Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia

Eu Chang Hwang; Shreyas Gandhi; Jae Hung Jung; Mari Imamura; Myung Ha Kim; Ran Pang; Philipp Dahm

doi:10.1002/14651858.CD007360.pub3

. 2018 Oct 11;2018(10):CD007360. doi: 10.1002/14651858.CD007360.pub3

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia

Eu Chang Hwang ^1,^✉, Shreyas Gandhi ², Jae Hung Jung ^3,⁴, Mari Imamura ⁵, Myung Ha Kim ⁶, Ran Pang ⁷, Philipp Dahm ⁸

Editor: Cochrane Urology Group

PMCID: PMC6516835 PMID: 30306544

Abstract

Background

Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease‐related complications. Naftopidil is an alpha‐blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant.

Objectives

To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH.

Search methods

We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018

Selection criteria

We included all parallel RCTs. We also included cross‐over design trials.

Data collection and analysis

Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random‐effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach.

Main results

We included 22 RCTs with 2223 randomised participants across four comparisons for short‐term follow‐up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5‐alpha reductase inhibitors (5‐ARIs) to combination therapy with other ABs and any 5‐ARIs.

All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.

Naftopidil versus tamsulosin

Based on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) –0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI –0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.

Naftopidil versus silodosin

Based on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI –0.78 to 2.85), QoL (MD 0.21, 95% CI –0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events.

Authors' conclusions

Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.

Plain language summary

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia

Review question

What are the effects of naftopidil in men with bothersome urinary symptoms due to an enlarged prostate?

Background

An enlarged prostate (called benign prostatic hyperplasia) can cause bothersome lower urinary tract symptoms such as having to urinate often during the day or at night, having a weak urine stream, and having the feeling of not emptying the bladder completely. A common reason for these complaints is an enlarged prostate, which is common in older men. Naftopidil is a medication that may help with these symptoms and possibly cause fewer unwanted effects than other medications used for this problem. In this review, we compared naftopidil to other medicines.

Study characteristics

We included 22 studies with 2223 men. The average age was 68.0 years. These men had mostly symptoms rated as moderate or severe.

Key results

Naftopidil may have had similar effects on urinary symptoms and QoL compared to tamsulosin and silodosin. In terms of unwanted effects, naftopidil may have had similar unwanted sexual side effects compared to tamsulosin but have fewer compared to silodosin.

Reliability of the evidence

The reliability of evidence for most symptoms was low. This means that the true effect may be substantially different from what this review shows.

Summary of findings

Background

Description of the condition

Benign prostatic hyperplasia (BPH) is a common condition in elderly men and refers to the non‐malignant proliferation of smooth muscle, connective tissue, and glandular epithelium within the prostate, which may result in prostatic urethra obstruction (Roehrborn 2008). The exact aetiology of BPH is currently unknown. Several suggestive risk factors are ageing, familial history, changes in hormonal levels, elevated markers of inflammation, and metabolic syndrome (Russo 2015). Cellular proliferations in the periurethral and transition zones lead to the formation of nodular adenomas, potentially distorting the bladder neck and prostatic urethra. Such occurrence of anatomical changes and prostatic obstruction result in lower urinary tract symptoms (LUTS). There are two categories of LUTS; voiding symptoms (which include hesitancy, weak stream, urinary retention, postmicturition dribble, straining, and incomplete emptying) and storage symptoms (such as frequency, urgency, and nocturia) (McVary 2011).

Generally, greater severity of LUTS relates to more detrimental quality of life (QoL) and a greater desire for treatment (Agarwal 2014). Patient self‐report using a validated urinary symptom scale, such as International Prostate Symptom Score (IPSS), is used to evaluate symptom severity and QoL; this is an integral part of epidemiological and treatment studies (Barry 1995). Increasing IPSS symptom severity (LUTS severity) is also associated with patient perception of bladder condition, which is regarded as men's overall distress and increased healthcare seeking (Chapple 2017). In this Cochrane Review, we used the term BPH as prostatic enlargement with LUTS through which to define the disease condition and potential need for intervention.

Many of the complications of progressive BPH are rare, even though untreated; however, bladder stones, bladder decompensation, urinary tract infections, haematuria, and azotaemia can occur, requiring medical or surgical intervention. BPH has also been related with other medical conditions, reduced QoL, and increased annual healthcare costs (Kaplan 2015; Kozminski 2015; Martin 2014).

Diagnosis

The diagnosis of BPH is based on followed clinical features; a prostate enlargement, bothersome LUTS, and no other identified causes for the urinary problems. The initial evaluation of BPH includes medical history, symptom score questionnaires (IPSS), physical examination including a digital rectal examination, urinalysis, prostate‐specific antigen (PSA) blood test, and frequency volume chart (EAU 2017; McVary 2011). The IPSS questionnaire is composed of three domains related to storage symptoms (frequency, urgency, and nocturia); four domains related to voiding symptoms (hesitancy, weak stream, intermittence, and incomplete emptying); and one QoL domain (AUA Practice Guidelines Committee 2003; Barry 1992). Seven symptom domains use a 6‐point scale ranging from 0 (none) to 5 (five or more) (Barry 1992). The QoL domain is assigned a score from 1 to 6 (ordinal and range from 0 to 6: 0 = delighted, 1 = pleased, 2 = mostly satisfied, 3 = mixed, 4 = mostly dissatisfied, 5 = unhappy, 6 = terrible) (AUA Practice Guidelines Committee 2003; Barry 1992). Another validated symptom score questionnaire, BPH Impact Index (BII), was developed to assess the effect of LUTS/BPH on men's health. The BII questionnaire is composed of four items: physical discomfort (0 = none, 1 = only a little, 2 = some, 3 = a lot); worry item (0 = none, 1 = only a little, 2 = some, 3 = a lot); bother item (0 = not at all bothersome, 1 = bothers me a little, 2 = bothers me some, 3 = bothers me a lot); the interference with usual activities item (0 = none of the time, 1 = a little of the time, 2 = some of the time, 3 = most of the time, 4 = all of the time) (Barry 1995). Symptom score questionnaires should be delivered to objectively identify and quantify LUTS. These are also sensitive to symptom changes and treatment monitoring (EAU 2017; McVary 2011). A digital rectal examination is an important examination and may help to determine the coexistence of prostate cancer. Urinalysis is useful for differential diagnosis to urinary tract infection. Together with a digital rectal examination, a PSA test increases the detection rate of prostate cancer, but would be performed if life expectancy is greater than 10 years and if a diagnosis of prostate cancer would modify the management approach (EAU 2017; McVary 2011). Measurement of urinary flow rates and residual urine are helpful in diagnostic evaluation and treatment response (EAU 2017; McVary 2011). A decreased urinary flow rate and large residual urine are risk factors of symptom aggravation (Crawford 2006). Other tests include radiological imaging, pressure flow study, and urethrocystoscopy are not recommended as a routine diagnostic procedure except in selective conditions which affect treatment decisions (McVary 2011).

Treatment

The role of treatment for any disease process depends on the magnitude of the clinical effect and the incidence and severity of treatment‐related morbidity. In addition, the degree of bother resulting from BPH is the main factor for receiving a treatment. A significant proportion of men with LUTS will not choose medical or surgical intervention because the symptoms are not bothersome. These men are suitable for watchful waiting (Netto 1999) and lifestyle modification (Yap 2009). Men who complain of moderate‐to‐severe bother with symptoms are likely to benefit from medical (alpha‐blockers (ABs), 5‐alpha reductase inhibitors (5‐ARIs), and combination therapy) or surgical treatment (EAU 2017; McVary 2011). ABs reduce smooth muscle tone in the prostate and bladder neck with/without 5‐ARIs, which reduces prostate volume by inducing epithelial atrophy. They are an established treatment in LUTS/BPH and have been widely used as first‐line therapy since the late 1990s (McConnell 2003; Milani 2005; Yoo 2012). In particular, ABs that can decrease smooth muscle tone in the prostate and bladder neck have been considered as fundamental pharmacotherapy for men with BPH (Cornu 2010; Milani 2005; Yoo 2012). Prior systematic reviews have shown that ABs can typically reduce IPSS by 20% to 50% and increase Q_max by 15% to 45% (MacDonald 2005; Wilt 2006). ABs are the most commonly prescribed category of drug for LUTS/BPH, accounting for about 70% of all medications prescribed in 2008 (Cornu 2010). Adverse effects of ABs include postural hypotension, dizziness, headache, asthenia, syncope, peripheral oedema, and retrograde ejaculation, which cause approximately 4% to 10% of men to withdraw from AB treatment (Djavan 1999; Gacci 2014; MacDonald 2005; Schulman 2003; Wilt 2006). Other medical therapies, such as anticholinergics and desmopressin, have been used with ABs, depending on the main symptoms (Brasure 2016; Dahm 2017; EAU 2017). Also, a phosphodiesterase type 5 inhibitor, tadalafil (5 mg once daily), has been licensed for the treatment of male LUTS, and various plant extracts (e.g., Cucurbita pepo; pumpkin seeds, Hypoxis rooperi; South African star grass, Pygeum africanum; bark of the African plum tree, Secale cereale; rye pollen, Serenoa repens; saw palmetto and Urtica dioica; roots of the stinging nettle) have been proposed for the treatment of male LUTS (EAU 2017; Keehn 2016; Oelke 2012). Surgical treatment was considered in cases of symptoms refractory to medical treatment or traditional absolute indications (e.g. acute urinary retention (AUR), recurrent urinary tract infection, bladder stones or diverticula, haematuria, or renal insufficiency) (EAU 2017; McVary 2011).

Description of the intervention

Naftopidil is selective for the A1d adrenergic receptor with a three‐ to 17‐fold higher affinity than for the A1a and A1b adrenergic receptor subtypes based on in vitro studies and was approved in Japan in 1998 (Takei 1999). Naftopidil should be more effective for storage symptoms measured by IPSS due to its selectivity for the bladder via the A1d receptor subtype. Initial randomised controlled trials (RCTs) found no significant difference in IPSS and QoL (QoL) compared with tamsulosin (Ikemoto 2003; Ju 2002). Along with these studies, several RCTs also reported that naftopidil was as effective as tamsulosin (Momose 2007; Nishino 2006). There were no significant differences in the incidence of adverse events between the naftopidil and tamsulosin groups (Ikemoto 2003; Ju 2002; Momose 2007; Nishino 2006; Singh 2013; Ukimura 2008).

How the intervention might work

The A1a adrenergic receptors are a class of G protein‐coupled receptors that consist of three homologous subtypes, including A1a, A1b, and A1d receptors. The A1a receptor subtype predominates in the human prostate, bladder neck, and urethra (Lepor 2016; Michel 2000; Schwinn 2008). A1b receptor subtypes are mainly expressed in the peripheral vasculature and are important in the regulation of blood pressure. The A1d receptor is expressed in the detrusor muscle of the bladder and the sacral region of the spinal cord (Lepor 2016; Michel 2000; Schwinn 2008). Naftopidil, which shows greater selectivity for A1d over the A1a subtype, was reported to be more effective in improving storage symptoms than tamsulosin with greater selectivity for the A1a over the A1d subtype (Nishino 2006; Perumal 2015; Ukimura 2008). In addition, experimental studies have shown that A1d‐ARs greatly outnumber A1a‐ARs in the bladder and are upregulated in bladder outlet obstruction (Hampel 2002). Therefore, naftopidil may have a therapeutic effect for BPH improving obstruction symptoms and storage symptoms with similar vascular adverse effects, such as dizziness, orthostatic hypotension, which were commonly observed in other ABs.

