Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia

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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a,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)	⊕⊕⊝⊝ Low^a,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 low^a,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 risk^e
				61 per 1000	17 more per 1000 (20 fewer to 88 more)
Sexual adverse events Follow‐up: mean 3 months	1967 (4 RCTs)	⊕⊕⊝⊝ Moderate^a	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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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 low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	‐	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)	⊕⊕⊝⊝ Low^a,c	Not estimable	Study population
				‐	‐
Cardiovascular adverse events Follow‐up: mean 3 months	60 (1 RCT)	⊕⊕⊝⊝ Low^a,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 risk^d
				44 per 1000	15 fewer per 1000 (11 fewer to 28 more)
Sexual adverse events Follow‐up: mean 3 months	95 (1 RCT)	⊕⊕⊝⊝ Moderate^a	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 risk^d
				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.

Antecedentes

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Descripción de la afección

La hiperplasia prostática benigna (HPB) se caracteriza por un proceso proliferativo no regulado del tejido conjuntivo, músculo liso y epitelio glandular en el interior de la próstata, y es una de las afecciones más frecuentes en los hombres mayores (Roehrborn 2008). La prevalencia de la HPB aumenta de manera significativa con el aumento de la edad. En estudios de autopsias se ha observado una prevalencia histológica de un 40% y un 70% en el sexto y octavo decenios de la vida, respectivamente (Barry 1997; Egan 2016; Roehrborn 2008). La HPB puede causar síntomas urinarios bajos (SUB) molestos, como los trastornos del almacenamiento (como urgencia urinaria diurna y nicturia) o de la micción (como dificultad para iniciar la micción, chorro urinario débil, esfuerzo miccional y micción prolongada) o ambos (AUA Practice Guidelines Committee 2003; EAU 2017; McVary 2011). Los SUB secundarios a la HPB (SUB/HPB) pueden repercutir negativamente en la salud pública y reducir la calidad de vida porque la HPB puede progresar con el transcurso del tiempo y causar graves consecuencias, como retención urinaria aguda (RUA), infección urinaria y deterioro de las vías urinarias altas (Crawford 2006; Kozminski 2015; Martin 2014). En 2000, el costo del tratamiento directo para SUB/HPB en los EE.UU. fue de más de mil millones de dólares estadounidenses. Sobre la base de los datos del Hospital Episode Statistics del Reino Unido, SUB/HPB es la quinta enfermedad más costosa y cuesta 1160 millones de libras esterlinas por año (Cornu 2010).

Diagnóstico

La evaluación inicial de SUB/HPB incluye el interrogatorio del paciente, la revisión de los fármacos actuales, la exploración física incluido tacto rectal, análisis de orina, registro de frecuencia y volumen y cuestionarios de síntomas validados como la International Prostate Symptom Score (IPSS) y el BPH Impact Index (BII) (EAU 2017; Juliao 2012; McVary 2011). El cuestionario IPSS está compuesto de tres dominios relacionados con los síntomas de almacenamiento (frecuencia, urgencia y nicturia); cuatro dominios relacionados con los síntomas miccionales (dificultad para iniciar la micción, chorro débil, intermitencia y evacuación incompleta); y un dominio de calidad de vida (AUA Practice Guidelines Committee 2003; Barry 1992). Siete dominios de síntomas usan una escala de seis puntos que varía de 0 (ninguno) a 5 (5 o más) (Barry 1992). Al dominio de calidad de vida se le asigna una puntuación de 1 a 6 (ordinal; intervalo de 0 a 6: 0 = muy complacido, 1 = complacido, 2 = en su mayoría satisfecho, 3 = contradictorio, 4 = en su mayoría insatisfecho, 5 = infeliz, 6 = muy mal) (AUA Practice Guidelines Committee 2003; Barry 1992).

De manera simultánea con el IPSS, el BII se desarrolló para evaluar el efecto de SUB/HPB sobre la salud de los pacientes. El cuestionario BII está compuesto de cuatro ítems: malestar físico (0 = ninguno, 1 = poco, 2 = bastante, 3 = mucho); preocupación (0 = ninguna, 1 = poca, 2 = bastante, 3= mucha); molestia (0 = ninguna, 1 = poca, 2 = bastante, 3 = mucha); interferencia en las actividades cotidianas (0 = nunca, 1= a veces, 2 = bastante, 3 = casi siempre, 4 = todo el tiempo) (Barry 1995). Además, la medición de la velocidad de flujo máxima (Qmax) y el residuo posmiccional (RPM) son pruebas no invasivas ampliamente usadas para evaluar el funcionamiento compartido entre la vejiga y la próstata (EAU 2017; McVary 2011). Aunque no se han determinado los umbrales de diagnóstico de Qmax y RPM, el Qmax bajo y el RPM grande se han asociado con un mayor riesgo de deterioro de los síntomas (Crawford 2006; Kozminski 2015). Otros exámenes optativos son los estudios por imágenes de las vías urinarias y la próstata, la evaluación urodinámica de la función vesical y la cistoscopia para predecir la respuesta al tratamiento médico o determinar la necesidad de tratamiento invasivo y, en consecuencia, el mejor abordaje (EAU 2017; McVary 2011).

