosin 10 mg | 30 | 30 | 30 (100.0) | ||
| Total | 90 | 90 | 90 (100.0) | ||
| Marks 2009 | Silodosin 8 mg | 2849/923 | 466 | 466 | 413 (88.6) |
| Placebo | 457 | 457 | 419 (91.6) | ||
| Total | 923 | 923 | 832 (90.1) | ||
| Masuda 2012 | Silodosin 4 mg or 8 mg | NR/92 | 44 | 30/83a | 30 (68.1) |
| Naftopidil 50 mg or 75 mg | 48 | 34/79a | 34 (70.8) | ||
| Total | 92 | 64/162a | 64 (69.5) | ||
| Matsukawa 2016 | Silodosin 4 mg followed by 8 mg | NR/350 | 175 | 157 | 157 (89.7) |
| Naftopidil 50 mg followed by 75 mg | 175 | 157 | 157 (89.7) | ||
| Total | 350 | 314 | 314 (89.7) | ||
| Miyakita 2010 | Silodosin 8 mg | NR/97 | 46 | 34 | 34 (73.9) |
| Tamsulosin 0.2 mg | 51 | 31 | 31 (60.7) | ||
| Total | 97 | 65 | 65 (67.0) | ||
| Natarajan 2015 | Silodosin 8 mg | NR/57 | 28 | NR | NR |
| Tamsulosin 0.4 mg | 29 | NR | NR | ||
| Total | 57 | NR | NR | ||
| NCT00793819 | Silodosin 8 mg | 215/209 | 111 | 111 | 97 (87.3) |
| Placebo | 98 | 98 | 89 (90.8) | ||
| Total | 209 | 209 | 186 (88.9) | ||
| Pande 2014 | Silodosin 8 mg | 102/61 | 32 | 26 | 26 (81.2) |
| Tamsulosin 0.4 mg | 29 | 27 | 27 (93.1) | ||
| Total | 61 | 53 | 53 (86.8) | ||
| Shirakawa 2013 | Silodosin 8 mg | NR/121 | 61 | 56/59a | 56 (91.8) |
| Naftopidil 50 mg | 60 | 56/57a | 56 (93.3) | ||
| Total | 121 | 112/116a | 112 (92.5) | ||
| Takeshita 2016 | Silodosin 4 mg | NR/34 | 18 | 16 | 16 (88.8) |
| Tamsulosin 0.2 mg | 16 | 14 | 14 (87.5) | ||
| Total | 34 | 30 | 30 (88.2) | ||
| Watanabe 2011 | Silodosin 4 mg | NR/102 | 51 | 42/88a | 42 (82.3) |
| Tamsulosin 0.2 mg | 51 | 42/91a | 42 (82.3) | ||
| Total | 102 | 84/179a | 42 (82.3) | ||
| Yamaguchi 2013 | Silodosin 8 mg | 109/109 | 58 | 53 | 53 (91.3) |
| Naftopidil 75 mg | 51 | 44 | 44 (86.2) | ||
| Total | 109 | 97 | 97 (88.9) | ||
| Yamanishi 2011 | Silodosin 8 mg | NR/149 | 75 | NR | NR |
| Tamsulosin 0.2 ‐ 0.4 mg | 74 | NR | NR | ||
| Total | 149 | NR | NR | ||
| Yokoyama 2011 | Silodosin 8 mg | 136/136 | 45 | 41 | 41 (91.1) |
| Tamsulosin 0.2 mg | 45 | 39 | 39 (86.6) | ||
| Naftopidil 50 mg | 46 | 42 | 42 (91.3) | ||
| Total | 136 | 122 | 122 (89.7) | ||
| Yokoyama 2012 | Silodosin 8 mg | NR/46 | 23 | 23 | 23 (100.0) |
| Tamsulosin 0.2 mg | 23 | 23 | 23 (100.0) | ||
| Total | 46 | 46 | 46 (100.0) | ||
| Yu 2011 | Silodosin 8 mg | NR/209 | 105 | 87 | 87 (82.8) |
| Tamsulosin 0.2 mg | 104 | 83 | 83 (79.8) | ||
| Total | 209 | 170 | 170 (81.3) | ||
| Grand total | Interventions: silodosin | 1955 | 1684b | ||
| Compartors: placebo | 834 | 769 (92.2) | |||
| Compartors: tamsulosin | 1049 | 888b | |||
| Compartors: naftopidil | 380 | 333 (87.6) | |||
| Comparator: alfuzosin | 77 | 77 (100.0) | |||
| Overall | 4295 | 3751b | |||
N: number; NR: not reported
a Efficacy analysis/safety analysis. b The number of participants who finished trials were not reported in two included studies (Natarajan 2015; Yamanishi 2011).
Source of data
We included 16 published studies, two abstract proceedings (Jung 2012; Yamanishi 2011), and one record (NCT00793819) from a trials register. Of 16 published studies, we found two studies (Pande 2014; Yokoyama 2011) by searching the reference lists of an existing review (Brasure 2016) and the remaining studies were identified through our electronic database search. Eighteen studies were published in English and one was published in Japanese (Masuda 2012), which was translated into English using Google translator. We attempted to contact all corresponding authors of included trials to obtain additional information on study methodology and results, and received replies from nine (Chapple 2011; Jung 2012; Masuda 2012; Pande 2014; Takeshita 2016; Yamaguchi 2013; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; see Appendix 2).
Study design and settings
We included 14 parallel, randomized controlled trials (Chapple 2011; Jung 2012; Kawabe 2006a; Manjunatha 2016a; Marks 2009; Matsukawa 2016; Natarajan 2015; NCT00793819; Pande 2014; Shirakawa 2013; Yamaguchi 2013; Yamanishi 2011; Yokoyama 2011; Yu 2011) and five cross‐over trials (Masuda 2012; Miyakita 2010; Takeshita 2016; Watanabe 2011; Yokoyama 2012). Five of 19 studies were reported as 'double‐blinded'. The participants and investigators were blinded in three studies (Marks 2009; NCT00793819; Yu 2011) and participants and personnel were blinded in one study (Chapple 2011). One study was reported to be 'double‐blinded' but it was not clear who was blinded (Kawabe 2006a). Four studies were open‐label trials (Jung 2012; Manjunatha 2016a; Matsukawa 2016; Shirakawa 2013). The remaining five trials had no information regarding blinding. There were three trials with run‐in periods (Chapple 2011; Marks 2009; Yu 2011).
All studies were likely conducted in an outpatient clinic setting. Three studies explicitly stated that the trial was conducted in an outpatient clinic setting (Kawabe 2006a; Matsukawa 2016; Pande 2014). Most of the included studies (Jung 2012; Kawabe 2006a; Manjunatha 2016a; Masuda 2012; Matsukawa 2016; Miyakita 2010; Natarajan 2015; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yokoyama 2011; Yokoyama 2012; Yu 2011) were performed in Asia, except two studies, which were performed in Europe (Chapple 2011) and the USA (Marks 2009). Eight trials (Chapple 2011; Kawabe 2006a; Marks 2009; Masuda 2012; Matsukawa 2016; Miyakita 2010; Takeshita 2016; Watanabe 2011) were multicenter trials. The studies were performed from 2005 to 2015.
Participants
We included a total of 4295 randomized participants (silodosin 1955, placebo 834, tamsulosin 1049, naftopidil 380, alfuzosin 77), of which a total of 3751 finished the trials (silodosin 1684, placebo 769, tamsulosin 888, naftopidil 333, alfuzosin 77). However, two studies (Natarajan 2015; Yamanishi 2011), that compared silodosin to tamsulosin, did not report the number of participants who completed the trial in each group. All studies included men aged over 40 years. The mean age, prostate volume, prostate specific antigen (PSA), International Prostate Symptom Score (IPSS), and maximum flow rate (Qmax) of the participants were 66.5 years, 38.2 mL, 3.14 ng/mL, 19.1, and 9.5 mL/s, respectively.
Most of the studies included participants with lower urinary tract symptoms (LUTS) of a total IPSS more than 8 (Kawabe 2006a; Manjunatha 2016a; Masuda 2012; Matsukawa 2016; Miyakita 2010; Natarajan 2015; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012). Participants with IPSS more than 13 were included in three studies (Chapple 2011; Marks 2009; Yu 2011). Two studies (abstract Jung 2012, protocol NCT00793819) did not specify the inclusion criteria for LUTS in detail. Eight out of 19 studies included participants with a prostate volume greater than 20 mL (Kawabe 2006a; Masuda 2012; Matsukawa 2016; Miyakita 2010; Shirakawa 2013; Takeshita 2016; Yamanishi 2011; Yu 2011). Nine studies used 15mL/s or less in Qmax as an inclusion criterion (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Marks 2009; Matsukawa 2016; Miyakita 2010; Shirakawa 2013; Yamanishi 2011; Yu 2011). Major exclusion criteria included LUTS from any cause other than benign prostatic hyperplasia (BPH), prior treatment with other BPH medical therapy, recent acute urinary retention (AUR), raised prostate‐specific antigen (PSA) level suspicious of prostate cancer, a history of prostate cancer or prior prostate‐related surgery. Chapple 2011 excluded men with improvement in the IPSS total score of 25% or more in the run‐in period and Marks 2009 excluded 615 participants due to adverse events, investigator recommendation, lack of efficacy, loss‐to‐follow‐up, protocol violation, voluntary withdrawal, or other issues during the run‐in period.
Intervention(s) and comparator(s)
Silodosin was administered as an oral dose of 8 mg (8 mg once daily or 4 mg twice daily) in all studies except one (Takeshita 2016; 4 mg once daily). Two studies titrated the drug dose (4 mg followed by 8 mg) during the study period (Masuda 2012; Matsukawa 2016).
Four agents, namely placebo, tamsulosin, naftopidil, and alfuzosin were used as comparators. All comparators were administrated orally. Placebo was administrated in accordance with frequencies of silodosin (Chapple 2011; Kawabe 2006a; Marks 2009; NCT00793819). Tamsulosin was administered as an oral dose of 0.2 mg (Jung 2012; Kawabe 2006a; Miyakita 2010; Takeshita 2016; Watanabe 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) or 0.4 mg once daily (Chapple 2011; Manjunatha 2016a; Natarajan 2015; Pande 2014). One study did not specify the exact dose of tamsulosin (Yamanishi 2011). Naftopidil was administered as an oral dose of 50 mg (Shirakawa 2013; Yokoyama 2011) or 75 mg once daily (Yamaguchi 2013). Two studies titrated the drug dose (50 mg followed by 75 mg) during the study period (Masuda 2012; Matsukawa 2016). Alfuzosin was administered as an oral dose of 10 mg once daily (Jung 2012; Manjunatha 2016a).
The duration of intervention was 12 weeks in 11 (of 19) studies (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Marks 2009; Matsukawa 2016; Natarajan 2015; Pande 2014; NCT00793819; Yamaguchi 2013; Yokoyama 2011; Yu 2011). Jung 2012 and Shirakawa 2013 followed the participants for four weeks and eight weeks only, respectively. Yamanishi 2011 reported 12‐month follow‐up data. For cross‐over trials, three (Miyakita 2010; Takeshita 2016; Watanabe 2011), one (Masuda 2012), and one study (Yokoyama 2012) reported 4 weeks', 6 weeks', and 12 weeks' follow‐up outcomes before the cross‐over, respectively.
Comparisons
We included four comparisons in this review: four studies compared silodosin to placebo (Chapple 2011; Kawabe 2006a; Marks 2009; NCT00793819). Thirteen (Chapple 2011; Jung 2012; Kawabe 2006a; Manjunatha 2016a; Miyakita 2010; Natarajan 2015; Pande 2014; Takeshita 2016; Watanabe 2011; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) compared silodosin to tamsulosin, five (Masuda 2012; Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) compared silodosin to naftopidil, and two studies (Jung 2012; Manjunatha 2016a) compared silodosin to alfuzosin. All studies used silodosin, placebo, or other ABs as monotherapy. There were no trials that compared combination therapy with silodosin or any 5‐ARIs to combination therapy with other ABs and any 5‐ARIs.
Outcomes
We identified all primary outcomes in each of the included studies for four comparisons. No trial reported on our predefined secondary outcomes of AUR or surgical intervention for LUTS/BPH. However, we were able to obtain additional information by contact with the study authors (Chapple 2011; Pande 2014; Yamaguchi 2013; Yokoyama 2011) which we used for the data analysis across three comparisons. Given the nature of cross‐over design studies, we assumed they were not applicable to the outcomes of AUR and surgical intervention for LUTS/BPH for the analysis. Other secondary outcomes were reported in at least one of the included studies.
Funding sources and conflicts of interest
Four reported no funding source (Jung 2012; Kawabe 2006a; Manjunatha 2016a; Yokoyama 2012), and five were supported by pharmaceutical companies (Chapple 2011; Marks 2009; NCT00793819; Pande 2014; Yu 2011). The remaining did not mention a funding source.
Nine studies reported no conflicts of interest (Kawabe 2006a; Manjunatha 2016a; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yokoyama 2011; Yokoyama 2012), and four reported having relationships with pharmaceutical companies (Chapple 2011; Marks 2009; NCT00793819; Yu 2011). The remaining did not mention conflicts of interest.
Excluded studies
We excluded 23 studies (24 records) out of 58 studies (80 records) after evaluation of the full‐text publications. Seven studies were reviews (Abramowicz 2009; Alcántara Montero 2016; Curran 2011; Montorsi 2010; Montorsi 2013; Prescrire Int 2011; Prescrire Int 2012). Six studies had the wrong comparator (Cakiroglu 2016; JPRN‐UMIN000007917; Matsukawa 2012; Matsukawa 2017; Yoshida 2017; Yoshihisa 2012). Each of four studies had the wrong study design (Araki 2013; Boeri 2016; Chapple 2009; Kawabe 2006b) and wrong study outcome (Kobayashi 2008; Kobayashi 2009; Manjunatha 2016b; Zhou 2011), respectively. Two studies had the wrong population (Michel 2011; Roehrborn 2009). Details of excluded studies are presented elsewhere (see Characteristics of excluded studies).