Why it is important to do this review

Naftopidil is not available in Western countries because of non‐Asian randomised clinical trials and lack of placebo‐controlled trials. Therefore, the potential advantages or harms of naftopidil (selective A1d‐AR blockade) in the treatment of LUTS cannot be assessed until a drug with appropriate subtype selectivity becomes available for clinical evaluation (Andersson 2007). One previous Cochrane Review for naftopidil for the treatment of LUTSs compatible with BPH based on RCTs demonstrated that IPSS and QoL improvement were similar to low‐dose tamsulosin (0.2 mg/day) but more improved compared to phytotherapy (Eviprostat) and adverse events due to naftopidil were few and usually mild (Garimella 2009). After publication of the Garimella 2009 review, Cochrane introduced more rigorous methodology, which included assessment of risk of bias and production of 'Summary of findings' tables (the GRADE approach). Furthermore, results of several randomised trials for naftopidil have been reported since the Garimella 2009 review. Therefore, the previous review must be considered outdated. This is an update of the Cochrane Review first published in 2009 (Garimella 2009).

Objectives

To evaluate the effects of naftopidil, for the treatment of LUTS associated with BPH.

Methods

Criteria for considering studies for this review

Types of studies

We included parallel, RCTs regardless of their publication status or language of publication. We also included cross‐over designs.

Types of participants

We included adult men (aged 40 years and over) with LUTS/BPH. The age limitation was based on the observation that the prevalence of BPH increases in middle‐aged and older men (Barry 1997; Egan 2016), and is infrequent in younger men.

We excluded trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease, and men who had been previously treated with surgery for BPH. We included studies that their data were available separately for analysis rather than using the whole population.

Types of interventions

We investigated the following comparisons of experimental intervention versus comparator intervention. Concomitant interventions were allowed but had to be the same in the experimental and comparator groups to establish fair comparisons.

Experimental interventions

Naftopidil.
Naftopidil plus any 5‐ARIs (if available).

In the past, naftopidil 25 mg/day was initially administered, increasing to 50 mg/day to 75 mg/day over an interval of one to two weeks if needed (Yokoyama 2006). Currently, naftopidil 50 mg/day is the initial clinical recommended dosage (Masumori 2011). One study reported that naftopidil 75 mg/day was also useful for Korean men with BPH to improve total IPSS and OABSS (Kwon 2018). We included trials with doses of naftopidil at 25 mg/day, 50 mg/day, and 75 mg/day.

Comparator interventions

Placebo.
Other ABs.
Other ABs plus any 5‐ARIs (if available).
Anticholinergics.
Phytotherapy. (e.g. plant extracts)

Comparisons

Naftopidil versus placebo.
Naftopidil versus other ABs.
Naftopidil plus any 5‐ARIs (If available) versus other ABs plus any 5‐ARIs (if available).
Naftopidil versus anticholinergics.
Naftopidil versus phytotherapy.

Types of outcome measures

Primary outcomes

Urological symptom scores.
QoL.
Treatment withdrawals for any reason.

Secondary outcomes

Treatment withdrawals due to adverse events.
AUR.
Surgical intervention for LUTS/BPH.
Cardiovascular adverse events.
Sexual adverse events.

Method and timing of outcome measurement

Urological symptom scores: final value or change from baseline assessed with a validated scale (such as IPSS).
QoL: final value or change from baseline assessed with a validated scale (such as IPSS‐Quality of Life or BII scores).
Treatment withdrawals for any reason: defined as treatment discontinuation for any cause at any time after participants were randomised to intervention/comparator groups.
Treatment withdrawals due to adverse events: defined as treatment discontinuation due to adverse events at any time after participants were randomised to intervention/comparator groups.
AUR: events requiring catheterisation.
Surgical intervention for LUTS/BPH: events requiring other surgical treatment modalities (e.g. transurethral resection of the prostate (TURP)).
Cardiovascular adverse events: such as dizziness, headache, orthostatic hypotension, and syncope.
Sexual adverse events: such as retrograde ejaculation, anejaculation, and decreased libido.

We used clinically important differences for the outcomes when available to judge the magnitude of the effect in the context of rating the certainty of the evidence in the ''Summary of finding' tables (Jaeschke 1989; Johnston 2013). When the mean difference (MD) or risk ratio (RR) was equal to or larger than the minimal clinically important difference (MCID), we assumed that many participants may have gained a clinically meaningful improvement from treatment.

We considered MCID in the IPSS to be 3 point, BII score to be 0.5 points, and IPSS‐Quality of Life to be 0.5 points (Barry 1995; Brasure 2016; Rees 2015). We did not establish thresholds for treatment withdrawals due to adverse events, AUR, surgical intervention for LUTS/BPH, cardiovascular adverse events, and sexual adverse events. We considered the clinically important differences of all listed outcomes above as a RR increase of at least 25% (Guyatt 2011a). We considered outcomes measured up to and including 12 months after randomisation as short term, and later than 12 months as long term.

Up to 12 months (short term).
More than 12 months (long term).

Main outcomes for 'Summary of findings' tables

We presented 'Summary of findings' tables reporting the following outcomes listed according to the perceived priority to men with LUTS/BPH.

Urological symptom scores.
QoL.
Treatment withdrawals for any reason.
Cardiovascular adverse events.
Sexual adverse events.

Search methods for identification of studies

We performed a comprehensive search with no restrictions on the language of publication or publication status. We updated searches within three months prior to the anticipated publication of the review.

Electronic searches

We initially searched the following sources from inception of each database to 8 October 2017. The date of last search of all databases was 31 May 2018. See Appendix 1.

Cochrane Library (via Wiley):
- Cochrane Database of Systematic Reviews;
- Cochrane Central Register of Controlled Trials (CENTRAL);
- Database of Abstracts of Reviews of Effects;
- Health Technology Assessment Database.
MEDLINE (PubMed).
Embase (Ovid).
Scopus.
LILAC (bvsalud.org/en).
Web of Science.

We also searched the following trials registers on 8 October 2017 and 31 May 2018.

ClinicalTrials.gov (www.clinicaltrials.gov).
World Health Organization International Clinical Trials Registry Platform search portal (apps.who.int/trialsearch/).
Grey Literature Report (www.opengrey.eu).

Searching other resources

We searched the reference lists of retrieved included trials, reviews, meta‐analyses, and health technology assessment reports to identify other potentially eligible trials or ancillary publications. We contacted study authors of included trials to identify any further studies that we might have missed. We contacted drug/device manufacturers for ongoing or unpublished trials. We searched for unpublished studies by handsearching the abstract proceedings of the annual meetings of the American Urological Association, European Association of Urology, and International Continence Society for 2015 to 2017 and then updated the search in 2018.

Data collection and analysis

Selection of studies

We used reference management software to identify and remove potential duplicate records (EndNote). Two review authors (ECH, JHJ) independently scanned the abstract, title, or both, of remaining records retrieved to determine which studies should be assessed further. Two review authors (ECH, JHJ) investigated all potentially relevant records as full text; mapped records to studies; and classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies, in accordance with the criteria for each provided in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We used Covidence for title/abstract, and full‐text screening. We resolved any discrepancies through consensus or recourse to a third review author (PD). If resolution of a disagreement was not possible, we designated the study as 'awaiting classification' and contacted study authors for clarification. We documented reasons for exclusion of studies that may have reasonably been expected to be included in the review in the Characteristics of excluded studies table. We presented an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).

Data extraction and management

We developed a dedicated data abstraction form that we pilot tested ahead of time. For studies that fulfilled the inclusion criteria, two review authors (ECH, JHJ) independently abstracted the following information, which we provided in the Characteristics of included studies table.

Study design.
Study dates.
Study settings and country.
Participant inclusion and exclusion criteria (e.g. age, baseline IPSS).
Participant details, baseline demographics (e.g. age, ethnic background, IPSS).
Number of participants by study and by study arm.
Details of relevant experimental and comparator interventions such as frequency (e.g. once daily or twice daily) and treatment duration (in weeks or months).
Definitions of relevant outcomes and method (e.g. type of instrument such as IPSS) and timing of outcome measurement (e.g. in weeks or months) as well as any relevant subgroups (e.g. based on age).
Study funding sources.
Declarations of interest by primary investigators.

We extracted outcome data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we obtained numbers of events and totals for completion of a 2 × 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we obtained means and standard deviations or data necessary to calculate this information. We attempted to contact authors of included and excluded studies to obtain key missing data as needed.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we maximised yield of information by mapping all publications to unique studies and collating all available data. We used the most complete data‐set aggregated across all known publications. In case of doubt, we gave priority to the publication reporting the longest follow‐up associated with our primary or secondary outcomes.

Assessment of risk of bias in included studies

Two review authors (SG, JHJ) independently assessed the risk of bias of each included study. We resolved disagreements by consensus, or by consultation with a third review author (PD).

We assessed risk of bias using Cochrane's 'Risk of bias' assessment tool for the following domains (Higgins 2011b).

Random sequence generation (selection bias).
Allocation concealment (selection bias).
Blinding of participants and personnel (performance bias).
Blinding of outcome assessment (detection bias).
Incomplete outcome data (attrition bias).
Selective reporting (reporting bias).
Other sources of bias (e.g. run‐in period, absence of washout period in cross‐over trial, baseline imbalance).

We judged risk of bias domains as 'low risk,' 'high risk,' or 'unclear risk' and evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We presented a 'Risk of bias' summary figure to illustrate these findings. For selection bias (random sequence generation and allocation concealment), we evaluated risk of bias at a trial level. For performance bias (blinding of participants and personnel), we considered that all outcomes were susceptible to performance bias and assessed in one group. For detection bias (blinding of outcome assessment), we grouped outcomes as susceptible to detection bias (subjective) or not susceptible to detection bias (objective) outcomes. We defined the following outcomes as susceptible to bias (subjective outcomes).

Urological symptom scores.
QoL.
Treatment withdrawals for any reason.
Treatment withdrawals due to adverse events.
Cardiovascular adverse events.
Sexual adverse events.

We defined the following outcomes as not susceptible to bias (objective outcomes).

AUR.
Surgical intervention for LUTS/BPH.

We initially assessed attrition bias (incomplete outcome data) on a per‐outcome basis but created groups of outcomes based on similar reporting characteristic.

For reporting bias (selective reporting), we evaluated risk of bias on a trial level.

We further summarised the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome, in accordance with the approach for summary assessments of the risk of bias presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Measures of treatment effect

We expressed dichotomous data as RRs with 95% confidence intervals (CIs). We expressed continuous data as MDs with 95% CIs unless different studies used different measures to assess the same outcome, in which case we expressed data as standardised MDs with 95% CIs.

Unit of analysis issues

The unit of analysis was the individual participant. For cross‐over trials or trials with more than two intervention groups, we planned to incorporate these study designs in meta‐analyses in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c).