Tratamiento

Las decisiones terapéuticas se basan en los síntomas y el grado de molestia (EAU 2017; McVary 2011). La conducta expectante es una estrategia terapéutica razonable para los hombres con SUB leves (IPSS: 0 a 7) o los que no perciben los síntomas como especialmente molestos (Netto 1999). Las intervenciones del estilo de vida como la modificación de la ingestión de líquidos o la higiene pueden usarse como tratamientos conservadores en los hombres con SUB leves (Yap 2009). En pacientes con SUB molestos, moderados (IPSS: 8 a 19) a severos (IPSS: 20 a 35), los tratamientos quirúrgicos y médicos son la opción terapéutica, y la elección del tratamiento depende de ciertos factores como la gravedad de la enfermedad, el riesgo de evolución, la preferencia del paciente y la morbilidad (EAU 2017; McVary 2011).

Recientemente, se ha dilucidado el componente dinámico de la HPB, con un énfasis en los síntomas en lugar del aumento de volumen prostático, que ha llevado a un cambio de la cirugía al tratamiento médico (Yoo 2012). Los bloqueadores de los receptores alfa (BA), que reducen el tono del músculo liso de la próstata y del cuello vesical, con o sin inhibidores de la 5 alfa reductasa (I‐5AR), que reducen el volumen prostático a través de la inducción de atrofia epitelial, son un tratamiento establecido en SUB/HPB y han sido ampliamente usados como tratamiento de primera línea durante decenios (McConnell 2003; Milani 2005; Yoo 2012). Sobre todo los BA, que pueden disminuir el tono de músculo liso de la próstata y cuello vesical, se han considerado la farmacoterapia fundamental para los pacientes con HPB (Cornu 2010; Milani 2005; Yoo 2012). En revisiones sistemáticas previas, se ha indicado que los BA pueden reducir típicamente la IPSS en un 20% a un 50% y aumentar el Qmax en un 15% a un 45% (MacDonald 2005; Wilt 2006). Los BA son la categoría más comúnmente prescrita de fármacos y representan cerca de un 70% de todos los fármacos prescritos en 2008 (Cornu 2010). Los efectos adversos de los BA incluyen: hipotensión postural, mareos, cefalea, astenia, síncope, edema periférico y eyaculación retrógrada, que hacen que cerca de un 4% a un 10% de los hombres dejen el tratamiento (Djavan 1999; Gacci 2014; MacDonald 2005; Schulman 2003; Wilt 2006).

Se han usado otros tratamientos médicos, como los anticolinérgicos y la desmopresina, con los BA, según los síntomas principales de los pacientes (Brasure 2016; Dahm 2016; EAU 2017). Alternativamente, un inhibidor de la fosfodiesterasa tipo 5, tadalafil (5 mg una vez al día), se ha autorizado para el tratamiento de los SUB masculinos en los últimos años, y se han propuesto diversos extractos vegetales para el tratamiento de SUB masculinos (EAU 2017; Keehn 2016; Oelke 2012). En pacientes con SUB/HPB con escasa respuesta al tratamiento conservador/médico o en los casos de indicaciones clínicas absolutas (p.ej. RUA, infección urinaria recurrente, cálculos o divertículos vesicales, hematuria o insuficiencia renal), deben considerarse las técnicas quirúrgicas (EAU 2017; McVary 2011). La resección transuretral de la próstata (RTUP) se considera el procedimiento quirúrgico estándar para el tratamiento de los SUB/HPB (EAU 2017; Juliao 2012; McVary 2011). Recientemente, las terapias con láser mínimamente invasivas, como la resección de la próstata con láser de holmio y la vaporización fotoselectiva fueron introducidas como opciones terapéuticas de la RTUP (Nair 2016).