Studies awaiting classification and ongoing trials
We found 12 studies awaiting classification (CTRI/2010/091/000526; Devana 2014; Jha 2015; JPRN‐UMIN000003125; JPRN‐UMIN000005151; JPRN‐UMIN000008538; JPRN‐UMIN000011556; Mandal 2013; Manohar 2014; Miyamae 2011; NCT01222650; Pawar 2015) that did not provide usable outcome data and two ongoing studies (JPRN‐UMIN000003609; CTRI/2013/10/004112). Details of studies awaiting classification and ongoing trials are presented elsewhere (see Characteristics of studies awaiting classification; Characteristics of ongoing studies).
Risk of bias in included studies
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
Random sequence generation
We rated 10 studies as low risk of bias (Chapple 2011; Manjunatha 2016a; Marks 2009; Matsukawa 2016; Pande 2014; Shirakawa 2013; Takeshita 2016; Yamaguchi 2013; Yokoyama 2011; Yokoyama 2012) and one study as high risk of bias (Masuda 2012). The remaining were judged as unclear risk of bias.
Allocation concealment
We rated six studies as low risk of bias (Chapple 2011; Manjunatha 2016a; Marks 2009; Pande 2014; Takeshita 2016; Yokoyama 2011) and the remaining as unclear risk of bias.
Blinding
Blinding of participants and personnel
We rated four studies as low risk of bias (Chapple 2011; Marks 2009; NCT00793819; Yu 2011). We judged 10 studies (Jung 2012; Manjunatha 2016a; Matsukawa 2016; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yokoyama 2011; Yokoyama 2012) as high risk of bias and the remaining as unclear risk of bias.
Blinding of outcome assessment
Subjective outcomes: we rated three studies as low risk of bias for subjective outcomes (Marks 2009; NCT00793819; Yu 2011). We judged nine studies (Jung 2012; Manjunatha 2016a; Matsukawa 2016; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yokoyama 2012) as high risk of bias and the remaining as unclear risk of bias for subjective outcomes. (Subjective outcomes: urologic symptom scores, quality of life, treatment withdrawal for any reason, treatment withdrawal due to adverse events, cardiovascular adverse events, and sexual adverse events.)
Objective outcomes: we rated all studies as low risk of bias for objective outcomes because objective outcomes are not likely to be affected by lack of blinding. (Objective outcomes: AUR and surgical intervention for LUTS/BPH.)
Incomplete outcome data
Urologic symptom scores and quality of life: we rated four studies as low risk of bias (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Shirakawa 2013). We judged four studies (Masuda 2012; Miyakita 2010; Yamaguchi 2013; Yamanishi 2011) as high risk of bias and the remaining as unclear risk of bias.
Treatment withdrawal for any reason: we rated 16 studies (Chapple 2011; Manjunatha 2016a; Marks 2009; Masuda 2012; Matsukawa 2016; Miyakita 2010; NCT00793819; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) as low risk of bias and three studies (Jung 2012; Kawabe 2006a; Natarajan 2015) as unclear risk of bias. None of the studies were rated as high risk of bias.
Treatment withdrawal due to adverse events: we rated 14 studies (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Marks 2009; Masuda 2012; Matsukawa 2016; Miyakita 2010; NCT00793819; Pande 2014; Shirakawa 2013; Takeshita 2016; Watanabe 2011; Yamaguchi 2013; Yokoyama 2012) as low risk of bias and the remaining studies as unclear risk of bias.
AUR and surgical intervention for LUTS/BPH: we rated four studies (Chapple 2011; NCT00793819; Pande 2014; Yamaguchi 2013) as low risk of bias and the remaining studies as unclear risk of bias.
Cardiovascular adverse events: we rated 11 studies (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Marks 2009; Miyakita 2010; NCT00793819; Pande 2014; Shirakawa 2013; Takeshita 2016; Yamaguchi 2013; Yokoyama 2012) as low risk of bias and the remaining studies as unclear risk of bias.
Sexual adverse events: we rated 11 studies (Chapple 2011; Kawabe 2006a; Marks 2009; Miyakita 2010; NCT00793819; Pande 2014; Shirakawa 2013; Takeshita 2016; Yamaguchi 2013; Yokoyama 2011; Yokoyama 2012) as low risk of bias and the remaining studies as unclear risk of bias.
Selective reporting
We rated six studies as low risk of bias (Manjunatha 2016a; Marks 2009; NCT00793819; Pande 2014; Shirakawa 2013; Takeshita 2016). We judged three studies (Chapple 2011; Kawabe 2006a; Natarajan 2015) as high risk of bias and the remaining as unclear risk of bias.
Other potential sources of bias
We rated five studies as low risk of bias (Matsukawa 2016; Pande 2014; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2012). We judged five studies (Kawabe 2006a; Manjunatha 2016a; Marks 2009; Yokoyama 2011; Yu 2011) as high risk of bias due to clinically important imbalances in baseline characteristics and high exclusion rates after placebo run‐in periods; the remaining studies were rated as unclear risk of bias.
Effects of interventions
See: Table 1; Table 2; Table 3; Table 4
Details are presented elsewhere (see Table 1; Table 2; Table 3; Table 4).
1. Silodosin versus placebo
1.1. Urologic symptom scores
We included three randomized controlled trials (RCTs) (Chapple 2011; Kawabe 2006a; Marks 2009) with 1743 participants in the analysis (silodosin 1012, placebo 731). Silodosin may reduce urologic symptom scores in an appreciable number of men (MD ‐2.65, 95% CI ‐3.23 to ‐2.08; I2 = 0%). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 1.1).
1.1. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 1 Urologic symptom scores (short term).
1.2. Quality of life
We included two RCTs (Chapple 2011; Kawabe 2006a) with 820 participants in the analysis (silodosin 546, placebo 274). Silodosin likely results in little or no difference in quality of life (MD ‐0.42, 95% CI ‐0.71 to ‐0.13; I2 = 57%). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 1.2).
1.2. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 2 Quality of life (short term).
1.3. Treatment withdrawal for any reason
We included three RCTs (Chapple 2011; Marks 2009; NCT00793819) with 1703 participants in the analysis (silodosin 958, placebo 745). Silodosin may result in little or no difference in treatment withdrawal for any reason (RR 1.08, 95% CI 0.70 to 1.66; I2 = 42%). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 1.3).
1.3. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 3 Treatment withdrawal due to any reason (short term).
1.4. Treatment withdrawal due to adverse events
We included four RCTs (Chapple 2011; Kawabe 2006a; Marks 2009; NCT00793819) with 1967 participants in the analysis (silodosin 1133, placebo 834). Silodosin likely increases treatment withdrawal due to adverse events (RR 2.29, 95% CI 1.41 to 3.72; I2 = 0%). Assuming a baseline risk of treatment withdrawal due to adverse events to be 13.0% (Preston 2000), silodosin would result in 168 more treatment withdrawals per 1000 men (95% CI 53 more to 354 more). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 1.4).
1.4. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 4 Treatment withdrawal due to adverse events (short term).
1.5. AUR
We included two RCTs (Chapple 2011; NCT00793819) with 780 participants in the analysis (silodosin 492, placebo 288). We found no event for AUR in either study group.
1.6. Surgical intervention for LUTS/BPH
We included two RCTs (Chapple 2011; NCT00793819) with 780 participants in the analysis (silodosin 492, placebo 288). We found no event for surgical intervention for LUTS/BPH in either study group.
1.7. Cardiovascular adverse events
We included four RCTs (Chapple 2011; Kawabe 2006a; Marks 2009; NCT00793819) with 1967 participants in the analysis (silodosin 1133, placebo 834). We are uncertain about the effect of silodosin on cardiovascular adverse events (RR 1.28, 95% CI 0.67 to 2.45; I2 = 55%). We rated the quality of the evidence as very low, downgrading for study limitations, inconsistency, and imprecision (Analysis 1.5).
1.5. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 5 Cardiovascular adverse events (short term).
1.8. Sexual adverse events
We included four RCTs (Chapple 2011; Kawabe 2006a; Marks 2009; NCT00793819) with 1967 participants in the analysis (silodosin 1133, placebo 834). Silodosin likely increases sexual adverse events (RR 26.07, 95% CI 12.36 to 54.97; I2 = 0%). Silodosin would result in 180 more sexual adverse events per 1000 men (95% CI 82 more to 388 more). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 1.6).
1.6. Analysis.
Comparison 1 Silodosin versus placebo, Outcome 6 Sexual adverse events (short term).
Subgroup analysis
We were unable to perform any predefined subgroup analyses because there were no relevant data in the included studies. While we found pooled analyses (Novara 2015) from two included studies (Chapple 2011; Marks 2009) that evaluated the efficacy and safety of silodosin versus placebo, we were unable to replicate these analyses ourselves.
Sensitivity analysis
We rated three RCTs (Chapple 2011; Marks 2009; NCT00793819) as low risk of bias and reanalyzed the data focused on these studies alone.
Urologic symptom scores: we found an MD of ‐2.60 (95% CI ‐3.28 to ‐1.92) with the studies rated as low risk of bias (Chapple 2011; Marks 2009) versus an MD of ‐2.65 (95% CI ‐3.23 to ‐2.08) with all included studies (Chapple 2011; Kawabe 2006a; Marks 2009).
Quality of life: we found an MD of ‐0.30 (95% CI ‐0.51 to ‐0.09) with the study rated as low risk of bias (Chapple 2011) versus an MD of ‐0.42 (95% CI ‐0.71 to ‐0.13) with all included studies (Chapple 2011; Kawabe 2006a).
Treatment withdrawal for any reason: we rated all included studies as low risk of bias and we were unable to perform sensitivity analyses for this outcome.
2. Silodosin versus tamsulosin
2.1. Urologic symptom scores
We included 10 RCTs (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Miyakita 2010; Pande 2014; Takeshita 2016; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) with 1708 participants in the analysis (silodosin 859, tamsulosin 849). We used the final value in one study (Pande 2014) and change from baseline in the remaining studies. Silodosin may result in little to no difference in urologic symptom scores (MD ‐0.04, 95% CI ‐1.31 to 1.24; I2 = 87%). We rated the quality of the evidence as low, downgrading for study limitations and inconsistency (Analysis 2.1).
2.1. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 1 Urologic symptom scores (short term).
2.2. Quality of life
We included 10 RCTs (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Miyakita 2010; Pande 2014; Takeshita 2016; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) with 1707 participants in the analysis (silodosin 859, tamsulosin 848). We used the final value in two studies (Miyakita 2010; Pande 2014) and change from baseline in the remaining studies. Silodosin may result in little to no difference in quality of life (MD ‐0.15, 95% CI ‐0.53 to 0.22; I2 = 93%). We rated the quality of the evidence as low, downgrading for study limitations and inconsistency (Analysis 2.2).
2.2. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 2 Quality of life (short term).
2.3. Treatment withdrawal for any reason
We included 10 RCTs (Chapple 2011; Manjunatha 2016a; Natarajan 2015; Pande 2014; Takeshita 2016; Watanabe 2011; Yamanishi 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) with 1573 participants in the analysis (silodosin 788, tamsulosin 785). For the cross‐over trial Watanabe 2011, we applied the conservative approach of only using the number of participants who had been initially randomized, due to lack of information about the number of participants in the analysis. We are uncertain about the effect of silodosin on treatment withdrawal for any reason (RR 1.02, 95% CI 0.62 to 1.69; I2 = 60%). We rated the quality of the evidence as very low, downgrading for study limitations, inconsistency, and imprecision (Analysis 2.3).
2.3. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 3 Treatment withdrawal due to any reason (short term).
2.4. Treament withdrawal due to adverse events
We included nine RCTs (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Natarajan 2015; Pande 2014; Takeshita 2016; Watanabe 2011; Yokoyama 2011; Yokoyama 2012) with 1572 participants in the analysis (silodosin 779, tamsulosin 793). For the cross‐over trials Watanabe 2011 and Yokoyama 2012, we used only the number of participants who had been initially randomized due to lack of information about the number of participants in the analysis. Silodosin may or may not result in an important increase in treatment withdrawal due to adverse events (RR 1.96, 95% CI 1.12 to 3.44; I2 = 0%). Silodosin would result in 21 more treatment withdrawals for any reason per 1000 men (95% CI 3 more to 52 more). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 2.4).
2.4. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 4 Treatment withdrawal due to adverse events (short term).
2.5. AUR
We included three RCTs (Chapple 2011; Pande 2014; Yokoyama 2011) with 906 participants in the analysis (silodosin 454, tamsulosin 452). We found no event for AUR in either study group.
2.6. Surgical intervention for LUTS/BPH
We included three RCTs (Chapple 2011; Pande 2014; Yokoyama 2011) with 906 participants in the analysis (silodosin 454, tamsulosin 452). We found no event for surgical intervention for LUTS/BPH in either study group.
2.7. Cardiovascular adverse events
We included 11 RCTs (Chapple 2011; Kawabe 2006a; Manjunatha 2016a; Miyakita 2010; Natarajan 2015; Pande 2014; Takeshita 2016; Watanabe 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) with 1955 participants in the analysis (silodosin 967, tamsulosin 988). For cross‐over trials, we took all measurements from silodosin periods and all measurements from tamsulosin periods in Watanabe 2011 and analysed these as if the trial were a parallel‐group trial of silodosin versus tamsulosin. However, we used only the number of participants who had been initially randomized due to lack of information about the number of participants in the analysis (Miyakita 2010; Takeshita 2016; Yokoyama 2012). Silodosin may result in little to no difference in cardiovascular adverse events (RR 0.77, 95% CI 0.53 to 1.12; I2 = 3%). We rated the quality of the evidence as low downgrading for study limitations and imprecision (Analysis 2.5).
2.5. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 5 Cardiovascular adverse events (short term).
2.8. Sexual adverse events
We included 10 RCTs (Chapple 2011; Jung 2012; Kawabe 2006a; Natarajan 2015; Pande 2014; Takeshita 2016; Watanabe 2011; Yokoyama 2011; Yokoyama 2012; Yu 2011) with 1849 participants in the analysis (silodosin 920, tamsulosin 929). For cross‐over trials, we took all measurements from silodosin periods and all measurements from tamsulosin periods in Watanabe 2011. However, we used only the number of participants who had been initially randomized due to lack of information about the number of participants in the analysis (Yokoyama 2012). Silodosin likely increases sexual adverse events (RR 6.05, 95% CI 3.55 to 10.31; I2 = 27%). Silodosin would result in 141 more sexual adverse events per 1000 men (95% CI 71 more to 261 more). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 2.6).