Dealing with missing data

We obtained missing data from study authors and performed intention‐to‐treat analyses if data were available; we otherwise performed available‐case analyses. We investigated attrition rates, for example, dropouts, losses to follow‐up, and withdrawals, and critically appraised issues of missing data. We did not impute missing data.

Assessment of heterogeneity

We identified heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs, and the I² statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity in the meta‐analysis (Higgins 2002; Higgins 2003); we interpreted the I² statistic as follows (Deeks 2011):

0% to 40%: may not be important;
30% to 60%: may indicate moderate heterogeneity;
50% to 90%: may indicate substantial heterogeneity;
75% to 100%: considerable heterogeneity.

When we found heterogeneity, we attempted to determine possible reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We attempted to obtain study protocols to assess for selective outcome reporting. If we included 10 or more studies contributing in a meta‐analysis, we used funnel plots to assess small‐study effects (Sterne 2011). Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials), and publication bias. Therefore, we interpreted results carefully.

Data synthesis

We summarised data using a random‐effects model. We interpreted random‐effects meta‐analyses with due consideration of the whole distribution of effects. In addition, we performed statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). For dichotomous outcomes, we used the Mantel‐Haenszel method; for continuous outcomes, we used the inverse variance method. We used Review Manager 5 to perform analyses (Review Manager 2014).

Subgroup analysis and investigation of heterogeneity

We expected the following characteristics to possibly introduce clinical heterogeneity, and planned to carry out subgroup analyses with investigation of interactions.

Severity of baseline symptoms based on IPSS (0 to 7 = mildly symptomatic; 8 to 19 = moderately symptomatic; 20 to 35 = severely symptomatic).
Participant age (less than 65 years versus 65 years and older).

These subgroup analyses were based on the following observations.

Relationship between changes in IPSS and participant global ratings of improvement is influenced by the baseline scores (Barry 1995).
Tolerability of other ABs (as the main comparator) may differ by participant age (Kozminski 2015; Lepor 2007).

We planned to perform subgroup analyses limited to the primary outcomes.

Sensitivity analysis

We planned to perform sensitivity analyses limited to the primary outcomes to explore the influence of the following factors (when applicable) on effect sizes.

Restricting the analysis by taking into account risk of bias, by excluding studies at 'high risk' or 'unclear risk' of bias.

'Summary of findings' tables

We presented the certainty of the evidence for each outcome according to the GRADE approach, which takes into account five criteria related to internal validity (risk of bias, inconsistency, imprecision, publication bias) and external validity (directness of results) (Guyatt 2008). For each comparison, two review authors (ECH, JHJ) independently rated the certainty of the evidence for each outcome as 'high,' 'moderate,' 'low,' or 'very low' using GRADEpro GDT 2015. We resolved any discrepancies by consensus, or, if needed, by arbitration by a third review author (PD). For each comparison, we presented a summary of the evidence for the main outcomes in the 'Summary of findings' tables, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011b; Schünemann 2011).

Results

Description of studies

Results of the search

We identified 537 records through electronic database searching, five records in trials registers, and two records in reference lists of reviews. We found no records in the grey literature repository or through handsearching abstract proceedings of relevant meetings from 2015 to 2017. After removal of duplicates, we screened the titles and abstracts of 309 records, and excluded 267 obviously irrelevant records. We screened 42 full‐text articles (34 studies), and excluded 10 records (10 studies) that did not meet the inclusion criteria or were not relevant to the review. Two studies are awaiting classification. We included 22 studies (30 records) in the review. The flow of literature through the assessment process is shown in the PRISMA flowchart (Figure 1).

Included studies

Details of included studies are presented in the Characteristics of included studies table; Table 5; and Table 6.

1. Baseline characteristics of included studies.

Study name	Trial period (year to year)	Country	Setting	Description of participants	Intervention(s) and comparator(s)	Duration of intervention (duration of follow‐up)	Mean age (± SD; years)	Mean prostate volume (± SD; mL)	IPSS (± SD)
Fujihara 2010	NR	Japan	Multicentre	Men with LUTS with OAB symptoms	Naftopidil 50–75 mg once daily	12 weeks	NR	NR	17.61 ± 5.8 (estimated from the figure)
					Tamsulosin 0.2 mg once daily		NR	NR	15.72 ± 6.96 (estimated from the figure)
Gotoh 2005	NR	Japan	Multicentre (16 investigational sites)	Men aged ≥ 50 years, IPSS ≥ 8, Q_max < 15 mL/s (voided volume ≥ 150 mL), prostate ≥ 20 mL	Naftopidil 25 mg/day for 2 weeks, followed by 50 mg/day for 10 weeks	12 weeks	68.0 ± 7.2 (calculated from 95% CI 66.4 to 69.8)	29.0 ± 10.2 (calculated from 95% CI 27.2 to 32.0)	15.5 ± 5.7 (calculated from 95% CI 14.1 to 16.8)
					Tamsulosin 0.2 mg/day for 12 weeks		68.5 ± 6.8 (calculated from 95% CI 67.0 to 70.1)	33.6 ± 18.1 (calculated from 95% CI 29.5 to 37.7)	17.1 ± 6.18 (calculated from 95% CI 15.7 to 18.5)
Griwan 2014	NR	India	Single institution	Men aged ≥ 45 years, daytime frequency > 8, nocturnal frequency > 2, Q_max 5–15 mL/s (150 mL voided volume), PVR < 150 mL, IPSS > 13, IPSS bother score > 3	Naftopidil 75 mg/day	3 months	NR	56.81 ± 6.45	21.31 ± 4.04
					Tamsulosin 0.4 mg/day		NR	57.73 ± 7.33	21.95 ± 4.46
Hanyu 2010	2005–2008	Japan	Multicentre (4 centres)	Men aged ≥ 50 years at first visit, total IPSS ≥ 8, QoL index score ≥ 2 prostate volume ≥ 20 mL, PVR < 100 mL	Naftopidil 50 mg/day	12 weeks	70.5 ± 5.8	40.2 ± 16.3	14.8 ± 5.7
					Tamsulosin 0.2 mg/day		70.9 ± 5.8	41.0 ± 19.3	13.5 ± 5.0
Ikemoto 2003	2000–2002	Japan	3 hospitals in single institute	IPSS ≥ 8; Q_max < 12 mL/s (150 mL voiding);, if prior BPH medication, 1 month washout period	Naftopidil 25 mg/day for first 2 weeks, then 50 mg once daily for 6 weeks then tamsulosin 0.2 mg for 8 weeks	8 weeks (additional 8 weeks after cross‐over/no washout)	66.6 ± 7.6	38.9 ± 11.8	17.4 ± 6.0
					Tamsulosin 0.2 mg for 8 weeks then naftopidil 25 mg for 2 weeks, then 50 mg for 6 weeks		63.8 ± 9.1	32.7 ± 9.4	16.8 ± 7.2
Ju 2002	2011	China	Single institution	Men aged 50–75 years with BPH, IPSS ≥ 13, PSA ≤ 4 ng/mL, Q_max 5–15 mL/s when urine volume > 150 mL	Naftopidil 25 mg once daily	6 weeks	62.5 ± 5.26	NR	18.79 ± 4.8
					Tamsulosin 0.2 mg once daily		66.5 ± 5.8	NR	19.71 ± 4.7
Kwon 2018	2015	Korea	Multicentre	94 men who had been taking tamsulosin for more than 8 weeks; however, men who persisted > 3 points of OABSS, especially > 2 points of OABSS question 3	Naftopidil 75 mg/day for 8 weeks	8 weeks	66.0 ± 6.3	36.8 ± 14.6	16.9 ± 6.2
					Tamsulosin 0.2 mg once daily for 8 weeks		64.8 ± 7.7	37.5 ± 22.4	19.1 ± 7.2
Li 2007	2002–2003	China	Multicentre (9 centres)	Men with BPH/LUTS aged 50–75 years, total IPSS ≥ 13, prostate volume > 20 mL, Q_max < 15 mL/s, PVR < 60 mL	Naftopidil 25 mg once daily	12 month	67.7 ± 5.5	38.1 ± 15.4	20.6 ± 5.4
					Tamsulosin 0.2 mg once daily		66.8 ± 5.4	43.1 ± 17.7	21.1 ± 5.6
Masuda 2012	2009–2011	Japan	Multicentre	Men with LUTS/BPH, prostate volume ≥ 20 cm³, IPSS ≥ 8, QoL score ≥ 3, clinical diagnosis of BPH, aged ≥ 50 years, no prior treatment for BPH	Naftopidil 50–75 mg once/ daily for 2 weeks, then 75 mg once daily for 4 weeks	6 weeks (additional 6 weeks after cross‐over, no washout)	68.5 ± 5.7	45.7 ± 17.8	17.6 ± 5.0
					Silodosin 2–4 mg twice daily for 2 weeks, then 4 mg twice daily for 4 weeks		66.5 ± 5.6	38.8 ± 13.1	18.6 ± 5.5
Masumori 2009	2005–2006	Japan	Multicentre (17 centres)	Men with LUTS/BPH, aged 51–79 years, IPSS ≥ 8	Naftopidil 50 mg once daily	12 weeks	64.5 ± 7.7	35.9 ± 15.3	15.0 ± 5.9
					Tamsulosin 0.2 mg once daily		65.2 ± 7.5	34.4 ± 13.7	17.8 ± 5.7
Matsukawa 2017	2012–2013	Japan	Multicentre	Men aged ≥ 50 years, total IPSS ≥ 8, IPSS‐QoL score ≥ 3, total OABSS ≥ 3, ≥ 1 urinary urgency episodes/week, prostate volume ≥ 20 mL on transabdominal ultrasonography, Q_max < 15 mL/s at a voided volume of ≥ 100 mL and PVR < 150 mL	Naftopidil 50 mg/day for 4 weeks, followed by 75 mg/day for 8 weeks	12 weeks	70.3 ± 7.8	38.6 ± 14.8	18.9 ± 6.1
					Silodosin 4 mg/day for 4 weeks, followed by 8 mg/day for 8 weeks		70.6 ± 7.8	39.6 ± 16.7	18.8 ± 6.2
Momose 2007	2002–2003	Japan	Single centre	Men with LUTS with BPH	Naftopidil 50 mg/day for 4 weeks then tamsulosin 0.2 mg/day for 4 weeks	28 days (additional 28 days after cross‐over, no washout)	65.3 ± 5.5	30.7 ± 13.8	19.6 ± 7.0
					Tamsulosin 0.2 mg/day for 4 weeks and naftopidil 50 mg/day 4 weeks		68.2 ± 7.7	47.2 ± 22.6	18.4 ± 6.9
Nishino 2006	NR	Japan	Single centre	Men with LUTS secondary to BPH	Naftopidil 50 mg/day for 4 weeks then tamsulosin 0.2 mg for 4 weeks	4 weeks: data analysis (4 weeks before cross‐over. 1‐week washout, and additional 4 weeks after cross‐over)	73.2 ± 4.1	20.6 ± 3.7	20.7 ± 4.3
					Tamsulosin 0.2 mg/day for 4 weeks then naftopidil 50 mg for 4 weeks		71.5 ± 4.5	18.9 ± 2.8	20.1 ± 2.7
Perumal 2015	2011–2013	India	Single centre	Men aged > 50 years, clinical symptoms of BPE, LUTS, with or without raised PVR urine	Naftopidil 50 mg once daily	30 days	59.9 ± 5.5	NR	19.97 ± 2.53
					Tamsulosin 0.4 mg once daily		60.1 ± 5.0	NR	21.3 ± 2.84
Shirakawa 2013	2007–2011	Japan	Kobe University School or other collaborating institutions	Men with BPH/LUTS, total IPSS 8 points, QoL index 3 points, Q_max < 15 mL/s, prostate volume 20 mL; either men without history of using any a1‐receptor blocker (hereafter, drug‐naive group) or men who had continued to use tamsulosin 0.2 mg once daily for ≥ 3 months and wanted to switch the medication to another oral drug (hereafter, drug‐switching group).	Naftopidil 50 mg once daily	8 consecutive weeks	70.50 ± 6.58	39.39 ± 25.96	17.56 ± 6.73
					Silodosin 4 mg twice daily		70.98 ± 6.69	38.24 ± 12.94	17.53 ± 5.4
Singh 2013	2010–2012	India	Single institution	Men with BPH; IPSS > 8 or > 3 points for frequency, nocturia, and urgency on IPSS; prostate volume > 15 mL, or peak flow rate < 10 mL for voided volume > 150 mL	Naftopidil 50 mg once daily	12 weeks	61.69	31.38	21.06
					Tamsulosin 0.4 mg once daily		61.15	30.01	21.53
Ub 2016	2009–2013	Japan	Multicentre	Men with OAB and BPH, who met the following criteria and were not administered medication (except herbal preparation) for urinary disorder: IPSS ≥ 2, QoL score ≥ 2, OABSS ≥ 3 (urgency score ≥ 2)	Naftopidil 75 mg/day	8 weeks (additional 8 weeks after cross‐over, no washout: authors judged that evaluation without washout period would be feasible)	74.7 ± 8.0	NR	17.4 ± 6.7
					Tamsulosin 0.2 mg/day + solifenacin 5 mg/day		71.9 ± 8.3	NR	18.1 ± 5.4
Ukimura 2008	2004–2007	Japan	Multicentre	Men aged ≥ 50 years, number of nocturia ≥ 2, IPSS ≥ 8, QoL index ≥ 3, residual urine volume < 50 mL (evaluated by ultrasound estimation), maximum voiding flow rate < 15 mL/s (preferably with a urination volume ≥ 150 mL), prostate volume < 50 mL	Naftopidil 50 mg once daily	6–8 weeks	69.6 ± 6.8	24.4 ± 6.9	17.2 ± 6.4
					Tamsulosin 0.2 mg once daily		68.8 ± 8.2	26.7 ± 7.9	18.9 ± 6.6
Yamaguchi 2013	2007–2010	Japan	Multicentre	Men with BPH aged ≥ 50 years, significant LUTS and deteriorated QoL, IPSS ≥ 8, IPSS‐QoL score ≥ 3	Naftopidil 75 mg/day	12 weeks	70.0 ± 7.0	39.5 ± 18.0	18.9 ± 7.0
					Silodosin 8 mg/day		69.3 ± 7.8	33.2 ± 21.2	16.9 ± 5.5
Yamanishi 2004	NR	Japan	Single centre	IPSS ≥ 8, Q_max < 12 mL/s, prostate volume ≥ 15 mL, obstructive (or equivocal) condition on International Continence Society nomogram as assessed in a pressure/flow study	Naftopidil 25 mg once daily for 2 weeks, then 50 mg once daily for 2 weeks, then 75 mg once daily for 2 weeks	6 weeks	67.5 ± 8.2	29.7 ± 14.9	15.4 ± 5.7
					Eviprostat 6 tablets daily		69.0 ± 6.5	29.5 ± 15.9	16.0 ± 6.9
Yokoyama 2009	2004–2007	Japan	2 centres	Men aged ≥ 50 years, IPSS ≥ 8, 2‐day frequency volume chart showing ≥ 1 episode/day of urinary urgency, daytime voiding frequency ≥ 8 episodes/day, night‐time voiding frequency ≥ 1 episode/night, PVR ≤ 50 mL. Men with elevated serum PSA level (> 10 ng/mL) were confirmed as having BPH before the treatment by transrectal ultrasound‐guided prostate sextant biopsies.	Naftopidil 50 mg/day	4 weeks	69.1 ± 8.3	26.6 ± 12.3	18.2 ± 5.7
					Propiverine hydrochloride 20 mg/day		70.9 ± 6.7	25.3 ± 7.7	18.2 ± 7.0
Yokoyama 2011	NR	Japan	2 centres	Men with LUTS aged 50–80 years, IPSS ≥ 8	Naftopidil 50 mg once daily	12 weeks	69.1 ± 1.2	35.0 ± 3.1	17.4 ± 0.8
					Tamsulosin 0.2 mg once daily		71.5 ± 1.1	32.5 ± 2.0	18.0 ± 1.1
					Silodosin 4 mg twice daily		70.2 ± 0.9	33.3 ± 2.3	18.7 ± 0.7