Descripción de la intervención

La silodosina es un nuevo subtipo selectivo de BA que se aprobó en Japón en 2006 y más recientemente en los EE.UU. y Europa (Kawabe 2006a; Yoshida 2007). Un ensayo inicial aleatorio, controlado con placebo, que se realizó en Japón mostró una mayor reducción de la IPSS después del tratamiento de 12 semanas en comparación con tamsulosina (un BA bien establecido para los SUB) y un placebo. Además, se halló un beneficio clínico de la IPSS en el grupo de silodosina sobre el placebo de la primera semana en adelante (Kawabe 2006a). No hubo diferencias significativas de la incidencia de los efectos adversos cardiovasculares entre los grupos de silodosina y tamsulosina. La eyaculación anormal fue más frecuente en el grupo de silodosina que en el grupo de tamsulosina (22,3% versus 1,6%) pero sólo cinco hombres (2,9%) interrumpieron el tratamiento por esta razón (Kawabe 2006a).

De qué manera podría funcionar la intervención

Los receptores adrenérgicos A1a son una clase de receptores acoplados a la proteína G que consta de tres subtipos homólogos: A1a, A1b y A1d. El subtipo receptor A1a predomina en la próstata, el cuello vesical y la uretra humanas (Minneman 1994; Schilit 2009). Por otro lado, los subtipos de receptores A1b se expresan principalmente en la vasculatura periférica y son importantes en la regulación de la presión arterial. El receptor A1d se expresa en el músculo detrusor de la vejiga y la región sacra de la médula espinal (Minneman 1994; Schilit 2009). En el estudio in vitro inicial, se mostró que la silodosina tuvo un alto cociente de unión (162:1) a los receptores A1a versus A1b, que pueden ser más específicos de las vías urinarias inferiores, y por lo tanto pueden inducir un efecto terapéutico sin efectos secundarios cardiovasculares, como mareos, cefalea e hipotensión ortostática relacionada a la vasodilatación, en comparación con otros BA, que no tienen ninguna selectividad específica para los diferentes subtipos de receptores adrenérgicos (alfuzosina, doxazosina, terazosina) o una selectividad limitada para el receptor A1a (tamsulosina) (Osman 2012; Schilit 2009; Yoshida 2007).

Por qué es importante realizar esta revisión

No está claro si la alta afinidad de la silodosina para el receptor adrenérgico A1a se traduce en más beneficios y menos efectos adversos clínicos en la práctica clínica (Cui 2012; Novara 2013). Aunque hay revisiones sistemáticas que comparan silodosina con otros agentes usados para tratar a los pacientes con SUB/HPB, ninguno hasta el presente ha usado la misma metodología rigurosa que las revisiones Cochrane, que incluyen el enfoque GRADE (Cui 2012; Fusco 2016; Novara 2013). En esta época, con la disponibilidad de numerosos BA para tratar SUB/HPB, los resultados de esta revisión Cochrane serán relevantes para los elaboradores de políticas, los profesionales de la salud y los pacientes.

Objetivos

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Evaluar los efectos de la silodosina para el tratamiento de los SUB en pacientes con HPB.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Se incluyeron ensayos controlados aleatorios y paralelos de forma independiente del estado o el idioma de la publicación. También se incluyeron diseños cruzados.

Tipos de participantes

Se incorporaron pacientes adultos (a partir de los 40 años) con SUB/HPB. La limitación de edad se basó en la observación de que la prevalencia de la HPB aumenta en los hombres de mediana edad y mayores (Barry 1997; Egan 2016) y es poco frecuente en los hombres más jóvenes.

Se excluyeron los ensayos de pacientes con vejiga neurogénica conocida por lesiones de la médula espinal, esclerosis múltiple o enfermedades del sistema nervioso central, y los pacientes que ya han sido tratados con cirugía para la HPB. Se incluyeron estudios en los que sólo un subconjunto de participantes era relevante para esta revisión.

Tipos de intervenciones

Se programó investigar las siguientes comparaciones de la intervención experimental versus la intervención de comparación. Las intervenciones concomitantes debían ser las mismas en los grupos intervención y comparador para establecer comparaciones justas.

Intervenciones experimentales

Silodosina
Silodosina + cualquier 5‐IRA (si estaban disponibles)

La silodosina 8 mg/día es la dosificación clínicamente recomendada en Japón, Europa y los EE.UU. (Chapple 2011; Kawabe 2006a; Marks 2009). Un estudio reciente informó que la silodosina 4 mg/día fue también útil en pacientes japoneses con HPB para mejorar el cumplimiento del tratamiento (Seki 2015). Se incluyeron ensayos con una dosificación de silodosina de 8 mg/día (4 mg dos veces al día o 8 mg una vez al día) y 4 mg/día.