2.6. Analysis.
Comparison 2 Silodosin versus tamsulosin, Outcome 6 Sexual adverse events (short term).
Subgroup analysis
We found one cross‐over trial that reported subgroup analyses according to age (70 years or older) and symptom severity (IPSS 20 or more) (Watanabe 2011). We were unable to perform preplanned subgroup analysis due to lack of information in within‐study comparisons.
Sensitivity analysis
We rated only one study (Chapple 2011) as low risk of bias and were unable to perform a sensitivity analysis.
3. Silodosin versus naftopidil
3.1. Urologic symptom scores
We included five RCTs (Masuda 2012; Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 652 participants in the analysis (silodosin 325, naftopidil 327). We used final value in one study (Masuda 2012) and change from baseline in the remaining studies. Silodosin may result in little to no difference in urologic symptom scores (MD ‐0.85, 95% CI ‐2.57 to 0.87; I2 = 84%). We rated the quality of the evidence as low, downgrading for study limitations and inconsistency (Analysis 3.1).
3.1. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 1 Urologic symptom scores (short term).
3.2. Quality of life
We included five RCTs (Masuda 2012; Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 652 participants in the analysis (silodosin 325, naftopidil 327). We used the final values in one study (Masuda 2012) and change from baseline in the remaining studies. Silodosin may result in little to no difference in quality of life (MD ‐0.17, 95% CI ‐0.60 to 0.27; I2 = 91%). We rated the quality of the evidence as low, downgrading for study limitations and inconsistency (Analysis 3.2).
3.2. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 2 Quality of life (short term).
3.3. Treatment withdrawal for any reason
We included four RCTs (Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 659 participants in the analysis (silodosin 334, naftopidil 325). Silodosin may result in little to no difference in treatment withdrawal for any reason (RR 1.25, 95% CI 0.81 to 1.93; I2 = 0%). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 3.3).
3.3. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 3 Treatment withdrawal due to any reason (short term).
3.4. Treament withdrawal due to adverse events
We included five RCTs (Masuda 2012; Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 738 participants in the analysis (silodosin 372, naftopidil 366). For the cross‐over trial Masuda 2012, we used only the number of participants who had been initially randomized due to lack of information about the number of participants in the analysis. Silodosin may result in little to no difference in treatment withdrawal due to adverse events (RR 1.38, 95% CI 0.66 to 2.89; I2 = 0%). We rated the quality of the evidence as low downgrading for study limitations and imprecision (Analysis 3.4).
3.4. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 4 Treatment withdrawal due to adverse events (short term).
3.5. AUR
We included two RCTs (Yamaguchi 2013; Yokoyama 2011) with 180 participants in the analysis (silodosin 94, naftopidil 86). We found no event for AUR in either study group.
3.6. Surgical intervention for LUTS/BPH
We included two RCTs (Yamaguchi 2013; Yokoyama 2011) with 180 participants in the analysis (silodosin 94, naftopidil 86). We found no event for surgical intervention for LUTS/BPH in either study group.
3.7. Cardiovascular adverse events
We included five RCTs (Masuda 2012; Matsukawa 2016; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 808 participants in the analysis (silodosin 411, naftopidil 397). For cross‐over trials, we took all measurements from silodosin periods and all measurements from tamsulosin periods in Masuda 2012. Silodosin may result in little to no difference in cardiovascular adverse events (RR 1.02, 95% CI 0.41 to 2.56; I2 = 0%). We rated the quality of the evidence as low downgrading for study limitations and imprecision (Analysis 3.5).
3.5. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 5 Cardiovascular adverse events (short term).
3.8. Sexual adverse events
We included four RCTs (Masuda 2012; Shirakawa 2013; Yamaguchi 2013; Yokoyama 2011) with 405 participants in the analysis (silodosin 206, naftopidil 199). For cross‐over trials, we took all measurements from silodosin periods and all measurements from tamsulosin periods in Masuda 2012. Silodosin likely increases sexual adverse events (RR 5.93, 95% CI 2.16 to 16.29; I2 = 0%). Silodosin would result in 74 more sexual adverse events per 1000 men (95% CI 17 more to 231 more). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 3.6).
3.6. Analysis.
Comparison 3 Silodosin versus naftopidil, Outcome 6 Sexual adverse events (short term).
Subgroup analysis
We were unable to perform any subgroup analyses because there were no relevant data in the included studies.
Sensitivity analysis
We rated all of the included studies as high or unclear risk of bias and were unable to perform a sensitivity analysis.
4. Silodosin versus alfuzosin
4.1. Urologic symptom scores
We included one RCT (Manjunatha 2016a) with 60 participants in the analysis (silodosin 30, alfuzosin 30). Silodosin may or may not result in a clinically important increase in urologic symptom scores (MD 3.83, 95% CI 0.12 to 7.54). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 4.1).
4.1. Analysis.
Comparison 4 Silodosin versus alfuzosin, Outcome 1 Urologic symptom scores (short term).
4.2. Quality of life
We included one RCT (Manjunatha 2016a) with 60 participants in the analysis (silodosin 30, alfuzosin 30). Silodosin likely results in little to no difference in quality of life (MD 0.14, 95% CI ‐0.46 to 0.74). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 4.2).
4.2. Analysis.
Comparison 4 Silodosin versus alfuzosin, Outcome 2 Quality of life (short term).
4.3. Treatment withdrawal for any reason
We included one RCT (Manjunatha 2016a) with 60 participants in the analysis (silodosin 30, alfuzosin 30). We found no event in treatment withdrawal for any reason in either study group.
4.4. Treatment withdrawal due to adverse events
We included one RCT (Manjunatha 2016a) with 60 participants in the analysis (silodosin 30, alfuzosin 30). We found no event in treatment withdrawal due to adverse events in either study group.
4.5. AUR
We did not find any study that reported this outcome.
4.6. Surgical intervention for LUTS/BPH
We did not find any study that reported this outcome.
4.7. Cardiovascular adverse events
We included one RCT (Manjunatha 2016a) with 60 participants in the analysis (silodosin 30, alfuzosin 30). Silodosin may result in little to no difference in cardiovascular adverse events (RR 0.67, 95% CI 0.36 to 1.24). We rated the quality of the evidence as low, downgrading for study limitations and imprecision (Analysis 4.3).
4.3. Analysis.
Comparison 4 Silodosin versus alfuzosin, Outcome 3 Cardiovascular adverse events (short term).
4.8. Sexual adverse events
We included one RCT (Jung 2012) with 95 participants in the analysis (silodosin 48, alfuzosin 47). Silodosin likely increases sexual adverse events (RR 37.21, 95% CI 5.32 to 260.07). Assuming a baseline risk of 0.6% (Van Kerrebroec 2002), silodosin would result in 217 more sexual adverse events per 1000 men (95% CI 26 more to 1000 more). We rated the quality of the evidence as moderate, downgrading for study limitations (Analysis 4.4).
4.4. Analysis.
Comparison 4 Silodosin versus alfuzosin, Outcome 4 Sexual adverse events (short term).
Subgroup analysis and sensitivity analysis
We were unable to perform secondary analyses because there were no relevant data or too few data in the included studies.
Discussion
Summary of main results
We included 19 unique studies with 4295 randomized participants across four comparisons for short‐term follow‐up. All studies included men aged over 40 years. The mean age and IPSS of the participants were 66.5 years and 19.1, respectively.
Silodosin versus placebo
Silodosin may reduce urologic symptom scores in an appreciable number of men but not improve quality of life appreciably. Treatment withdrawals for any reason do not appear increased. We are uncertain about the effect of silodosin on cardiovascular adverse events but silodosin likely increases sexual adverse events. There were no clinically important changes in treatment effects in a sensitivity analysis focused on low risk of bias studies.
Silodosin versus tamsulosin
Silodosin may result in little to no differences in urologic symptom scores and quality of life. We are uncertain about rates of treatment withdrawal for any reason. Silodosin may result in little to no difference in cardiovascular adverse events but likely increases sexual adverse events substantially.
Silodosin versus naftopidil
Silodosin may have similar effects in urologic symptom scores, quality of life, rates of treatment withdrawal for any reason and cardiovascular adverse events. Silodosin likely increases sexual adverse events substantially.
Silodosin versus alfuzosin
Silodosin may or may not result in a clinically important increase in urologic symptom scores and likely results in little to no difference in quality of life. We found no event in treatment withdrawal for any reason. Silodosin may not reduce cardiovascular adverse events but likely increases sexual adverse events substantially.
We were unable to perform any of the predefined subgroup analyses.
Overall completeness and applicability of evidence
There were a several limitations that related to overall completeness and applicability of evidence that deserve consideration.
Our ability to assess the longer‐term outcomes of silodosin compared to other drugs was limited given that follow‐up duration in almost all studies (18 of 19) was 12 weeks or less. Given the long‐term use of ABs for the treatment of LUTS/BPH in clinical practice, examining the efficacy and safety of silodosin over such a short term appears insufficient to provide assurance of long‐term outcomes.
Three of the larger trials included in this review used pre‐randomization run‐in periods (Chapple 2011; Marks 2009; Yu 2011). This may have led to the exclusion of men who were less likely to be compliant or more prone to experiencing adverse events, thereby limiting generalizability.
We were unable to determine the effect of silodosin on AUR or surgical interventions due to the lack of events in the included studies. This once again relates to the short follow‐up period. Additional information may have to be drawn from longer‐term observational studies.
Rates of adverse events in two studies available in abstract form only were higher than those reported in full‐text studies, raising concern about publication bias (Jung 2012; Yamanishi 2011).
Although ABs such as silodosin are commonly used in combination with 5‐ARIs, we did not find any eligible studies.
Quality of the evidence
We consistently downgraded the quality of the evidence by one or two steps to moderate or low. The most common reasons for downgrading were study limitations (issues surrounding allocation concealment and blinding), inconsistency (as reflected by high I2‐values), which we were unable to explain through secondary analyses, and imprecision (wide confidence intervals that crossed the assumed threshold of clinically important difference or due to few events).
Potential biases in the review process
Despite a comprehensive search strategy without any publication or language restrictions, it is possible that we may have missed relevant publications. A majority of studies originated from Japan and India. It is possible that some, in particular negative studies were published in non‐indexed journals or presented at local meetings only and therefore may have escaped our search, resulting in potential publication bias. The number of studies included in this review were insufficient to generate funnel plots; therefore, the risk of publication bias may have been underestimated. A future update of this review should consider the inclusion of regional bibliographic databases to further enhance the search.
We attempted to contact all the study authors on several occasions seeking feedback. While we received additional information from nine study authors, others did not reply. This may represent a source of bias.
For cross‐over trials, we tried to extract the data before cross‐over, as if the study were a parallel‐group trial, in accordance with Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). However, two cross‐over trials reported adverse events using all measurements from silodosin periods and all measurements from tamsulosin periods (Masuda 2012; Watanabe 2011). This may have given rise to a unit of analysis error. For other cross‐over trials, we used the number of participants initially randomized as a more conservative approach. In addition, one cross‐over trial used the event rate to report individual adverse events, which may also result in a unit of analysis error (double counting) (Masuda 2012).
Agreements and disagreements with other studies or reviews
To date, no published systematic review exists that focuses on silodosin and has applied the same rigorous methodology as this Cochrane Review, which includes a published protocol, a focus on patient‐important outcomes, an exhaustive literature search and an assessment of the quality of the evidence using GRADE.
In a recently reported systematic review and meta‐analysis, a variety of ABs including silodosin were found to have a similar efficacy compared to placebo but were associated with significantly higher incidences of total adverse events and treatment withdrawal (Novara 2013; Yuan 2015). On the other hand, Ding 2013 reported no significant difference in the incidence of ejaculation disorder between the silodosin and tamsulosin groups, but we are concerned that the numbers used in the meta‐analysis were not accurate. A systematic review of naftopidil reported that silodosin had comparable efficacy with naftopidil but was associated with a higher incidence of sexual adverse events (Castiglione 2014). However, no meta‐analysis was reported and the authors did not rate the quality of the evidence. Collectively, the results of the present review are largely consistent with those of previously published reviews compared to placebo, tamsulosin, and naftopidil.
We did not find any published systematic review comparing silodosin to alfuzosin: this review is the first.
Authors' conclusions
Implications for practice.
Based on our findings, the efficacy of silodosin appears to be similar to other ABs including tamsulosin, naftopidil, and alfuzosin but it is associated with increased sexual adverse effects, specifically abnormal ejaculation, which may be an issue for sexually active men.
Implications for research.
The major shortcoming of the current evidence base for silodosin is the short time‐horizon of most studies, limiting our understanding of the long‐term effectiveness and safety. Given that ABs such as silodosin are used for extended periods of time, typically years, longer‐term trials should be performed (and could be mandated by regulatory agencies). In their absence, observational studies may help inform this issue, however, based on a recent systematic review performed by an Evidence‐Based Practice Center in the United States few informative observational studies exist (Brasure 2016). There is also a consistent need for greater methodological rigor and reporting transparency.
Notes
We have based parts of the Methods section of this protocol on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group, which has been modified and adapted for use by Cochrane Urology.
Acknowledgements
We acknowledge the support received from the authors of included studies, Christopher R. Chapple, Gyung‐woo Jung, Leonard S. Marks, Satabdi Pande, Hideki Takeshita, Kenya Yamaguchi, Tomonori Yamanishi, and Teruhiko Yokoyama by providing additional data. We are very grateful to Christopher Filson, Herney Andrés García‐Perdomo, Hong Wook Kim, Stavros Gravas, and Valter Silva for having served as peer reviewers. We thank Cochrane Urology and our contact editors Mari Imamura and Muhammad Imran Omar for supporting this review.