Study name	Intervention(s) and comparator(s)	Screened/eligible (n)	Randomised (n)	Analysed (n)	Finishing trial (n (%))
Fujihara 2010	Naftopidil 50–75 mg once daily	NR/82	39	NR	NR
	Tamsulosin 0.2 mg once daily		43	NR	NR
	Total		82	NR	NR
Gotoh 2005	Naftopidil 25 mg/day for 2 weeks, followed by 50 mg/day for 10 weeks	185/144	69	69	69
	Tamsulosin 0.2 mg/day		75	75	75
	Total		144	144	144 (100)
Griwan 2014	Naftopidil 75 mg/day	NR/120	60	60	60
	Tamsulosin 0.4 mg/day		60	60	60
	Total		120	120	120 (100)
Hanyu 2010	Naftopidil 50 mg/day	NR/105	55	36	36
	Tamsulosin 0.2 mg/day		50	32	32
	Total		105	68	68 (64.8)
Ikemoto 2003	Naftopidil 25 mg/day for first 2 weeks, then 50 mg once daily for 6 weeks then tamsulosin 0.2 mg for 8 weeks	NR/96	43	31	31
	Tamsulosin 0.2 mg for 8 weeks then naftopidil 25 mg for 2 weeks, then 50 mg for 6 weeks		53	34	34
	Total		96	65	65 (67.7)
Ju 2002	Naftopidil 25 mg once daily	80/80	40	39	39
	Tamsulosin 0.2 mg once daily		40	38	38
	Total		80	77	77 (96.3)
Kwon 2018	Naftopidil 75 mg/day	NR/94	49	NR	NR
	Tamsulosin 0.2 mg once daily		45	NR	NR
	Total		94	—	—
Li 2007	Naftopidil 25 mg once daily	906/906	126	NR	NR
	Tamsulosin 0.2 mg once daily		138	NR	NR
	Total		264	—	—
Masuda 2012	Naftopidil 50–75 mg once for 2 weeks, then 75 mg once daily for 4 weeks	NR/92	48	34	34
	Silodosin 2–4 mg twice daily for 2 weeks, then 4 mg twice daily for 4 weeks		44	30	30
	Total		92	64	64 (69.6)
Masumori 2009	Naftopidil 50 mg/day	NR/95	48	38	38
	Tamsulosin 0.2 mg/day		47	35	35
	Total		95	73	73 (76.8)
Matsukawa 2017	Naftopidil 50 mg for 4 weeks, then 75 mg for 8 weeks	NR/350	175	157	157
	Silodosin 4 mg for 4 weeks, then 8 mg for 8 weeks		175	157	157
	Total		350	314	314 (89.7)
Momose 2007	Naftopidil 50 mg/ 4 weeks, then tamsulosin 0.2 mg/day for 4 weeks	NR/45	20	20	20
	Tamsulosin 0.2 mg for 4 weeks, then naftopidil 50 mg/day for 4 weeks		25	25	25
	Total		45	45	45 (100)
Nishino 2006	Naftopidil 50 mg/day 4 weeks, then tamsulosin 0.2 mg/day 4 weeks	NR/34	17	17	17
	Tamsulosin 0.2 mg/day 4 weeks, then naftopidil 50 mg/day 4 weeks		17	17	17
	Total		34	34	34 (100)
Perumal 2015	Naftopidil 50 mg once daily	NR/60	30	NR	NR
	Tamsulosin 0.4 mg once daily		30	NR	NR
	Total		60	NR	NR
Shirakawa 2013	Naftopidil 50 mg once daily	NR/121	60	56/57	56
	Silodosin 4 mg twice daily		61	56/59	56
	Total		121	112/116	112 (92.5)
Singh 2013	Naftopidil 50 mg once daily	NR/110	55	50	50
	Tamsulosin 0.4 mg once daily		55	51	51
	Total		110	101	101 (91.8)
Ub 2016	Naftopidil 75 mg/day	NR/59	NR	14	14
	Tamsulosin 0.2 mg/day + solifenacin 5 mg/day		NR	17	17
	Total		NR	31	31
Ukimura 2008	Naftopidil 50 mg once daily	NR/81	NR	31	31
	Tamsulosin 0.2 mg once daily		NR	28	28
	Total		NR	59	59
Yamaguchi 2013	Naftopidil 75 mg/day	109/109	51	44	44
	Silodosin 8 mg/day		58	53	53
	Total		109	97	97 (90.0)
Yamanishi 2004	Naftopidil 25 mg once daily for 2 weeks, then 50 mg once daily for 2 weeks, and then 75 mg once daily for 2 weeks	NR/49	36	36	36
	Eviprostat 6 tablets daily		13	13	13
	Total		49	49	49 (100)
Yokoyama 2009	Naftopidil 50 mg/day	NR/58	19	19	19
	Propiverine hydrochloride 20 mg/day		18	18	18
	Total		37	37	37 (100)
Yokoyama 2011	Naftopidil 50 mg once daily	136/136	46	42	42
	Tamsulosin 0.2 mg once daily		45	39	39
	Silodosin 4 mg twice daily		45	41	41
	Total		136	122	122 (89.7)
Overall total	Interventions: naftopidil	Ub 2016; Ukimura 2008 did not report	1086^a	—	793^b
	Comparator: tamsulosin	Ub 2016; Ukimura 2008 did not report	723^a	—	451^b
	Comparator: silodosin	—	383	—	337 (87.9)
	Comparator: propiverine	—	18	—	18 (100)
	Comparator: Eviprostat	—	13	—	13 (100)
	Overall	—	2223	—	1612 (72.5)