Intervenciones de comparación

Placebo
Otros BA
Otros BA + cualquier 5‐IRA (si estaban disponibles)

Comparaciones

Silodosina versus placebo
Silodosina versus otros BA
Silodosina + cualquier 5‐IRA versus otros BA + cualquier 5‐IRA (si estaban disponibles)

Tipos de medida de resultado

No se usó la medición de los resultados evaluados en esta revisión como criterio de elegibilidad.

Resultados primarios

Puntuaciones de los síntomas urológicos
Calidad de vida
Retiros del tratamiento por cualquier motivo

Resultados secundarios

Retiros del tratamiento debido a efectos adversos
RUA
Cirugía para SUB/HPB
Efectos adversos cardiovasculares
Efectos adversos sexuales

Método y momento adecuado de la medición de los resultados

Puntuaciones de los síntomas urológicos: valor final o cambio desde el inicio evaluados con una escala validada (como IPSS)
Calidad de vida: valor final o cambio desde el inicio evaluados con una escala validada (como las puntuaciones BII o IPSS‐calidad de vida)
Retiros del tratamiento por cualquier motivo: definidos como la interrupción del tratamiento por cualquier causa en cualquier momento después de que los participantes se asignaran al azar a grupos de intervención/comparadores
Retiros del tratamiento debido a efectos adversos: definidos como la interrupción del tratamientos por un evento adverso en cualquier momento después de que los participantes se asignaran al azar a grupos de intervención/comparadores
RUA: eventos que requirieron la colocación de una sonda después de la intervención
Cirugía para SUB/HPB: eventos que requirieron otras modalidades de tratamiento quirúrgico (p.ej. RTUP) después de la intervención
Efectos adversos cardiovasculares: como mareos, cefalea, hipotensión ortostática y síncope
Efectos adversos sexuales: como eyaculación retrógrada, aneyaculación y disminución de la libido

Se usó la diferencia clínicamente importante en los resultados de revisión para valorar la calidad de la evidencia en las tablas de "Resumen de resultados" (Jaeschke 1989; Johnston 2013). Cuando la diferencia de medias (DM) o el cociente de riesgos (CR) es igual o más grande que la diferencia mínima importante clínicamente (DMCI), se supondría que muchos pacientes pueden haber obtenido una mejoría clínicamente significativa con el tratamiento; cuando la DM es de al menos la mitad de la DMCI pero menor que la DMCI, un número apreciable de pacientes puede haber obtenido una mejoría clínicamente significativa; y cuando la DM es menos de la mitad de la DMCI, es poco probable que un número apreciable de pacientes haya logrado una mejoría clínicamente significativa (Johnston 2010). Se consideró que la DMCI en la puntuación IPSS y BII era de 3 y 0,5 puntos, respectivamente (Barry 1995). No se encontró información publicada sobre una DMCI para la pregunta IPSS‐calidad de vida. Se usó una DMCI de 1 para evaluar la eficacia y la efectividad comparativa (Brasure 2016). No se establecieron umbrales para los retiros del tratamiento por los efectos adversos, la RUA, la cirugía para SUB/HPB, los efectos adversos cardiovasculares ni los efectos adversos sexuales. Se consideraron las diferencias clínicamente importantes de todos los resultados enumerados anteriormente como un aumento del riesgo relativo de al menos un 25% (Guyatt 2011a).

Se consideraron los resultados medidos hasta 12 meses inclusive tras de la asignación al azar como corto plazo y después de los 12 meses como largo plazo.

Hasta 12 meses (corto plazo)
Más de 12 meses (largo plazo)

Resultados principales de la tabla "Resumen de los hallazgos"

Se presenta una tabla de "Resumen de los hallazgos" que informa los siguientes resultados enumerados según la prioridad.

Puntuaciones de los síntomas urológicos
Calidad de vida
Retiros del tratamiento por cualquier motivo
Efectos adversos cardiovasculares
Efectos adversos sexuales

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).

Figure 1

Flow diagram

Included studies

Details of included studies are presented elsewhere (see Characteristics of included studies; Table 1; Table 2).

Table 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

See: 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); Summary of findings 2 Silodosin compared to tamsulosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term); Summary of findings 3 Silodosin compared to naftopidil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term); Summary of findings 4 Silodosin compared to alfuzosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term)

Table 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	2849/923	457	457	419 (91.6)
	Total		923	923	832 (90.1)
Masuda 2012	Silodosin 4 mg or 8 mg	NR/92	44	30/83^a	30 (68.1)
	Naftopidil 50 mg or 75 mg	NR/92	48	34/79^a	34 (70.8)
	Total		92	64/162^a	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	NR/350	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	NR/97	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	NR/57	29	NR	NR
	Total		57	NR	NR
NCT00793819	Silodosin 8 mg	215/209	111	111	97 (87.3)
	Placebo	215/209	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	102/61	29	27	27 (93.1)
	Total		61	53	53 (86.8)
Shirakawa 2013	Silodosin 8 mg	NR/121	61	56/59^a	56 (91.8)
	Naftopidil 50 mg	NR/121	60	56/57^a	56 (93.3)
	Total		121	112/116^a	112 (92.5)
Takeshita 2016	Silodosin 4 mg	NR/34	18	16	16 (88.8)
	Tamsulosin 0.2 mg	NR/34	16	14	14 (87.5)
	Total		34	30	30 (88.2)
Watanabe 2011	Silodosin 4 mg	NR/102	51	42/88^a	42 (82.3)
	Tamsulosin 0.2 mg	NR/102	51	42/91^a	42 (82.3)
	Total		102	84/179^a	42 (82.3)
Yamaguchi 2013	Silodosin 8 mg	109/109	58	53	53 (91.3)
	Naftopidil 75 mg	109/109	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	NR/149	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	NR/46	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	NR/209	104	83	83 (79.8)
	Total		209	170	170 (81.3)
Grand total	Interventions: silodosin		1955		1684^b
	Compartors: placebo		834		769 (92.2)
	Compartors: tamsulosin		1049		888^b
	Compartors: naftopidil		380		333 (87.6)
	Comparator: alfuzosin		77		77 (100.0)
	Overall		4295		3751^b

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

See Figure 2; Figure 3.

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure 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

Details are presented elsewhere (see summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings 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).

1.2. 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).

1.3. 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).

1.4. 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).

1.5. 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).

1.8. 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).

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).

2.2. 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).

2.3. 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).

2.4. 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).

2.5. 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).

2.8. 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).

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).

3.2. 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).

3.3. 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).

3.4. 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).

3.5. 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).

3.8. 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).

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).

4.2. 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).

4.3. 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).

4.8. 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).

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.

Discusión

available in

Resumen de los resultados principales

Se incluyeron 19 estudios únicos con 4295 participantes asignados al azar a cuatro comparaciones para el seguimiento a corto plazo. Todos los estudios incluyeron hombres mayores de 40 años. La media de edad y de la IPSS de los participantes fueron de 66,5 años y 19,1; respectivamente.

Silodosina versus placebo

La silodosina puede reducir las puntuaciones de los síntomas urológicos en un número apreciable de pacientes pero no mejorar la calidad de vida de manera significativa. Los retiros del tratamiento por cualquier motivo no parecen aumentar. No hay seguridad acerca del efecto de la silodosina en los eventos adversos cardiovasculares aunque el fármaco puede aumentar los efectos adversos sexuales. No hubo ningún cambio clínicamente importante de los efectos del tratamiento en un análisis de sensibilidad centrado en los estudios de bajo riesgo.

Silodosina versus tamsulosina

La silodosina puede dar lugar a poca o ninguna diferencia de las puntuaciones de los síntomas urológicos y la calidad de vida. No hay seguridad acerca de las tasas de retiro del tratamiento por cualquier motivo. La silodosina puede dar lugar a poca o ninguna diferencia en los efectos adversos cardiovasculares pero puede aumentar los efectos adversos sexuales de manera significativa.

Silodosina versus naftopidil

La silodosina puede tener efectos similares en las puntuaciones de los síntomas urológicos, la calidad de vida, las tasas de retiro del tratamiento por cualquier motivo y los efectos adversos cardiovasculares. La silodosina puede aumentar los efectos adversos sexuales de manera significativa.

Silodosina versus alfuzosina

La silodosina puede o no dar lugar a un aumento clínicamente importante de las puntuaciones de los síntomas urológicos y puede resultar en poca o ninguna diferencia en la calidad de vida. No se encontró ningún efecto del retiro del tratamiento por cualquier motivo. La silodosina puede no reducir los efectos adversos cardiovasculares pero puede aumentar los efectos adversos sexuales de manera significativa.

No fue posible realizar ninguno de los análisis de subgrupos predefinidos.

Compleción y aplicabilidad general de las pruebas

Hubo varias limitaciones relacionadas con la totalidad y la aplicabilidad general de la evidencia que merecen consideración.

La capacidad de evaluar los resultados a más largo plazo de la silodosina en comparación con otros fármacos se vio limitada porque la duración del seguimiento en casi todos los estudios (18 de 19) fue de 12 semanas o menos. Dado el uso a largo plazo de los BA para el tratamiento de SUB/HPB en la práctica clínica, el estudio de la eficacia y la seguridad de la silodosina en tan corto plazo aparece como insuficiente para brindar seguridad de los resultados a largo plazo.
Tres de los ensayos más grandes incluidos en esta revisión usaron períodos previos antes de la asignación al azar (Chapple 2011; Marks 2009; Yu 2011). Este hecho puede haber llevado a la exclusión de pacientes con menos probabilidades de cumplir con el tratamiento o más propensos a presentar efectos adversos, con lo que se limita la generalizabilidad.
No fue posible determinar el efecto de la silodosina sobre la RUA ni las intervenciones quirúrgicas por la ausencia de eventos en los estudios incluidos. Esto se corresponde una vez más al período de seguimiento corto. La información adicional puede tener que extraerse de los estudios observacionales a más largo plazo.
Las tasas de efectos adversos en dos estudios disponibles en forma de resumen sólo fueron más altas que las informadas en los estudios de texto completo, lo que genera inquietudes con respecto al sesgo de publicación (Jung 2012; Yamanishi 2011).
Aunque los BA como la silodosina se usan comúnmente en combinación con los 5‐IRA, no se encontró ningún estudio elegible.

Calidad de la evidencia

Se disminuyó sistemáticamente la calidad de la evidencia en una o dos categorías a moderara o baja. Los motivos más frecuentes para disminuir la calidad fueron: las limitaciones de los estudios (problemas con la ocultación de la asignación y el cegamiento), la inconsistencia (como lo representan los altos valores de I²), que no se pudo explicar con análisis secundarios, y la imprecisión (intervalos de confianza amplios que cruzaron el umbral supuesto de diferencia clínicamente importante o por los pocos eventos).

Sesgos potenciales en el proceso de revisión

A pesar de la estrategia integral de búsqueda sin ninguna publicación o restricción de idioma, es posible que se hayan omitido publicaciones relevantes. La mayoría de los estudios se originó de Japón y la India. Es posible que algunos estudios, sobre todo los negativos, fueran publicados en revistas no indizadas o presentadas en reuniones locales solamente, y por lo tanto, pueden haber sido omitidos en la búsqueda, lo que resulta en sesgo de publicación potencial. El número de estudios incluidos en esta revisión fueron insuficientes para generar gráficos en embudo; por lo tanto, puede haberse subestimado el riesgo de sesgo de publicación. Una actualización futura de esta revisión debe considerar la inclusión de las bases de datos bibliográficas regionales para mejorar aún más la búsqueda.

Se intentó contactar con todos los autores de los estudios en varias ocasiones para obtener información. Aunque se recibió información adicional de nueve autores de estudios, otros no respondieron. Ésta puede ser una fuente de sesgo.

Para los ensayos cruzados, se intentaron extraer los datos antes del cruzamiento, como si el estudio fuera un ensayo de grupos paralelos, en conformidad con el Manual Cochrane de Revisiones Sistemáticas de Intervenciones (Higgins 2011c). Sin embargo, dos ensayos cruzados informaron los efectos adversos con todas las mediciones de los períodos de silodosina y de tamsulosina (Masuda 2012; Watanabe 2011). Este hecho puede haber originado una unidad de error de análisis. Para otros ensayos cruzados, se usó el número de participantes inicialmente asignados como un enfoque más conservador. Además, un ensayo cruzado usó la tasa del evento para informar los efectos adversos individuales, que también pueden dar lugar a una unidad de error de análisis (recuento duplicado) (Masuda 2012).

Acuerdos y desacuerdos con otros estudios o revisiones

Hasta la fecha, no hay ninguna revisión sistemática que se centre en la silodosina y haya aplicado la misma metodología rigurosa como esta revisión Cochrane, que incluye un protocolo publicado, un énfasis en los resultados importantes para los pacientes, una búsqueda bibliográfica exhaustiva y una evaluación de la calidad de la evidencia mediante GRADE.

En una revisión y metanálisis sistemático recientemente informados, se encontró que diversos BA (incluida la silodosina) tuvieron una eficacia similar en comparación con el placebo pero se asociaron con una incidencia significativamente mayores de efectos adversos totales y retiro del tratamiento (Novara 2013; Yuan 2015). Por otro lado, Ding 2013 no informó ninguna diferencia significativa en la incidencia de trastorno de la eyaculación entre los grupos de silodosina y de tamsulosina, pero preocupa que los números usados en el metanálisis no fueran exactos. Una revisión sistemática sobre naftopidil informó que la silodosina tuvo una eficacia equivalente al naftopidil pero se asoció con una incidencia mayor de efectos adversos sexuales (Castiglione 2014). Sin embargo, no se informó ningún metanálisis y los autores no calificaron la calidad de la evidencia. En conjunto, los resultados de la presente revisión en gran parte son compatibles con los de las revisiones publicadas anteriormente en comparación con un placebo, la tamsulosina y el naftopidil.

No se encontró ninguna revisión sistemática publicada que comparara la silodosina con la alfuzosina: esta revisión es la primera.

Figure 1

Flow diagram

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Analysis 1.1

Comparison 1 Silodosin versus placebo, Outcome 1 Urologic symptom scores (short term).

Analysis 1.2

Comparison 1 Silodosin versus placebo, Outcome 2 Quality of life (short term).

Analysis 1.3

Comparison 1 Silodosin versus placebo, Outcome 3 Treatment withdrawal due to any reason (short term).

Analysis 1.4

Comparison 1 Silodosin versus placebo, Outcome 4 Treatment withdrawal due to adverse events (short term).

Analysis 1.5

Comparison 1 Silodosin versus placebo, Outcome 5 Cardiovascular adverse events (short term).

Analysis 1.6

Comparison 1 Silodosin versus placebo, Outcome 6 Sexual adverse events (short term).

Analysis 2.1

Comparison 2 Silodosin versus tamsulosin, Outcome 1 Urologic symptom scores (short term).

Analysis 2.2

Comparison 2 Silodosin versus tamsulosin, Outcome 2 Quality of life (short term).

Analysis 2.3

Comparison 2 Silodosin versus tamsulosin, Outcome 3 Treatment withdrawal due to any reason (short term).

Analysis 2.4

Comparison 2 Silodosin versus tamsulosin, Outcome 4 Treatment withdrawal due to adverse events (short term).

Analysis 2.5

Comparison 2 Silodosin versus tamsulosin, Outcome 5 Cardiovascular adverse events (short term).

Analysis 2.6

Comparison 2 Silodosin versus tamsulosin, Outcome 6 Sexual adverse events (short term).

Analysis 3.1

Comparison 3 Silodosin versus naftopidil, Outcome 1 Urologic symptom scores (short term).

Analysis 3.2

Comparison 3 Silodosin versus naftopidil, Outcome 2 Quality of life (short term).

Analysis 3.3

Comparison 3 Silodosin versus naftopidil, Outcome 3 Treatment withdrawal due to any reason (short term).

Analysis 3.4

Comparison 3 Silodosin versus naftopidil, Outcome 4 Treatment withdrawal due to adverse events (short term).

Analysis 3.5

Comparison 3 Silodosin versus naftopidil, Outcome 5 Cardiovascular adverse events (short term).

Analysis 3.6

Comparison 3 Silodosin versus naftopidil, Outcome 6 Sexual adverse events (short term).

Analysis 4.1

Comparison 4 Silodosin versus alfuzosin, Outcome 1 Urologic symptom scores (short term).

Analysis 4.2

Comparison 4 Silodosin versus alfuzosin, Outcome 2 Quality of life (short term).

Analysis 4.3

Comparison 4 Silodosin versus alfuzosin, Outcome 3 Cardiovascular adverse events (short term).

Analysis 4.4

Comparison 4 Silodosin versus alfuzosin, Outcome 4 Sexual adverse events (short term).

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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a,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)	⊕⊕⊝⊝ Low^a,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 low^a,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 risk^e
				61 per 1000	17 more per 1000 (20 fewer to 88 more)
Sexual adverse events Follow‐up: mean 3 months	1967 (4 RCTs)	⊕⊕⊝⊝ Moderate^a	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 for the main comparison. Silodosin compared to placebo for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term)

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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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 low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	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 2. Silodosin compared to tamsulosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term)

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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	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 3. Silodosin compared to naftopidil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term)

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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	‐	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)	⊕⊕⊝⊝ Low^a,c	Not estimable	Study population
				‐	‐
Cardiovascular adverse events Follow‐up: mean 3 months	60 (1 RCT)	⊕⊕⊝⊝ Low^a,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 risk^d
				44 per 1000	15 fewer per 1000 (11 fewer to 28 more)
Sexual adverse events Follow‐up: mean 3 months	95 (1 RCT)	⊕⊕⊝⊝ Moderate^a	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 risk^d
				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.

Summary of findings 4. Silodosin compared to alfuzosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (short term)

Table 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

Table 1. Baseline characteristics of included studies

Table 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	2849/923	457	457	419 (91.6)
	Total		923	923	832 (90.1)
Masuda 2012	Silodosin 4 mg or 8 mg	NR/92	44	30/83^a	30 (68.1)
	Naftopidil 50 mg or 75 mg	NR/92	48	34/79^a	34 (70.8)
	Total		92	64/162^a	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	NR/350	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	NR/97	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	NR/57	29	NR	NR
	Total		57	NR	NR
NCT00793819	Silodosin 8 mg	215/209	111	111	97 (87.3)
	Placebo	215/209	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	102/61	29	27	27 (93.1)
	Total		61	53	53 (86.8)
Shirakawa 2013	Silodosin 8 mg	NR/121	61	56/59^a	56 (91.8)
	Naftopidil 50 mg	NR/121	60	56/57^a	56 (93.3)
	Total		121	112/116^a	112 (92.5)
Takeshita 2016	Silodosin 4 mg	NR/34	18	16	16 (88.8)
	Tamsulosin 0.2 mg	NR/34	16	14	14 (87.5)
	Total		34	30	30 (88.2)
Watanabe 2011	Silodosin 4 mg	NR/102	51	42/88^a	42 (82.3)
	Tamsulosin 0.2 mg	NR/102	51	42/91^a	42 (82.3)
	Total		102	84/179^a	42 (82.3)
Yamaguchi 2013	Silodosin 8 mg	109/109	58	53	53 (91.3)
	Naftopidil 75 mg	109/109	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	NR/149	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	NR/46	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	NR/209	104	83	83 (79.8)
	Total		209	170	170 (81.3)
Grand total	Interventions: silodosin		1955		1684^b
	Compartors: placebo		834		769 (92.2)
	Compartors: tamsulosin		1049		888^b
	Compartors: naftopidil		380		333 (87.6)
	Comparator: alfuzosin		77		77 (100.0)
	Overall		4295		3751^b
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).

Table 2. Participants in included studies

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) Show forest plot	3	1743	Mean Difference (IV, Random, 95% CI)	‐2.65 [‐3.23, ‐2.08]

2 Quality of life (short term) Show forest plot	2	820	Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.71, ‐0.13]

3 Treatment withdrawal due to any reason (short term) Show forest plot	3	1703	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.70, 1.66]

4 Treatment withdrawal due to adverse events (short term) Show forest plot	4	1967	Risk Ratio (M‐H, Random, 95% CI)	2.29 [1.41, 3.72]

5 Cardiovascular adverse events (short term) Show forest plot	4	1967	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.67, 2.45]

6 Sexual adverse events (short term) Show forest plot	4	1967	Risk Ratio (M‐H, Random, 95% CI)	26.07 [12.36, 54.97]

Comparison 1. Silodosin versus placebo

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) Show forest plot	10	1708	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐1.31, 1.24]

2 Quality of life (short term) Show forest plot	10	1707	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.53, 0.22]

3 Treatment withdrawal due to any reason (short term) Show forest plot	10	1573	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.62, 1.69]

4 Treatment withdrawal due to adverse events (short term) Show forest plot	9	1572	Risk Ratio (M‐H, Random, 95% CI)	1.96 [1.12, 3.44]

5 Cardiovascular adverse events (short term) Show forest plot	11	1955	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.53, 1.12]

6 Sexual adverse events (short term) Show forest plot	10	1849	Risk Ratio (M‐H, Random, 95% CI)	6.05 [3.55, 10.31]

Comparison 2. Silodosin versus tamsulosin

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) Show forest plot	5	652	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐2.57, 0.87]

2 Quality of life (short term) Show forest plot	5	652	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.60, 0.27]

3 Treatment withdrawal due to any reason (short term) Show forest plot	4	659	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.81, 1.93]

4 Treatment withdrawal due to adverse events (short term) Show forest plot	5	738	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.66, 2.89]

5 Cardiovascular adverse events (short term) Show forest plot	5	808	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.41, 2.56]

6 Sexual adverse events (short term) Show forest plot	4	405	Risk Ratio (M‐H, Random, 95% CI)	5.93 [2.16, 16.29]

Comparison 3. Silodosin versus naftopidil

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) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	3.83 [0.12, 7.54]

2 Quality of life (short term) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.14 [‐0.46, 0.74]

3 Cardiovascular adverse events (short term) Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.36, 1.24]

4 Sexual adverse events (short term) Show forest plot	1	95	Risk Ratio (M‐H, Random, 95% CI)	37.21 [5.32, 260.07]

Comparison 4. Silodosin versus alfuzosin