Appendices
Appendix 1. Search strategies
| Cochrane Library (via Wiley) search strategy |
| 1. "Prostatic Hyperplasia" [Mesh] 2. (hyperplasia NEAR/3 prostat*):ti,ab,kw 3. "hyperplasia of the prostate":ti,ab,kw 4. "prostatic hyperplasia":ab,ti 5. (hypertrophy NEAR/3 prostat*):ti,ab,kw 6. (adenoma* NEAR/3 prostat*):ti,ab,kw 7. "lower urinary tract symptom" [Mesh] 8. "lower urinary tract": ti,ab,kw 9. LUTS: ti,ab,kw 10. "prostatism": ti,ab,kw 11. "prostatism"[Mesh] 12. "Urinary Bladder Neck Obstruction" [Mesh] 13. "bladder outlet obstruction": ti,ab,kw 14. (prostat* NEAR/3 enlarg*): ti,ab,kw 15. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 16. silodosin: ti,ab,kw 17. "KMD‐3213": ti,ab,kw 18. 16 or 17 |
| MEDLINE (via Pubmed) search strategy |
| 1. "Prostatic Hyperplasia" [Mesh] or prostatic hyperplasia [TIAB] 2. "Lower Urinary Tract Symptoms" [Mesh] or lower urinary tract [TIAB] or LUTS [TIAB] 3. hyperplasia of the prostate [TIAB] 4. "Prostatic hypertrophy" [TIAB] 5. "Prostatic adenoma" [TIAB] 6. "Prostatism" [Mesh] or Prostatism [TIAB] 7. "Urinary Bladder Neck Obstruction" [Mesh] or "Urinary Bladder Neck Obstruction" [TIAB] 8. bladder outlet obstruction [TIAB] 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. silodosin [Supplementary Concept] 11. silodosin [TIAB] 12. KMD‐3213 [TIAB] 13. rapaflo [TIAB] 14. urief [TIAB] 15. urorec [TIAB] 16. 10 or 11 or 12 or 13 or 14 or 15 17. randomized controlled trial [PT] 18. controlled clinical trial [PT] 19. randomized [TIAB] 20. placebo [TIAB] 21. drug therapy [Sh] 22. randomly [TIAB] 23. trial [TIAB] 24. groups [TIAB] 25. 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 26. 9 AND 16 AND 25 27. (animals [Mesh]) NOT (humans [Mesh] and animals [Mesh]) 28. 26 NOT 27 |
| EMBASE (via Elsevier) search strategy |
| 1. 'prostate hypertrophy'/exp 2. (hyper* NEAR/3 prostat*):ab,ti 3. (adenoma* NEAR/3 prostat*):ab,ti 4. 'BPH' or 'BPO' or 'BPE':ab,ti 5. 'lower urinary tract symptom'/exp 6. 'lower urinary tract' or 'LUTS':ab,ti 7. 'prostatism':ab,ti 8. 'prostatism'/exp 9. 'bladder obstruction'/exp 10. ('bladder* NEAR/3 obstruct*)' or 'BOO' :ab,ti 11. (prostat* NEAR/3 (enlarg* or obstruct*)):ab,ti 12. ((urinary or urethra* or urination or LUT*) NEAR/3 (symptom* or complain*)):ab,ti 13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 14. 'silodosin'/exp 15. silodosin or 'KMD‐3213' or kad3213 or rapaflo or silodyx or urief or urorec or Silofast or Thrupas:tw 16. '160970‐54‐7' or '160970‐64‐9' or '169107‐04‐4':rn 17. 14 or 15 or 16 18. random$ or factorial$ or crossover$ or cross over$ or 'cross‐over$' or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$:tw 19. 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp 20. 18 or 19 21. 13 AND 17 AND 20 22. ('animals'/exp) NOT ('humans'/exp and 'animals'/exp) 23. 21 NOT 22 |
| Scopus search strategy |
| 1. TITLE‐ABS‐KEY (hyperplasia W/3 prostat*) 2. TITLE‐ABS‐KEY (hypertrophy W/3 prostat*) 3. TITLE‐ABS‐KEY (adenoma* W/3 prostat*) 4. TITLE‐ABS‐KEY (prostat* W/3 (enlarg* or obstruct*)) 5. TITLE‐ABS‐KEY ((urinary OR urethra* OR urination OR lut*) W/3 (symptom* OR complain*)) 6. TITLE‐ABS‐KEY (prostatism) 7. TITLE‐ABS‐KEY (bladder* W/3 obstruct*) 8. TITLE‐ABS‐KEY ("lower urinary tract") 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. TITLE‐ABS‐KEY (silodosin or 'KMD‐3213' or rapaflo or silodyx or urief or urorec or Silofast or Thrupas) 11. CASREGNUMBER (160970‐54‐7 OR 160970‐64‐9 OR 169107‐04‐4) 12. 10 or 11 13. TITLE‐ABS‐KEY ("Double blind*" OR "Single Blind*" OR "Cross over stud*") 14. 9 AND 12 AND 13 |
| Google Scholar search strategy |
| allintitle: ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND (silodosin OR KMD‐3213 OR rapaflo OR Silodyx OR kad3213 OR urief OR urorec OR Silodal OR Rapilif OR Silofast OR Thrupas) |
| Web of Science search strategy |
| 1. TS = (hyper* NEAR/3 prostat*) OR (adenoma* NEAR/3 prostat*) OR "BPH" OR "BPO" OR "BPE" OR "lower urinary tract" OR "luts" OR prostatism OR ("bladder NEAR/3 obstruct*") OR "BOO" OR (prostat* NEAR/3 (enlarg* or obstruct*)) OR ((urinary or urethra* or urination or LUT*) NEAR/3 (symptom* or complain*)) 2. TS = (silodosin OR KMD‐3213 OR rapaflo OR urief) 3. TS = "clinical trial*" OR "controlled trial*" OR "randomized controlled trial*" OR (single blind*) OR (double blind*) 4. 1 AND 2 AND 3 |
| ClinicalTrials.gov |
| Basic search = ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND (silodosin OR KMD‐3213 OR rapaflo OR urief OR Thrupas) |
| World Health Organization International Clinical Trials Registry Platform Search Portal |
| In the title = ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND In the intervention= (silodosin OR KMD‐3213 OR rapaflo OR Silodyx OR urief OR urorec OR Silodal OR Thrupas) |
Appendix 2. Survey of trial investigators providing information on included trials
| Date trial author contacted (first) | Date trial author provided data (latest) |
Data trial author provided (short summary) |
|
| Chapple 2011 | 22 Jan 2017 | 2 Feb 2017 | Unadjusted change from baseline in IPSS and QoL, mean and standard deviation of IPSS and QoL at endpoint (12 weeks), the number of participants with acute urinary retention and surgical intervention. |
| Jung 2012 | 18 Jan 2017 | 28 Feb 2017 | Author reply: "Full text was not published". |
| Marks 2009 | 23 Jan 2017 | 23 Jan 2017 | Author reply: "Pharmaceutics only have a data". We cannot contact study supporter in pharmaceutics due to wrong email address. |
| Pande 2014 | 24 Jan 2017 | 18 May 2017 | Mean and standard deviation of IPSS and QoL at baseline and endpoint (12 weeks), the number of participants with acute urinary retention, surgical intervention, cardiovascular adverse events, and sexual adverse events. |
| Takeshita 2016 | 24 Oct 2017 | 3 Nov 2017 | Change from baseline to 4 weeks (before cross‐over) IPSS and QoL (mean and standard deviation). Treatment withdrawal and adverse events at 4 weeks (before cross‐over). Method of random sequence generation and allocation concealment. |
| Yamaguchi 2013 | 27 Jan 2017 | 1 Feb 2017 | Change from baseline in IPSS and QoL (mean and standard deviation), the number of participants with treatment withdrawal, acute urinary retention, surgical intervention, and cardiovascular adverse events. Method of random sequence generation and blinding. |
| Yamanishi 2011 | 27 Jan 2017 | 31 Jan 2017 | Author reply: "Full text was not published". |
| Yokoyama 2011 | 30 Jan 2017 | 13 March 2017 | Dates when study was conducted, study duration (intervention), exclusion criteria, conflicts of interest, mean and standard deviation of IPSS and QoL at baseline and endpoint (12 weeks), the number of participants with acute urinary retention and surgical intervention. Method of random sequence generation and blinding. |
| Yokoyama 2012 | 24 Oct 2017 | 29 Oct 2017 | Total number of participants who were analyzed and finishing the trial at 3 months (before cross‐over), change from baseline to 3 months (before cross‐over) in IPSS and QoL (mean and standard deviation), Treatment withdrawal at 3 months (before cross‐over). Method of random sequence generation and blinding. Presence of published protocol. |
Footnotes
IPSS: International Prostate Symptom Score; QoL: quality of life
Data and analyses
Comparison 1. Silodosin versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Urologic symptom scores (short term) | 3 | 1743 | Mean Difference (IV, Random, 95% CI) | ‐2.65 [‐3.23, ‐2.08] |
| 2 Quality of life (short term) | 2 | 820 | Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐0.71, ‐0.13] |
| 3 Treatment withdrawal due to any reason (short term) | 3 | 1703 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.70, 1.66] |
| 4 Treatment withdrawal due to adverse events (short term) | 4 | 1967 | Risk Ratio (M‐H, Random, 95% CI) | 2.29 [1.41, 3.72] |
| 5 Cardiovascular adverse events (short term) | 4 | 1967 | Risk Ratio (M‐H, Random, 95% CI) | 1.28 [0.67, 2.45] |
| 6 Sexual adverse events (short term) | 4 | 1967 | Risk Ratio (M‐H, Random, 95% CI) | 26.07 [12.36, 54.97] |
Comparison 2. Silodosin versus tamsulosin.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Urologic symptom scores (short term) | 10 | 1708 | Mean Difference (IV, Random, 95% CI) | ‐0.04 [‐1.31, 1.24] |
| 2 Quality of life (short term) | 10 | 1707 | Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐0.53, 0.22] |
| 3 Treatment withdrawal due to any reason (short term) | 10 | 1573 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.62, 1.69] |
| 4 Treatment withdrawal due to adverse events (short term) | 9 | 1572 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [1.12, 3.44] |
| 5 Cardiovascular adverse events (short term) | 11 | 1955 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.53, 1.12] |
| 6 Sexual adverse events (short term) | 10 | 1849 | Risk Ratio (M‐H, Random, 95% CI) | 6.05 [3.55, 10.31] |
Comparison 3. Silodosin versus naftopidil.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Urologic symptom scores (short term) | 5 | 652 | Mean Difference (IV, Random, 95% CI) | ‐0.85 [‐2.57, 0.87] |
| 2 Quality of life (short term) | 5 | 652 | Mean Difference (IV, Random, 95% CI) | ‐0.17 [‐0.60, 0.27] |
| 3 Treatment withdrawal due to any reason (short term) | 4 | 659 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [0.81, 1.93] |
| 4 Treatment withdrawal due to adverse events (short term) | 5 | 738 | Risk Ratio (M‐H, Random, 95% CI) | 1.38 [0.66, 2.89] |
| 5 Cardiovascular adverse events (short term) | 5 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.41, 2.56] |
| 6 Sexual adverse events (short term) | 4 | 405 | Risk Ratio (M‐H, Random, 95% CI) | 5.93 [2.16, 16.29] |
Comparison 4. Silodosin versus alfuzosin.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Urologic symptom scores (short term) | 1 | 60 | Mean Difference (IV, Random, 95% CI) | 3.83 [0.12, 7.54] |
| 2 Quality of life (short term) | 1 | 60 | Mean Difference (IV, Random, 95% CI) | 0.14 [‐0.46, 0.74] |
| 3 Cardiovascular adverse events (short term) | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.36, 1.24] |
| 4 Sexual adverse events (short term) | 1 | 95 | Risk Ratio (M‐H, Random, 95% CI) | 37.21 [5.32, 260.07] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Chapple 2011.
| Methods |
Study design: double‐blind, placebo‐ and active‐controlled, parallel‐group clinical study Setting/Country: 72 hospital clinics and inpatient units in 11 countries/Europe Dates when study was conducted: May 2006‐May 2007 |
|
| Participants |
Inclusion criteria: men ≥ 50 years with LUTS (defined by a stable IPSS total score ≥ 13 points), bladder outlet obstruction (defined by a Qmax 4 mL/s‐15 mL/s, with a minimum voided volume of ≥ 125 mL), and the evidence of satisfactory compliance with study medication (80%–120% during the placebo run‐in period) Exclusion criteria: men with improvement in the IPSS total score ≥ 25% in the run‐in period, PVR ≥ 250 mL, intravesical obstruction from any cause other than BPH, history of any procedure considered an intervention for BPH, active urinary tract infection or history of recurrent urinary tract infections, current prostatitis or diagnosis of chronic prostatitis, history of prostate or invasive bladder cancer, significant postural hypotension, use of 5‐ARIs within 6 months, or use of an a‐blocker or phytotherapy within 2 weeks before entry Total number of participants randomly assigned: 955 Group A (Silodosin)
Group B (Tamsulosin)
Group C (Placebo)
|
|
| Interventions |
Run‐in period: 4 weeks, single‐blind, placebo run‐in period Group A: silodosin 8 mg once daily Group B: tamsulosin 0.4 mg once daily Group C: placebo once daily Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: at screening, at baseline, and after 7, 14, 28, 56, and 84 d of treatment Time points reported: baseline and end of study Secondary outcome
How measured: IPSS questionnaire, uroflowmetry Time points measured: IPSS: see primary outcome/Qmax: at the same time periods as IPSS Time points reported: baseline and end of study Safety outcomes How measured: adverse events, physical examination (BP, heart rate), laboratory tests, and a 12‐lead electrocardiogram Time points measured: at each visit Time points reported: at each visit Subgroup: a post hoc analysis was conducted in the subgroup of participants with nocturia at baseline (defined as at least two voids per night), as assessed by question 7 of the IPSS |
|
| Funding sources | Recordati Ireland Ltd | |
| Declarations of interest | Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Christopher R. Chapple and Francesco Montorsi are consultants and researchers for Recordati. Teuvo L.J. Tammela, Manfred Wirth, Evert Koldewijn, and Eldiberto Fernandez Fernandez are researchers for Recordati | |
| Notes |
Language of publication: English Data (unadjusted IPSS and IPSS‐QoL, AUR, and surgical intervention) were given by contact with study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomly assigned (in a ratio of 2:2:1, with stratification by center, with blocks of five assigned to each center, produced and managed centrally by an international contract research organization)" |
| Allocation concealment (selection bias) | Low risk | Quote: "managed centrally by an international contract research organization" |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "A multicenter double‐blind, placebo‐ and active‐controlled parallel group clinical study, all study personnel and participants were blinded to treatment assignment for the entire duration of the study" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Low risk | Judgement: 10/381 (2.6%) in silodosin, 8/384 (2.1%) in tamsulosin, and 5/190 (2.6%) in placebo group were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | High risk | Judgement: Protocol (NCT00359905) was revised after completion of study (2009) and percentage of treatment responders was added as secondary outcome. All primary and secondary endpoints were measured at 7, 14, 28, 56, 84 day, but only reported at 12 weeks Unadjusted data for analysis for IPSS and QoL were not reported |
| Other bias | Unclear risk | Judgement: 4 weeks' placebo run‐in period |
Jung 2012.