Naftopidil compared to tamsulosin (alpha‐blocker) for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (short term)
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: naftopidil Comparator: tamsulosin
Outcomes	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with tamsulosin	Risk difference with naftopidil
Urological symptom scores  assessed with: IPSS  Scale from: 0 (best: not at all) to 35 (worst: almost always)  Follow‐up: 4–12 weeks	965  (12 RCTs)	⊕⊕⊕⊝  Moderate^a	—	The mean urological symptom scores ranged from 9.2 to 10.7 (from 4 studies) and mean change of urological symptom scores ranged from –9.8 to –3.3 (from 8 studies)	MD 0.47 higher  (0.09 lower to 1.04 higher)
Quality of life  assessed with: IPSS‐Quality of Life  Scale from: 0 (best: delighted) to 6 (worst: terrible)  Follow‐up: 4–12 weeks	878  (11 RCTs)	⊕⊕⊝⊝  Low^a,b	—	The mean quality of life ranged from 2.7 to 3.1 (from 3 studies) and mean change of quality of life ranged from –2.75 to –0.7 (from 8 studies)	MD 0.11 higher  (0.09 lower to 0.30 higher)
Treatment withdrawals for any reason  Follow‐up: 4–12 weeks	668  (8 RCTs)	⊕⊕⊝⊝  Low^a,c	RR 0.92  (0.64 to 1.34)	Study population
				90 per 1000	7 fewer per 1000  (32 fewer to 31 more)
Cardiovascular adverse events  Follow‐up: 4–12 weeks	824  (9 RCTs)	⊕⊕⊝⊝  Low^a,c	RR 0.97  (0.52 to 1.80)	Study population
				58 per 1000	2 fewer per 1000  (28 fewer to 47 more)
Sexual adverse events  Follow‐up: 4–12 weeks	397  (5 RCTs)	⊕⊕⊝⊝  Low^a,c	RR 0.54  (0.24 to 1.22)	Study population
				57 per 1000	26 fewer per 1000  (43 fewer to 13 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; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Naftopidil compared to silodosin (alpha‐blocker) for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (short term)
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: naftopidil Comparator: silodosin
Outcomes	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with silodosin	Risk difference with naftopidil
Urological symptom scores  Assessed with: IPSS  Scale from: 0 (best: not at all) to 35 (worst: almost always)  Follow‐up: 6–12 weeks	652  (5 RCTs)	⊕⊕⊝⊝  Low^a,b	—	The mean change of urological symptom scores ranged from –8.6 to –4.9	MD 1.04 higher  (0.78 lower to 2.85 higher)
Quality of life  Assessed with: IPSS‐QoL  Scale from: 0 (best: delighted) to 6 (worst: terrible)  Follow‐up: 6–12 weeks	652  (5 RCTs)	⊕⊕⊝⊝  Low^a,b	—	The mean change of quality of life ranged from –2.0 to –0.98	MD 0.21 higher  (0.23 lower to 0.66 higher)
Treatment withdrawals for any reason Follow‐up: 8–12 weeks	659  (4 RCTs)	⊕⊕⊝⊝  Low^a,c	RR 0.80  (0.52 to 1.23)	Study population
				129 per 1000	26 fewer per 1000  (62 fewer to 30 more)
Cardiovascular adverse events Follow‐up: 6–12 weeks	808  (5 RCTs)	⊕⊕⊝⊝  Low^a,c	RR 0.98  (0.39 to 2.44)	Study population
				24 per 1000	0 fewer per 1000  (15 fewer to 35 more)
Sexual adverse events Follow‐up: 6–12 weeks	348  (4 RCTs)	⊕⊕⊕⊝  Moderate^a	RR 0.15  (0.06 to 0.42)	Study population
				148 per 1000	126 fewer per 1000  (139 fewer to 86 fewer)
*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; IPSS‐QoL: International Prostate Symptom Score – Quality of Life; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Naftopidil compared to propiverine (anticholinergic) for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (short term)
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: naftopidil Comparator: propiverine
Outcomes	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with propiverine	Risk difference with naftopidil
Urological symptom scores  assessed with: IPSS  Scale from: 0 (best: not at all) to 35 (worst: almost always)  Follow‐up: mean 4 weeks	37  (1 RCT)	⊕⊕⊝⊝  Low^a,b	—	The mean change of urological symptom scores was –2.1	MD 2.8 lower  (6.99 lower to 1.39 higher)
Quality of life  assessed with: IPSS‐QoL  Scale from: 0 (best: delighted) to 6 (worst: terrible)  Follow‐up: mean 4 weeks	37  (1 RCT)	⊕⊕⊝⊝  Low^a,b	—	The mean change of quality of life was –1.0	MD 0.1 higher  (0.56 lower to 0.76 higher)
Treatment withdrawals for any reason^c  follow‐up: mean 4 weeks	37  (1 RCT)	—	Not reported	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
Cardiovascular adverse events^c  follow‐up: mean 4 weeks	37  (1 RCT)	—	Not reported	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
Sexual adverse events^c  follow‐up: mean 4 weeks	37  (1 RCT)	—	Not reported	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
*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; IPSS‐QoL: International Prostate Symptom Score – Quality of Life; RCT: randomised controlled trial.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Naftopidil compared to Eviprostat (phytotherapy) for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (short term)
Participants: men with lower urinary tract symptoms suggesting benign prostatic hyperplasia Setting: likely outpatients Intervention: naftopidil Comparator: Eviprostat
Outcomes	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with Eviprostat	Risk difference with Naftopidil
Urological symptom scores  assessed with: IPSS  Scale from: 0 (best: not at all) to 35 (worst: almost always)  Follow‐up: mean 6 weeks	49  (1 RCT)	⊕⊕⊕⊝  Moderate^a	—	The mean change of urological symptom scores was 0.4	MD 6.3 lower  (9.46 lower to 3.14 lower)
Quality of life  assessed with: IPSS‐QoL  Scale from: 0 (best: delighted) to 6 (worst: terrible)  Follow‐up: mean 6 weeks	49  (1 RCT)	⊕⊕⊕⊝  Moderate^a	—	The mean change of quality of life was 0	MD 1.5 lower  (2.36 lower to 0.64 lower)
Treatment withdrawals for any reason  Follow‐up: mean 6 weeks	49  (1 RCT)	⊕⊕⊝⊝  Very low^a,b	RR approximately 1 with wide CI	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
Treatment withdrawals due to adverse events  Follow‐up: mean 6 weeks	49  (1 RCT)	⊕⊕⊝⊝  Very low^a,b	RR approximately 1 with wide CI	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
Cardiovascular adverse events^c  Follow‐up: mean 6 weeks	49  (1 RCT)	—	Not reported	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
Sexual adverse events^c  Follow‐up: mean 6 weeks	49  (1 RCT)	—	Not reported	Study population
				0 per 1000	0 fewer per 1000  (0 fewer to 0 fewer)
*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; IPSS‐QoL: International Prostate Symptom Score – Quality of Life; RCT: randomised controlled trial.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
19 April 2018	New citation required and conclusions have changed	In this update we added 16 new studies and excluded 2 studies included in the previous review due to a wrong comparator. We applied current MECIR standards as well as GRADE to assess the certainty of evidence. The conclusions of this review have changed.
17 January 2012	Amended	Added grant 5R01DK63300‐4 info.

The Cochrane Library (via Wiley) search strategy
1	'MeSH descriptor: [Prostatic Hyperplasia] explode all trees
2	(prostat* near/3 hyperplasia*):ti,ab,kw (Word variations have been searched)
3	(prostat* near/3 hypertroph*):ti,ab,kw (Word variations have been searched)
4	(prostat* near/3 adenoma*):ti,ab,kw (Word variations have been searched)
5	(BPH or BPO or BPE):ti,ab,kw (Word variations have been searched)
6	(prostat* near/3 (enlarg* or obstruct*)):ti,ab,kw (Word variations have been searched)
7	MeSH descriptor: [Prostatism] explode all trees
8	prostatism:ti,ab,kw (Word variations have been searched)
9	MeSH descriptor: [Urinary Bladder Neck Obstruction] explode all trees
10	((bladder* near/3 obstruct*) or BOO):ti,ab,kw (Word variations have been searched)
11	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
12	'(Naftopidil or BM‐15275 or KT‐611 or R9PHW59SFN):ti,ab,kw (Word variations have been searched)
13	#11 and #12
MEDLINE (via PubMed) search strategy
1	exp Prostatic Hyperplasia/
2	(Prostat* adj3 hyperplasia*).tw.
3	(Prostat* adj3 hypertroph*).tw.
4	(Prostat* adj3 adenoma*).tw.
5	(BPH or BPO or BPE).tw.
6	(prostat* adj3 (enlarg* or obstruct*)).tw.
7	exp Prostatism/
8	Prostatism.tw.
9	exp Urinary Bladder Neck Obstruction/
10	(Bladder* adj3 obstruct*).tw.
11	BOO.tw.
12	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13	'(Naftopidil or BM‐15275 or KT‐611 or R9PHW59SFN).nm,tw.
14	'(Flivas or Nafodil or Naftomax or Dishuang or Ge Rui Jia or Jun Lie Xin or Kun Da or Lai Luo Er or Na Tuo or Pu Chang or Shu Er or Sitandi or Yu Chang or Zai Chang).nm,tw.
15	'57149‐07‐2.rn.
16	13 or 14 or 15
17	12 and 15
18	randomized controlled trial.pt.
19	controlled clinical trial.pt.
20	randomized.ab.
21	placebo.ab.
22	drug therapy.fs.
23	randomly.ab.
24	trial.ab.
25	groups.ab.
26	19 or 20 or 21 or 22 or 23 or 24 or 25 or 26
27	exp animals/ not humans.sh.
28	27 not 28
29	18 and 29
Embase (via Elsevier) search strategy
1	''prostate hypertrophy'/exp
2	(Prostat* NEAR/3 hyperplasia*):ab,ti
3	(Prostat* NEAR/3 hypertroph*):ab,ti
4	(Prostat* NEAR/3 adenoma*):ab,ti
5	''bph':ab,ti OR 'bpo':ab,ti OR 'bpe':ab,ti
6	(prostat* NEAR/3 (enlarg* or obstruct*)):ab,ti
7	''prostatism'/exp
8	''prostatism':ab,ti
9	''bladder obstruction'/exp
10	(bladder* NEAR/3 obstruct*):ab,ti
11	''BOO':ab,ti
12	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
13	''naftopidil'/exp
14	'(Naftopidil or BM‐15275 or KT‐611 or R9PHW59SFN):ab,ti,tn
15	'(Flivas or Nafodil or Naftomax or Dishuang or 'Ge Rui Jia' or 'Jun Lie Xin' or 'Kun Da' or 'Lai Luo Er' or 'Na Tuo' or 'Pu Chang' or 'Shu Er' or 'Sitandi' or 'Yu Chang' or 'Zai Chang'):ab,ti,tn
16	''57149‐07‐2':rn
17	#13 OR #14 OR #15 OR #16
18	#12 AND #17
19	''crossover procedure':de OR 'double‐blind procedure':de OR 'randomized controlled trial':de OR 'single‐blind procedure':de OR random:de,ab,ti OR factorial:de,ab,ti OR crossover:de,ab,ti OR ((cross NEXT/1 over):de,ab,ti) OR placebo:de,ab,ti OR ((doubl NEAR/1 blind):de,ab,ti) OR ((singl NEAR/1 blind):de,ab,ti) OR assign:de,ab,ti OR allocat:de,ab,ti OR volunteer:de,ab,ti
20	'animals'/exp NOT ('humans'/exp AND 'animals'/exp)
21	#19 NOT #20
22	#18 AND #21
Scopus search strategy
1	TITLE‐ABS‐KEY((hyperplasia* W/3 prostat) OR (hypertroph W/3 prostat) OR (adenoma W/3 prostat) OR (prostat W/3 (enlarg* OR obstruct)) OR (bph OR bpo OR bpe OR boo) OR prostatism OR (bladder W/3 obstruct*))
2	TITLE‐ABS‐KEY(Naftopidil or BM‐15275 or KT‐611 or R9PHW59SFN or Flivas or Nafodil or Naftomax or Dishuang or "Ge Rui Jia" or "Jun Lie Xin" or "Kun Da" or "Lai Luo Er" or "Na Tuo" or "Pu Chang" or "Shu Er" or "Sitandi" or "Yu Chang" or "Zai Chang")
3	CASREGNUMBER ( 57149‐07‐2 )
4	CHEMNAME ( naftopidil OR bm‐15275 OR kt‐611 OR r9phw59sfn OR flivas OR nafodil OR naftomax OR dishuang OR "Ge Rui Jia" OR "Jun Lie Xin" OR "Kun Da" OR "Lai Luo Er" OR "Na Tuo" OR "Pu Chang" OR "Shu Er" OR "Sitandi" OR "Yu Chang" OR "Zai Chang" )
5	#2 OR #3 OR #4
6	#1 AND #5
Web of Science search strategy
1	TS= ((hyperplasia* NEAR/3 prostat) OR (hypertroph NEAR/3 prostat) OR (adenoma NEAR/3 prostat) OR (prostat NEAR/3 (enlarg* OR obstruct)) OR (bph OR bpo OR bpe OR boo) OR prostatism OR (bladder NEAR/3 obstruct*))
2	TS= (Naftopidil or BM‐15275 or KT‐611 or R9PHW59SFN or Flivas or Nafodil or Naftomax or Dishuang or "Ge Rui Jia" or "Jun Lie Xin" or "Kun Da" or "Lai Luo Er" or "Na Tuo" or "Pu Chang" or "Shu Er" or "Sitandi" or "Yu Chang" or "Zai Chang")
3	1 AND 2
LILAC search strategy
1	(mh:("Prostatic Hyperplasia" OR prostatism OR "Urinary Bladder Neck Obstruction")) OR (tw:("Prostatic Hyperplasia" OR "Prostatic Adenoma" OR "Prostatic Hypertrophy" OR "Prostatic Enlargement" OR bph OR bpo OR bpe OR prostatism OR "Bladder Neck Obstruction" OR "Bladder Outlet Obstruction" OR boo)) AND (tw:(naftopidil OR bm‐15275 OR kt‐611 OR r9phw59sfn OR flivas OR nafodil OR naftomax OR dishuang OR "Ge Rui Jia" OR "Jun Lie Xin" OR "Kun Da" OR "Lai Luo Er" OR "Na Tuo" OR "Pu Chang" OR "Shu Er" OR "Sitandi" OR "Yu Chang" OR "Zai Chang")) AND (instance:"regional")
World Health Organization International Clinical Trials Registry Platform Search Portal
1	prostat* AND naftopidil
ClinicalTrials.gov
1	Prostate
2	Naftopidil
3	1 AND 2
Grey literature (Open Grey)
1	prostat* AND naftopidil