| Methods |
Study design: open‐label, randomized comparative study Setting/Country: not reported/South Korea Dates when study was conducted: not reported |
|
| Participants |
Inclusion criteria: sexually active men with BPH Exclusion criteria: not reported Total number of participants randomly assigned: 138 Group A (Silodosin)
Group B (Tamsulosin)
Group C (Alfusocin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 8 mg once daily Group B: tamsulosin 0.2 mg once daily Group C: alfuzosin 10 mg once daily Duration: 4 weeks |
|
| Outcomes |
How measured: IPSS, MSHQ Time points measured: baseline and on the 4th week of medication Time points reported: baseline and on the 4th week of medication Subgroup: none |
|
| Funding sources | None | |
| Declarations of interest | Not reported | |
| Notes |
Language of publication: English Publication status: abstract (full text has not been published; study author reply) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "open‐label, randomized comparative study" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "open‐label, randomized comparative study" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: the number of participants excluded in analysis was not reported |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: the number of participants excluded in analysis was not reported |
| Selective reporting (reporting bias) | Unclear risk | Judgement: protocol was not published and no information related to the review outcomes given |
| Other bias | Unclear risk | Judgement: abstract only |
Kawabe 2006a.
| Methods |
Study design: randomized, double‐blind, placebo‐controlled study Setting/Country: 88 centers/outpatient/Japan Dates when study was conducted: not reported |
|
| Participants |
Inclusion criteria: men ≥ 50 years with total IPSS of ≥ 8, an associated QoL score of ≥ 3, prostate volume (measured by transabdominal or transrectal US) of ≥ 20 mL, a Q max of < 15 mL/s with a voided volume of ≥ 100 mL and a PVR of < 100 mL Exclusion criteria: men who had antiandrogen preparations for 1 year before the study or had a prostatectomy, intrapelvic radiation therapy or prostatic hyperthermia (transurethral microwave hyperthermia or transurethral needle ablation). Men who had prostate cancer or suspected prostate cancer, neurogenic bladder, bladder neck constriction, urethral stricture, bladder calculus, severe bladder diverticulum, active urinary tract infection requiring medical treatment, renal impairment (serum creatinine ≥ 2.0 mg/dL) and other complications considered likely to affect micturition, severe hepatic disorders, severe cardiovascular disease and a history of orthostatic hypotension Total number of participants randomly assigned: 457 Group A (Silodosin)
Group B (Tamsulosin)
Group C (Placebo)
|
|
| Interventions |
Run‐in period: none Group A: oral silodosin 4 mg twice daily Group B: oral tamsulosin 0.2 mg once daily Group C: oral placebo twice daily Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: at the end of wash‐out period and at 1, 2, 4, 8 and 12 weeks during the treatment period Time points reported: at the end of wash‐out period and at 1, 2, and 12 weeks during the treatment period Secondary outcome
How measured: IPSS questionnaire, uroflowmetry Time points measured: at the end of wash‐out period and at 1, 2, 4, 8 and 12 weeks during the treatment period Time points reported: at the end of wash‐out period and 12 weeks Safety outcomes How measured: adverse events, physical examinations (BP and heart rate), clinical laboratory tests (hematology, blood chemistry and urine analysis) Time points measured: at the start of the observation period and at 4 and 12 weeks of treatment (follow‐up visit) Time points reported: at the start of the observation period and at 12 weeks of treatment Subgroup: analysis based on LUTS severity, post hoc investigation in Qmax among the 3 treatment groups in the overall subgroup of participants with a change in voided volume of < 50% before and after treatment |
|
| Funding sources | None | |
| Declarations of interest | None | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "randomized, double‐blind, placebo controlled study" Judgement: the randomization method was not defined |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "randomized, double‐blind, placebo controlled study" Judgement: placebo‐controlled study, but double‐blind was not clear who was blinded |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Quote: "randomized, double‐blind, placebo controlled study" Judgement: double‐blind was not clear who was blinded |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Low risk | Judgement: 1/176 (0.5%) in silodosin group, 0/192 (0%) in tamsulosin, and 0/89 (0%) were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: 1/176 (0.5%) in silodosin group, 0/192 (0%) in tamsulosin, and 0/89 (0%) were not included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: 1/176 (0.5%) in silodosin group, 0/192 (0%) in tamsulosin, and 0/89 (0%) were not included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: 1/176 (0.5%) in silodosin group, 0/192 (0%) in tamsulosin, and 0/89 (0%) were not included in analysis |
| Selective reporting (reporting bias) | High risk | Judgement: protocol was not published and additional post hoc subgroup investigation was not defined in method section |
| Other bias | High risk | Judgement: baseline imbalance in QoL; primary endpoint was adjusted analysis by baseline QoL. Drug administration times were different between groups |
Manjunatha 2016a.
| Methods |
Study design: prospective, randomized, comparative, open‐label study Setting/Country: tertiary care hospital/India Dates when study was conducted: June 2013‐June 2014 |
|
| Participants |
Inclusion criteria: men ≥ 45 years with symptomatic BPH with IPSS of ≥ 8, QoL of ≥ 3, and Qmax of < 15 mL/s, but > 4 mL/s with a voided volume of > 100 mL Exclusion criteria: severe hepatic or renal insufficiency, urinary tract infections, urethral stricture, neurogenic bladder, PSA ≥ 5 ng/mL, history of urethral or prostatic surgery, hypotension or severe untreated hypertension, history of esophageal or intestinal obstruction, history of multiple drug abuse, significant psychiatric problems, serious disease or malignancy, increased risk of QTc (corrected QT Interval in the heart's electrical cycle) prolongation (e.g. hypokalemia, concomitant use of Class Ia and III antiarrhythmics, antipsychotics, tricyclic antidepressants, etc.), concomitant use of 5‐ARIs and strong cytochrome P450 3A4 inhibitors, likelihood of requiring catheterization within next 3 months Total number of participants randomly assigned: 90 Group A (Silodosin)
Group B (Tamsulosin)
Group C (Alfuzosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin capsule 8 mg once daily in the morning (before breakfast) Group B: tamsulosin tablet/capsule 0.4 mg (before meals) once daily at bedtime Group C: alfuzosin sustained release tablet 10 mg (immediately after meals) once daily Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: baseline, after 2 weeks (visit 1), 4 weeks (visit 2), 8 weeks (visit 3), and 12 weeks (visit 4) Time points reported: baseline, after 2 weeks (visit 1), 4 weeks (visit 2), 8 weeks (visit 3), and 12 weeks (visit 4) Secondary outcome
How measured: uroflowmetry, IPSS questionnaire Time points measured: baseline, after 2 weeks (visit 1), 4 weeks (visit 2), 8 weeks (visit 3), and 12 weeks (visit 4) Time points reported: baseline, after 2 weeks (visit 1), 4 weeks (visit 2), 8 weeks (visit 3), and 12 weeks (visit 4) Safety outcomes How measured: side effects, cardiovascular parameters, pulse rate, and BP (supine and standing) Time points measured: baseline, after 2 weeks (visit 1), 4 weeks (visit 2), 8 weeks (visit 3), and 12 weeks (visit 4) Time points reported: cumulative results from follow‐up visits Subgroup: none |
|
| Funding sources | None | |
| Declarations of interest | None | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "prospective, randomized". Judgement: random number table in protocol |
| Allocation concealment (selection bias) | Low risk | Judgement: no information in article, but "Sequentially numbered, sealed, opaque envelopes" in protocol |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement: open‐label randomized study |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Judgement: open‐label randomized study |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Low risk | Quote: "there were no drop‐outs or protocol violations during the study and all the ninety subjects were included in the analysis" |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Quote: "there were no drop‐outs or protocol violations during the study and all the ninety subjects were included in the analysis" |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Quote: "there were no drop‐outs or protocol violations during the study and all the ninety subjects were included in the analysis" |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Quote: "there were no drop‐outs or protocol violations during the study and all the ninety subjects were included in the analysis" |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: the number of participants with sexual adverse events in tamsulosin and alfuzosin group were not reported |
| Selective reporting (reporting bias) | Low risk | Judgement: protocol (Clinical Trials Registry‐India (CTRI/2013/07/003805)) was published and the prespecified outcomes were well described. |
| Other bias | High risk | Judgement: probably, baseline imbalance in IPSS score, PSA, PVR (silodosin group has markedly lower) and prostate volume (alfuzosin group has markedly higher prostate volume). |
Marks 2009.
| Methods |
Study design: parallel‐group, double‐blind, randomized study Setting/Country: multicenter/USA Dates when study was conducted: May 2005‐August 2006 |
|
| Participants |
Inclusion criteria: men aged ≥ 50 years with an IPSS of ≥ 13, a Qmax of 4 mL/s‐15 mL /s and a PVR < 250 mL Exclusion criteria: men with intravesical obstruction unrelated to BPH; bladder calculi; history of or current condition affecting bladder function; prior surgical intervention to relieve BPH or bladder neck obstruction; active urinary tract infection or history of recurrent urinary tract infection within the past 2 years; prostatitis within the past 3 months; BPH‐unrelated urinary retention within the past 3 months; and a history of recurring prostatitis (> 3 times within the past year), prior or current prostate cancer or PSA > 10 ng/mL; prior invasive bladder cancer; bladder catheterization or bladder or prostate instrumentation within the past 30 days and history of or current significant postural hypotension, including changes in systolic (> 30 mm Hg) or diastolic (> 20 mm Hg) BP or heart rate (more than 20 beats per minute), and lightheadedness, fainting, blurred vision, profound weakness or syncope upon change in position Total number of participants randomly assigned: 923 Group A (Silodosin)
Group B (Placebo)
|
|
| Interventions |
Run‐in period: single‐blind, placebo run in for 4 weeks Group A: silodosin 8 mg once daily with breakfast Group B: placebo once daily with breakfast Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: at weeks 0 (baseline), 0.5, 1, 2, 4 and 12 Time points reported: at weeks 0 (baseline), 0.5, 1, 2, 4 and 12 Secondary outcome
How measured: uroflow assessed by study investigator and a blinded central reader Time points measured: at baseline, 2‐6 h after the first dose, and at weeks 1, 2, 4 and 12 Time points reported: at baseline, 2‐6 h after the first dose, and at weeks 1, 2, 4 and 12 Safety outcomes How measured: adverse event/additional safety assessments included 12‐lead electrocardiograms, clinical laboratory tests and vital sign measurements including postural hypotension tests and physical examinations Time points measured: at every visit except at post‐randomization week 0.5 Time points reported: cumulative results from follow‐up visits Subgroup: none |
|
| Funding sources | Allergan, American Medical Systems, Astellas, Bayer, Beckman Coulter, Diagnostic Ultrasound, GTX, GlaxoSmithKline, Gen‐Probe, Indevus, Light Sciences Oncology, Lilly/ICOS, Merck, Novartis, Onconome, Pfizer, Sanofi, Solvay, Watson, National Institutes of Health, CapCURE, Pardee Foundation and Seder Foundation | |
| Declarations of interest | Allergan, American Medical Systems, Astellas, Bayer, Beckman Coulter, Diagnostic Ultrasound, GTX, GlaxoSmithKline, Gen‐Probe, Indevus, Light Sciences Oncology, Lilly/ICOS, Merck, Novartis, Onconome, Pfizer, Sanofi, Solvay, Watson, National Institutes of Health, CapCURE, Pardee Foundation and Seder Foundation | |
| Notes |
Language of publication: English Study author reply: "Pharmaceutics only have the data". We cannot contact study supporter in pharmaceutics due to wrong email address |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomly assigned (1:1) to double‐blind treatment, randomization schedule using PROC PLAN in SAS." |
| Allocation concealment (selection bias) | Low risk | Judgement: no information in article, but "Sequentially numbered, sealed, opaque envelopes" in protocol |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Blinding was maintained throughout the study by the use of identical medication packaging with placebo matching silodosin in size and external appearance. Emergency information labels that indicated the patient’s assigned treatment were available to the investigator should knowledge of treatment assignment be needed to ensure the patient’s well‐being. If unblinding of the investigator, site personnel or the patient was required in a particular case that patient was to be discontinued from the study." |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Low risk | Quote: "Blinding was maintained throughout the study by the use of identical medication packaging with placebo matching silodosin in size and external appearance. Emergency information labels that indicated the patient’s assigned treatment were available to the investigator should knowledge of treatment assignment be needed to ensure the patient’s well‐being. If unblinding of the investigator, site personnel or the patient was required in a particular case that patient was to be discontinued from the study." |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: discontinued/lost to follow‐up were 53/466 (11.4%) and 38/457 (8.3%), Loss of follow‐up 6/466 (1.3%) and 3/457 (0.3%), but discrepancies in the reason of discontinuation (47/466, 35/457) between intervention and placebo group. Last observations were carried forward to impute values missing for week 12 |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Low risk | Judgement: protocols (NCT00224107, NCT00224120) were published and the prespecified outcomes were well described |
| Other bias | High risk | Judgement: single‐blind placebo run‐in for 4 weeks; participants with ≥ 30% decrease in IPSS or an increase in Qmax of ≥ 3 mL/s during the run‐in period were excluded from randomization |
Masuda 2012.