Study	Date trial author contacted (first)	Date trial author provided data (latest)	Data trial author provided  (short summary)
Kwon 2018	23 October 2017	23 October 2017	All data provided
Yamaguchi 1992	29 May 2018	4 June 2018	We requested full data set; however, we received author's reply as follows; "I have no way to access information on these old studies."
Yamaguchi 1997	29 May 2018	4 June 2018	We requested full data set; however, we received author's reply as follows; "I have no way to access information on these old studies."
Yamaguchi 2013	17 January 2017	30 January 2017	All data provided
Yokoyama 2011	30 January 2017	13 March 2017	Dates when study was conducted, study duration (intervention), exclusion criteria, conflicts of interest, mean and standard deviation of IPSS and QoL at baseline and endpoint (12 weeks), the number of participants with acute urinary retention, and surgical intervention. Method of random sequence generation and blinding.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 International Prostate Symptom Score	12	965	Mean Difference (IV, Random, 95% CI)	0.47 [‐0.09, 1.04]
2 International Prostate Symptom Score‐Quality of Life	11	878	Mean Difference (IV, Random, 95% CI)	0.11 [‐0.09, 0.30]
3 Treatment withdrawals for any reason	8	668	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.64, 1.34]
4 Treatment withdrawals due to adverse events	9	735	Risk Ratio (M‐H, Random, 95% CI)	1.82 [0.72, 4.61]
5 Acute urinary retention	3	272	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.23, 2.86]
6 Surgical intervention	2	171	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Cardiovascular adverse events	9	824	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.52, 1.80]
8 Sexual adverse events	5	397	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.24, 1.22]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 International Prostate Symptom Score	5	652	Mean Difference (IV, Random, 95% CI)	1.04 [‐0.78, 2.85]
2 International Prostate Symptom Score‐Quality of Life	5	652	Mean Difference (IV, Random, 95% CI)	0.21 [‐0.23, 0.66]
3 Treatment withdrawals for any reason	4	659	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.52, 1.23]
4 Treatment withdrawals due to adverse events	5	738	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.35, 1.51]
5 Acute urinary retention	2	180	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Surgical intervention	2	180	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Cardiovascular adverse events	5	808	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.39, 2.44]
8 Sexual adverse events	4	348	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.06, 0.42]

Methods	Study design: parallel randomised clinical study Setting/country: multicentre (9 centre)/China Study dates: September 2002 to December 2003
Participants	Ethnicity: NR (China) Inclusion criteria Men with BPH/LUTS aged 50–75 years Total IPSS ≥ 13 Prostate volume > 20 mL, Q_max < 15 mL/s, PVR < 60 mL Exclusion criteria Other diseases, such as neurogenic bladder, bladder stone, urethral stone, prostate cancer, urethral stricture, or active UTI Men who underwent or needed to receive invasive intervention for BPH Severe diabetes, heart disease, lung disease, liver diseases, or renal diseases Received pharmacological treatment for BPH in past 1 month Without a history of postural hypotension Mental disorder Total number of participants randomised Screened: 906 Eligible: 906 Group A (naftopidil) Number of participants randomised: 126 Age (years) (mean ± SD): 67.7 ± 5.5 Prostate volume (mL) (mean ± SD): 38.1 ± 15.4 PSA (ng/mL) (mean ± SD): 2.5 ± 1.4 IPSS (mean ± SD): 20.6 ± 5.4 Q_max (mL/s) (mean ± SD): 11.1 ± 3.1 Group B (tamsulosin) Number of participants randomised: 138 Age (years) (mean ± SD): 66.8 ± 5.4 Prostate volume (mL) (mean ± SD): 43.1 ± 17.7 PSA (ng/mL) (mean ± SD): 2.4 ± 1.1 IPSS (mean ± SD): 21.1 ± 5.6 Q_max (mL/s) (mean ± SD): 10.7 ± 2.8 Other active: terazosin; doxazosin; finasteride; epristeride; cernilton
Interventions	Run‐in period: none Group A: naftopidil 25 mg once daily Group B: tamsulosin 0.2 mg once daily Other active: terazosin 2 mg once daily; doxazosin 4 mg once daily; finasteride 5 mg once daily; epristeride 5 mg twice daily; cernilton 70 mg twice daily Duration: 12 months
Outcomes	Primary outcomes IPSS, QoL Index, Q_max, PVR How measured: questionnaire (IPSS, QoL), Q_max (NR), PVR (US) Time of measurement: before; 3, 6, 9, 12 months Time of reporting: before; 3, 6, 9, 12 months Secondary outcome NR Safety outcome NR Subgroup: none
Funding sources	Chinese National Programs for Science and Technology Development
Declarations of interest	NR
Notes	Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of selection bias was unclear.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "randomised, open‐label, controlled multicenter study" Comment: open‐label trial; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Quote: "randomised, open‐label, controlled multicenter study" Comment: open‐label trial; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	High risk	Comment: protocol was not published and QoL (secondary outcome) was not reported.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias found; therefore, risk of other bias was low.

Methods	Randomised, double‐blind, parallel group design
Participants	Inclusion criteria Aged 50–90 years Signs and symptoms of BPH IPSS ≥ 10 Prostate volume ≥ 20 mL PVR > 150 mL Exclusion criteria History of allergy to an alpha‐blocker Treatment with antiandrogen drugs Drugs with anticholinergic activity Significant history of orthostatic hypotension Concomitant neurological diseases Known or suspected neurogenic bladder dysfunction Carcinoma of prostate or bladder Previous surgery for BPH or bladder neck obstruction History of recurrent UTI Concomitant active UTI
Interventions	Group A: naftopidil 25 mg for 2 weeks then 50 mg for 10 weeks Group B: tamsulosin 0.4 mg/day for 12 weeks
Outcomes	Primary outcome IPSS (2, 4, 8, 12 weeks) Secondary outcome Adverse effect (2, 4, 8, 12 weeks)
Notes	Funding sources: Apsen Farmaceutica S.A. Publication status: NCT01203371 (final publication status has not been clarified)

Methods	Placebo‐controlled, randomised, double‐blind, double‐dummy, parallel‐group, fixed‐dose design
Participants	Inclusion criteria Aged ≥ 45 years with BPH Exclusion criteria Uncontrolled blood pressure Hepatic or renal dysfunction Prostate cancer Received treatments for BPH using other alpha‐blockers within 2 weeks
Interventions	Group A: naftopidil dose 2 Group B: placebo Group C: naftopidil dose 1
Outcomes	Primary outcome IPSS change (baseline to 12 weeks (end of treatment)) Secondary outcome IPSS, uroflowmetry, LUTS‐GAQ (baseline to 12 weeks (end of the treatment))
Notes	Funding sources: Dong‐A Pharmaceutical Co., Ltd. Publication status: NCT01922375 (final publication status has not been clarified)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 International Prostate Symptom Score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 International Prostate Symptom Score‐Quality of Life	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Methods	Study design: prospective randomised clinical study Setting/country: multicentre (4 centres)/Japan Study dates: May 2005 to May 2008
Participants	Ethnicity: Japan Inclusion criteria Men aged ≥ 50 years at first visit Total IPSS ≥ 8, QoL index score ≥ 2 Prostate volume ≥ 20 mL PVR < 100 mL Exclusion criteria People with prostate cancer, bladder cancer, neurogenic bladder, urethral stricture, or UTI Administration of hormonal agents for BPH within 1 month before study Administration of drugs considered to affect urination within 2 weeks before study (e.g. alpha‐blocker, beta‐blocker, anticholinergic agents, cholinergic agonist, antidepressant) Serious liver or kidney disorder, cardiac disorder Total number of participants randomised Screened: NR Eligible: 105 Group A (naftopidil) Number of participants randomised: 55 Age (years) (mean ± SD): 70.5 ± 5.8 Prostate volume (mL) (mean ± SD): 40.2 ± 16.3 PSA: NR IPSS (mean ± SD): 14.8 ± 5.7 Q_max (mL/s) (mean ± SD): 9.5 ± 3.4 Group B (tamsulosin) Number of participants randomised: 50 Age (years) (mean ± SD): 70.9 ± 5.8 Prostate volume (mL) (mean ± SD): 41.0 ± 19.3 PSA: NR IPSS (mean ± SD): 13.5 ± 5.0 Q_max (mL/s) (mean ± SD): 8.6 ± 3.5
Interventions	Run‐in period: none Group A: naftopidil 50 mg/day Group B: tamsulosin 0.2 mg/day Duration: 12 weeks
Outcomes	Primary outcomes IPSS, QoL Index How measured: questionnaire Time of measurement: before; 4, 12 weeks Time of reporting: before; 4, 12 weeks Secondary outcomes Q_max, PVR/clinical efficacy evaluated based on IPSS and QoL How measured: NR/according to "criteria for treatment efficacy in BPH" in the "voiding dysfunction clinical trial guideline" proposed by the Japanese Urological Association Time of measurement: before; 4, 12 week Time of reporting: before; 4, 12 weeks Safety outcome Adverse effect How measured: NR Time of measurement: NR Time of reporting: not specified but assumed to be last follow‐up (12 weeks) Subgroup: none
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: Japanese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "random assignment", "using a random number table" Comment: method of random sequence generation had low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Comment: owing to insufficient information, risk of detection bias was unclear.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	High risk	Comment: 19/55 (34.5%) participants in naftopidil group and 18/50 (36.0%) participants in tamsulosin group were not included in the analysis. Owing to a large proportion of participants lost to follow‐up (> 20%), risk of attrition bias was high.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Unclear risk	Comment: no cardiovascular adverse events reported in naftopidil group, but 1/40 (2.5%) reported in tamsulosin group. Owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: protocol not published.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias found; therefore, risk of other bias was low.