| Methods |
Study design: randomized, cross‐over study Setting/Country: multicenter/Japan Dates when study was conducted: November 2009‐March 2011 |
|
| Participants |
Inclusion criteria: men ≥ 50 years with prostate estimated volume of > 20 cm3, IPSS of ≥ 8, a QoL score of ≥ 3 points Exclusion criteria: men with organic diseases other than BPH (prostate cancer, bladder tumor, prostatitis, urethral stricture, etc.), transurethral resection of prostate or minimally invasive treatment, under catheterization and under self‐donating urination, active urinary tract infections, combined neuropathic bladder and nervous system disorder, received hormone‐based prostatic hyperplasia treatment medicine 6 months before the start of the study, received androgen‐receptor blocking agent 6 weeks before the study, and those judged unsuitable by the attending physician Total number of participants randomly assigned: 92 Group A (Silodosin)
Group B (Naftopidil)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 2 mg‐4 mg twice a day for 2 weeks in the morning and evening, and 4 mg twice daily in the morning and evening for 4 more weeks, if there were no problems such as side effects Group B: naftopidil 50 mg‐75 mg once in the morning for 2 weeks, and if there were no problems such as side effects 75 mg was administered once in the morning for 4 more weeks Duration: 6 weeks (before cross‐over)/total 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: before and after treatment (6 weeks and 12 weeks) Time points reported: before and after treatment (6 weeks and 12 weeks) Secondary outcome
How measured: IPSS: IPSS questionnaire/OABSS: OABSS questionnaire/PVR: abdominal US/patient preference: questionnaire survey Time points measured: before administration of the drug and 4 weeks, 8 weeks Time points reported: before administration of the drug and 4 weeks, 8 weeks Safety outcomes How measured: adverse events Time points measured: not reported Time points reported: at the end of study (12 weeks) Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes |
Language of publication: Japanese No wash‐out period between cross‐over |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Quote: "all patients who got consent were assigned in turn to 'Naf‐Silo group' and 'Silo‐Naf group' alternately" |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | High risk | Judgement: 14/44 (31.9%) and 14/48 (29.2%) participants in the silodosin and naftopidil group were not included in the analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: not available (cross‐over trial) |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: 5/88 (5.7%) and 17/96 (17.8%) participants in the silodosin and tamsulosin group were not included in the analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: 5/88 (5.7%) and 17/96 (17.8%) participants in the silodosin and tamsulosin group were not included in the analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: prespecified study outcomes were well described but protocol was not published |
| Other bias | Unclear risk | Judgement: no wash‐out period |
Matsukawa 2016.
| Methods |
Study design: prospective, open‐label, randomized study Setting/Country: 52 urologists participated at a total of 44 investigational sites/outpatients/Japan Dates when study was conducted: May 2012‐September 2013 |
|
| Participants |
Inclusion criteria: men with total IPSS 8 or greater, IPSS QoL score 3 or greater, total OABSS 3 or greater, 1 or more urinary urgency episodes per week, prostate volume 20 ml or greater on transabdominal US, Qmax less than 15 ml per second at a voided volume of 100 ml or greater and PVR less than 150 ml, and age 50 years or greater Exclusion criteria: men received oral treatment with a1‐blockers, anticholinergic agents, 5a‐reductase inhibitors, antidepressants, anti‐anxiety agents or sex hormonal agents, they had neurogenic bladder dysfunction, bladder calculi or active urinary tract infection, severe cardiac disease, renal dysfunction (serum creatinine levels 2 mg/dl or more) or hepatic dysfunction (aspartate and alanine aminotransferase concentrations more than twice normal values) Total number of participants randomly assigned: 350 Group A (Silodosin)
Group B (Naftopidil)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg per day for 4 weeks, followed by 8 mg per day for 8 weeks Group B: naftopidil 50 mg per day for 4 weeks, followed by 75 mg per day for 8 weeks Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS and OABSS questionnaire Time points measured: baseline 4 and 12 weeks after the start of treatment Time points reported: baseline 4 and 12 weeks after the start of treatment Secondary outcome
How measured: uroflowmetry Time points measured: baseline 4 and 12 weeks after the start of treatment Time points reported: baseline 4 and 12 weeks after the start of treatment Safety outcomes How measured: not reported Time points measured: not reported Time points reported: not reported Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Simple randomization using a random number table" |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "prospective, open label, randomized" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "prospective, open label, randomized" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 18/175 (10.2%) and 18/175 (10.2%) participants in silodosin and naftopidil group were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all subjects who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all subjects who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: information was partly reported (the number of withdrawal due to cardiovascular adverse events were only reported) |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: no information given |
| Selective reporting (reporting bias) | Unclear risk | Judgement: prespecified outcomes were well described, but protocol was not published |
| Other bias | Low risk | Judgement: not detected |
Miyakita 2010.
| Methods |
Study design: randomized, cross‐over study Setting/Country: multicenter/Japan Dates when study was conducted: May 2006‐July 2007 |
|
| Participants |
Inclusion criteria: men with IPSS ≥ 8 points; QoL score ≥ 3 points; prostate volume measured by US ≥ 20 mL; void volume ≥ 100 mL; and Qmax < 15 mL/s Exclusion criteria: already used any a1‐blocker for the treatment of hypertension; taking vardenafil hydrochloride hydrate; and otherwise judged by an attending physician to be inappropriate Total number of participants randomly assigned: 97 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 8 mg/d (4 mg/dose, twice daily) Group B: tamsulosin 0.2 mg/d (0.2 mg/dose, once daily) Duration: 4 weeks (before cross‐over)/total 8 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: before administration of the drug and 1, 2, 4, 6 and 8 weeks after initiation of administration Time points reported: before administration of the drug, and 4 weeks and 8 weeks Secondary outcome
How measured: not reported Time points measured: before administration of the drug, and 4 weeks and 8 weeks Time points reported: before administration of the drug, and 4 weeks and 8 weeks Safety outcomes How measured: adverse events Time points measured: throughout the study period Time points reported: throughout the study period Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes |
Language of publication: English No wash‐out period between cross‐over |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | High risk | Judgement: 12/46 (26.1%) and 20/51 (39.3%) participants in the silodosin and tamsulosin group were not included in the analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: not available (cross‐over trial) |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: prespecified outcomes were well described, but protocol was not published |
| Other bias | Unclear risk | Judgement: no wash‐out period |
Natarajan 2015.
| Methods |
Study design: parallel, randomized Setting/Country: tertiary hospital/Tamil Nadu, India Dates when study was conducted: August 2013‐April 2015 |
|
| Participants |
Inclusion criteria: men > 50 years with bothersome LUTS from BPH and IPSS > 7 Exclusion criteria: history of LUTS but not BPH, AUR in past 6 months, raised PSA level at baseline, serious co‐morbidity of vital organs, use of concomitant medication having anticholinergic, androgenic or estrogenic influence, on other α‐adrenergic antagonists or diuretics or with a history of prostatic or per urethral surgery or substance abuse Total number of participants randomly assigned: 57 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 8 mg capsule once daily after dinner Group B: tamsulosin 0.4 mg controlled‐release capsule once daily after dinner Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: baseline and 12 weeks Time points reported: baseline and 12 weeks Secondary outcome
How measured: IPSS, US by blinded radiologist, uroflowmetry by blinded operator Time points measured: baseline and 12 weeks Time points reported: symptom free and change in Qmax not reported; change in prostate size, baseline and 12 weeks Safety outcomes How measured: adverse affects Time points measured: at follow‐up visits (4, 8, 12 weeks) Time points reported: cumulative results from follow‐up visits Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: no information given |
| Selective reporting (reporting bias) | High risk | Quote: "Silodosin showed a significant decrease in IPSS versus tamsulosin at 2 weeks" Judgement: protocol was not published and there was no information of 2 weeks' follow‐up. Secondary endpoints (proportion of participants who became completely or relatively symptom free (IPSS < 8), changes in Qmax) were not reported |
| Other bias | Unclear risk | Judgement: no data on baseline characteristics |
NCT00793819.
| Methods |
Study design: parallel, randomized, double‐blinded study Setting/Country: NR Dates when study was conducted: January 2009‐October 2009 |
|
| Participants |
Inclusion criteria: men in good general health and ≥ 50 years, with symptoms of moderate‐severe BPH and nocturia (≥ 2 episodes per night) Exclusion criteria: men with 1) medical conditions that would confound the efficacy evaluation 2) medical conditions in which it would be unsafe to use an alpha‐blocker 3) the use of concomitant drugs that would confound the efficacy evaluation 4) the use of concomitant drugs that would be unsafe with this alpha‐blocker Total number of participants randomly assigned: 209 Group A (Silodosin)
Group B (Placebo)
|
|
| Interventions |
Run‐in period: not reported Group A: silodosin 8 mg daily Group B: 1 placebo capsule daily Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: not reported Time points measured: before and 12 weeks after treatment Time points reported: before and 12 weeks after treatment Secondary outcomes
How measured: not reported Time points measured: before and 12 weeks after treatment Time points reported: before and 12 weeks after treatment Subgroup: not reported |
|
| Funding sources | Watson Pharmaceuticals | |
| Declarations of interest | Watson Pharmaceuticals | |
| Notes |
Language of publication: English Publication status: NCT00793819 (results in clinicaltrials.gov) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "parallel randomized double blinded (Participant, Investigator)" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Low risk | Quote: "parallel randomized double blinded (Participant, Investigator)" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Low risk | Judgement: protocol (NCT00793819) was published and the prespecified outcomes were well described |
| Other bias | Unclear risk | Judgement: protocol only |
Pande 2014.
| Methods |
Study design: single‐blind, parallel‐group, randomized, controlled trial Setting/Country: outpatient/tertiary care hospital/Kolkata, India Dates when study was conducted: July 2012‐June 2013 |
|
| Participants |
Inclusion criteria: ambulatory, treatment naïve, men > 50 years with bothersome LUTS from BPH and IPSS > 7 Exclusion criteria: history of LUTS but not BPH, AUR in past 6 months, raised PSA level at baseline, serious co‐morbidity of vital organs, use of concomitant medication having anticholinergic, androgenic or estrogenic influence, on other α‐adrenergic antagonists or diuretics or with a history of prostatic or per urethral surgery or substance abuse Total number of participants randomly assigned: 61 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 8 mg capsule once daily Group B: tamsulosin 0.4 mg controlled‐release capsule once daily Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: at 4, 8 and 12 weeks Time points reported: at 4, 8 and 12 weeks Secondary outcome
How measured: IPSS questionnaire, US by blinded radiologist, uroflowmetry by blinded investigator Time points measured: baseline and 12 weeks Time points reported: baseline and 12 weeks Safety outcomes How measured: vital signs, treatment‐emergent adverse events, postural hypotension and retrograde ejaculation, laboratory investigations (complete blood count, fasting plasma glucose, routine liver function tests and creatinine level) Time points measured: lab ‐ at baseline and study end/others ‐ each visit Time points reported: lab ‐ at baseline and study end/others ‐ cumulative results from follow up visits Subgroup: none |
|
| Funding sources | M/s Cipla Limited, Mumbai, donated both study drugs and reimbursed part of the cost of laboratory investigations on request | |
| Declarations of interest | None | |
| Notes |
Language of publication: English Data (IPSS, QoL, AUR, surgical intervention, cardiovascular, sexual adverse events) were given by contact with study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomized in 1:1 ratio to one of the two study groups in fixed blocks of 8, using computer generated random number list" |
| Allocation concealment (selection bias) | Low risk | Quote: "Allocation concealment was achieved using the serially numbered, opaque, sealed envelope technique" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "single blind, parallel group, randomized, controlled trial", "The capsules were removed from their commercial blister strip packaging and repackaged in air‐tight, screw cap containers and suitably labelled and coded as trial medication. Repackaging was done with the help of residents not otherwise involved in the study. Capsule identity was not revealed to the patients who received the total medication in three installments" Judgement: participants were blinded, but investigator and observer might be not blinded |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "single blind, parallel group, randomized, controlled trial", "The capsules were removed from their commercial blister strip packaging and repackaged in air‐tight, screw cap containers and suitably labelled and coded as trial medication. Repackaging was done with the help of residents not otherwise involved in the study. Capsule identity was not revealed to the patients who received the total medication in three installments" Judgement: participants were blinded, but investigator and observer might be not blinded |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 6/32 (18.7%) in silodosin, 2/29 (6.9%) in tamsulosin lost to follow‐up: missing data were imputed by last observation carried forward strategy |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Low risk | Judgement: all participants who were randomized in each group were included in analysis. We received the data after contacting the study author. |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Low risk | Judgement: protocol (Clinical Trials Registry‐India (CTRI/2014/01/004366)) was published and the prespecified outcomes were well described. Data (AUR, surgical intervention, cardiovascular, sexual adverse events) were given by contact with study author |
| Other bias | Low risk | Judgement: not detected |
Shirakawa 2013.
| Methods |
Study design: randomized, open‐label, controlled, multicenter study Setting/Country: Kobe University School or other collaborating institutions/Japan Dates when study was conducted: July 2007‐March 2011 |
|
| Participants |
Inclusion criteria: men with: BPH/ LUTS with a total IPSS ≥ 8 points; QoL index ≥ 3 points; Qmax < 15 mL/s; prostate volume ≥ 20 mL; and either without a history of using any a1‐receptor blocker (hereafter, drug‐naive group) or who had continued to use tamsulosin (0.2 mg once daily) for ≥ 3 months and wanted to switch the medication to another oral drug (hereafter, drug‐switching group) Exclusion criteria: other diseases such as prostate cancer, bladder tumor, cystolithiasis, prostatitis, urethral stricture, or active urinary tract infection; complication of neurogenic bladder or disease suspected of neurogenic bladder; and whose participation in the study was deemed inappropriate by their primary physician(s) Total number of participants randomly assigned: 121 Group A (Silodosin)
Group B (Naftopidil)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg twice daily Group B: naftopidil 50 mg once daily Duration: 8 consecutive weeks |
|
| Outcomes |
How measured: IPSS questionnaire Time points measured: at baseline, 4 and 8 weeks Time points reported: at baseline, 4 and 8 weeks Safety outcomes How measured: adverse events Time points measured: not reported Time points reported: cumulative results from follow‐up visits Subgroup: drug‐naïve/drug‐switching |
|
| Funding sources | Not reported | |
| Declarations of interest | None | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomly assigned (using a random number table)" |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "randomized, open‐label, controlled multicenter study" Judgement: no one was blinded (protocol) |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "randomized, open‐label, controlled multicenter study" Judgement: no one was blinded (protocol) |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Low risk | Judgement: 5/61 (8.2%) and 4/60 (6.7%) participants in silodosin and naftopidil were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | 2/61 (3.3%) and 3/60 (5.0%) participants in silodosin and naftopidil were not included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: 2/61 (3.3%) and 3/60 (5.0%) participants in silodosin and naftopidil were not included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: 2/61 (3.3%) and 3/60 (5.0%) participants in silodosin and naftopidil were not included in analysis |
| Selective reporting (reporting bias) | Low risk | Judgement: protocol (UMIN000008331) was published. While the results were shown separately in participants with drug naïve and switching group, review outcomes were well described |
| Other bias | Low risk | Not detected |
Takeshita 2016.
| Methods |
Study design: randomized, cross‐over study Setting/Country: 4 community‐based hospitals/Japan Dates when study was conducted: February 2011‐July 2014 |
|
| Participants |
Inclusion criteria: men aged ≥ 50 years with LUTS/BPH, an IPSS of ≥ 8, QoL score of ≥ 3, and US‐estimated prostatic volume of ≥ 20 mL Exclusion criteria: those that had taken any alpha‐blocker within the previous 28 days; those currently taking phosphodiesterase type 5 inhibitors, 5‐ARIs, or antiandrogens; those with severe renal dysfunction (estimated glomerular filtration rate < 30 mL/min per 1.73 m2); and those judged to be inappropriate by the attending physicians Total number of participants randomly assigned: 34 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg once daily in the morning Group B: tamsulosin 0.2 mg once daily in the morning Duration: 4 weeks (before cross‐over)/total 8 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: baseline to weeks 4 and 8 Time points reported: baseline to weeks 4 and 8 Secondary outcome
How measured: participant preference for the drug by self‐administered questionnaire Time points measured: before administration of the drug, and 4 weeks and 8 weeks Time points reported: before administration of the drug, and 4 weeks and 8 weeks Safety outcomes How measured: adverse events Time points measured: baseline to weeks 4 and 8 Time points reported: baseline to weeks 4 and 8 Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | None | |
| Notes |
Language of publication: English No wash‐out period between cross‐over Data (IPSS, QoL, treatment withdrawal, cardiovascular, sexual adverse events) were given by contact with study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement: author reply "random number table" |
| Allocation concealment (selection bias) | Low risk | Judgement: author reply "sealed opaque envelope" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "open‐label, randomized crossover study" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "open‐label, randomized crossover study" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 2/18 (11.2%) and 2/16 (12.5%) participants in the silodosin and tamsulosin group were not included in the analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: not available (cross‐over trial) |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Low risk | Judgement: protocol (JPRN‐UMIN000004918) was published and prespecified, study outcomes were analyzed as planned. Data (IPSS, QoL, treatment withdrawal, cardiovascular, sexual adverse events) were provided after contact with study author |
| Other bias | Unclear risk | Judgement: no wash‐out period |
Watanabe 2011.
| Methods |
Study design: randomized, cross‐over study Setting/Country: 3 institutions/Japan Dates when study was conducted: February 2008‐September 2009 |
|
| Participants |
Inclusion criteria: men with LUTS associated with BPH and had an IPSS ≥ 8 and an IPSS‐QoL score ≥ 2 Exclusion criteria: not reported Total number of participants randomly assigned: 102 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg, orally, twice daily Group B: tamsulosin 0.2 mg, orally, once daily Duration: 4 weeks (before cross‐over)/total 8 weeks |
|
| Outcomes |
Primary outcome
How measured: questionnaire and open question Time points measured: 8 weeks Time points reported: 8 weeks Secondary outcome
How measured: not reported Time points measured: baseline and at 4 and 8 weeks Time points reported: baseline and at 4 and 8 weeks Safety outcomes How measured: adverse events Time points measured: not reported Time points reported: during the study Subgroup: age ≥ 70/IPSS ≥ 20 |
|
| Funding sources | Not reported | |
| Declarations of interest | None | |
| Notes |
Language of publication: English No wash‐out period between cross‐over |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "open‐label study" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Quote: "open‐label study" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 9/51 (17.7%) and 9/51 (17.7%) participants in the silodosin and tamsulosin group were not included in the analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: not available (cross‐over trial) |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: 14/102 (13.8%) and 11/102 (10.8%) participants in the silodosin and tamsulosin group were not included in the analysis (study author reported the results after cross‐over) |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: 14/102 (13.8%) and 11/102 (10.8%) participants in the silodosin and tamsulosin group were not included in the analysis (study author reported the results after cross‐over) |
| Selective reporting (reporting bias) | Unclear risk | Judgement: no protocol available |
| Other bias | Unclear risk | Judgement: no wash‐out period |
Yamaguchi 2013.
| Methods |
Study design: parallel, randomized trial Setting/Country: Nihon University School of Medicine/Japan Dates when study was conducted: December 2007‐November 2010 |
|
| Participants |
Inclusion criteria: men with BPH≥ 50 years with significant LUTS and deteriorated QoL, with IPSS of ≥ 8 and its QoL score of ≥ 3 Exclusion criteria: established prostate cancer, neurogenic bladder and any other complications that affect micturitional status; underwent prostate surgery, intervention or radiation therapy Total number of participants randomly assigned: 109 Group A (Silodosin)
Group B (Naftopidil)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 8 mg/d Group B: naftopidil 75 mg/d Duration: 12 weeks |
|
| Outcomes |
How measured: questionnaire, uroflowmetry Time points measured: before and 4, 8, and 12 weeks after treatment Time points reported: IPSS, QoL, IIEF‐5: before and 4, 8, and 12 weeks after treatment/Qmax, PVR: before and 12 weeks after treatment Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | None | |
| Notes |
Language of publication: English Data (IPSS, QoL, treatment withdrawal, AUR, surgical intervention, cardiovascular adverse events) were given by contact with study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement: author reply "random number table envelope method" |
| Allocation concealment (selection bias) | Unclear risk | Judgement: author reply "random number table envelope method" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement: author reply "not blinded" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Judgement: author reply "not blinded" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | High risk | Judgement: 17/58 (29.3%) and 13/51 (25.5) participants in silodosin and naftopidil group were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis. We received the data after contacting the study author |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis. We received the data after contacting the study author |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Low risk | Judgement: all participants who were randomized in each group were included in analysis. We received the data after contacting the study author |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis. We received the data after contacting the study author |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all sexually active subjects (silodosin: 23/53 (44%), naftopidil: 21/44 (47%)) who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: data (treatment withdrawal, AUR, and surgical intervention) were given by contact with study author, but protocol was not published |
| Other bias | Low risk | Judgement: not detected |
Yamanishi 2011.
| Methods |
Study design: parallel, randomized trial Setting/Country: not reported Dates when study was conducted: not reported |
|
| Participants |
Inclusion criteria: men with IPSS total score ≥ 8, Qmax < 15 mL/s, total prostate volume measured by US > 20 mL Exclusion criteria: prostate cancer, urethral stricture, apparent neurogenic bladder and those on medication that might affect voiding function such as alpha‐blockers, anticholinergics and/or antiandrogen drugs Total number of participants randomly assigned: 149 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg twice daily Group B: tamsulosin 0.2 mg‐0.4 mg daily Duration: 12 months |
|
| Outcomes |
How measured: questionnaire, uroflowmetry Time points measured: before, and at 1, 3, 6 and 12 months after the therapy Time points reported: before, and at 1, 3, 6 and 12 months after the therapy Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes |
Language of publication: English Publication status: abstract (full text has not been published; study author reply) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | High risk | Judgement: 19/75 (25.3%) and 30/74 (40.5%) participants in silodosin and tamsulosin were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: no information given |
| Selective reporting (reporting bias) | Unclear risk | Judgement: protocol was not published and no information related to the review outcomes given |
| Other bias | Unclear risk | Judgement: abstract only |
Yokoyama 2011.
| Methods |
Study design: parallel, randomized trial Setting/Country: Kawasaki Medical School/Japan Dates when study was conducted: June 2007‐December 2008 |
|
| Participants |
Inclusion criteria: men with LUTS aged 50–80 years and with IPSS ≥ 8 Exclusion criteria: received oral treatment with 5‐ARIs, anticholinergic agents, antidepressants, or sex hormonal agents, had neurogenic bladder dysfunction, bladder calculi, or active urinary tract infection, or had severe cardiac disease, renal dysfunction (serum creatinine > 2 mg/dL), or hepatic dysfunction Total number of participants randomly assigned: 136 Group A (Silodosin)
Group B (Tamsulosin)
Group C (Naftopidil)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg twice a day Group B: tamsulosin 0.2 mg once a day Group C: naftopidil 50 mg once a day Duration: 12 weeks |
|
| Outcomes |
How measured: questionnaire (IPSS, QoL, IIEF), uroflowmetry, US (PVR) Time points measured: before, and 1 and 3 months Time points reported: before, and 1 and 3 months Subgroup: none |
|
| Funding sources | Not reported | |
| Declarations of interest | None (study author reply) | |
| Notes |
Language of publication: English Data (IPSS, QoL, AUR, and surgical intervention) from study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement: study author reply "Computer generated central randomization" |
| Allocation concealment (selection bias) | Low risk | Judgement: study author reply "Computer generated central randomization" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement: study author reply "participants were not blinded" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Unclear risk | Judgement: no information given |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 4/45 (8.9%), 6/45 (13.3%), and 4/46 (8.7) participants in silodosin, tamsulosin, and naftopidil group were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Unclear risk | Judgement: 4/45 (8.9%), 6/45 (13.3%), and 4/46 (8.7) participants in silodosin, tamsulosin, and naftopidil group were not included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: 4/45 (8.9%), 6/45 (13.3%), and 4/46 (8.7) participants in silodosin, tamsulosin, and naftopidil group were not included in analysis. We received the data after contacting the study author |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: 4/45 (8.9%), 6/45 (13.3%), and 4/46 (8.7) participants in silodosin, tamsulosin, and naftopidil group were not included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all sexually active subjects (silodosin: 11/45 (24.4%), tamsulosin 12/45 (26.6%), naftopidil: 15/46 (31.9%)) were included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: prespecified outcomes were well described and data were given by study author, but protocol was not published |
| Other bias | High risk | Judgement: drug administration times were different among groups. Baseline imbalance in PVR, but the fact that silodosin group had much higher PVR may underestimate the effect size |
Yokoyama 2012.
| Methods |
Study design: randomized, cross‐over study Setting/Country: single center/Japan Dates when study was conducted: June 2008‐March 2010 |
|
| Participants |
Inclusion criteria: men aged 50 years who had a total IPSS ≥ 8 and a QoL index ≥ 3 Exclusion criteria: prostate cancer, neurogenic bladder, urethral stricture, active urinary tract infection and other complications considered likely to affect micturition Total number of participants randomly assigned: 46 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: none Group A: silodosin 4 mg twice daily Group B: tamsulosin 0.2 mg once daily Duration: 3 months (before cross‐over)/1 month wash‐out/3 months (after cross‐over)/total 7 months |
|
| Outcomes |
How measured: IPSS questionnaire and transabdominal US (PVR) Time points measured: before and after treatment (not reported in method) Time points reported: before and after treatment (1 months, 3 months, 4 months, and 7 months) Safety outcomes How measured: adverse events Time points measured: not reported Time points reported: not reported Subgroup: none |
|
| Funding sources | None | |
| Declarations of interest | None | |
| Notes |
Language of publication: English One month wash‐out period between cross‐over Data (IPSS, QoL, treatment withdrawal for any reason, method of random sequence generation, allocation concealment, and blinding) were given by contact with study author |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement: study author reply "random number table" |
| Allocation concealment (selection bias) | Unclear risk | Judgement: study author reply "sealed envelope" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement: study author reply "participants were blinded" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | High risk | Judgement: study author reply "participants were blinded" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 5/46 (10.9%) participants were not included in the analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: not available (cross‐over trial) |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: prespecified outcomes are well described and data were given by study author, but protocol was not published (study author confirmed via email) |
| Other bias | Low risk | Judgement: not detected |
Yu 2011.
| Methods |
Study design: parallel, randomized, double‐blinded Setting/Country: 9 medical centers/Taiwan Dates when study was conducted: July 2007‐September 2008 |
|
| Participants |
Inclusion criteria: men aged ≥ 40 years with an IPSS of ≥ 13, a health‐related QoL score of ≥ 3, a prostate volume of ≥ 20 mL, and a Qmax of < 15 mL/s with a voided volume of ≥ 100 mL Exclusion criteria: men with a history of previous prostate surgery, prostate cancer, neurogenic bladder, bladder neck constriction, urethral stricture, bladder calculus, active urinary tract infection, a PVR of > 250 mL, exposure to sex hormone within 3 months prior to the wash‐out period, renal dysfunction (serum creatinine of > 2.0 mg/dL), a history of severe liver impairment, severe cardiovascular diseases, severe hypotension, and known hypersensitivity or history of active substance abuse (including alcohol) within the past 2 years Total number of participants randomly assigned: 209 Group A (Silodosin)
Group B (Tamsulosin)
|
|
| Interventions |
Run‐in period: 7‐day wash‐out and 7‐day observation periods Group A: silodosin 4 mg twice daily Group B: tamsulosin 0.2 mg in the morning and one placebo capsule in the evening Duration: 12 weeks |
|
| Outcomes |
Primary outcome
How measured: IPSS questionnaire Time points measured: 0 (initiation of treatment), 2, 4, 8, and 12 weeks Time points reported: 0 (initiation of treatment), 2, 4, 8, and 12 weeks in figure Secondary outcome
How measured: uroflowmetry, IPSS questionnaire Time points measured: 0, 4 and 12 weeks/0 (initiation of treatment), 2, 4, 8, and 12 weeks Time points reported: 0 and 12 weeks Safety outcomes How measured: all adverse events/BP/pulse rate/laboratory tests Time points measured: 0 (initiation of treatment), 2, 4, 8, and 12 weeks/0, 4 and 12 weeks/follow‐up visits Time points reported: 0 and 12 weeks/cumulative results from follow‐up visits (adverse events) Subgroup: none |
|
| Funding sources | Synmosa pharmaceutical company | |
| Declarations of interest | All authors were study investigators for Synmosa | |
| Notes | Language of publication: English | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement: no information given |
| Allocation concealment (selection bias) | Unclear risk | Judgement: no information given |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "both investigators and patients were ‘blinded’ to treatment" |
| Blinding of outcome assessment (detection bias) Subjective outcomes | Low risk | Quote: "both investigators and patients were ‘blinded’ to treatment" |
| Blinding of outcome assessment (detection bias) Objective outcomes | Low risk | Judgement: objective outcomes are not likely affected by lack of blinding |
| Incomplete outcome data (attrition bias) Urologic symptom scores/ QoL | Unclear risk | Judgement: 18/105 (17.1%), 21/104 (20.2%) participants who were randomized in silodosin, tamsulosin group were not included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal for any reason | Low risk | Judgement: all participants who were randomized in each group were included in analysis |
| Incomplete outcome data (attrition bias) Treatment withdrawal due to adverse events | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) AUR/ surgical intervention | Unclear risk | Judgement: no information given |
| Incomplete outcome data (attrition bias) Cardiovascular adverse events | Unclear risk | Judgement: 18/105 (17.1%), 21/104 (20.2%) participants who were randomized in silodosin, tamsulosin group were not included in analysis |
| Incomplete outcome data (attrition bias) Sexual adverse events | Unclear risk | Judgement: 18/105 (17.1%), 21/104 (20.2%) participants who were randomized in silodosin, tamsulosin group were not included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Judgement: protocol was published, but protocol was not found due to the absence of protocol number |
| Other bias | High risk | Judgement: serious baseline imbalance in age, IPSS, prostate volume, health‐related QoL, Qmax in as treated analysis. Two weeks' observation run‐in period |
5‐ARIs: 5‐alpha reductase inhibitors; AUR: acute urinary retention; BP: blood pressure; BPH: benign prostatic hyperplasia; IIEF: International Index of Erectile Function; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; OABSS: Overactive Bladder Symptom Score; PSA: prostate‐specific antigen; PVR: postvoid residual; Qmax; maximum flow rate; QoL: quality of life; US: ultrasound
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Abramowicz 2009 | Review |
| Alcántara Montero 2016 | Review |
| Araki 2013 | Wrong study design (non randomized trial) |
| Boeri 2016 | Wrong study design (study design not described, silodosin versus silodosin plus Serenoa repens) |
| Cakiroglu 2016 | Wrong comparator (silodosin versus transurethral incision of prostate) |
| Chapple 2009 | Wrong study design (integrated safety analysis) |
| Curran 2011 | Review |
| JPRN‐UMIN000007917 | Wrong comparator (silodosin 4 mg once daily versus silodosin 4 mg twice daily) |
| Kawabe 2006b | Wrong study design (non randomized study) |
| Kobayashi 2008 | Wrong outcome (semen parameters) |
| Kobayashi 2009 | Wrong outcome (semen parameters) |
| Manjunatha 2016b | Wrong outcome (cost effectiveness) |
| Matsukawa 2012 | Wrong comparator (silodosin versus silodosin and propiverine) |
| Matsukawa 2017 | Wrong comparator (silodosin and dutasteride versus dutasteride) |
| Michel 2011 | Wrong study population (participants with ≥ 2 voids per night ) |
| Montorsi 2010 | Review |
| Montorsi 2013 | Review |
| Prescrire Int 2011 | Review (medical article) |
| Prescrire Int 2012 | Review (medical article) |
| Roehrborn 2009 | Wrong study population (participants with retrograde ejaculation as adverse event) |
| Yoshida 2017 | Wrong comparator (silodosin versus phosphodiesterase 5 inhibitor) |
| Yoshihisa 2012 | Wrong comparator (silodosin versus silodosin and propiverine) |
| Zhou 2011 | Wrong outcome (pharmacokinetics and adverse events (not available)) |
Characteristics of studies awaiting assessment [ordered by study ID]
CTRI/2010/091/000526.
| Methods | Randomized, parallel‐group, active, controlled trial |
| Participants |
Inclusion criteria
|
| Interventions |
Group A: silodosin capsule 8 mg Group B: tamsulosin ER capsules 0.4 mg Duration: 12 weeks |
| Outcomes |
|
| Notes |
Funding source: MSN Laboratories Ltd Publication status: CTRI/2010/091/000526 (final publication status has not been clarified) |
Devana 2014.
| Methods | Open‐label, parallel study |
| Participants |
Inclusion criteria: men with symptomatic BPH aged 50‐80 years, with IPSS > 8 or QoL score > 2 Exclusion criteria: not reported |
| Interventions |
Group A: silodosin 8 mg/d Group B: tamsulosin 0.4 mg/d Group C: alfuzosin 10 mg/d Duration: 1 month |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
Jha 2015.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria: not reported Exclusion criteria: not reported |
| Interventions |
Group A: silodosin 8 mg daily at night Group B: tamsulosin 0.4 mg daily at night Duration: 6 months |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
JPRN‐UMIN000003125.
| Methods | Open‐label, parallel, randomized study |
| Participants |
Inclusion criteria: male patients with newly diagnosed LUTS according to the treatment algorithm of the Clinical Practice Guidelines for male LUTS Exclusion criteria: men who meet any of the following criteria are excluded:
|
| Interventions |
Group A: silodosin 8 mg daily Group B: tamsulosin 0.2 mg daily Duration: not reported |
| Outcomes |
|
| Notes |
Funding source: none Publication status: JPRN‐UMIN000003125 (final publication status has not been clarified) |
JPRN‐UMIN000005151.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria Men aged ≥ 50 years with previously‐untreated BPH with total IPSS ≥ 8 and QoL score ≥ 2 |
| Interventions |
Group A: silodosin 4 mg twice daily Group B: tamsulosin hydrochloride 0.2 mg daily Duration: not reported |
| Outcomes |
|
| Notes |
Funding source: none Publication status: JPRN‐UMIN000005151 (final publication status has not been clarified) |
JPRN‐UMIN000008538.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria Men aged 50‐90 years 1) a total IPSS of ≥ 8 2) Qmax of ≤ 15 mL/s as evaluated by uroflowmetry 3) prostate volume of ≥ 15 mL as measured by prostatic US |
| Interventions |
Group A: silodosin Group B: tamsulosin Duration: not reported |
| Outcomes |
|
| Notes |
Funding source: Dokkyo Medical University Publication status: JPRN‐UMIN000008538 (final publication status has not been clarified) |
JPRN‐UMIN000011556.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria Men aged ≥ 50 years
|
| Interventions |
Group A: silodosin 4 mg, once daily after breakfast Group B: tamsulosin 0.2 mg, once daily after breakfast Duration: not reported |
| Outcomes |
|
| Notes |
Funding source: Kissei Pharmaceutical Co., Ltd Publication status: JPRN‐UMIN000011556 (final publication status has not been clarified) |
Mandal 2013.
| Methods | Open‐label, parallel study |
| Participants |
Inclusion criteria: men with symptomatic BPH aged 50‐80 years with IPSS > 8 or QoL score > 2 Exclusion criteria: other causes of bladder outlet obstruction, prostate and bladder malignancy, renal failure, hepatic failure and prior history of prostatectomy |
| Interventions |
Group A: silodosin 8 mg/d Group B: tamsulosin 0.4 mg/d Group C: alfuzosin 10 mg/d Duration: 1 month |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
Manohar 2014.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria: patients of LUTS in BPH Exclusion criteria: not reported |
| Interventions |
Group A: silodosin 8 mg once/d Group B: tamsulosin 0.4 mg once/d Group C: alfuzosin 10 mg once/d Duration: 12 weeks |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
Miyamae 2011.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria: men with untreated BPH
Exclusion criteria: not reported |
| Interventions |
Group A: silodosin 4 mg twice daily Group B: tamsulosin 0.2 mg once daily Duration: 1 week |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
NCT01222650.
| Methods | Parallel, randomized, double‐blind, placebo‐controlled study |
| Participants |
Inclusion criteria: men with BPH and LUTS Exclusion criteria: history of prostatectomy, intrapelvic radiation therapy, thermotherapy of prostate or prostatic hyperthermia, prostate cancer or suspected prostate cancer, any clinically relevant cardiovascular, hepatic or renal disorder |
| Interventions |
Group A: not reported Group B: not reported Duration: 12 weeks |
| Outcomes |
|
| Notes |
Funding source: Kissei Pharmaceutical Co., Ltd Publication status: NCT01222650 (final publication status has not been clarified) |
Pawar 2015.
| Methods | Parallel, randomized study |
| Participants |
Inclusion criteria: men > 45 years with symptomatic BPH (increased daytime frequency, urgency and nocturia and or voiding symptoms (hesitancy, incomplete voiding, impaired stream or interruption of stream), increased daytime micturition, nocturia > 2, maximum flow rate < 15 mL/sec with a voided volume of ≥ 150 mL, PVR < 100 mL by abdominal US, IPSS > 13 points, international prostatic symptom bother score > 3 points Exclusion criteria: not reported |
| Interventions |
Group A: silodosin 8 mg once daily Group B: tamsulosin 0.2 mg once daily Duration: 12 weeks |
| Outcomes |
|
| Notes | Publication status: abstract (final publication status has not been clarified) |
BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; PSA: prostate specific antigen; PVR: postvoid residual; Qmax; maximum flow rate; QoL: quality of life; US: ultrasound
Characteristics of ongoing studies [ordered by study ID]
CTRI/2013/10/004112.
| Trial name or title | A study to find out the medication which offers maximum health benefits with minimum spending by the patient among the three commonly used medications in the treatment of benign prostatic hyperplasia, a disease in aging men which results in bothersome urinary problems |
| Methods | Randomized, parallel group trial |
| Participants |
Inclusion criteria
|
| Interventions |
Group A: silodosin oral, 8 mg once daily Group B: tamsulosin oral, 0.4 mg once daily Group C: alfuzosin oral, 10 mg once daily Duration: 12 weeks |
| Outcomes | Treatment success is defined as ≥ 30% improvement in IPSS from baseline and its maintenance over the study period |
| Starting date | September 2013 |
| Contact information | manjunatha5ramaiah@gmail.com |
| Notes | Funding source: none |
JPRN‐UMIN000003609.
| Trial name or title | The effects of selective alpha‐1‐adrenergic receptor antagonists in patients with lower urinary tract symptoms caused by benign prostatic hyperplasia who failed to obtain sufficient efficacy by previous alpha‐1‐blockades. A comparison of naftopidil or silodosin |
| Methods | Parallel, randomized |
| Participants |
Inclusion criteria Men with LUTS caused by BPH who failed to obtain sufficient efficacy by naftopidil 50 mg and with IPSS of ≥ 9, a QoL score of ≥ 2, a prostate volume of ≥ 20 mL are eligible for enrolment |
| Interventions |
Group A: silodosin 8 mg Group B: naftopidil 75 mg Duration: not reported |
| Outcomes |
|
| Starting date | May 2010 |
| Contact information | Email address was not given |
| Notes | Funding source: none |
BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; Qmax; maximum flow rate; QoL: quality of life
Differences between protocol and review
This review was based on a published protocol with differences as described here.
Types of studies: we included parallel, randomized trials as well as cross‐over designs. We revised the 'Types of studies' and 'Unit of analysis issues' section accordingly.
Types of participants: we redefined the type of participants as adult men aged 40 years and over. Given that alpha‐blockers are used to treat patients with all degrees of LUTS, we deleted the IPSS criterion under ‘Types of participants’.
Types of outcome measures: we renamed primary and secondary outcomes and added details in 'method and timing of outcome measurement' for all outcomes.
Assessment of risk of bias in included studies: we added details with regards to assessing risk of bias. We considered all outcomes susceptible to performance bias and assessed them in one group. We redefined subjective and objective outcomes for detection bias.
Subgroup and sensitivity analysis: we planned to perform subgroup and sensitivity analyses limited to the primary outcomes.
Appendix: we have summarized the search strategy for each database in Appendix 1.
Contributions of authors
JH Jung (JHJ): conception and study design, drafting the protocol, searching for trials, study selection, extracting data, assessing risk of bias, performing data analysis, interpretation of data, and drafting the review.
J Kim (JK): drafting the protocol, searching for trials, study selection, extracting data, assessing risk of bias, performing data analysis, and drafting the review.
R MacDonald (RM): study design, drafting the protocol, providing clinical and methodological advices on the review, and final approval.
B Reddy (BR): providing clinical and methodological advice on the review, and drafting the review.
MH Kim (MHK): creating search strategies, drafting the protocol, and searching for trials.
P Dahm (PD): conception and study design, providing clinical and methodological advice on the review, and final approval.
Sources of support
Internal sources
Yonsei University Wonju College of Medicine, Korea, South.
Minneapolis VA Medical Center, Minneapolis, Minnesota, USA.
University of Minnesota, Minneapolis, Minnesota, USA.
External sources
No sources of support provided, Other.
Declarations of interest
JHJ: none known
JK: none known
RM: none known
BR: none known
MHK: none known
PD: PD serves as Co‐ordinating Editor of Cochrane Urology. However, he was not involved in the editorial processing or decision‐making for this review. Other editors of Cochrane Urology managed the editorial process, including final sign‐off for this review.
New
References
References to studies included in this review
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Abramowicz 2009 {published data only}
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Kawabe 2006b {published data only}
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Michel 2011 {published data only}
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References to studies awaiting assessment
CTRI/2010/091/000526 {unpublished data only}
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Devana 2014 {published data only}
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Jha 2015 {published data only}
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JPRN‐UMIN000003125 {unpublished data only}
- JPRN‐UMIN000003125. CLSS‐based assessment of alfa‐adrenoceptor blockers for male LUTS (CLAM‐STUDY). apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000003125 (date first received 01 September 2017).
JPRN‐UMIN000005151 {unpublished data only}
- JPRN‐UMIN000005151. The clinical study for evaluating the early efficacy and safety of alpha‐1‐adrenoreceptor antagonists in patient with benign prostatic hyperplasia. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000005151 (date first received 01 September 2017).
JPRN‐UMIN000008538 {unpublished data only}
- JPRN‐UMIN000008538. Comparison of the long‐term efficacy of silodosin and tamsulosin for the treatment of benign prostatic hyperplasia. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000008538 (date first received 01 September 2017).
JPRN‐UMIN000011556 {unpublished data only}
- JPRN‐UMIN000011556. Comparative study of early efficacy of once‐daily dosing between silodosin 4mg and tamsulosin 0.2mg for voiding symptoms associated with benign prostatic hyperplasia. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000011556 (date first received 01 September 2017).
Mandal 2013 {published data only}
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Manohar 2014 {published data only}
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Miyamae 2011 {published data only}
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NCT01222650 {unpublished data only}
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Pawar 2015 {published data only}
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References to ongoing studies
CTRI/2013/10/004112 {unpublished data only}
- CTRI/2013/10/004112. A study to find out the medication which offers maximum health benefits with minimum spending by the patient among the three commonly used medications in the treatment of benign prostatic hyperplasia, a disease in aging men which results in bothersome urinary problems. apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2013/10/004112 (date first received 01 September 2017).
JPRN‐UMIN000003609 {unpublished data only}
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