Methods	Study design: randomised cross‐over clinical study Setting/country: 3 hospitals in single institute/Japan Study dates: March 2000 to April 2002
Participants	Ethnicity: Japan Inclusion criteria IPSS ≥ 8, Q_max < 12 mL/s (150 mL voiding) if prior BPH medication, 1‐month washout period Exclusion criteria: NR Total number of participants randomised Screened: NR Eligible: 96 Group A (naftopidil) Number of participants randomised: 43 Age (years) (mean ± SD): 66.6 ± 7.6 Prostate volume (mL) (mean ± SD): 38.9 ± 11.8 PSA: NR IPSS (mean ± SD): 17.4 ± 6.0 Q_max (mL/s) (mean ± SD): 9.3 ± 4.0 Group B (tamsulosin) Number of participants randomised: 53 Age (years) (mean ± SD): 63.8 ± 9.1 Prostate volume (mL) (mean ± SD): 32.7 ± 9.4 PSA: NR IPSS (mean ± SD): 16.8 ± 7.2 Q_max (mL/s) (mean ± SD): 9.1 ± 6.0
Interventions	Run‐in period: none Group A: naftopidil 25 mg/day for first 2 weeks, then 50 mg once daily for 6 weeks then tamsulosin 0.2 mg for 8 weeks Group B: tamsulosin 0.2 mg for 8 weeks then naftopidil 25 mg for 2 weeks, then 50 mg for 6 weeks Duration: 8 weeks (additional 8 weeks after cross‐over/no washout)
Outcomes	Primary outcomes IPSS, QoL, Q_max, PVR How measured: questionnaire, uroflow, abdominal US Time of measurement: baseline, cross‐over, end of treatment Time of reporting: baseline, cross‐over, end of treatment Secondary outcome NR Safety outcome Safety How measured: questionnaire, uroflowmetry, abdominal US Time of measurement: NR Time of reporting: NR Subgroup: none
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: English No predefined primary or secondary outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly divided with the envelope method" Comment: method of random sequence generation was at low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Comment: owing to insufficient information, risk of detection bias was unclear.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	High risk	Comment: 12/43 (27.9%) participants in silodosin group and 18/53 (33.9%) participants in naftopidil group not included in analysis. Owing to a large proportion of participants lost to follow‐up (> 20%), risk of attrition bias was high.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: protocol not published.
Other bias	Unclear risk	Comment: no washout period

Methods	Study design: double‐blind parallel randomised clinical study Setting/country: single institute/China Study dates: June to November 2011
Participants	Ethnicity: NR (China) Inclusion criteria Men aged 50–75 years with BPH IPSS ≥ 13 PSA ≤ 4 ng/mL, Q_max 5–15 mL/s when urine volume > 150 mL Exclusion criteria Prostate cancer, hypotension, severe heart disease, lung disease, liver diseases, or renal diseases People who underwent or needed to receive invasive intervention for BPH Other diseases such as neurogenic bladder, bladder neck obstruction, bladder cancer, benign bladder tumour, bladder diverticular, urethral stricture, or active UTI Mental disorder People with poor compliance Doctor believed person could not take naftopidil Total number of participants randomised Screened: 80 Eligible: 80 Group A (naftopidil) Number of participants randomised: 40 Age (years) (mean ± SD): 62.5 ± 5.26 Prostate volume: NR PSA: NR IPSS (mean ± SD): 18.79 ± 4.8 Q_max (mL/s) (mean ± SD): 11.24 ± 3.22 Group B (tamsulosin) Number of participants randomised: 40 Age (years) (mean ± SD): 66.5 ± 5.8 Prostate volume: NR PSA: NR IPSS (mean ± SD): 19.71 ± 4.7 Q_max (mL/s) (mean ± SD): 11.32 ± 3.29
Interventions	Run‐in period: none Group A: naftopidil 25 mg once daily Group B: tamsulosin 0.2 mg once daily Duration: 6 weeks
Outcomes	Primary outcomes IPSS, Q_max How measured: questionnaire, Q_max (NR) Time of measurement: baseline, 6 weeks Time of reporting: baseline, 6 weeks Secondary outcomes QoL, PVR, prostate volume How measured: questionnaire, PVR (US), prostate volume (US) Time of measurement: baseline, 6 weeks Time of reporting: baseline, 6 weeks Safety outcome Adverse reactions How measured: adverse reactions (record) Time of measurement: baseline, 6 weeks Time of reporting: baseline, 6 weeks Subgroup: none
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of selection bias was unclear.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Quotes: "double blinded" Comment: no description who was blinded, owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Quotes: "double blinded" Comment: no description who was blinded, owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Low risk	Comment: 1/40 (2.5%) participants in naftopidil group and 2/40 (5%) participants in tamsulosin group were not included in the analysis, owing to the small number of participants lost to follow‐up, risk of attrition bias was low.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: study did not address this outcome.
Selective reporting (reporting bias)	High risk	Comment: protocol was not published and QoL (secondary outcome) was not reported.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias found; therefore, risk of other bias was low.

Methods	Study design: parallel open‐label randomised clinical study Setting/country: multicentre/Japan Study dates: May 2012 to September 2013
Participants	Ethnicity: NR (Japan) Inclusion criteria Men aged ≥ 50 years Total IPSS ≥ 8, IPSS‐QoL score ≥ 3, total OABSS ≥ 3, ≥ 1 urinary urgency episodes/week Prostate volume ≥ 20 mL on transabdominal ultrasonography Q_max < 15 mL/s at a voided volume of ≥ 100 mL and PVR < 150 mL Exclusion criteria Received oral treatment with a1‐blockers, anticholinergic agents, 5‐alpha reductase inhibitors, antidepressants, antianxiety agents, or sex hormonal agents Neurogenic bladder dysfunction, bladder calculi or active UTI, severe cardiac disease, renal dysfunction (serum creatinine levels ≥ 2 mg/dL) or hepatic dysfunction (AST and ALT concentrations more than twice normal values) Prostate cancer confirmed by prostate biopsy Total number of participants randomised Screened: 350 Eligible: 350 Group A (naftopidil) Number of participants randomised: 175 Age (years) (mean ± SD): 70.3 ± 7.8 Prostate volume (mL) (mean ± SD): 38.6 ± 14.8 PSA (ng/mL) (mean ± SD): 3.0 ± 3.1 IPSS (mean ± SD): 18.9 ± 6.1 Q_max (mL/s) (mean ± SD): 8.4 ± 3.0 Group B (silodosin) Number of participants randomised: 175 Age (years) (mean ± SD): 70.6 ± 7.8 Prostate volume (mL) (mean ± SD): 39.6 ± 16.7 PSA (ng/mL) (mean ± SD): 3.0 ± 3.1 IPSS (mean ± SD): 18.8 ± 6.2 Q_max (mL/s) (mean ± SD): 8.2 ± 3.6
Interventions	Run‐in period: NR Group A: naftopidil 50 mg/day for 4 weeks, then 75 mg/day for 8 weeks Group B: silodosin 4 mg/day for 4 weeks, then 8 mg/day for 8 weeks Duration: 12 weeks
Outcomes	Primary outcomes IPSS, QoL Index, OABSS How measured: questionnaire Time of measurement: baseline; 4, 12 weeks Time of reporting: baseline; 4, 12 weeks Secondary outcomes Q_max, PVR How measured: uroflowmetry, PVR (NR) Time of measurement: baseline; 4, 12 weeks Time of reporting: baseline; 4, 12 weeks Safety outcome Adverse reactions How measured: NR Time of measurement: NR Time of reporting: NR Subgroup: NR
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomizations using a random number table at the study center." Comment: method of random sequence generation at low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "prospective, open label, randomised, multicenter study." Comment: open‐label trial; no blinding; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Susceptible	Low risk	Quote: "The data obtained were de‐identified and analysed independently by 2 of our research group members not involved in this study." Comment: open‐label trial; no blinding; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Unclear risk	Comment: 18/175 (10.2%) participants in naftopidil group and 18/175 (10.2%) participants in silodosin group were not included in analysis but missing outcome data balanced in numbers across intervention groups with similar reasons. Owing to the moderated number of participants lost to follow‐up (> 10%), risk of attrition bias was low.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all participants were enrolled in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all participants were enrolled in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Low risk	Comment: all participants were enrolled in analysis.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: review outcomes are well described, but protocol was not published.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias could be found; therefore, risk of other bias was low.

Methods	Study design: cross‐over randomised clinical study Setting/country: single centre/Japan Study dates: February 2002 to December 2003
Participants	Ethnicity: NR (Japan) Inclusion criteria Men with LUTS with BPH Exclusion criteria Drugs that might affect urinary excretion function, prostate cancer, neurogenic bladder suspected, UTI, chronic bacterial prostatitis, etc. Total number of participants randomised Screened: NR Eligible: 45 Group A (naftopidil) Number of participants randomised: 20 Age (years) (mean ± SD): 65.3 ± 5.5 Prostate volume (mL) (mean ± SD): 30.7 ± 13.8 PSA: NR IPSS (mean ± SD): 19.6 ± 7.0 Q_max (mL/s) (mean ± SD): 9.4 ± 3.2 Group B (tamsulosin) Number of participants randomised: 25 Age (years) (mean ± SD): 68.2 ± 7.7 Prostate volume (mL) (mean ± SD): 47.2 ± 22.6 PSA: NR IPSS (mean ± SD): 18.4 ± 6.9 Q_max (mL/s) (mean ± SD): 9.2 ± 3.3
Interventions	Run‐in period: NR Group A: naftopidil 50 mg/day for 4 weeks, then tamsulosin 0.2 mg/day for 4 weeks Group B: tamsulosin 0.2 mg/day for 4 weeks, then naftopidil 50 mg/day for 4 weeks Duration: 28 days (additional 28 days after cross‐over/no washout)
Outcomes	Primary outcomes Total IPSS, storage symptoms, voiding symptoms, QoL score How measured: questionnaire Time of measurement: baseline; 4, 8 weeks Time of reporting: baseline; 4, 8 weeks Secondary outcome NR Safety outcome Safety How measured: NR Time of measurement: NR Time of reporting: NR Subgroup: NR
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: English No predefined primary and secondary outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of selection bias was unclear.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Comment: owing to insufficient information, risk of detection bias was unclear.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Unclear risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: review outcomes were well described, but protocol was not published.
Other bias	Unclear risk	Comment: no washout period

Methods	Study design: prospective parallel randomised Setting/country: single centre/India Study dates: September 2011 to June 2013
Participants	Ethnicity: NR (India) Inclusion criteria Men aged > 50 years, clinical symptoms of BPE, LUTS, with or without raised PVR urine Exclusion criteria Untreated UTI, palpable nodule in the prostate, associated upper urinary tract changes and prostate size > 60 mL Total number of participants randomised Screened: NR Eligible: 60 Group A (naftopidil) Number of participants randomised: 30 Age (years) (mean ± SD): 59.9 ± 5.5 prostate volume: NR PSA: NR IPSS (mean ± SD): 19.97 ± 2.53 Q_max (mL/s) (mean ± SD): 8.63 ± 1.38 Group B (tamsulosin) Number of participants randomised: 30 Age (years) (mean ± SD): 60.1 ± 5.0 Prostate volume: NR PSA: NR IPSS (mean ± SD): 21.3 ± 2.84 Q_max (mL/s) (mean ± SD): 8.37 ± 1.22
Interventions	Run‐in period: NR Group A: naftopidil 50 mg once daily Group B: tamsulosin 0.4 mg once daily Duration: 30 days
Outcomes	Primary outcomes IPSS, Q_max, PVR How measured: questionnaire, uroflowmetry (Q_max), abdominal US Time of measurement: baseline, 15/30 days Time of reporting: baseline, 15/30 days Secondary outcome NR Safety outcome NR Subgroup: NR
Funding sources	Mahatma Gandhi Medical College and Research Institute
Declarations of interest	None
Notes	Language of publication: English No predefined secondary outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "who presented on odd numbered days were placed in Group A, patients who presented on even number days were placed in study Group B." Comment: method of random sequence generation at high risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: owing to insufficient information, risk of performance bias was unclear.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Comment: owing to insufficient information, risk of detection bias was unclear.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: adverse events were not reported and protocol was not published.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias could be found; therefore, risk of other bias was low.

Methods	Study design: randomised, open‐label, controlled Setting/country: Kobe University School or other collaborating institutions/Japan Study dates: July 2007 to March 2011
Participants	Ethnicity: NR (Japan) Inclusion criteria Men with BPH/LUTS, total IPSS 8 points, QoL index 3 points, Q_max < 15 mL/s, prostate volume 20 mL Men with BPH/LUTS without history of using any alpha blocker (hereafter, drug‐naive group) or men with BPH/LUTS who had continued to use tamsulosin 0.2 mg once daily for at least 3 months and wanted to switch the medication to another oral drug (hereafter, drug‐switching group). Exclusion criteria Other diseases such as prostate cancer, bladder tumour, cystolithiasis, prostatitis, urethral stricture, or active UTI Complication of neurogenic bladder or disease suspected of neurogenic bladder Participation in study deemed inappropriate by their primary physician Total number of participants randomised Screened: NR Eligible: 121 Group A (naftopidil) Number of participants randomised: 60 Age (years) (mean ± SD): 70.50 ± 6.58 Prostate volume (mL) (mean ± SD): 39.39 ± 25.96 PSA: NR IPSS (mean ± SD): 17.56 ± 6.73 Q_max (mL/s) (mean ± SD): 11.13 ± 6.53 Group B (silodosin) Number of participants randomised: 61 Age (years) (mean ± SD): 70.98 ± 6.69 Prostate volume (mL) (mean ± SD): 38.24 ± 12.94 PSA: NR IPSS (mean ± SD): 17.53 ± 5.4 Q_max (mL/s) (mean ± SD): 9.87 ± 4.50
Interventions	Run‐in period: NR Group A: naftopidil 50 mg once daily Group B: silodosin 4 mg twice daily Duration: 8 consecutive weeks
Outcomes	Primary outcomes Total IPSS, subtotal IPSS of storage symptoms, subtotal IPSS of voiding symptoms, postmicturition symptoms, QoL index How measured: IPSS questionnaire Time of measurement: baseline; 4, 8 weeks Time of reporting: baseline; 4, 8 weeks Secondary outcome NR Safety outcome Safety How measured: adverse events Time of measurement: NR Time of reporting: NR Subgroup Drug‐naive/drug‐switching
Funding sources	NR
Declarations of interest	None
Notes	Language of publication: English No predefined primary, secondary outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned, using a random number table" Comment: method of random sequence generation at low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "randomised, open‐label, controlled multicenter study" Comment: open‐label trial; no blinding; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Susceptible	High risk	Quote: "randomised, open‐label, controlled multicenter study" Comment: open‐label trial; no blinding; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Low risk	Comment: 4/60 (6.7%) participants in naftopidil group and 5/61 (8.2%) participants in silodosin group were not included in analysis. Owing to the small number of participants lost to follow‐up, risk of attrition bias was low.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: 3/60 (5.0%) participants in naftopidil group and 2/61 (3.3%) participants in silodosin group were not included in analysis. Owing to the small number of participants lost to follow‐up, risk of attrition bias was low.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Low risk	Comment: 3/60 (5.0%) participants in naftopidil group and 2/61 (3.3%) participants in silodosin group were not included in analysis. Owing to the small number of participants lost to follow‐up, risk of attrition bias was low.
Incomplete outcome data (attrition bias)   Sexual adverse events	Low risk	Comment: 3/60 (5.0%) participants in naftopidil group and 2/61 (3.3%) participants in silodosin group were not included in analysis. Owing to the small number of participants lost to follow‐up, risk of attrition bias was low.
Selective reporting (reporting bias)	Low risk	Comment: protocol (UMIN000008331) was published. While results were shown separately in participants with drug naive and switching group, review outcomes were well described.
Other bias	Low risk	Study appeared free of other sources of bias. Comment: no other sources of bias could be found; therefore, risk of other bias was low.

Methods	Study design: single‐blind, randomised parallel clinical study Setting/country: single centre/Japan Study dates: NR
Participants	Ethnicity: NR (Japan) Inclusion criteria IPSS ≥ 8, Q_max < 12 mL/s, prostate volume ≥ 15 mL Obstructive (or equivocal) condition on International Continence Society nomogram as assessed in a pressure/flow study. Exclusion criteria Complete urinary retention Prostatic cancer, prostatitis, and urethral stricture Severe cardiac or cerebrovascular disorders, hepatic disorders, renal dysfunction, or orthostatic hypotension Medication with anticholinergics, other ABs, beta‐agonists, or beta‐antagonists Total number of participants randomised Screened: NR Eligible: 49 Group A (naftopidil) Number of participants randomised: 36 Age (years) (mean ± SD): 67.5 ± 8.2 Prostate volume (mL) (mean ± SD): 29.7 ± 14.9 PSA: NR IPSS (mean ± SD): 15.4 ± 5.7 Q_max (mL/s) (mean ± SD): 9.8 ± 4.4 Group B (Eviprostat) Number of participants randomised: 13 Age (years) (mean ± SD): 69.0 ± 6.5 Prostate volume (mL) (mean ± SD): 29.5 ± 15.9 PSA: NR IPSS (mean ± SD): 16.0 ± 6.9 Q_max (mL/s) (mean ± SD): 8.5 ± 4.4
Interventions	Run‐in period: 1 weeks Group A: naftopidil 25 mg once daily for 2 weeks, then 50 mg once daily for 2 weeks, and then 75 mg once daily for 2 weeks Group B: Eviprostat 6 tablets daily Duration: 6 weeks
Outcomes	Primary outcomes IPSS, QoL, Q_max, PVR, urodynamic parameters How measured: questionnaire, uroflowmetry, catheterisation, video‐urodynamic studies Time of measurement: baseline, 4–6 weeks (endpoint) Time of reporting: baseline, 4–6 weeks (endpoint) Secondary outcome NR Safety outcome NR Subgroup: none
Funding sources	NR
Declarations of interest	NR
Notes	Language of publication: English No predefined primary or secondary outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "using an envelope indicating one of the two groups." Comment: method of random sequence generation at low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Comment: owing to insufficient information, risk of allocation concealment was unclear.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "single‐blind, randomised controlled study." Comment: no description who was blinded, single blinding; therefore, risk of performance bias was high.
Blinding of outcome assessment (detection bias)   Susceptible	Unclear risk	Quote: "single‐blind, randomised controlled study" Comment: no description who was blinded, single blinding; therefore, risk of detection bias was high.
Blinding of outcome assessment (detection bias)   Not susceptible	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias)   IPSS/QoL	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal for any reason	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   Treatment withdrawal due to adverse events	Low risk	Comment: all randomised participants were included in analysis.
Incomplete outcome data (attrition bias)   AUR/Surgical intervention	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Cardiovascular adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Incomplete outcome data (attrition bias)   Sexual adverse events	Unclear risk	Comment: owing to insufficient information to permit judgement, risk of attrition bias was unclear.
Selective reporting (reporting bias)	Unclear risk	Comment: protocol was not published.
Other bias	Unclear risk	Comment: "observation run‐in period of 1 week"

Study	Reason for exclusion
Carson 2017	Commentary
Hayashi 2002	Ineligible study design (non‐randomised trial)
Hiroshi 2011	Ineligible comparator (naftopidil 25 mg vs 50 mg vs 75 mg)
Ikemoto 2010	Review
Maruyama 2006	Ineligible comparator (naftopidil 25–75 mg vs naftopidil 25–75 mg + oxybutynin hydrochloride 4–8 mg or naftopidil 25–75 mg + propiverine hydrochloride 10–20 mg)
Sakai 2011	Ineligible comparator (naftopidil 50 mg morning medication vs naftopidil 50 mg evening medication)
Tsuritani 2010	Ineligible comparator (naftopidil 75 mg once daily in the evening vs 25 mg 3 times daily)
Yamaguchi 1992	Ineligible outcomes (symptom improvement rates, outcome not measured)
Yamaguchi 1997	Ineligible outcomes (symptom improvement rates, outcome not measured)
Yokoyama 2006	Ineligible comparator (naftopidil 75 mg/day vs 25 mg/day)

PERMALINK

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia

Eu Chang Hwang

Shreyas Gandhi

Jae Hung Jung

Mari Imamura

Myung Ha Kim

Ran Pang

Philipp Dahm

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Diagnosis

Treatment

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Experimental interventions

Comparator interventions

Comparisons

Types of outcome measures

Primary outcomes

Secondary outcomes

Method and timing of outcome measurement

Main outcomes for 'Summary of findings' tables

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Dealing with duplicate and companion publications

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

1. Baseline characteristics of included studies.

2. Participants in included studies.

Source of data

Study design and settings

Participants

Interventions

Comparators

Comparisons

Outcomes

Funding sources and conflicts of interest

Excluded studies

Studies awaiting classification

Ongoing trials

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation