Anticholinergics combined with alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction

Ran Pang; Xin-Yao Zhou; Xiangling Wang; Bin Wang; Xue-Lai Yin; Hai Bo; Jae Hung Jung

doi:10.1002/14651858.CD012336.pub2

. 2021 Feb 10;2021(2):CD012336. doi: 10.1002/14651858.CD012336.pub2

Anticholinergics combined with alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction

Ran Pang ^1,^✉, Xin-Yao Zhou ², Xiangling Wang ³, Bin Wang ⁴, Xue-Lai Yin ¹, Hai Bo ¹, Jae Hung Jung ^5,⁶

Editor: Cochrane Urology Group

PMCID: PMC8094929 PMID: 33567116

Abstract

Background

Lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) represent one of the most common clinical complaints in men. Alpha‐blockers are widely used as first‐line therapy for men with LUTS secondary to BPO, but up to one third of men report no improvement in their LUTS after taking alpha‐blockers. Anticholinergics used in addition to alpha‐blockers may help improve symptoms but it is uncertain how effective they are.

Objectives

To assess the effects of combination therapy with anticholinergics and alpha‐blockers in men with LUTS related to BPO.

Search methods

We performed a comprehensive search of medical literature, including the Cochrane Library, MEDLINE, Embase, and trials registries, with no restrictions on the language of publication or publication status. The date of the latest search was 7 August 2020.

Selection criteria

We included randomized controlled trials. Inclusion criteria were men with LUTS secondary to BPO, ages 40 years or older, and a total International Prostate Symptom Score of 8 or greater. We excluded trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease, and those examining medical therapy for men who were treated with surgery for BPO. We performed three comparisons: combination therapy versus placebo, combination therapy versus alpha‐blockers monotherapy, and combination therapy versus anticholinergics monotherapy.

Data collection and analysis

Two review authors independently screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random‐effects model and interpreted data according to the Cochrane Handbook for Systematic Reviews of Interventions. We used the GRADE approach to rate the certainty of evidence.

Main results

We included 23 studies with 6285 randomized men across three comparisons. The mean age of participants ranged from 54.4 years to 73.9 years (overall mean age 65.7 years). Of the included studies, 12 were conducted with a single‐center setting, while 11 used a multi‐center setting. We only found short‐term effect (12 weeks to 12 months) of combination therapy based on available evidence.

Combination therapy versus placebo: based on five studies with 2369 randomized participants, combination therapy may result in little or no difference in urologic symptom scores (mean difference (MD) –2.73, 95% confidence interval (CI) –5.55 to 0.08; low‐certainty evidence). We are very uncertain about the effect of combination therapy on quality of life (QoL) (MD –0.97, 95% CI –2.11 to 0.16; very low‐certainty evidence). Combination therapy likely increases adverse events (risk ratio (RR) 1.24, 95% CI 1.04 to 1.47; moderate‐certainty evidence); based on 252 adverse events per 1000 participants in the placebo group, this corresponds to 61 more adverse events (95% CI 10 more to 119 more) per 1000 participants treated with combination therapy.

Combination therapy versus alpha‐blockers alone: based on 22 studies with 4904 randomized participants, we are very uncertain about the effect of combination therapy on urologic symptom scores (MD –2.04, 95% CI –3.56 to –0.52; very low‐certainty evidence) and QoL (MD –0.71, 95% CI –1.03 to –0.38; very low‐certainty evidence). Combination therapy may result in little or no difference in adverse events rate (RR 1.10, 95% CI 0.90 to 1.34; low‐certainty evidence); based on 228 adverse events per 1000 participants in the alpha‐blocker group, this corresponds to 23 more adverse events (95% CI 23 fewer to 78 more) per 1000 participants treated with combination therapy.

Combination therapy compared to anticholinergics alone: based on three studies with 1218 randomized participants, we are very uncertain about the effect of combination therapy on urologic symptom scores (MD –3.71, 95% CI –9.41 to 1.98; very low‐certainty evidence). Combination therapy may result in an improvement in QoL (MD –1.49, 95% CI –1.88 to –1.11; low‐certainty evidence). Combination therapy likely results in little to no difference in adverse events (RR 1.26, 95% CI 0.81 to 1.95; moderate‐certainty evidence); based on 115 adverse events per 1000 participants in the anticholinergic alone group, this corresponds to 4 fewer adverse events (95% CI 7 fewer to 13 more) per 1000 participants treated with combination therapy.

Authors' conclusions

Based on the findings of the review, combination therapy with anticholinergics and alpha‐blockers are associated with little or uncertain effects on urologic symptom scores compared to placebo, alpha‐blockers, or anticholinergics monotherapy. However, combination therapy may result in an improvement in quality of life compared to anticholinergics monotherapy, but an uncertain effect compared to placebo, or alpha‐blockers. Combination therapy likely increases adverse events compared to placebo, but not compared to alpha‐blockers or anticholinergics monotherapy. The findings of this review were limited by study limitations, inconsistency, and imprecision. We were unable to conduct any of the predefined subgroup analyses.

Keywords: Adult; Aged; Humans; Male; Middle Aged; Adrenergic alpha-Antagonists; Adrenergic alpha-Antagonists/adverse effects; Adrenergic alpha-Antagonists/therapeutic use; Bias; Cholinergic Antagonists; Cholinergic Antagonists/adverse effects; Cholinergic Antagonists/therapeutic use; Drug Therapy, Combination; Drug Therapy, Combination/adverse effects; Drug Therapy, Combination/methods; Lower Urinary Tract Symptoms; Lower Urinary Tract Symptoms/drug therapy; Lower Urinary Tract Symptoms/etiology; Prostatic Hyperplasia; Prostatic Hyperplasia/complications; Quality of Life; Randomized Controlled Trials as Topic

Plain language summary

Anticholinergics combined with alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction

Review question

Is combination therapy with anticholinergics, a type of medicine that can relieve abnormal bladder contraction (where a man cannot control when he urinates), and alpha‐blockers, a type of medicine that can relax the urethral muscle (the tube that carries urine from the bladder out through the penis during urination), effective and safe for managing urination difficulties and urgency related to enlarged prostate?

Background

Urination difficulties and urgency caused by enlarged prostate (a male organ near the bladder and surrounding a part of the urethra) are common in men. Although alpha‐blockers have been used to relieve the urinary symptoms, up to one third of men get no benefit. Combination therapy with alpha‐blockers and anticholinergics provides a treatment option for men with urinary symptoms.

Study characteristics

The search is up‐to‐date to 7 August 2020. We identified 23 studies involving 6285 men. Five studies compared combination therapy with anticholinergics and alpha‐blockers versus placebo (a pill with no therapeutic effects). A total of 22 studies compared combination therapy with anticholinergics and alpha‐blockers versus alpha‐blockers alone. Three studies compared combination therapy with anticholinergics and alpha‐blockers versus anticholinergics alone. The follow‐up period in the studies ranged from 12 weeks to one year.

Key results

Combination therapy versus placebo: combination therapy with anticholinergics and alpha‐blockers was associated with little effect in urinary symptoms and uncertain improvement on quality of life, but combination therapy may increase unwanted side effects.

Combination therapy versus alpha‐blockers: combination therapy with anticholinergics and alpha‐blockers may have uncertain effects on improvement of urinary symptoms and quality of life compared to alpha‐blockers alone. Combination therapy may not increase unwanted side effects.

Combination therapy compared to anticholinergics: combination therapy with anticholinergics and alpha‐blockers may be associated with uncertain effects on urinary symptoms, but an improvement in quality of life in comparison with anticholinergics alone. Combination therapy may not increase unwanted side effects.

Quality of the evidence

A majority of included studies were not well conducted or reported, which is why we rated down the certainty of evidence (the confidence to state the conclusion is right) to moderate, low or very low. This means that the true effect may be substantially different from what this review found.

Summary of findings

Summary of findings 1. Combination therapy versus placebo for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Combination therapy versus placebo for treating lower urinary tract symptoms related to benign prostatic obstruction (short term)
Patient or population: men with lower urinary tract symptoms related to benign prostatic obstruction Setting: multi‐center/outpatients/China, USA, Europe Intervention: combination therapy Comparison: placebo
Outcomes	No of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with placebo (short term)	Risk difference with combination therapy
Urologic symptom scores assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: range 12–24 weeks	1792 (4 RCTs)	⊕⊕⊝⊝ Low^a^,b,c	—	The mean change of urologic symptom scores ranged from –7.2 to –5.4	MD 2.73 lower (5.55 lower to 0.08 higher)
QoL assessed with: IPSS‐QoL Scale from: 0 (delighted) to 6 (terrible) Follow‐up: range 12–24 weeks	991 (2 RCTs)	⊕⊝⊝⊝ Verylow^a^,c,d	—	The mean change of QoL ranged from –1.6 to –0.9	MD 0.97 lower (2.11 lower to 0.16 higher)
Adverse events Follow‐up: 12 weeks	1848 (3 RCTs)	⊕⊕⊕⊝ Moderate^d	RR 1.24 (1.04 to 1.47)	Study population
				252 per 1000	61 more per 1000 (10 more to 119 more)
AUR Follow‐up: range 12–24 weeks	2369 (5 RCTs)	⊕⊝⊝⊝ Verylow^a^,e,f	RR 1.94 (0.41 to 9.08)	Study population
				—	—
Surgical intervention – not reported	—	—	—	—	—
*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). AUR: acute urinary retention; CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCT: randomized 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.

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^aDowngraded one level for study limitations: unclear or high risk of bias in one or more domain for selection, attrition, or reporting bias in half or more included studies. ^bNot downgraded for inconsistency despite substantial or considerable heterogeneity: study limitations of Cai 2016 may cause inconsistency. ^cDowngraded one level for inconsistency: substantial or considerable heterogeneity. ^dDowngraded one level for imprecision: confidence interval crossed assumed threshold of clinically important difference. ^eDowngraded two levels for imprecision: wide confidence interval crossed assumed threshold of clinically important difference and very rare event. ^fNo event in control group.

Summary of findings 2. Combination therapy versus alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Combination therapy versus alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction (short term)
Patient or population: men with lower urinary tract symptoms related to benign prostatic obstruction Setting: outpatients/Asia, USA, Europe Intervention: combination therapy Comparison: alpha‐blockers
Outcomes	No of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with alpha‐blockers (short term)	Risk difference with combination therapy
Urologic symptom scores assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: range 12 weeks to 12 months	3631 (19 RCTs)	⊕⊝⊝⊝ Verylow^a^,b,c	—	The mean change of urologic symptom scores ranged from –11.9 to –2.1	MD 2.04 lower (3.56 lower to 0.52 lower)
QoL assessed with: IPSS‐QoL Scale from: 0 (delighted) to 6 (terrible) Follow‐up: range 12 weeks to 12 months	2687 (15 RCTs)	⊕⊝⊝⊝ Verylow^a^,b,c	—	The mean change of QoL ranged from –2.9 to 0.2	MD 0.71 lower (1.03 lower to 0.38 lower)
Adverse events Follow‐up: range 12 weeks to 12 months	3561 (12 RCTs)	⊕⊕⊝⊝ Low^a^,b	RR 1.10 (0.90 to 1.34)	Study population
				228 per 1000	23 more per 1000 (23 fewer to 78 more)
AUR Follow‐up: range 12 weeks to 12 months	4669 (19 RCTs)	⊕⊕⊝⊝ Low^a^,b	RR 2.03 (0.97 to 4.23)	Study population
				4 per 1000	4 more per 1000 (0 to 12 more)
Surgical intervention Follow‐up: range 12–26 weeks	454 (4 RCTs)	⊕⊝⊝⊝ Verylow^d^,e,f	RR 1.72 (0.34 to 8.63)	Study population
				122 per 1000	71 more per 1000 (77 fewer to 424 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). AUR: acute urinary retention; CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life. RCT: randomized 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.

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^aDowngraded one level for study limitations: unclear or high risk of bias in one or more domain in half or more included studies. ^bDowngraded one level for imprecision: confidence interval crossed assumed threshold of clinically important difference. ^cDowngraded one level for inconsistency: substantial or considerable heterogeneity. ^dDowngraded one level for study limitations: unclear or high risk of selection, performance, detection, reporting bias. ^eDowngraded two levels for imprecision: wide confidence interval crossed assumed threshold of clinically important difference and very rare event. ^fNo event in control group.

Summary of findings 3. Combination therapy versus anticholinergics for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Combination therapy versus anticholinergics for treating lower urinary tract symptoms related to benign prostatic obstruction (short term)
Patient or population: men with lower urinary tract symptoms related to benign prostatic obstruction Setting: multi‐center/outpatients/China, USA, Europe Intervention: combination therapy Comparison: anticholinergics
Outcomes	No of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with anticholinergics (short term)	Risk difference with combination therapy
Urologic symptom scores assessed with: IPSS Scale from: 0 (best: not at all) to 35 (worst: almost always) Follow‐up: range 12–24 weeks	710 (2 RCTs)	⊕⊝⊝⊝ Verylow^a^,b,c	—	The mean change of urologic symptom scores ranged from –6.5 to –5.7	MD 3.71 lower (9.41 lower to 1.98 higher)
QoL assessed with: IPSS‐QoL Scale from: 0 (delighted) to 6 (terrible) Follow‐up: 24 weeks	56 (1 RCT)	⊕⊕⊝⊝ Low^a^,d	—	The mean change of QoL was –1.41	MD 1.49 lower (1.88 lower to 1.11 lower)
Adverse events Follow‐up: 12 weeks	661 (1 RCTs)	⊕⊕⊕⊝ Moderate^c	RR 1.26 (0.81 to 1.95)	Study population
				155 per 1000	40 more per 1000 (29 fewer to 147 more)
AUR Follow‐up: range 12–24 weeks	1178 (3 RCTs)	⊕⊕⊝⊝ Low^a^,c,e	RR 0.55 (0.11 to 2.65)	Study population
				8 per 1000	4 fewer per 1000 (7 fewer to 13 more)
Surgical intervention – not reported	—	—	—	—	—
*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). AUR: acute urinary retention; CI: confidence interval; IPSS: International Prostate Symptom Score; MD: mean difference; QoL: quality of life; RCT: randomized 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.

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^aDowngraded one level for study limitations: unclear or high risk of bias in one or more domain for selection, attrition, or reporting bias. ^bDowngraded one level for inconsistency: substantial or considerable heterogeneity. ^cDowngraded one level for imprecision: confidence interval crossed assumed threshold of clinically important difference. ^dDowngraded one level for imprecision: insufficient information size. ^eWide confidence interval in relative effect, but small risk difference in absolute effect.

Background

Description of the condition

Lower urinary tract symptoms (LUTS) are a complaint in elderly men (Oelke 2013). Benign prostatic obstruction (BPO) is a main etiology for aging men to experience LUTS and it differs from benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE). BPH is a histologic diagnosis characterized by the proliferation of epithelial and stromal cells within the prostate gland (Hansen 1995). BPE refers to an increase in volume of the prostate due to BPH. BPO is an obstruction that results from BPE, which can be confirmed by pressure flow studies, or be highly suspected from flow rates and if the gland is enlarged (Abrams 2013). The prevalence of LUTS/BPH varies in different studies, ranging from 39% to 90% (Hansen 2004; Seftel 2013; Solvang 2018), and rises significantly with increased age. It is estimated that 70% of men between 60 and 70 years old and 80% of men over 70 years old are affected by BPH in the USA (Wei 2005). Based on one prospective, community‐based cohort study, the Rancho Bernardo study, 56% of men younger than 80 years of age, 70% of men 80 to 89 years of age, and 90% of men older than 90 years of age experience LUTS (Parsons 2008). According to the result from one Chinese national cross‐sectional survey, the adjusted odds ratio (OR) for the prevalence of LUTS/BPH is 1.50 (95% confidence intervals (CI) 1.20 to 1.87) in men aged 60 to 69 years and 2.09 (95% CI 1.58 to 2.78) in men aged more than 70 years compared to men aged less than 60 years (Zhang 2019). In general, LUTS are divided into storage LUTS (increased daytime frequency, nocturia, urgency, and incontinence), voiding LUTS (slow stream, splitting or spraying, intermittent stream, hesitancy, straining, and terminal dribble), and postmicturition LUTS (feeling of incomplete emptying and postmicturition dribble) (Abrams 2002). All the symptoms significantly reduce men's quality of life (QoL) and storage LUTS is more bothersome compared to voiding LUTS (NICE 2015). Besides the negative impact on public health, the cost related to LUTS has been a social and economic burden. During 2000, the direct treatment expenditure for LUTS related to BPO was USD 1.1 billion in the USA (Wei 2008). Based on Hospital Episode Statistics data (2007 to 2008), LUTS secondary to BPO have been the fifth most expensive disease to the UK National Health Service (NHS) and account for a cost of GBP 1.16 billion each year (Kirby 2010). The TRIUMPH study found the annual cost for LUTS suggestive of BPH ranged from EUR 292 to EUR 1337 per patient in six European countries (Van Exel 2006).

Description of the intervention

Alpha‐adrenergic antagonists (alpha‐blockers) have been considered as the first‐line pharmacotherapy for men with LUTS related to BPO due to their well‐documented efficacy (Gravas 2015). It is confirmed that alpha‐blockers can relieve BPO by decreasing smooth muscle tone in the prostate and bladder neck (Chapple 2004). The American Urological Association (AUA) has determined that the alpha‐blockers alfuzosin, doxazosin, tamsulosin, and terazosin are appropriate and effective treatments for men with LUTS secondary to BPO (McVary 2011). Clinical studies have shown that these alpha‐blockers can typically reduce the International Prostate Symptom Score (IPSS) by approximately 20% to 50% and increase the maximum urine flow (Qmax) by approximately 15% to 45% (MacDonald 2005; Wilt 2006). One study further showed that alpha‐blockers could improve Qmax more effectively in younger men (less than 65 years old) as compared to older men (65 years and older) (Novara 2015). Furthermore, one systematic review and meta‐analysis suggests that evaluation using Qmax may underestimate a real effect of alpha‐blockers on BPO, since urodynamic study confirms that small improvements in Qmax correspond to relevant improvements in BPO (Fusco 2016). Adverse effects of alpha‐blockers include postural hypotension, dizziness, headache, asthenia, syncope, peripheral edema, retrograde ejaculation and intraoperative floppy iris syndrome, which cause approximately 4% to 10% of men to withdraw from alpha‐blocker treatment (Djavan 1999; Yu 2020).

Anticholinergics are considered as one of the standard pharmacotherapies for people with overactive bladder (Gormley 2015). These agents can block the combination of acetylcholine and muscarinic receptors on detrusor smooth muscle, which can improve storage LUTS by relieving the detrusor overactivity (Andersson 2004; Reynard 2004). The licensed agents for treating storage LUTS include darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride (Gravas 2015; Yamada 2018). Adverse effects of anticholinergics mainly include dry mouth, pruritus, constipation, micturition difficulties, nasopharyngitis, and dizziness (Yu 2020). Moreover, as the most serious adverse effect, anticholinergics may lead to acute urinary retention (AUR) due to their inhibitory action on detrusor contraction (Yu 2020). One retrospective cohort study revealed that the short term (30 days or fewer) and long term (more than 30 days) use of anticholinergics were associated with a relative risk of AUR of 8.3 (short term) and 2.0 (long term) (Martin‐Merino 2009). Additionally, it has been shown that cumulative anticholinergic exposure is associated with an increased risk of dementia (Coupland 2019; Wang 2019).

Combination therapy with an alpha‐blocker and an anticholinergic can achieve synergistic effect of these two classes of drugs by blocking both alpha‐adrenergic receptors and muscarinic cholinergic receptors in the lower urinary tract. Randomized controlled trials (RCTs) (Chapple 2009; Kaplan 2006; Lee 2011; MacDiarmid 2008; Van Kerrebroeck 2013a; Yamaguchi 2011), and RCT‐based meta‐analyses (Filson 2013; Xin 2013), have provided evidence for the advantage of combination therapy in management of male storage LUTS.

How the intervention might work

There are two types of alpha‐adrenergic receptors, alpha‐1 receptor and alpha‐2 receptor, in human central and peripheral nervous systems. Of those, alpha‐1 receptors are mainly located on the urinary bladder base and prostatic urethra (Kunisawa 1985). There are three different alpha‐1 receptor subtypes: alpha‐1A, alpha‐1B, and alpha‐1D (Oelke 2013). Alpha‐1A subtype primarily mediates smooth muscle tone in the prostate and bladder neck, while alpha‐1B subtype generally mediates vascular smooth muscle contraction (Fine 2008). The alpha‐1D subtype is believed to function as a mediator for lower urinary tract function through regulation of bladder muscle contraction and sacral spinal cord innervation (Fine 2008). alpha‐blockers can inhibit the activation of these alpha‐1 receptors, which results in decreased intracellular Ca²⁺ and subsequently causes smooth muscle relaxation. Consequently, the prostatic urethral opening secondary to smooth muscle relaxation can help men to relieve their voiding LUTS.

Acetylcholine is the predominant neurotransmitter in the lower urinary tract that can combine with muscarinic receptors on the surface of various cells, such as smooth muscle cells, urothelial cells, nerve cells, or epithelial cells. Five different muscarinic receptor subtypes have been identified in humans: M₁, M₂, M₃, M₄, and M₅ receptors. Of these, M₂ and M₃ subtypes primarily express on the surface of the detrusor muscle, which is involved in bladder contractions (Braverman 2006; Chess‐Williams 2001). Anticholinergics can inhibit the activation of these two subtypes of muscarinic receptors, which suppresses the release of Ca²⁺ mediated by G‐protein and the opening of calcium channels in cell membranes, and, consequently, results in the relaxation of the detrusor muscle. The detrusor relaxation allows the bladder to store more urine, which can help men to relieve their storage LUTS.

Combination therapy with alpha‐blockers and anticholinergics can inhibit alpha‐adrenergic and muscarinic receptors simultaneously, which may improve LUTS related to BPO.

Why it is important to do this review

Although voiding and postmicturition LUTS are typically related to BPO (Abrams 2002), as many as 50% of men with BPO experience storage LUTS (Reynard 2004). Alpha‐blockers are considered the first‐line drug for men with LUTS secondary to BPO (Gravas 2015; Yu 2020), but up to one third of men report no improvement in their LUTS (Djavan 1999), especially storage LUTS, after taking this drug. To relieve storage LUTS more effectively, combination therapy with alpha‐blockers and anticholinergics has been tried in some clinical trials. However, the results are inconsistent due to different study designs, which causes the effect of combination therapy with alpha‐blockers and anticholinergics on LUTS to be controversial. Moreover, it is reported that anticholinergics may result in urinary retention in men with BPO (Vande Griend 2012; Zhou 2015). Additionally, the long‐term effects of combination therapy with alpha‐blockers and anticholinergics for LUTS related to BPO are unclear. Therefore, it is desirable to conduct a systematic review. Although two systematic reviews and meta‐analyses have shown that combination therapy is associated with greater benefit than alpha‐blockers monotherapy (Filson 2013; Xin 2013), some later trials revealed that the addition of anticholinergics cannot further improve LUTS secondary to BPO (Ko 2014; Lee 2014). There have been no recent systematic reviews to further analyze the efficacy of combination therapy. In addition, unlike the published meta‐analyses, this systematic review will use the GRADE approach to rate the certainty of the evidence.

Objectives

To assess the effects of combination therapy with anticholinergics and alpha‐blockers in men with LUTS related to BPO.

Methods

Criteria for considering studies for this review

Types of studies

We included parallel‐group RCTs. We excluded quasi‐randomized studies, cross‐over studies, cluster‐randomized studies, and observational studies (cohort, case‐control, and cross‐sectional). We included studies regardless of their publication status or language of publication.

Types of participants

Men with LUTS secondary to BPO that was confirmed by pressure flow studies, or highly suspected from flow rates when an enlarged prostate volume was detected (Abrams 2013), ages 40 years or older (since hyperplasia of the prostate gland starts at approximately 40 years of age; Berry 1984; Ramsamy 2016), and a total IPSS of 8 or greater.

We excluded trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease. We also excluded studies that examined medical therapy for men treated with surgery for BPO.

We included studies in which only a subset of participants was relevant to this review, if data were available separately for the relevant subset.

Types of interventions

We performed the following comparisons.

Combination therapy with anticholinergics (e.g. darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride) and alpha‐blockers (e.g. alfuzosin, doxazosin, naftopidil, silodosin, tamsulosin, and terazosin) versus placebo.
Combination therapy with anticholinergics and alpha‐blockers versus other medical treatments for LUTS related to BPO, including alpha‐blockers monotherapy and anticholinergics monotherapy.

Types of outcome measures

We did not use the measurement of the outcomes assessed in this review as an eligibility criterion. We calculated the minimal clinically important difference (MCID) for each outcome to aid our interpretation of the results. We considered outcomes measured up to and including 12 months after randomization as short term, and beyond 12 months as long term.

Primary outcomes

Urologic symptom scores: change from baseline assessed with a validated scale (such as the IPSS; an MCID of 3 points in the IPSS was used to assess the clinically meaningful improvement, as defined by the AUA (AUA 2018)). For studies that only reported final values, we combined these final values with changes from baseline for meta‐analysis.
QoL: change from baseline assessed with IPSS bother score (we used an MCID of 1 point for IPSS‐QoL (AUA 2018)). For studies that only reported final values, we combined these final values with changes from baseline for meta‐analysis.
Adverse events: adverse events graded as the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life‐threatening or disabling; Grade 5 = death‐related; we considered the definition the trial authors used in each clinical trial). We considered the MCID for adverse events as a relative risk reduction of at least 25% (Guyatt 2011a).

Secondary outcomes

AUR: events requiring catheterization after intervention with an MCID defined as relative risk reduction of at least 25% (Guyatt 2011a).
Surgical intervention: events requiring other surgical treatment modalities (e.g. transurethral resection of the prostate (TURP)) after intervention with an MCID defined as relative risk reduction of at least 25% (Guyatt 2011a).

Main outcomes for 'Summary of findings' table

We presented a 'Summary of findings' table and reported the following outcomes, which we have listed according to priority.

Urologic symptom scores.
QoL.
Adverse effects.
AUR.
Surgical intervention.

Search methods for identification of studies

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

Electronic searches

We searched the following electronic sources on 7 August 2020.

The Cochrane Library via Wiley (from 1990 to present) (Appendix 1):
- Cochrane Central Register of Controlled Trials (CENTRAL);
- Health Technology Assessment Database (HTA).
MEDLINE via PubMed (1953 to present) (Appendix 2).
Embase via Elsevier (1947 to present) (Appendix 3).
Web of Science, Core Collection (1975 to present) (Appendix 4):
- Science Citation Index;
- Conference Proceedings Citation Index.
Chinese Biomedical Literature Database via SinoMed (1978 to present) (search in Chinese) (Appendix 5).
Latin American and Caribbean Health Sciences Literature (1982 to present) (Appendix 6).
ClinicalTrials.gov (clinicaltrials.gov/) (Appendix 7).
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/) (Appendix 8).
OpenGrey (opengrey.eu/) (Appendix 9).

We presented the search strategy for each electronic sources in the appendices of the review.

Searching other resources

We identified other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, reviews, meta‐analyses, and health technology assessment reports. We contacted producers/manufacturers of currently available anticholinergics and alpha‐blockers to identify ongoing or unpublished trials. We searched the abstracts of relevant meetings of the AUA (auanet.org/) and the International Continence Society (ics.org) from 2015 to 2018.

Data collection and analysis

Selection of studies

We used reference management software to identify and remove potential duplicate records (EndNote 2016). Two review authors (RP, XYZ) independently assessed the titles, abstract, or both, of records we identified from the literature searches against the predefined inclusion criteria to determine which studies to assess further. Two review authors (RP, XYZ) investigated all potentially relevant records as full‐text articles, mapped records to studies, and classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We resolved any discrepancies through discussion or arbitration by a third review author (XLW). If resolution of a disagreement was not possible, we designated the study as 'awaiting classification' and contacted the study authors for clarification. We documented the 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 to show the process of study selection (Liberati 2009).

If any records identified in the search were reported in languages other than English or Chinese, we obtained translation assistance (from Prof Chunlan Jin, from the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences) to English or Chinese to enable assessment.

Data extraction and management

We developed a dedicated data abstraction form that we tested for usability.

For studies that fulfilled inclusion criteria, two review authors (RP, XYZ) 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.
Participant details, baseline demographics.
Number of participants by study and by study arm.
Details of relevant experimental and comparator interventions such as dose, route, frequency, and duration.
Definitions of relevant outcomes, and method and timing of outcome measurement as well as any relevant subgroups.
Study funding sources.
Declarations of interest by primary investigators.

We extracted outcomes data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we attempted to obtain numbers of events and totals for population of a 2 × 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we attempted to obtain means and standard deviations (SDs) or data necessary to calculate this information.

We resolved any disagreements by discussion, or, if required, we consulted a third review author (XLW).

We attempted to contact authors of included studies to obtain key missing data as needed.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we maximized the 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 that reported the longest follow‐up associated with our primary or secondary outcomes.

Assessment of risk of bias in included studies

Two review authors (XLW, BW) independently assessed the risk of bias of each included study. We resolved disagreements by consensus, or we consulted a third review author (RP, JHJ).

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

Random sequence generation (selection bias).
Allocation concealment (selection bias).
Blinding of participants and personnel (performance bias).
Blinding of outcome assessment (detection bias).
Incomplete outcome data (attrition bias).
Selective reporting (reporting bias).
Other sources of bias.

We judged 'Risk of bias' domains as 'low risk', 'high risk,' or 'unclear risk' and evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We presented a 'Risk of bias' summary figure to illustrate these findings.

For selection bias (random sequence generation and allocation concealment), we evaluated risk of bias at a trial level.

For performance bias (blinding of participants and personnel), we considered that all outcomes were susceptible to performance bias and assessed in one group.

For detection bias (blinding of outcome assessment), we grouped outcomes as susceptible to detection bias (subjective outcomes) or not susceptible to detection bias (objective outcomes).

We defined the following endpoints as subjective outcomes:

urologic symptom scores;
QoL.

We defined the following endpoints as objective outcomes:

adverse events;
AUR;
surgical intervention.

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

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

Measures of treatment effect

We analyzed the data using Review Manager 5 (Review Manager 2014). We expressed dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We expressed continuous data as mean differences (MDs) with 95% CIs unless different studies use different measures to assess the same outcome, in which case we expressed data as standardized mean differences (SMDs) with 95% CIs.

Unit of analysis issues

The unit of analysis was the individual participant. When we identified trials with more than two intervention groups for inclusion in the review, we handled these 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, if feasible, and performed intention‐to‐treat (ITT) analyses if data were available; we otherwise performed available‐case analyses. We investigated attrition rates (e.g. dropouts, losses to follow‐up, and withdrawals), and critically appraised issues of missing data. We did not impute missing data.

Assessment of heterogeneity

In the event of excessive heterogeneity that was unexplained by subgroup analyses, we did not report outcome results as the pooled effect estimate in a meta‐analysis but provided a narrative description of the results of each study.

We assessed the heterogeneity (inconsistency) of included studies using the Chi² test, and we considered a P value less than 0.10 as statistically significant heterogeneity. Furthermore, we measured the quantity of inconsistency using the I² statistic (Higgins 2003). We interpret the I² statistic as follows:

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

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

Assessment of reporting biases

We attempted to obtain study protocols to assess for selective outcome reporting.

If we included 10 studies or more that investigated a particular outcome, we used funnel plots to assess small‐study effects. Several explanations could 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 summarized the 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 (Higgins 2011a). 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 introduce clinical heterogeneity, and planned to perform subgroup analyses limited to primary outcomes and investigate interactions.

Age (less than 65 years versus 65 years or older).
Serum prostate‐specific antigen (PSA) level (less than 1.3 ng/mL versus 1.3 ng/mL or greater).
IPSS (moderate (8 to 19) versus severe (20 to 35)).

Based on literature in this field (Kozminski 2015), the important characteristics to analyze in LUTS secondary to BPO included age, PSA level, and the IPSS.

The results from a secondary analysis of Medical Therapy of Prostatic Symptoms (MTOPS) data showed that age, PSA level, and the IPSS significantly correlate with the progression of LUTS secondary to BPO (Kozminski 2015). Additionally, Roehrborn 2008 suggested that men with PSA levels less than 1.3 ng/mL (smaller prostates) might profit more from anticholinergenic drugs.

We used the test for subgroup differences in Review Manager 5 to compare subgroup analyses if there were a sufficient number of included studies (Review Manager 2014).

Sensitivity analysis

We planned to perform sensitivity analyses limited to 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 exclusion of the studies with non‐blinded design.

Summary of findings and assessment of the certainty of the evidence

We presented the overall 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 also to external validity, such as directness of results (Guyatt 2008). For each comparison, two review authors (XLW, BW) independently assessed the certainty of the evidence for each outcome as 'high,' 'moderate,' 'low,' or 'very low' using the GRADEpro Guideline Development Tool (GDT) (GRADEpro GDT). We resolved any discrepancies by consensus, or, if needed, by arbitration by a third review author (RP, JHJ). For each comparison, we presented a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011b; Schünemann 2011).

Results

Description of studies

Through database searching, we identified 1656 records (see Figure 1). We found no additional record through other sources.

Results of the search

After removal of duplicates, we screened the titles and abstracts of 1201 records, and excluded 1138 records. We screened 63 full‐text articles, and excluded 25 studies (26 articles) that did not meet the inclusion criteria or were not relevant (Aldemir 2010; Ali 2020; Chen 2018; Deva 2017; Du 2015; Fang 2012; Fujihara 2010; Gan 2011; Gao 2014; He 2019; Kosilov 2018; Lee 2014; Malkoç 2012; Maruyama 2006; NCT02972268; Qin 2019; Rovner 2008; Sakalis 2016; Takahashi 2013; Wang 2013; Xin 2016; Xu 2015; Yan 2018; Yang 2014; Zhao 2011). We included 23 studies (37 articles) in the review (Cai 2016; Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). The flow of literature through this assessment process is shown in the PRISMA flowchart (Figure 1).

Included studies

Details of the included studies are presented in the Characteristics of included studies table and the baseline characteristics are shown in Table 4. We included 23 trials that randomized 6285 men with LUTS due to BPO, published between 2006 and 2018. Of those, 16 were published in English language (Cai 2016; Cho 2017; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2017); six in Chinese language (He 2012; Liu 2013; Shen 2011; Wang 2015; Wu 2009; Yu 2010); and one in Korean language (Kang 2009). In addition, we tried to contact each author of the studies to obtain the additional information, but we only received three responses (Cai 2016; Nishizawa 2011; Van Kerrebroeck 2013b). The additional information is summarized in the survey of trial investigators providing information on included trials (Appendix 10).

1. Baseline characteristics.

Study	Intervention(s) and comparator(s)	Duration of intervention (duration of follow‐up)	Description of participants	Trial period	Country	Setting	Ethnic groups (%)	Duration of disease
Cai 2016	I1: tamsulosin + tolterodine ER	24 weeks (24 weeks)	Men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; TPV ≥ 25 mL	December 2009 to March 2015	China	Multi‐center/outpatients	100% Chinese	—
	C1: tamsulosin + placebo
	C2: tolterodine ER + placebo
	C3: placebo + placebo
Cho 2017	I1: alfuzosin + imidafenacin	12 weeks (12 weeks)	Men ages ≥ 45 yr; with LUTS and storage symptoms for > 3 months; IPSS ≥ 12; IPSS question 4 score ≥ 2; TPV > 20 mL; micturitions ≥ 8 per 24 h; 5 mL/s ≤ Qmax ≤ 15 mL/s	—	South Korea	Multi‐center/outpatients	—	—
	C1: alfuzosin + placebo
He 2012	I1: tamsulosin + solifenacin	12 weeks (12 weeks)	Men ages ≥ 50 yr; IPSS ≥ 8; QoL score ≥ 3; OABSS ≥ 3; Qmax < 15 mL/s; PRV < 60 mL	June 2010 to December 2011	China	Single‐center/outpatients	—	—
	C1: tamsulosin
Kang 2009	I1: tamsulosin + propiverine	12 weeks (12 weeks)	Men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; TPV ≥ 25 mL	May 2007 to April 2008	South Korea	Single‐center/outpatients	—	—
	C1: tamsulosin
Kaplan 2006	I1: tamsulosin + tolterodine ER	12 weeks (12 weeks)	Men ages ≥ 40 yr; IPSS ≥ 12; QoL score ≥ 3; micturition frequency ≥ 8 per 24 h and urgency ≥ 3 per 24 h	November 2004 to May 2006	USA	Multi‐center/outpatients	82.5% white and 17.5% non‐white (black, Asian, other)	—
	C1: tamsulosin + placebo
	C2: tolterodine ER + placebo
	C3: placebo + placebo
Kaplan 2009	I1: tamsulosin + solifenacin	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 13; PPBC ≥ 3; Qmax ≥ 5 mL/s with volume ≤ 200 mL	May 2006 to January 2007	USA	Single‐center/outpatients	83.4% white and 16.6% non‐white (black, other)	—
	C1: tamsulosin + placebo
Kaplan 2013	I1: tamsulosin OCAS 0.4 mg + solifenacin 6 mg	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 8; Bladder Outlet Obstruction Index ≥ 20; Qmax ≤ 12 mL/s with volume ≥ 120 mL	June 2007 to August 2008	USA	Multi‐center/outpatients	96.4% white and 3.6% non‐white (black, Asian, other)	—
	I2: tamsulosin OCAS 0.4 mg + solifenacin 9 mg
	C1: placebo
Lee 2011	I1: doxazosin GITS + tolterodine ER	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 14 (voiding subscore ≥ 8 and storage subscore ≥ 6); QoL ≥ 3; micturition frequency ≥ 8 per 24 h; urgency ≥ 1 per 24 h; TPV ≥ 20 mL; Qmax ≤ 15 mL/s with volume ≥ 125 mL	—	South Korea	Multi‐center/outpatients	—	—
	C1: doxazosin GITS + placebo
Lee 2016	I1: tamsulosin 0.2 mg + solifenacin 5 mg	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 8; OABSS ≥ 3; Question 2 of OABSS ≥ 2; TPV ≥ 20 mL	—	South Korea	Single‐center/outpatients	—	—
	I2: tamsulosin 0.2 mg + solifenacin 10 mg
	C1: tamsulosin
Liu 2013	I1: tamsulosin + solifenacin	12 weeks (12 weeks)	Men ages > 50 yr; IPSS > 8; OABSS > 3; Qmax < 5 mL/s; micturition ≥ 8; nocturia ≥ 3 per 24 h	—	China	Single‐center/outpatients	—	—
	C1: tamsulosin
MacDiarmid 2008	I1: tamsulosin + oxybutynin ER	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 13 and storage IPSS ≥ 8; Qmax ≥ 8 mL/s with volume ≥ 125 mL; PVR ≤ 150 mL	March 2004 to June 2005	USA	Multi‐center/outpatients	—	—
	C1: tamsulosin
Matsukawa 2016	I1: silodosin + propiverine	1 year (1 year)	Men ages ≥ 50 yr; IPSS ≥ 8; QoL score ≥ 3; OABSS ≥ 3; urinary urgency episodes ≥ 1 per week; TPV ≥ 25 mL; Qmax < 15 mL/s with volume ≥ 100 mL; PVR < 150 mL	August 2011 and June 2013	Japan	Single‐center/outpatients	—	—
	C1: silodosin
Memon 2014	I1: alfuzosin + tolterodine	12 weeks (12 weeks)	Men ages ≥ 40 yr; IPSS 15–30; Qmax < 5 mL/s with volume ≥ 100 mL	May 2012 and September 2013	Pakistan	Single‐center/outpatients	—	—
	C1: alfuzosin
Nishizawa 2011	I1: tamsulosin 0.2 mg + propiverine 10 mg	12 weeks (12 weeks)	Men ages ≥ 50 yr; IPSS ≥ 8 with urgency item score ≥ 1; QoL ≥ 2; Qmax < 15 mL/s with volume ≥ 150 mL; 8 micturitions and 1 urgency per 24 h	October 2004 to September 2008.	Japan	Multi‐center/outpatients	—	—
	I2: tamsulosin 0.2 mg + propiverine 20 mg
	C1: tamsulosin, daily
Sakalis 2018	I1: tamsulosin OCAS + solifenacin	26 weeks (26 weeks)	Men ages ≥ 50 yr; IPSS storage subscore ≥ voiding subscore and score ≥ 3 in the IPSS urgency question; ≥ 3 urgency episodes per 24 h; prostate volume ≥ 30 mL; Qmax ≥ 10 mL/s; PVR ≤ 100 mL; PSA ≤ 4 ng/mL. Participants with suspicious rectal exam or PSA values 4–10 ng/mL (or both) were included only after negative prostate biopsy	October 2013 to June 2015.	Greece	Single‐center/outpatients	100% white	—
	C1: tamsulosin OCAS
Sener 2013	I1: propiverine + terazosin	1 year (1 year)	Men ages ≥ 40 yr; IPSS > 12; micturition frequency > 8 per 24 h; urgency episodes > 3 per 24 h; PSA < 2.5 ng/mL; having documented detrusor pressure > 10 cmH₂O in urodynamic studies	May 2009 to November 2012	Turkey	Multi‐center/outpatients	—	—
	C1: placebo + terazosin
Shen 2011	I1: terazosin+ tolterodine	12 weeks (12 weeks)	Men ages ≥ 60 yr; IPSS ≥ 8; TPV < 60 mL; Qmax < 15 mL/s	January 2010 to October 2010	China	Single‐center/outpatients	—	—
	C1: terazosin
Van Kerrebroeck 2013b	I1: tamsulosin OCAS 0.4 mg + solifenacin 6 mg	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 13; Qmax 4–12 mL/s with volume ≥ 120 mL; micturition frequency ≥ 8 per 24 h; urgency episodes ≥ 2 per 24 h	January 2010 to March 2011	Europe	Multi‐center/outpatients	99.2% white and 0.8% non‐white (black, Asian, other)	—
	I2: tamsulosin OCAS 0.4 mg + solifenacin 9 mg
	C1: tamsulosin OCAS + placebo
	C2: placebo + placebo
Van Kerrebroeck 2013c	I1: solifenacin 3 mg + tamsulosin OCAS 0.4 mg	12 weeks (12 weeks)	Men ages ≥ 45 yr; IPSS ≥ 13; Qmax 4–15 mL/s with volume ≥ 120 mL	—	Europe	Multi‐center/outpatients	99.6% white and 0.4% non‐white (black, other)	—
	I2: solifenacin 6 mg + tamsulosin OCAS 0.4 mg
	I3: solifenacin 9 mg + tamsulosin OCAS 0.4 mg
	C1: placebo + placebo
	C2: solifenacin 3 mg + placebo
	C3: solifenacin 6 mg + placebo
	C4: solifenacin 9 mg + placebo
	C5: tamsulosin OCAS 0.4 mg + placebo
Wang 2015	I1: tamsulosin 0.2 mg + fesoterodine 4 mg	12 weeks (12 weeks)	Men ages ≥ 50 yr; IPSS > 8 and storage IPSS ≥ 6; QoL score ≥ 3; Qmax < 15 mL/s with volume ≥ 200 mL; PRV < 60 mL	January 2013 to September 2014	China	Single center/outpatients	—	—
	C1: tamsulosin 0.2 mg
Wang 2017	I1: tamsulosin 0.2 mg + solifenacin 5 mg	12 weeks (12 weeks)	Men; IPSS ≥ 8; OABSS ≥ 3; mean urination frequency ≥ 8 times/day; nocturia episodes ≥ 2; urine volume ≥ 200 mL	April 2014 to December 2015	China	Single‐center/outpatients	—	—
	C1: tamsulosin 0.2 mg
Wu 2009	I1: tamsulosin 0.2 mg + tolterodine 2 mg	12 weeks (12 weeks)	Men ages > 50 yr; IPSS > 8 and storage IPSS ≥ 6; QoL score ≥ 3; Qmax < 15 mL/s with volume ≥ 200 mL; PRV < 60 mL	June 2006 to June 2008	China	Single‐center/outpatients	—	—
	C1: tamsulosin 0.2 mg
Yu 2010	I1: doxazosin 4 mg + tolterodine 2 mg	12 weeks (12 weeks)	Men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; complain of urgency and frequency with volume < 300 mL	October 2007 to December 2009	China	Single‐center/outpatients	—	—
	C1: doxazosin 4 mg

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— denotes not reported.

C: comparator; I: intervention; ER: extended release; GITS: gastrointestinal therapeutic system; h: hour; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; OABSS: Overactive Bladder Symptom Score; OCAS: oral controlled absorption system; PPBC: Patient Perception of Bladder Condition; PRV: postvoid residual; Qmax: maximum flow rate; QoL: quality of life; s: second; SD: standard deviation; TPV: total prostate volume; yr: year.

Design

All the 23 studies were parallel RCTs. Eleven studies were multi‐centered (Cai 2016; Cho 2017; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; MacDiarmid 2008; Nishizawa 2011; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c), and 12 were single‐centered (He 2012; Kang 2009; Lee 2016; Liu 2013; Matsukawa 2016; Memon 2014; Sakalis 2018; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010). In terms of location, eight were conducted in China (Cai 2016; He 2012; Liu 2013; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010), four in South Korea (Cho 2017; Kang 2009; Lee 2011; Lee 2016), four in the USA (Kaplan 2006; Kaplan 2009; Kaplan 2013; MacDiarmid 2008), three in Europe (Sakalis 2018; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c), two in Japan (Matsukawa 2016; Nishizawa 2011), one in Turkey (Sener 2013), and one in Pakistan (Memon 2014).

Participants

All participants were over the age of 40 years. Sener 2013 studied the youngest population (mean 54.4 years, SD 6), while Shen 2011 studied the oldest one (mean 73.9 years, SD 5). The ethnic composition of participants were described in Cai 2016 (100% Chinese), Kaplan 2006 (82.5% white and 17.5% non‐white (black, Asian, other)), Kaplan 2009 (83.4% white and 16.6% non‐white (black, other)), Kaplan 2013 (96.4% white and 3.6% non‐white (black, Asian, other)), MacDiarmid 2008 (90.2% white and 9.8% non‐white (black, Asian, other)), Sakalis 2018 (100% white Caucasians), Van Kerrebroeck 2013b (99.2% white and 0.8% non‐white (black, Asian, other)), and Van Kerrebroeck 2013c (99.6% white and 0.4% non‐white (black, other)).

In terms of the severity of LUTS by IPSS, Nishizawa 2011 focused on the men with lower severity (mean 13, SD 6.4), whereas Sener 2013 centered on men with greater severity (mean 29, SD 2). The baseline prostate volume was reported in Cai 2016 (mean 41.8 mL, SD 16.1), Cho 2017 (mean 36.0 mL, range 20 to 92.4), Kang 2009 (mean 31.1 mL, SD 8.8), Lee 2011 (mean 34.5 mL, SD 4), Matsukawa 2016 (mean 45.7 mL, SD 17.3), Nishizawa 2011 (mean 28.9 mL, SD 26.7), and Sakalis 2018 (mean 50.8 mL, SD 23.9).

Several trials failed to report some baseline characteristics. Yu 2010 did not report age of participants. Fifteen studies did not report ethnicity of participants (Cho 2017; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sener 2013; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Fifteen studies did not report prostate volume (He 2012; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2016; Liu 2013; MacDiarmid 2008; Memon 2014; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wu 2009; Yu 2010).

Interventions

The details of interventions are presented in Table 5. All studies used combination therapy with anticholinergics and alpha‐blockers as the experimental intervention; nine trials used solifenacin combined with tamsulosin (He 2012; Kaplan 2009; Kaplan 2013; Lee 2016; Liu 2013; Sakalis 2018; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2017); seven trials used tolterodine combined with tamsulosin (Cai 2016; Kaplan 2006; Wu 2009), doxazosin (Lee 2011; Yu 2010), alfuzosin (Memon 2014), or terazosin (Shen 2011); four trials used propiverine combined with tamsulosin (Kang 2009; Nishizawa 2011), silodosin (Matsukawa 2016), or terazosin (Sener 2013); one trial used imidafenacin with alfuzosin (Cho 2017); the remaining trials used oxybutynin (MacDiarmid 2008) or fesoterodine (Wang 2015) with tamsulosin.

2. Description of Interventions.

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^aThe term 'clinical practice setting' refers to the specification of the intervention/comparator as used in the course of a standard medical treatment (such as dose, dose escalation, dosing scheme, provision for contraindications, and other important features).

C: comparator; I: intervention; N/CPS: no specification of clinical practice setting possible; ER: extended release; GITS: gastrointestinal therapeutic system; OCAS: oral controlled absorption system.

Five trials used placebo was used the comparator intervention (Cai 2016; Kaplan 2006; Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). Alpha‐blocker and anticholinergic in comparator group were the same in the experimental group to establish fair comparisons.

Duration of treatment ranged from 12 weeks to one year. Of the 23 included studies, 19 provided 12 weeks' treatment (Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; Shen 2011; MacDiarmid 2008; Memon 2014; Nishizawa 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Two performed 24 weeks' (Cai 2016) and 26 weeks' (Sakalis 2018) treatment. Two studies conducted one year' treatment (Matsukawa 2016; Sener 2013).

Comparisons

Five trials compared combination therapy to placebo (Cai 2016; Kaplan 2006; Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c), and 22 trials conducted the comparison between combination therapy and alpha‐blockers (Cai 2016; Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Three studies compared combination therapy and anticholinergics (Cai 2016; Kaplan 2006; Van Kerrebroeck 2013c). Seven trials had one or more comparisons (Cai 2016; Kaplan 2006; Kaplan 2013; Lee 2016; Nishizawa 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c).

Outcomes

For primary outcomes, all the 23 included studies reported urologic symptom score assessed by IPSS, and 18 reported QoL assessed using IPSS‐QoL score (Cai 2016; Cho 2017; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Twenty‐two studies reported adverse events (Cai 2016; Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Of these, nine studies reported the overall adverse events (Cho 2017; Kaplan 2009; Kaplan 2013; Liu 2013; MacDiarmid 2008; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2017), and the other 13 studies only reported the individual adverse events (Cai 2016; He 2012; Kang 2009; Kaplan 2006; Lee 2011; Lee 2016; Matsukawa 2016; Memon 2014; Sakalis 2018; Shen 2011; Wang 2015; Wu 2009; Yu 2010). After contacting the authors, four confirmed the overall adverse events (He 2012; Shen 2011; Wang 2015; Yu 2010).

For secondary outcomes, only Liu 2013 reported AUR as one of outcomes and another 19 studies reported it within adverse events (Cai 2016; Cho 2017; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wu 2009; Wang 2017; Yu 2010). Only four studies reported surgical intervention, which was described in adverse events (Kang 2009; Liu 2013; Sakalis 2018; Yu 2010).

All studies reported short‐term outcomes only.

Funding and conflicts of interest

Seven studies specified funding sources: Cai 2016 – Chinese Capital Medical Development Science Fund; Kaplan 2006 – Research Grant from Pfizer Inc.; Kaplan 2013 – Research Grant from Astellas Pharma US Inc.; Lee 2016 – Astellas Pharmaceuticals research fund; MacDiarmid 2008 – McNeil Consumer and Specialty Pharmaceuticals; Van Kerrebroeck 2013b – Research Grant from Astellas Pharma Europe B.V.; Van Kerrebroeck 2013c – Research Grant from Astellas Pharma Europe B.V. Eleven studies did not mention funding source (Cho 2017; He 2012; Kang 2009; Kaplan 2009; Lee 2011; Liu 2013; Sener 2013; Shen 2011; Wang 2015; Wu 2009; Yu 2010), and the remaining trials reported no funding source (Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Wang 2017).

Seven study declared conflicts of interest. Kaplan 2006 declared three researchers were employees of pharmaceutical companies and two other researchers received fees from pharmaceutical companies; Kaplan 2009 declared four researchers received fees from pharmaceutical companies; Kaplan 2013 declared three researchers were employees of pharmaceutical companies and another researcher received fees from pharmaceutical companies; MacDiarmid 2008 declared three researchers received fees from pharmaceutical companies; Sakalis 2018 declared two researchers were funded by grant from the EU and Greek national resources; Van Kerrebroeck 2013b declared three researchers were employees of pharmaceutical companies and four other researchers received fees from pharmaceutical companies; Van Kerrebroeck 2013c declared three researchers were employees of pharmaceutical companies and four other researchers received fees from pharmaceutical companies. The other 16 studies declared no conflict of interest (Cai 2016; Cho 2017; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sener 2013; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010).

Excluded studies

We excluded 25 studies and presented the details in the Characteristics of excluded studies table. Seven studies were not RCTs (Deva 2017; Fang 2012; Gan 2011; Gao 2014; Maruyama 2006; Wang 2013; Xin 2016); two studies used combination therapy in both study arms (Du 2015; Lee 2014); one study treated both arms using alpha‐blockers monotherapy (Fujihara 2010); one study did not have a control arm (Aldemir 2010); six studies conducted four or eight weeks' follow‐up, which did not meet our criteria of follow‐up (He 2019; Kosilov 2018; Qin 2019; Xu 2015; Yang 2014; Zhao 2011); one study did not meet our criteria of outcomes (Rovner 2008), and the population from five other studies did not meet criteria of our review (Chen 2018; Malkoç 2012; Sakalis 2016; Takahashi 2013; Yan 2018). In addition, two studies did not provide available data for this review (Ali 2020; NCT02972268).

Studies awaiting classification

We found no studies awaiting classification.

Ongoing trials

We found no ongoing trials.

Risk of bias in included studies

We extracted the methodological details of the studies from the published data and presented details in the Characteristics of included studies table. We presented the summary of judgment about risk of bias in Figure 2 and Figure 3.

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

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

Allocation

Random sequence generation

Eight studies reported adequate methodological details for sequence generation and were at low risk of bias (Cai 2016; Cho 2017; Kaplan 2006; Kaplan 2009; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Van Kerrebroeck 2013b). The other 15 included studies did not provide sufficient information for the method of sequence generation and were at unclear risk of bias (He 2012; Kang 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Memon 2014; Sener 2013; Shen 2011; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010).

Allocation concealment

Three studies reported the specific method for allocation concealment and were at low risk of bias (Memon 2014; Nishizawa 2011; Van Kerrebroeck 2013b), and other 20 included studies did not provide sufficient information to allow an assessment and at unclear risk of bias (Cai 2016; Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010).

Blinding

Blinding of participants and personnel

We considered 13 studies at high risk of bias for blinding participants and personnel, since these studies were open‐label and all outcomes are susceptible to bias (He 2012; Kang 2009; Lee 2016; Liu 2013; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Two studies provided sufficient details for blinding performance (Kaplan 2006; Lee 2011) and eight were placebo‐controlled studies (Cai 2016; Cho 2017; Kaplan 2009; Kaplan 2013; MacDiarmid 2008; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c), which were at low risk of bias.

Blinding of outcome assessment

For subjective outcomes, 13 studies were at high risk of bias since they were open‐label (He 2012; Kang 2009; Lee 2016; Liu 2013; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010), and three studies were at low risk of bias since sufficient information was provided for the blinding of assessor (Cho 2017; Kaplan 2006; Lee 2011). In the other seven studies, although blinding of outcome assessment was not reported, we considered them at low risk of bias since they were placebo‐controlled trials (Cai 2016; Kaplan 2009; Kaplan 2013; MacDiarmid 2008; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). For objective outcomes, all 23 included studies were at low risk of bias since these outcomes are likely not affected by lack of blinding.

Incomplete outcome data

For urologic symptoms scores and QoL assessed by IPSS questionnaire, we considered 17 studies at low risk of bias since less than 10% of randomized participants were not included in final analysis (Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Liu 2013; MacDiarmid 2008; Memon 2014; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). Three studies were at high risk of bias since more than 20% of randomized participants were not involved in analysis (Cai 2016; Kaplan 2013; Lee 2011), and three other studies were at unclear risk of bias because the percentage of randomized participants who were not included in analysis were moderate (10% to 20%) (Lee 2016; Matsukawa 2016; Nishizawa 2011). In terms of adverse events, AUR, and surgical intervention, we classified 21 studies at low risk of bias since almost all randomized participants were included in analysis in these studies (Cai 2016; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Kaplan 2013; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). We considered two studies at unclear risk of bias because these outcomes were not reported in the study (Cho 2017; Memon 2014).

Selective reporting

We judged six studies at low risk of bias since they were performed as planned in the protocol (Kaplan 2006; Kaplan 2009; Kaplan 2013; Sakalis 2018; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c), and one study at high risk of bias as some outcomes proposed in protocol were not reported (Cai 2016). Other 16 studies were at unclear risk of bias since there was no protocol available (Cho 2017; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sener 2013; Shen 2011; Wang 2015; Wang 2017; Wu 2009; Yu 2010).

Other potential sources of bias

The other potential sources of bias we considered in the review included: Was the trial stopped early due to some data‐dependent process? Was there extreme baseline imbalance?

We identified no other potential sources of bias in the included studies.

Effects of interventions

See: Table 1; Table 2; Table 3

1. Combination therapy versus placebo (short term)

We included five studies in this comparison (Cai 2016; Kaplan 2006; Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c).

See Table 1.

1.1 Primary outcomes

1.1.1 Urologic symptom scores

We included four studies with 1792 participants (Cai 2016; Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). Combination therapy may result in little or no difference in urologic symptom scores (MD –2.73, 95% CI –5.55 to 0.08; I² = 94%; Analysis 1.1). We rated the certainty of evidence as low, downgrading for study limitations and imprecision.

1.1 — Comparison 1: Combination therapy versus placebo (short term), Outcome 1: Urologic symptom scores

1.1.2 Quality of life

We included two studies with 991 participants (Cai 2016; Van Kerrebroeck 2013b). We are very uncertain about the effect of combination therapy on QoL (MD –0.97, 95% CI –2.11 to 0.16; I² = 96%; Analysis 1.2). We rated the certainty of evidence as very low, downgrading for study limitations, inconsistency, and imprecision.

1.2 — Comparison 1: Combination therapy versus placebo (short term), Outcome 2: Quality of life

1.1.3 Adverse events

We included three studies with 1848 participants (Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). Combination therapy likely increases adverse events (RR 1.24, 95% CI 1.04 to 1.47; I² = 0%; Analysis 1.3); this corresponded to 61 more adverse events (95% CI 10 more to 119 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as moderate, downgrading for imprecision.

1.3 — Comparison 1: Combination therapy versus placebo (short term), Outcome 3: Adverse events

1.2 Secondary outcomes

1.2.1 Acute urinary retention

We included five studies with 2369 participants (Cai 2016; Kaplan 2006; Kaplan 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). We are very uncertain about the effect of combination therapy on AUR (RR 1.94, 95% CI 0.41 to 9.08; I² = 0%; Analysis 1.4). We rated the certainty of evidence as very low, downgrading for serious study limitations and very serious imprecision.

1.4 — Comparison 1: Combination therapy versus placebo (short term), Outcome 4: Acute urinary retention

1.2.2 Surgical intervention

None of the studies reported data on number of men with a need of surgical intervention.

1.3 Subgroup analysis

We were unable to perform any of the planned secondary analyses due to lack of relevant data.

1.4 Sensitivity analysis

We rated all included studies at low risk of performance and detection bias, therefore the sensitivity analyses were identical with main analyses.

2. Combination therapy versus alpha‐blockers (short term)

We included 22 studies for this comparison (Cai 2016; Cho 2017; He 2012; Kang 2009; Kaplan 2006; Kaplan 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010).

See Table 2.

2.1 Primary outcomes

2.1.1 Urologic symptom scores

We included 19 studies with 3631 participants (Cai 2016; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Memon 2014; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Wu 2009; Yu 2010). We are very uncertain about the effect of combination therapy on urologic symptom scores (MD –2.04, 95% CI –3.56 to –0.52; I² = 97%; Analysis 2.1). We rated the certainty of evidence as very low, downgrading for study limitations, inconsistency, and imprecision.

2.1 — Comparison 2: Combination therapy versus alpha‐blockers (short term), Outcome 1: Urologic symptom scores

2.1.2 Quality of life

We included 15 studies with 2687 participants (Cai 2016; He 2012; Kang 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Van Kerrebroeck 2013b; Wu 2009; Wang 2017; Yu 2010). We are very uncertain about the effect of combination therapy on QoL (MD –0.71, 95% CI –1.03 to –0.38; I² = 95%; Analysis 2.2). We rated the certainty of evidence as very low, downgrading for study limitations, inconsistency, and imprecision.

2.2 — Comparison 2: Combination therapy versus alpha‐blockers (short term), Outcome 2: Quality of life

2.1.3 Adverse events

We included 12 studies with 3561 participants (Cho 2017; He 2012; Kaplan 2009; Liu 2013; MacDiarmid 2008; Nishizawa 2011; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wang 2015; Wang 2017; Yu 2010). Combination therapy may result in little or no difference in adverse event rate (RR 1.10, 95% CI 0.90 to 1.34; I² = 40%; Analysis 2.3); this corresponded to 23 more adverse events (95% CI 23 fewer to 78 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as low, downgrading for study limitations and imprecision.

2.3 — Comparison 2: Combination therapy versus alpha‐blockers (short term), Outcome 3: Adverse events

2.2 Secondary outcomes

2.2.1 Acute urinary retention

We included 19 studies with 4669 participants (Cai 2016; Cho 2017; Kang 2009; Kaplan 2006; Kaplan 2009; Lee 2011; Lee 2016; Liu 2013; MacDiarmid 2008; Matsukawa 2016; Nishizawa 2011; Sakalis 2018; Sener 2013; Shen 2011; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c; Wu 2009; Wang 2017; Yu 2010). Combination therapy may result in little to no difference in AUR (RR 2.03, 95% CI 0.97 to 4.23; I² = 0%; Analysis 2.4); this corresponded to 4 more AUR (95% CI 0 to 12 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as low, downgrading for study limitations and imprecision.

2.4 — Comparison 2: Combination therapy versus alpha‐blockers (short term), Outcome 4: Acute urinary retention

2.2.2 Surgical intervention

We included four studies with 454 participants (Kang 2009; Liu 2013; Sakalis 2018; Yu 2010). We are very uncertain about the effect of combination therapy on surgical intervention (RR 1.72, 95% CI 0.34 to 8.63; I² = 61%; Analysis 2.5); this corresponded to 71 more AUR (95% CI 77 fewer to 424 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as very low, downgrading for study limitations, inconsistency, and very serious imprecision.

2.5 — Comparison 2: Combination therapy versus alpha‐blockers (short term), Outcome 5: Surgical intervention

2.3 Subgroup analysis

We were unable to perform any of the planned subgroup analysis due to a lack of relevant data.

2.4 Sensitivity analysis

We perform the sensitive analysis by restricting the analysis by considering risk of bias, excluding studies with non‐blinded design.

2.4.1 Urologic symptom scores

We included six studies with 2308 participants (1484 men in combination therapy arm, 824 men in alpha‐blockers arm) (Cai 2016; Lee 2011; MacDiarmid 2008; Sener 2013; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). The MD for this sensitivity analysis was –2.62 (95% CI –5.83 to 0.58), which altered the treatment effect compared to the main analysis with a MD of –2.04 (95% CI –3.26 to –0.52). We rated the certainty of evidence as low, downgrading for inconsistency and imprecision.

2.4.2 Quality of life

We included five studies with 1608 participants (960 men in combination therapy arm, 648 men in alpha‐blockers arm) (Cai 2016; Lee 2011; MacDiarmid 2008; Sener 2013; Van Kerrebroeck 2013b). The MD for this sensitivity analysis was –1.07 (95% CI –1.95 to –0.18), which did not alter the treatment effect compared to the main analysis with a MD of –0.71 (95% CI –1.03 to –0.38). We rated the certainty of evidence as low, downgrading for inconsistency and imprecision.

2.4.3 Adverse events

We included five studies with 2732 participants (1714 men in combination therapy arm, 1018 men in alpha‐blockers arm) (Cho 2017; Kaplan 2009; MacDiarmid 2008; Van Kerrebroeck 2013b; Van Kerrebroeck 2013c). The sensitivity analysis (RR 1.11, 95% CI 0.95 to 1.28) did not differ from the main analysis (RR 1.1, 95% CI 0.9 to 1.34). We rated the certainty of evidence as moderate, downgrading for imprecision.

3. Combination therapy versus anticholinergics (short term)

We included three studies for this comparison (Cai 2016; Kaplan 2006; Van Kerrebroeck 2013c).

See Table 3.

3.1 Primary outcomes

3.1.1 Urologic symptom scores

We included two studies with 710 participants (Cai 2016; Van Kerrebroeck 2013c). We are very uncertain about the effect of combination therapy on urologic symptom scores (MD –3.71, 95% CI –9.41 to 1.98; I² = 98%; Analysis 3.1). We rated the certainty of evidence as very low, downgrading for study limitations, inconsistency, and very serious imprecision.

3.1 — Comparison 3: Combination therapy versus anticholinergics (short term), Outcome 1: Urologic symptom scores

3.1.2 Quality of life

One study with 56 participants reported data for QoL (Cai 2016). Combination therapy may result in an improvement in QoL (MD –1.49, 95% CI –1.88 to –1.11; Analysis 3.2). We rated the certainty of evidence as low, downgrading for study limitations and imprecision.

3.2 — Comparison 3: Combination therapy versus anticholinergics (short term), Outcome 2: Quality of life

3.1.3 Adverse events

One studies with 661 participants reported data for adverse events (Van Kerrebroeck 2013c). Combination therapy likely results in little to no difference in adverse events (RR 1.26, 95% CI 0.81 to 1.95; Analysis 3.3); this corresponded to 40 more adverse events (95% CI 29 fewer to 147 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as moderate, downgrading for imprecision.

3.3 — Comparison 3: Combination therapy versus anticholinergics (short term), Outcome 3: Adverse events

3.2 Secondary outcomes

3.2.1 Acute urinary retention

We included three studies with 1178 participants (Cai 2016; Kaplan 2006; Van Kerrebroeck 2013c). Combination therapy may result in little to no difference in AUR (RR 0.55, 95% CI 0.11 to 2.65; I² = 0%; Analysis 3.4); this corresponded to 4 fewer AUR (95% CI 7 fewer to 13 more) per 1000 participants treated with combination therapy. We rated the certainty of evidence as low, downgrading for study limitations and imprecision.

3.4 — Comparison 3: Combination therapy versus anticholinergics (short term), Outcome 4: Acute urinary retention

3.2.2 Surgical intervention

None of the studies reported data on number of men with a need of surgical intervention.

3.3 Subgroup analysis

We were unable to perform any of the planned secondary analyses due to a lack of relevant data.

3.4 Sensitivity analysis

We rated all included studies at low risk of performance and detection bias, therefore the sensitivity analyses were identical with main analyses.

Discussion

Summary of main results

We included 23 studies in this review, involving 6285 men with LUTS/BPO and performed three comparisons (combination therapy with anticholinergics and alpha‐blockers versus placebo; combination therapy with anticholinergics and alpha‐blockers versus alpha‐blockers monotherapy; combination therapy with anticholinergics and alpha‐blockers versus anticholinergics monotherapy).

1. Combination therapy versus placebo

While combination therapy may have little or uncertain effects on urologic symptom scores and QoL, combination therapy likely increases the rate of adverse events. Using GRADE, we rated the certainty of evidence as very low to moderate.

2. Combination therapy versus alpha‐blockers

Combination therapy had an uncertain effect on urologic symptom scores and QoL. Combination therapy appears not to have a significant effect on adverse events rate. Using GRADE, we rated the certainty of evidence as very low to low.

3. Combination therapy versus anticholinergics

Combination therapy had an uncertain effect on urologic symptom scores, but may result in an improvement in QoL without additional adverse events. Using GRADE, we rated the certainty of evidence as very low to moderate.

Overall completeness and applicability of evidence

Although many studies provide evidence for this review, several issues deserve consideration.

The included studies were conducted worldwide including Asia, Europe, and the USA and about half of included studies were multi‐centered. However, most of participants in the studies to compare combination therapy to placebo, or anticholinergics were limiting applicability to men with different ethnic backgrounds. In addition, most included studies did not describe the baseline characteristics of the participants well in terms of race/ethnicity, body mass index, and prostate volume.
The trials provided incomplete information on secondary outcomes; only one study reported AUR as an outcome and 19 studies only described it as one of the adverse events. Only two studies reported the number of participants receiving subsequent surgical interventions. Given the relatively high dropout rate with anticholinergics, more focused studies on the specific adverse events such as dry mouth, acute urinary retention, and the need of surgical intervention are needed. In addition, non‐randomized studies may be helpful to better understand the long‐term effectiveness and adverse events, but these were beyond the scope of this review.
We were unable to perform any predefined subgroup analysis according to age, PSA, and severity of LUTS. To clarify the effects of combination therapy, we would need more studies for the population with different clinical settings to use our evidence directly.
The body of evidence was limited to short‐term follow‐up of 12 months or less; most trials provided outcomes at 12 weeks. This appears insufficient to provide assurance of long‐term effectiveness and safety of combination therapy. More high‐quality studies with long‐term follow‐up are needed to address these limitations.

Quality of the evidence

We assessed the certainty of evidence using the GRADE approach and rated it as very low or low for most outcomes and comparisons. Our confidence in the estimates of effect were lowered for the following reasons.

Study limitation: mainly issues surrounding allocation concealment and blinding.
Inconsistency: high I² values reflecting clinically relevant heterogeneity, which we were unable to explain through secondary analyses.
Imprecision: CIs that were wide and crossed assumed thresholds of clinically important differences.

Potential biases in the review process

While we performed a comprehensive literature search including trial registries and grey literatures for unpublished, planned, or ongoing studies without restrictions on language of publication or publication status, we should consider the presence of unpublished data with non‐statistical results (e.g. time lag bias).
We tried to contact study authors to obtain additional information on several occasions. However, we received feedback only from three authors (Cai 2016; Nishizawa 2011; Van Kerrebroeck 2013b). This may represent a source of bias with potential under‐reporting.
To minimize variability between participants, we performed data analysis based on mean changes from baseline. For some included studies that did not report mean changes and SDs, we calculated those values. However, calculation of changes may result in risks of increased measurement error.

Agreements and disagreements with other studies or reviews

We identified three systematic reviews assessing the efficacy and safety of combination therapy with alpha‐blockers and anticholinergics for men with LUTS/BPO (Filson 2013; Kim 2017; Xin 2013). The result from Filson 2013 showed that combination therapy resulted in a significant improvement in IPSS storage sub‐score and urinary frequency, without increased risk of AUR compared to alpha‐blockers alone. Another review also found that combination therapy was associated with an significant improvement in total IPSS, IPSS storage sub‐score, QoL, urgency, and frequency compared to alpha‐blockers (Xin 2013). By contrast, our review used overall IPSS as a primary outcome and found that combination therapy had a similar or uncertain effect on IPSS compared to alpha‐blockers. Similar to our finding, Kim 2017 showed that combination therapy did not result in clinically important improvements in urologic symptoms, QoL, and acute urinary retention rate compared to alpha‐blockers. The potential reason for the contradictory finding between previously published reviews and ours may result from the difference in included studies. Filson 2013 only included placebo‐controlled RCTs and Xin 2013 included quasi‐randomized studies as well. In addition, our review only included studies with at least 12 weeks of follow‐up and interpreted the study results using thresholds of minimal clinical important differences. Our interpretation is also more critical as we use GRADE including the domains of imprecision to rate the certainty of evidence which led us to rate many results as very uncertain.

Authors' conclusions

Implications for practice.

Based on the findings of the review, combination therapy with anticholinergics and alpha‐blockers was associated with little or uncertain effects on urologic symptom scores compared to placebo, alpha‐blockers, or anticholinergics monotherapy. However, combination therapy may result in an improvement in quality of life compared to anticholinergics monotherapy, but an uncertain effect compared to placebo, or alpha‐blockers. Combination therapy likely increases adverse events compared to placebo, but not compared to alpha‐blockers or anticholinergics monotherapy.

Implications for research.

Given the very low‐ to low‐certainty evidence that characterizes most of the reported analyses, there is need for additional research to explore the effectiveness and safety of combination therapy on lower urinary tract symptoms/benign prostatic obstruction. Future trials should be conducted according to higher methodological standards with regards to allocation concealment and blinding to minimize concerns about selection, performance, and detection bias. Furthermore, trials with long‐term follow‐up are also needed to assess the long‐term efficacy and safety of combination therapy.

History

Protocol first published: Issue 9, 2016 Review first published: Issue 2, 2021

Notes

We based parts of the Methods section of this review on a standard template developed by Cochrane Metabolic and Endocrine Disorders Group, which Cochrane Urology has modified and adapted for use.

Acknowledgements

We thank Dr Weina Peng and Dr Changhe Yu for helping us to revise the search strategies. We also acknowledge Dr Philipp Dahm, Co‐ordinating Editor, of Cochrane Urology and the entire Editorial Team for their help and support.

Appendices

Appendix 1. Cochrane Library search strategy

1. MeSH descriptor Lower Urinary Tract Symptoms explode all trees

2. MeSH descriptor Urination Disorders explode all trees

3. LUTS

4. (urinary OR bladder OR urethra* OR urination OR LUT) NEAR/3 (symptom* OR complain*)

5. frequency OR urgency OR nocturia OR hesitancy

6. MeSH descriptor Prostatic Hyperplasia explode all trees

7. prostat* NEAR/3 (hyper* OR obstruct* OR enlarge*)

8. BPO OR BPH OR BPE

9. 1 OR 2 OR 3 OR 4 OR 5

10. 6 OR 7 OR 8

11. 9 AND 10

12. MeSH descriptor Urological Agents explode all trees

13. MeSH descriptor Adrenergic Alpha‐antagonists explode all trees

14. MeSH descriptor Sulfonamides explode all trees

15. MeSH descriptor Quinazolines explode all tree

16. MeSH descriptor Doxazosin explode all tree

17. alpha NEAR/4 (block* OR antagonist*)

18. doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin

19. 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18

20. MeSH descriptor Cholinergic Antagonists explode all trees

21. MeSH descriptor Benzhydryl Compounds explode all trees

22. MeSH descriptor Quinuclidines explode all trees

23. (muscarinic OR ((M OR M1 OR M3 OR M4) NEAR receptor*) OR mACHR*) NEAR/4 (block* OR antagonist*)

24. cholinergic NEAR/4 (antagonist* or block*)

25. anticholinergic* OR antimuscarinic*

26. fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium

27. 12 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26

28. 19 AND 27

29. 11 AND 28

Appendix 2. MEDLINE (via PubMed) search strategy

#1 randomised controlled trial [pt]

#2 controlled clinical trial [pt]

#3 randomised [tiab]

#4 placebo [tiab]

#5 drug therapy [sh]

#6 randomly [tiab]

#7 trial [tiab]

#8 groups [tiab]

#9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

#10 animals [mh] NOT humans [mh]

#11 #9 NOT #10

#12 Lower Urinary Tract Symptoms [mh]

#13 Urination Disorders [mh]

#14 LUTS [tw]

#15 ((urinary OR bladder OR urethra* OR urination OR LUT) AND (symptom* OR complain*)) [tw]

#16 (frequency OR urgency OR nocturia OR hesitancy) [tw]

#17 Prostatic Hyperplasia [mh]

#18 (prostat* AND (hyper* OR obstruct* OR enlarge*)) [tw]

#19 (BPO OR BPH OR BPE) [tw]

#20 #12 OR #13 OR #14 OR #15 OR #16

#21 #17 OR #18 OR #19

#22 #20 AND #21

#23 Urological Agents [mh]

#24 Adrenergic Alpha‐antagonists [mh]

#25 Sulfonamides [mh]

#26 Quinazolines [mh]

#27 Doxazosin [mh]

#28 (alpha AND (block* OR antagonist*)[tw]

#29 (doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin) [tw]

#30 #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29

#31 Cholinergic Antagonists [mh]

#32 Benzhydryl Compounds [mh]

#33 Quinuclidines [mh]

#34 ((muscarinic OR ((M OR M1 OR M3 OR M4) AND receptor*) OR mACHR*) AND (block* OR antagonist*)) [tw]

#35 (cholinergic AND (antagonist* OR block*)) [tw]

#36 (anticholinergic* OR antimuscarinic*) [tw]

#37 (fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium) [tw]

#38 #23 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37

#39 #30 AND #38

#40 #22 AND #39

#41 #11 AND #40

Appendix 3. Embase (via Elsevier) search strategy

1. exp randomised controlled trial/

2. exp clinical trial/

3. exp randomisation/

4. exp placebo/

5. exp control group/

6. (random$ OR place$ OR group$).tw

7. (clin$ adj3 trial$).tw

8. ((singl$ OR doubl$ OR tripl$ OR trebl$) adj3 (blind$ OR mask$)).tw

9. (animal OR animal experiment).sh

10. human.sh

11. 9 NOT 10

12. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8

13. 12 NOT 11

14. exp Lower Urinary Tract Symptoms/

15. exp Micturition Disorder/

16. LUTS.tw

17. ((urinary or bladder or urethra$ or urination or LUT) adj3 (symptom$ or complain$)).tw

18. (frequency OR urgency OR nocturia OR hesitancy).tw

19. exp prostate hypertrophy/

20. (prostat* adj3 (hyper* or obstruct* or enlarge*)).tw

21. (BPO OR BPH OR BPE).tw

22. 14 OR 15 OR 16 OR 17 OR 18

23. 19 OR 20 OR 21

24. 22 AND 23

25. exp alpha adrenergic receptor blocking agent/

26. (alpha adj4 (antagonist$ OR block$)).tw

27. (doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin).tw

28. exp cholinergic receptor blocking agent/

29. (muscarinic OR ((M OR M1 OR M3 OR M4) adj receptor*) OR mACHR*) adj4 (block* OR antagonist*).tw

30. cholinergic adj4 (antagonist* or block*).tw

31. (anticholinergic* OR antimuscarinic*).tw

32. (fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium).tw

33. 25 OR 26 OR 27

34. 28 OR 29 OR 30 OR 31 OR 32

35. 33 AND 34

36. 24 AND 35

37. 13 AND 36

Appendix 4. Web of Science search strategy

1. TS=clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow‐up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double blind*)

2. TS=("lower urinary tract symptom*" OR frequency OR urgency OR nocturia OR hesitancy OR LUTS)

3. TS=((urinary OR bladder OR urethra* OR urination OR LUT) NEAR/3 (symptom* OR complain*))

4. TS=( prostat* NEAR/3 (hyper* OR obstruct* OR enlarge*))

5. TS=( BPO OR BPH OR BPE)

6. TS=(alpha NEAR/4 (block* OR antagonist*))

7. TS=( doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin)

8. TS= ((muscarinic OR ((M OR M1 OR M3 OR M4) NEAR receptor*) OR mACHR*) NEAR/4 (block* OR antagonist*))

9. TS=(cholinergic NEAR/4 (antagonist* or block*))

10. TS=(anticholinergic* OR antimuscarinic* OR fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium)

11. #2 OR #3

12. #4 OR #5

13. #6 OR #7

14. #8 OR #9 OR #10

15. #11 AND #12

16. #13 AND #14

17. #15 AND #16

18. #1 AND #17

Appendix 5. Chinese Biomedical Literature Database (via SinoMed) search strategy

#1 主题词=="随机对照试验/全部副主题"

#2 主题词=="对照临床试验/全部副主题"

#3 主题词=="随机分配"

#4 主题词=="双盲法"

#5 主题词=="单盲法"

#6 单盲OR 双盲 OR 三盲 OR 盲法 OR安慰剂 OR 随机

#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6

#8 动物 in CT

#9 人类 in CT

#10 #8 NOT #9

#11 #7 NOT #10

#12 主题词=="下尿路症状/全部副主题"

#13 下尿路症状 OR 尿频 OR 尿急 OR 排尿等待 OR排尿困难 OR 排尿费力 OR 夜尿 OR 尿滴沥

#14 主题词=="前列腺增生/全部副主题"

#15 前列腺肥大 OR 前列腺梗阻 OR 前列腺疾病 OR 前列腺增生

#16 #12 OR #13

#17 #14 OR #15

#18 #16 AND #17

#19 主题词=="肾上腺素受体阻断药/全部副主题"

#20肾上腺素 AND 受体 AND（拮抗 OR 阻断）

#21特拉唑嗪 OR 阿呋唑嗪 OR 坦索罗辛 OR 多沙唑嗪 OR萘哌地尔 OR赛洛多辛 OR 酚苄明 OR 哌唑嗪 OR 酚妥拉明

#22主题词=="胆碱能受体阻断药/全部副主题"

#23（胆碱能 OR M OR M1 OR M3 or M4) AND 受体AND（拮抗 OR阻断）

#24 托特罗定 OR 索利那新 OR 奥昔布宁 OR非索罗定 OR 达非那新 OR丙哌维林 OR曲司氯铵

#25 #19 OR #20 OR #21

#26 #22 OR #23 OR #24

#27 #25 AND #26

#28 #18 AND #27

#29 #11 AND #28

Appendix 6. LILACS search strategy

(mh:("Prostatic Hyperplasia")) OR (ti:("prostatic hyperplasia")) OR (ab:("prostatic hyperplasia")) OR (ti:("prostatic obstruction")) OR (ab:("prostatic obstruction")) OR (ti:("prostatic enlargement")) OR (ab:("prostatic enlargement")) OR (ti:("BPH")) OR (ab:("BPH")) OR (ti:("BPO")) OR (ab:("BPO")) OR (ti:("BPE")) OR (ab:("BPE")) AND db:("LILACS") AND type_of_study:("clinical_trials")

RCTs filter:

((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado" OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudios multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego" OR MH:"metodo simple‐ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos OR PT:"in vitro")

Appendix 7. ClinicalTrials.gov (advanced search)

Search terms: (lower urinary tract symptoms OR LUTS OR urinary symptom OR “urinary symptoms” OR “urinary complain” OR “urinary complains” OR bladder symptom OR “bladder symptoms” OR “bladder complain” OR “bladder complains “” OR “urethra symptom” OR “urethra symptoms” OR “urethral symptom” OR “urethral symptoms” OR “urethra complain” OR ““urethra complains” OR urethral complain” OR ““urethral complains”OR urination symptom OR “urination symptoms” OR “urination complain” OR “urination complains OR frequency OR urgency OR nocturia OR hesitancy ) AND (prostate hyperplasia OR prostate obstruction OR prostate enlargement OR prostatic hyperplasia OR prostatic obstruction OR prostatic enlargement OR BPH OR BPE OR BPO)

Study type: Interventional Studies

Interventions: (alpha blocker OR alpha blockers OR alpha antagonist OR alpha antagonists OR doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin) AND (cholinergic blocker OR cholinergic blockers OR cholinergic antagonist OR cholinergic antagonists OR muscarinic blocker OR muscarinic blockers OR muscarinic antagonist OR muscarinic antagonists OR anticholinergics OR muscarinics OR fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium)

Appendix 8. World Health Organization International Clinical Trials Registry Platform Search Portal (standard search)

(to be run as one search string)

prostat* hyper* AND doxazosin OR

prostat* hyper* AND alfuzosin OR

prostat* hyper* AND silodosin OR

prostat* hyper* AND tamsulosin OR

prostat* hyper* AND terazosin OR

prostat* hyper* AND naftopidil OR

prostat* hyper* AND phenoxybenzamine OR

prostat* hyper* AND prazosin OR

prostat* hyper* AND indoramin OR

prostat* hyper* AND fesoterodine OR

prostat* hyper* AND tolterodine OR

prostat* hyper* AND darifenacin OR

prostat* hyper* AND oxybutynin OR

prostat* hyper* AND propiverine OR

prostat* hyper* AND solifenacin OR

prostat* hyper* AND trospium OR

prostat* obstruct* AND doxazosin OR

prostat* obstruct*AND alfuzosin OR

prostat* obstruct* AND silodosin OR

prostat* obstruct* AND tamsulosin OR

prostat* obstruct* AND terazosin OR

prostat* obstruct* AND naftopidil OR

prostat* obstruct* AND phenoxybenzamine OR

prostat* obstruct* AND prazosin OR

prostat* obstruct* AND indoramin OR

prostat* obstruct* AND fesoterodine OR

prostat* obstruct* AND tolterodine OR

prostat* obstruct* AND darifenacin OR

prostat* obstruct* AND oxybutynin OR

prostat* obstruct* AND propiverine OR

prostat* obstruct* AND solifenacin OR

prostat* obstruct* AND trospium OR

prostat* enlarge* AND doxazosin OR

prostat* enlarge*AND alfuzosin OR

prostat* enlarge* AND silodosin OR

prostat* enlarge* AND tamsulosin OR

prostat* enlarge* AND terazosin OR

prostat* enlarge*AND naftopidil OR

prostat* enlarge* AND phenoxybenzamine OR

prostat* enlarge* AND prazosin OR

prostat* enlarge* AND indoramin OR

prostat* enlarge* AND fesoterodine OR

prostat* enlarge* AND tolterodine OR

prostat* enlarge* AND darifenacin OR

prostat* enlarge* AND oxybutynin OR

prostat* enlarge* AND propiverine OR

prostat* enlarge* AND solifenacin OR

prostat* enlarge* AND trospium OR

BPH AND doxazosin OR

BPH AND alfuzosin OR

BPH AND silodosin OR

BPH AND tamsulosin OR

BPH AND terazosin OR

BPH AND naftopidil OR

BPH AND phenoxybenzamine OR

BPH AND prazosin OR

BPH AND indoramin OR

BPH AND fesoterodine OR

BPH AND tolterodine OR

BPH AND darifenacin OR

BPH AND oxybutynin OR

BPH AND propiverine OR

BPH AND solifenacin OR

BPH AND trospium OR

BPO AND doxazosin OR

BPO AND alfuzosin OR

BPO AND silodosin OR

BPO AND tamsulosin OR

BPO AND terazosin OR

BPO AND naftopidil OR

BPO AND phenoxybenzamine OR

BPO AND prazosin OR

BPO AND indoramin OR

BPO AND fesoterodine OR

BPO AND tolterodine OR

BPO AND darifenacin OR

BPO AND oxybutynin OR

BPO AND propiverine OR

BPO AND solifenacin OR

BPO AND trospium OR

BPE AND doxazosin OR

BPE AND alfuzosin OR

BPE AND silodosin OR

BPE AND tamsulosin OR

BPE AND terazosin OR

BPE AND naftopidil OR

BPE AND phenoxybenzamine OR

BPE AND prazosin OR

BPE AND indoramin OR

BPE AND fesoterodine OR

BPE AND tolterodine OR

BPE AND darifenacin OR

BPE AND oxybutynin OR

BPE AND propiverine OR

BPE AND solifenacin OR

BPE AND trospium OR

Appendix 9. OpenGrey search strategy

(lower urinary tract symptoms OR LUTS OR urinary symptom* OR urinary complain* OR bladder symptom* OR bladder complain* OR urethra* symptom* OR urethra* complain* OR urination symptom* OR frequency OR urgency OR nocturia OR hesitancy ) AND (prostat* hyper* OR prostat* obstruct* OR prostat* enlarge* OR BPH OR BPE OR BPO) AND (alpha blocker* OR alpha antagonist* OR doxazosin OR alfuzosin OR silodosin OR tamsulosin OR terazosin OR naftopidil OR phenoxybenzamine OR prazosin OR indoramin) AND (cholinergic blocker* OR cholinergic antagonist* OR muscarinic blocker* OR muscarinic antagonist* anticholinergics OR muscarinics OR fesoterodine OR tolterodine OR darifenacin OR oxybutynin OR propiverine OR solifenacin OR trospium)

Appendix 10. Survey of trial investigators providing information on included trials

Study	Date trial author contacted (first)	Date trial author provided data (latest)	Data trial author provided (short summary)
Cai 2016	15 January 2017	2 May 2017	Provided the follow‐up data
Nishizawa 2011	15 January 2017	17 April 2017	Randomization and allocation concealment were realized by a web‐based randomization service. Provided the standard deviation for the outcomes.
Van Kerrebroeck 2013b	15 January 2017	16 April 2017	Confirmed the data about surgical intervention were not collected in the trial.

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Appendix 11. Abbreviations

Abbreviations	Full name
AUA	American Urological Association
AUR	Acute urinary retention
BPE	Benign prostatic enlargement
BPH	Benign prostatic hyperplasia
BPO	Benign prostatic obstruction
CI	Confidence interval
IPSS	International Prostate Symptom Score
Qmax	Maximum urine flow
QoL	Quality of life
LUTS	Lower urinary tract symptoms
PSA	prostate‐specific antigen
PVR	Postvoid residual
RCT	Randomized controlled trial

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Data and analyses

Comparison 1. Combination therapy versus placebo (short term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Urologic symptom scores	4	1792	Mean Difference (IV, Random, 95% CI)	‐2.73 [‐5.55, 0.08]
1.2 Quality of life	2	991	Mean Difference (IV, Random, 95% CI)	‐0.97 [‐2.11, 0.16]
1.3 Adverse events	3	1848	Risk Ratio (M‐H, Random, 95% CI)	1.24 [1.04, 1.47]
1.4 Acute urinary retention	5	2369	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.41, 9.08]

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Comparison 2. Combination therapy versus alpha‐blockers (short term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Urologic symptom scores	19	3631	Mean Difference (IV, Random, 95% CI)	‐2.04 [‐3.56, ‐0.52]
2.2 Quality of life	15	2687	Mean Difference (IV, Random, 95% CI)	‐0.71 [‐1.03, ‐0.38]
2.3 Adverse events	12	3561	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.90, 1.34]
2.4 Acute urinary retention	19	4669	Risk Ratio (M‐H, Random, 95% CI)	2.03 [0.97, 4.23]
2.5 Surgical intervention	4	454	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.34, 8.63]

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Comparison 3. Combination therapy versus anticholinergics (short term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Urologic symptom scores	2	710	Mean Difference (IV, Random, 95% CI)	‐3.71 [‐9.41, 1.98]
3.2 Quality of life	1	56	Mean Difference (IV, Random, 95% CI)	‐1.49 [‐1.88, ‐1.11]
3.3 Adverse events	1	661	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.81, 1.95]
3.4 Acute urinary retention	3	1178	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.11, 2.65]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cai 2016.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: December 2009 to March 2015 Study setting: multi‐center/outpatients/China
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; TPV ≥ 25 mL Exclusion criteria: neurologic bladder dysfunction; BOO from causes other than BPH; PVR ≥ 200 mL; Qmax ≤ 5 mL/s; significant hepatic or renal disease; history of postural hypotension and glaucoma; history of AUR requiring catheterization; using an indwelling catheter or self‐catheterization program; history of prostatic surgery or other invasive therapy; history of prostate cancer; serum total PSA level ≥ 10 ng/mL Total number of participants randomly assigned: 152 Group A Number of participants randomly assigned: 38 Age, yr (mean): 69.5 (SD 6.5) IPSS (mean): 19.1 (SD 4.6) Prostate volume, mL (mean): 43.6 (SD 18.1) Qmax, mL/s (mean): 12.0 (SD 3.3) Group B Number of participants randomly assigned: 38 Age, yr (mean): 69.3 (SD 7.5) IPSS (mean): 17.8 (SD 5.2) Prostate volume, mL (mean): 42.3 (SD 16.6) Qmax, mL/s (mean): 12.1 (SD 3.7) Group C Number of participants randomly assigned: 38 Age, yr (mean): 68.4 (SD 7.4) IPSS (mean): 17.6 (SD 5.1) Prostate volume, mL (mean): 38.8 (SD 15.7) Qmax, mL/s (mean): 11.8 (SD 3.2) Group D Number of participants randomly assigned: 38 Age, yr (mean): 70.8 (SD 7.8) IPSS (mean): 18.8 (SD 4.9) Prostate volume, mL (mean): 42.4 (SD 13.8) Qmax, mL/s (mean): 11.9 (SD 2.9)
Interventions	Group A: placebo + placebo Group B: tamsulosin (0.2 mg, once a day) + placebo Group C: tolterodine ER (4 mg, once a day) + placebo Group D: tamsulosin (0.2 mg, once a day) + tolterodine ER (4 mg, once a day) Follow‐up/treatment duration: 24 weeks
Outcomes	Total IPSS/storage subscore/voiding subscore/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 4 weeks, 12 weeks, and 24 weeks after intervention Time point reported: baseline, 4 weeks, 12 weeks, and 24 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 4 weeks, 12 weeks, and 24 weeks after intervention Time point reported: baseline, 4 weeks, 12 weeks, and 24 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks, 12 weeks, and 24 weeks after intervention Time point reported: 24 weeks after intervention
Funding sources	Chinese Capital Medical Development Science Fund (No. 2007‐3114).
Declarations of interest	None
Notes	Protocol: ChiCTR‐TRC‐09000596 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used a random number table.
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment.
Blinding of participants and personnel (performance bias)	Low risk	Placebo‐controlled study. Quote: "Placebo had the same pack, colour, and odour as the corresponding drug."
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Placebo‐controlled study. Quote: "Data were collected by one special investigator and analysed by one appointed statistician."
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	High risk	In terms of IPSS and QoL, 8/38 (21.0%) randomized participants in group A, 6/38 (15.7%) in group B, 11/38 (28.9%) in group C, and 9/38 (23.6%) in group D were not included in the analysis. The percentage of missing data was about 20%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	High risk	Some outcomes planned in the protocol of the study (ChiCTR‐TRC‐09000596), such as prostate volume, serum PSA, and blood pressure, were not reported in final published study.
Other bias	Low risk	Study appeared free of other sources of bias.

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Cho 2017.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: no information Study setting: multi‐center/outpatients/South Korea
Participants	Inclusion criteria: men ages ≥ 45 yr; with LUTS and storage symptoms for > 3 months; IPSS ≥ 12; IPSS question 4 score ≥ 2; TPV > 20 mL; micturitions ≥ 8 per 24 h; 5 mL/s ≤ Qmax ≤ 15 mL/s Exclusion criteria: urinary retention; PVR ≥ 150 mL; any condition that contraindicated the use of anticholinergic agents; acute urinary infections within last 1 month; treated with alpha‐blockers or anticholinergics within last 1 month; treated with 5‐alpha‐reductase inhibitors within last 3 months; treated with electrostimulation, biofeedback, or extracorporeal magnetic innervation therapy; history of surgery involving the urethra, prostate, or bladder neck; urologic neoplasms; Parkinson disease; stroke; multiple myeloma; spinal cord diseases; amyotrophic lateral sclerosis; neurogenic bladder; urethral strictures; urologic diseases that influenced voiding function, including bladder calculi or renal tuberculosis; PSA ≥ 4 ng/mL Total number of participants randomly assigned: 221 Group A Number of participants randomly assigned: 111 Age, yr (mean): 66 (range 50–85) IPSS (mean): 22.18 (SD 0.58) Prostate volume, mL (mean): 36.92 (range 20.0–92.4) Qmax, mL/s (mean): 10.84 (SD 2.78) Group B Number of participants randomly assigned: 110 Age, yr (mean): 69 (range 48–80) IPSS (mean): 21.94 (SD 0.58) Prostate volume, mL (mean): 35.15 (range 20.0–74.2) Qmax, mL/s (mean): 10.46 (SD 2.62)
Interventions	Group A: alfuzosin (10 mg, once a day) + placebo Group B: alfuzosin (10 mg, once a day) + imidafenacin (0.1 mg, twice daily) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscore/voiding subscore/IPSS‐QoL/PPIUS How measured: IPSS/PPIUS questionnaire Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention Micturition number per 24 h/daytime micturition number per 24 h/nocturia episodes per 24 h/urgency episodes per 24 h How measured: bladder diary Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patient randomization performed using a randomization table.
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment.
Blinding of participants and personnel (performance bias)	Low risk	Quote: "The patients and the investigators were blinded with respect to the type of additional medication prescribed."
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Quote: "The patients and the investigators were blinded with respect to the type of additional medication prescribed."
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Unclear risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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He 2012.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: June 2010 to December 2011 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 8; QoL score ≥ 3; OABSS ≥ 3; Qmax < 15 mL/s; PRV < 60 mL Exclusion criteria: significant BOO (PVR ≥ 200 mL and Qmax < 5 mL/s); significant cardiac, pulmonic, hepatic, or renal disease; history of prostatic surgery or other invasive therapy; treated with an alpha‐blocker or anticholinergic within last 2 weeks. Total number of participants randomly assigned: 85 Group A Number of participants randomly assigned: 45 Age, yr (mean): 71.3 (SD 5.8) IPSS (mean): 22.35 (SD 3.12) Prostate volume: not reported Qmax, mL/s (mean): 11.25 (SD 2.10) Group B Number of participants randomly assigned: 40 Age, yr (mean): 72.50 (SD 4.9) IPSS (mean): 21.50 (SD 3.37) Prostate volume: not reported Qmax, mL/s (mean): 12.10 (SD 3.8)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + solifenacin (5 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL/OABSS How measured: IPSS/OABSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "Patients were allocated randomly into two groups" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Kang 2009.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: May 2007 to April 2008 Study setting: single‐center/outpatients/South Korea
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; TPV ≥ 25 mL Exclusion criteria: history of prostatic surgery; treated with an alpha‐blocker within last 3 months; urologic cancer; neurogenic bladder or urethral stricture; PVR > 100 mL Total number of participants randomly assigned: 119 Group A Number of participants randomly assigned: 74 Age, yr (mean): 67.3 (SD 7.8) IPSS (mean): 21.9 (SD 7.0) Prostate volume, mL (mean): 30.9 (SD 9.2) Qmax, mL/s (mean): 10.4 (SD 3.9) Group B Number of participants randomly assigned: 45 Age, yr (mean): 66.3 (SD 8.2) IPSS (mean): 21.1 (SD 7.8) Prostate volume, mL (mean): 31.5 (SD 8.2) Qmax, mL/s (mean): 11.3 (SD 4.5)
Interventions	Group A: tamsulosin (0.2 mg, once a day) + propiverine HCl (10 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscore/voiding subscore/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Korean
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "Patients were allocated randomly into two groups" and no more information provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 4/74 (5.4%) randomized participants in group A and 0/45 (0%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events, AUR, and surgical intervention, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Kaplan 2006.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: November 2004 to May 2006 Study setting: multi‐center/outpatients/US
Participants	Inclusion criteria: men ages ≥ 40 yr; IPSS ≥ 12; QoL score ≥ 3; micturition frequency ≥ 8 per 24 h and urgency ≥ 3 per 24 h Exclusion criteria: clinically significant BOO (PVR > 200 mL and Qmax < 5 mL/s); PSA > 10 ng/mL; history of postural hypotension or syncope; significant hepatic or renal disease; neurologic conditions (e.g. multiple sclerosis, spinal cord injury, Parkinson disease); prostate cancer; history of prostatic surgery or other intervention; history of AUR requiring catheterization; using an indwelling catheter or self‐catheterization program; BOO due to causes other than BPH; any condition for which antimuscarinic use was contraindicated; treated with an alpha‐blockers within last 2 weeks; treated with antimuscarinic, antispasmodic, saw palmetto, or electrostimulation within last 1 month; treated with any investigational drug within last 2 months; treated with a 5‐alpha‐reductase inhibitor within last 3 months Total number of participants randomly assigned: 879 Group A Number of participants randomly assigned: 215 Age, yr (mean): 62.8 (SD 9.7) IPSS (mean): 20.00 (SD 5.42) Prostate volume: not reported Qmax, mL/s (mean): 12.2 (SD 6.6) Group B Number of participants randomly assigned: 210 Age, yr (mean): 61.8 (SD 9.6) IPSS (mean): 19.53 (SD 5.15) Prostate volume: not reported Qmax, mL/s (mean): 13.3 (SD 7.8) Group C Number of participants randomly assigned: 209 Age, yr (mean): 61.7 (SD 10.5) IPSS (mean): 20.04 (SD 5.02) Prostate volume: not reported Qmax, mL/s (mean): 13.4 (SD 7.6) Group D Number of participants randomly assigned: 217 Age, yr (mean): 61.0 (SD 9.6) IPSS (mean): 20.10 (SD 5.49) Prostate volume: not reported Qmax, mL/s (mean): 12.7 (SD 6.8)
Interventions	Group A: placebo + placebo Group B: tamsulosin (0.4 mg, once a day) + placebo Group C: tolterodine ER (4 mg, once a day) + placebo Group D: tamsulosin (0.4 mg, once a day) + tolterodine ER (4 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Patient perception of treatment benefit How measured: 2 questions Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention Urinary incontinence episodes/urgency episodes/total micturitions/nocturia per 24 h How measured: bladder diary Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention IPSS How measured: IPSS questionnaire Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 1 week, 6 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	This study was funded by Pfizer Inc.
Declarations of interest	Mr Carlsson and Drs Bavendam and Guan are employed by Pfizer Inc. Dr Kaplan is a paid consultant, speaker, and meeting participant for Pfizer and is a consultant for Astellas, GlaxoSmithKline, Allergan, and Sanofi. Dr Kaplan is also a speaker for Sanofi Aventis and a principal investigator for the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Roehrborn is a paid consultant, speaker, and meeting participant for Pfizer. Dr Roehrborn is also a consultant for GlaxoSmithKline, Sanofi Aventis, and Lilly ICOS, a consultant for Allergan and Esprit, a speaker for Astellas and Esprit, and a study investigator for Allergan and Q‐Med.
Notes	Protocol: NCT00147654 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	All participant identification numbers and randomization numbers were assigned sequentially in ascending order beginning with the lowest number available.
Allocation concealment (selection bias)	Unclear risk	Author only stated, "randomised numbers were taken from the drug supply kit" and no other information was provided. We tried to email the author, but received no reply.
Blinding of participants and personnel (performance bias)	Low risk	All study medication and placebo were similar looking and smelling. Treatment allocations were balanced across the 4 treatment groups and blinded to participants, site investigators, and all study personal directly involved in conduct of the study.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	All study medication and placebo were similar looking and smelling. Treatment allocations were balanced across the 4 treatment groups and blinded to participants, site investigators, and all study personal directly involved in conduct of the study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 7/222 (3.2%) randomized participants in group A, 7/217 (3.2%) in group B, 6/215 (2.8%) in group C, and 8/225 (3.6%) in group D were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	Study was performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Kaplan 2009.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: May 2006 to January 2007 Study setting: multi‐center/outpatients/US
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 13; PPBC ≥ 3; Qmax ≥ 5 mL/s with volume ≤ 200 mL Exclusion criteria: urinary/gastric retention; ≥ 3 episodes of recurrent UTI within last 12 months; clinically significant BOO (PVR > 200 mL and Qmax < 5 mL/s); treated with antimuscarinic or participated in any trial involving an investigational drug (or both) within last 30 days; previous/planned prostatic surgery; treated with 5‐alpha‐reductase inhibitor within last 3 months; PSA > 10 ng/mL Total number of participants randomly assigned: 398 Group A Number of participants randomly assigned: 203 (202 were analyzed) Age, yr (mean): 64.8 (SD 9.06) IPSS (mean): 16.9 (SD 5.3) Prostate volume: not reported Qmax: not reported Group B Number of participants randomly assigned: 195 (195 were analyzed) Age, yr (mean): 65.2 (SD 10.2) IPSS (mean): 16.9 (SD 5.5) Prostate volume: not reported Qmax: not reported
Interventions	Group A: tamsulosin (0.4 mg, once a day) + solifenacin (5 mg, once a day) Group B: tamsulosin (0.4 mg, once a day) + placebo Follow‐up/treatment duration: 12 weeks
Outcomes	Total micturitions/urgency episodes per 24 h How measured: bladder diary Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Total IPSS/PPBC/UPS How measured: IPSS/PPBC/UPS questionnaire Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks, 8 weeks, and 12 weeks after intervention Time point measured: 12 weeks after intervention
Funding sources	No information
Declarations of interest	Steven A Kaplan had a financial interest or other relationship (or both) with Astellas, Watson, Neotract, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi‐Synthelabo and Pfizer. Kurt McCammon had a financial interest or other relationship (or both) with AMS, Astellas, and Engineers and Doctors. Allam Fakhoury and Weizhong He had financial interest or other relationship (or both) with Astellas.
Notes	Protocol: NCT00333112 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were assigned a sequential run‐in number and those meeting inclusion/exclusion criteria were randomized to 2 groups.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	Placebo‐controlled study. Quote: "SOL and PBO were identical in appearance to maintain blinding."
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Described as double‐blind, placebo‐controlled trial.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 19/203 (9.4%) randomized participants in group A and 9/195 (4.6%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	Study performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Kaplan 2013.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: June 2007 to August 2008 Study setting: multi‐center/outpatients/US
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 8; BOO Index ≥ 20; Qmax ≤ 12 mL/s with volume ≥ 120 mL Exclusion criteria: history of urinary retention ≥ 12 months; history or diagnosis of neurogenic bladder, chronic prostatitis, or other causes of outflow tract obstruction; ≥ 3 episodes of recurrent UTI within last 12 months; previous/planned prostatic surgery; treated with an alpha‐blocker or plant extracts within last 2 weeks; treated with a 5‐alpha‐reductase inhibitor within last 3 months Total number of participants randomly assigned: 222 Group A Number of participants randomly assigned: 74 Age, yr (mean): 64.3 (SD 7.6) IPSS (mean): 18.2 (SD 6.4) Prostate volume: not reported Qmax, mL/s (mean): 7.1 (SD 3.0) Group B Number of participants randomly assigned: 74 Age, yr (mean): 63.8 (SD 8.4) IPSS (mean): 17.5 (SD 5.8) Prostate volume: not reported Qmax, mL/s (mean): 8.2 (SD 3.1) Group C Number of participants randomly assigned: 74 Age, yr (mean): 65.6 (SD 8.3) IPSS (mean): 17.7 (SD 5.8) Prostate volume: not reported Qmax, mL/s (mean): 7.5 (SD 2.8)
Interventions	Group A: placebo Group B: coadministration of tamsulosin OCAS (0.4 mg, once a day) and solifenacin (6 mg, once a day) Group C: coadministration of tamsulosin OCAS (0.4 mg, once a day) and solifenacin (9 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Qmax and detrusor pressure at Qmax (PdetQmax)/BCI and percent BVE How measured: urodynamic test Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention PVR How measured: ultrasound Time point measured: baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Total IPSS/PPBC/ICIQMaleLUTS/ICIQ‐LUTSqol How measured: IPSS/PPBC/ICIQMaleLUTS questionnaire Time point measured: baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Volume voided per micturition/number of micturitions per 24 h/urgency episodes per 24 h/incontinence episodes per 24 h How measured: bladder diary Time point measured: baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 2 weeks, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	Study undertaken with a research grant from Astellas Pharma US Inc.
Declarations of interest	Steven A Kaplan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Steven A Kaplan has acted as a Consultant for Astellas Pharma US Inc. Weizhong He, Jana Cummings, and Allam Fakhoury are employees of Astellas Pharma Global Development. William D Koltun has no financial disclosures to declare. Tim Schneider has served on the speakers' bureau for Astellas Pharma US Inc.
Notes	Protocol: NCT00507455 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "eligible patients were randomised to once‐daily coadministration of TOCAS [tamsulosin oral controlled absorption system] 0.4 mg plus SOLI [solifenacin] 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or matching placebo for 12 wk" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	Placebo‐controlled study.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Placebo‐controlled study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	High risk	In terms of IPSS and QoL, 12/74 (16.2%) randomized participants in group A, 7/74 (9.5%) in group B, and 15/74 (20.3%) in group C were not included in the analysis. The percentage of missing data was about 20%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	Study was performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Lee 2011.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: no information Study setting: multi‐center/outpatients/South Korea
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 14 (voiding subscore ≥ 8 and storage subscore ≥ 6; QoL ≥ 3; micturition frequency ≥ 8 per 24 h; urgency ≥ 1 per 24 h; TPV ≥ 20 mL; Qmax ≤ 15 mL/s with volume ≥ 125 mL Exclusion criteria: neurogenic bladder; confirmed prostate cancer; acute or chronic urinary retention; acute or chronic prostatitis within last 3 months; history of recurrent UTI or bladder stones; medication history for BPH; previous surgical intervention related to BPO; PSA > 10 ng/mL Total number of participants randomly assigned: 176 Group A Number of participants randomly assigned: 91 Age, yr (mean): 61.3 (SD 5.3) IPSS (mean): 22.2 (SD 2.0) Prostate volume, mL (mean): 34.8 (SD 3.9) Qmax, mL/s (mean): 10.8 (SD 4.0) Group B Number of participants randomly assigned: 85 Age, yr (mean): 61.0 (SD 5.5) IPSS (mean): 20.6 (SD 2.6) Prostate volume, mL (mean): 34.1 (SD 4.1) Qmax, mL/s (mean): 11.1 (SD 2.9)
Interventions	Group A: doxazosin GITS (4 mg, once a day) + placebo Group B: doxazosin GITS (4 mg, once a day) + tolterodine SR (4 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscores/IPSS‐QoL/PPBC How measured: IPSS/PPBC questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Micturition frequency/urgency episodes per 24 h How measured: bladder diary Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention AUR How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were randomly assigned to receive doxazosin GITS plus placebo or doxazosin GITS plus tolterodine SR (4 mg)" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	Treatment allocations were blinded to participants, site investigators, and all study personal directly involved in conduct of this study.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Treatment allocations were blinded to participants, site investigators, and all study personal directly involved in conduct of this study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	High risk	In terms of IPSS and QoL, 28/91 (30.8%) randomized participants in group A and 21/85 (24.7%) in group B were not included in the analysis. The percentage of missing data was about 20%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Lee 2016.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: no information Study setting: single‐center/outpatients/South Korea
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 8; OABSS ≥ 3; Question 2 of OABSS ≥ 2; TPV ≥ 20 mL Exclusion criteria: significant renal or hepatic dysfunction; UTI; stroke or Parkinsonism; PSA > 10 ng/mL; PVR ≥ 200 mL Total number of participants randomly assigned: 146 Group A Number of participants randomly assigned: 44 Age, yr (mean): 66.3 (SD 8.3) IPSS (mean): 22.2 (SD 8.2) Prostate volume: not reported Qmax, mL/s (mean): 12.6 (SD 5.8) Group B Number of participants randomly assigned: 55 Age, yr (mean): 65.2 (SD 8.7) IPSS (mean): 20.1 (SD 6.4) Prostate volume: not reported Qmax, mL/s (mean): 14.1 (SD 6.6) Group C Number of participants randomly assigned: 47 Age, yr (mean): 65.7 (SD 7.8) IPSS (mean): 18.0 (SD 6.8) Prostate volume: not reported Qmax, mL/s (mean): 12.5 (SD 7.3)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + solifenacin (5 mg, once a day) Group C: tamsulosin (0.2 mg, once a day) + solifenacin (10 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL/OABSS/PPBC How measured: IPSS/OABSS/PPBC questionnaire Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 4 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	Study was supported by Astellas Pharmaceuticals research fund.
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "Patients (total n = 146) were randomly assigned to receive tamsulosin 0.2 mg only (Group I, n = 44), tamsulosin 0.2 mg plus solifenacin 5 mg (Group II, n = 55), or tamsulosin 0.2 mg plus solifenacin 10 mg" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Unclear risk	In terms of IPSS and QoL, 6/44 (13.6%) randomized participants in group A, 5/55 (9.1%) in group B, and 9/47 (19.1%) in group C were not included in the analysis. The percentage of missing data was 9.1–19.1%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Liu 2013.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: no information Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages > 50 yr; IPSS > 8; OABSS > 3; Qmax < 5 mL/s; micturition ≥ 8 and nocturia ≥ 3 per 24 h Exclusion criteria: significant BOO (PVR ≥ 200 mL and Qmax < 5 mL/s); acute urinary infection; neurogenic bladder, prostate cancer, urethral stricture, or bladder neck contracture; history of urethral or bladder surgery; underactive bladder (maximum detrusor pressure < 40 cmH₂O). Total number of participants randomly assigned: 105 Group A Number of participants randomly assigned: 50 Age, yr (mean): 55.0 (SD 4.5) IPSS (mean): 20.97 (SD 5.34) Prostate volume: not reported Qmax, mL/s (mean): 13.87 (SD 2.97) Group B Number of participants randomly assigned: 55 Age, yr (mean): 56.0 (SD 7.1) IPSS (mean): 21.31 (SD 5.50) Prostate volume: not reported Qmax, mL/s (mean): 14.10 (SD 3.84)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + solifenacin (5 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL/OABSS How measured: IPSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax How measured: uroflowmetry Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Micturition frequency/urgency episodes/urinary incontinence episodes per 24 h How measured: bladder diary Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects/AUR How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "Patients were randomly assigned to two groups" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 3/50 (6%) randomized participants in group A and 5/55 (9.1%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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MacDiarmid 2008.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: March 2004 to June 2005 Study setting: multi‐center/outpatients/US
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 13 and storage IPSS ≥ 8; Qmax ≥ 8 mL/s with volume ≥ 125 mL; PVR ≤ 150 mL Exclusion criteria: history of urinary retention; bladder or prostate cancer; PSA ≥ 4 ng/mL; angle‐closure glaucoma; history of surgical or procedural treatment of the prostate; serious medical comorbidity; treated with alpha‐1‐blockers other than tamsulosin, or 5‐alpha‐reductase agents initiated within past 4 months, or antimuscarinic agents Total number of participants randomly assigned: 420 Group A Number of participants randomly assigned: 210 (209 were analyzed) Age, yr (mean): 62.6 (SD 9.0) IPSS (mean): 20.2 (SD 5.0) Prostate volume: not reported Qmax, mL/s (mean): 15.7 (SD 7.1) Group B Number of participants randomly assigned: 210 (209 were analyzed) Age, yr (mean): 63.3 (SD 9.2) IPSS (mean): 20.5 (SD 4.9) Prostate volume: not reported Qmax, mL/s (mean): 14.6 (SD 6.6)
Interventions	Group A: tamsulosin (0.4 mg, once a day) + oxybutynin ER (10 mg, once a day) Group B: tamsulosin (0.4 mg, once a day) + placebo Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscores/IPSS‐QoL/SPI How measured: IPSS/SPI questionnaire Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	Study was designed and supported by McNeil Consumer and Specialty Pharmaceuticals.
Declarations of interest	Dr MacDiarmid is a speaker and consultant for Allergan, Astellas Pharma, Ortho‐McNeil Pharmaceutical, and Watson Pharmaceuticals. Dr Peters has received grants and research support from Pfizer and is a consultant for Allergan and Medtronic. Dr Nitti is a consultant for Astellas Pharma and Pfizer and is a speaker for Pfizer.
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "420 were randomised to treatment" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	Placebo‐controlled study. Quote: "all patients who were randomised to receive double‐blinded medication."
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Multicenter, double‐blind, randomized, parallel‐group, placebo‐controlled study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 7/210 (3.3%) randomized participants in group A and 4/210 (1.7%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, 1/210 (0.5%) randomized participants in group A and 1/210 (0.5%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Matsukawa 2016.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: August 2011 and June 2013 Study setting: single‐center/outpatients/Japan
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 8; QoL score ≥ 3; OABSS ≥ 3; urinary urgency episodes ≥ 1 per week; TPV ≥ 25 mL; Qmax < 15 mL/s with volume ≥ 100 mL; PVR < 150 mL Exclusion criteria: neurogenic bladder dysfunction, bladder calculi, or active UTI; severe cardiac, renal, or hepatic dysfunction; treated with alpha‐1‐blockers, anticholinergics, 5‐alpha‐reductase, antidepressants, antianxiety agents, or sex hormonal agents; prostate cancer Total number of participants randomly assigned: 120 Group A Number of participants randomly assigned: 60 (53 were analyzed) Age, yr (mean): 70.0 (SD 6.6) IPSS (mean): 18.6 (SD 6.6) Prostate volume, mL (mean): 47.3 (SD 18.2) Qmax, mL/s (mean): 7.8 (SD 4.3) Group B Number of participants randomly assigned: 60 (51 were analyzed) Age, yr (mean): 70.7 (SD 7.1) IPSS (mean): 18.4 (SD 5.6) Prostate volume, mL (mean): 44.1 (SD 16.4) Qmax, mL/s (mean): 7.9 (SD 3.7)
Interventions	Group A: silodosin (8 mg/day) Group B: silodosin (8 mg/day) + propiverine (20 mg/day) Follow‐up/treatment duration: 1 yr
Outcomes	Total IPSS/IPSS‐QoL/OABSS How measured: IPSS/OABSS questionnaire Time point measured: baseline, 12 weeks, and 1 yr after intervention Time point reported: baseline, 12 weeks, and 1 yr after intervention Qmax and PdetQmax/BOOI/FDV/MCC/DO/PVR How measured: urodynamic test Time point measured: baseline, 12 weeks, and 1 yr after intervention Time point reported: baseline, 12 weeks, and 1 yr after intervention Drug adverse effects How measured: record Time point measured: 12 weeks and 1 yr after intervention Time point reported: 1 yr after intervention
Funding sources	None
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Simple randomization using random number table.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Unclear risk	In terms of IPSS and QoL, 7/60 (11.7%) randomized participants in group A and 9/60 (15%) in group B were not included in the analysis. The percentage of missing data was 11.7–15%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Memon 2014.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: May 2012 and September 2013 Study setting: single‐center/outpatients/Pakistan
Participants	Inclusion criteria: men ages ≥ 40 yr; IPSS 15–30; with BPH diagnosed by ultrasound and OAB symptoms. Exclusion criteria: BOO (PVR < 150 mL and Qmax < 5 mL/s); conditions affecting bladder function, including multiple sclerosis, spinal cord injury, or Parkinson disease; history of prostate cancer or prostatic surgery; history of AUR requiring catheterization; indwelling catheter; conditions in which antimuscarinics and alpha‐blockers are contraindicated. Total number of participants randomly assigned: 70 Group A Number of participants randomly assigned: 35 Age, yr (mean): not reported (61.6 (SD 7.5) for overall participants) IPSS (mean): 23.66 (SD 3.7) Prostate volume: not reported Qmax: not reported Group B Number of participants randomly assigned: 35 Age, yr (mean): not reported (61.6 (SD 7.5) for overall participants) IPSS (mean): 23.74 (SD 3.27) Prostate volume: not reported Qmax: not reported
Interventions	Group A: alfuzosin (10 mg, once a day) Group B: alfuzosin (10 mg, once a day) + tolterodine (2 mg, twice a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS How measured: IPSS questionnaire Time point measured: baseline, 1 week, 3 weeks, 6 weeks and 12 weeks after intervention Time point reported: baseline, 1 week, 3 weeks, 6 weeks and 12 weeks after intervention
Funding sources	None
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were randomised" and no more information was provided.
Allocation concealment (selection bias)	Low risk	Quote: "by opaque envelop technique."
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Unclear risk	Not reported.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Nishizawa 2011.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: October 2004 to September 2008 Study setting: multi‐center/outpatients/Japan
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 8 with urgency item score ≥ 1; QoL ≥ 2; Qmax < 15 mL/s with volume ≥ 150 mL; 8 micturitions and 1 urgency per 24 h Exclusion criteria: clinically significant BOO (PVR > 100 mL and Qmax < 5 mL/s with volume > 150 mL); treated with alpha‐1‐blocker, antimuscarinics, antispasmodics, saw palmetto; prostate cancer; neurologic bladder conditions (e.g. multiple sclerosis, spinal cord injury, Parkinson disease); urethral stricture; history of prostatic surgery or previous treatment for BPH; history of irradiation to the pelvis; UTI or stones; interstitial cystitis; prostatitis; indwelling catheter or using self‐catheterization program; significant hepatic, renal, or heart disease; history of postural hypotension or syncope; obstruction of the gastric pylorus, duodenum, or intestine; atony of the stomach and intestine; any condition (e.g. glaucoma, myasthenia gravis) for which use of antimuscarinics was contraindicated. Total number of participants randomly assigned: 214 Group A Number of participants randomly assigned: 67 (60 were analyzed) Age, yr (mean): 70.0 (SD 8.1) IPSS (mean): 12.9 (SD 6.8) Prostate volume, mL (mean): 43.6 (SD 18.1) Qmax, mL/s (mean): 12.3 (SD 4.8) Group B Number of participants randomly assigned: 72 (60 were analyzed) Age, yr (mean): 70.9 (SD 8.7) IPSS (mean): 12.6 (SD 5.9) Prostate volume, mL (mean): 42.3 (SD 16.6) Qmax, mL/s (mean): 12.0 (SD 4.8) Group C Number of participants randomly assigned: 75 (62 were analyzed) Age, yr (mean): 69.8 (SD 7.6) IPSS (mean): 13.5 (SD 6.6) Prostate volume, mL (mean): 38.8 (SD 15.7) Qmax, mL/s (mean): 11.8 (SD 5.7)
Interventions	Group A: tamsulosin (0.2 mg, daily) Group B: tamsulosin (0.2 mg, daily) + propiverine (10 mg, daily) Group C: tamsulosin (0.2 mg, daily) + propiverine (20 mg, daily) Follow‐up/treatment duration: 12 weeks
Outcomes	Micturition frequency/urgency episodes per 24 h How measured: bladder diary Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Total IPSS/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	None
Declarations of interest	None
Notes	Protocol: not available All participants received tamsulosin 0.2 mg daily for 8 weeks before they were allocated into different groups. Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Authors only stated, "patients were assigned randomly to one of three treatment groups" in the publication. After contacting the author, he stated that a web‐based randomization was used.
Allocation concealment (selection bias)	Low risk	No information available in the publication. After contacting the author, he stated that a web‐based randomization was used.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Unclear risk	In terms of IPSS and QoL, 7/67 (10.4%) randomized participants in group A, 12/72 (16.7%) in group B, and 13/75 (17.3%) in group C were not included in the analysis. The percentage of missing data was 10.4–17.3%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Sakalis 2018.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: October 2013 to June 2015 Study setting: single‐center/outpatients/Greece
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS storage subscore ≥ voiding subscore and score ≥ 3 in the IPSS urgency question; ≥ 3 urgency episodes per 24 h; prostate volume ≥ 30 mL; Qmax ≥ 10 mL/s; PVR ≤ 100 mL; PSA ≤ 4 ng/mL. For men with suspicious rectal exam or PSA 4–10 ng/mL (or both) were included only after negative prostate biopsy Exclusion criteria: neurogenic LUT dysfunction; history of malignancy; any contraindication to the use of alpha‐blockers or antimuscarinics; metabolic conditions or use of medications that might affect LUT function, including phosphodiesterase‐5 inhibitors; psychiatric illnesses; chronic kidney, hepatic, or cardiac failure; history of urinary stone disease; urethral stricture; acute UTI or history of recurrent UTIs; positive urine culture; microscopic hematuria, proteinuria, or glucosuria. Total number of participants randomly assigned: 69 Group A Number of participants randomly assigned: 34 (31 were analyzed) Age, yr (mean): 69.1 (range 50–86) IPSS (mean): 20.1 (SD 4) Prostate volume, mL (mean): 48.93 (SD 13.6) Qmax, mL/s (mean): 11.9 (SD 4.5) Group B Number of participants randomly assigned: 35 (32 were analyzed) Age, yr (mean): 69.0 (range 50–83) IPSS (mean): 20.3 (SD 4.4) Prostate volume, mL (mean): 52.63 (SD 31) Qmax, mL/s (mean): 13.9 (SD 5.9)
Interventions	Group A: tamsulosin OCAS (0.4 mg, daily) Group B: tamsulosin OCAS (0.4 mg, daily) + solifenacin (5 mg, daily) Follow‐up/treatment duration: 26 weeks
Outcomes	Total IPSS/OABq How measured: IPSS/OABq questionnaire Time point measured: baseline, and 26 weeks after intervention Time point reported: baseline, and 26 weeks after intervention Micturition episodes per 24 h How measured: bladder diary Time point measured: baseline, and 26 weeks after intervention Time point reported: baseline, and 26 weeks after intervention TPV/adenoma volume/prostate vascularity/PVR/Qmax How measured: ultrasound/uroflowmetry Time point measured: baseline, and 26 weeks after intervention Time point reported: baseline, and 26 weeks after intervention Drug adverse effects How measured: record Time point measured: 26 weeks after intervention Time point reported: 26 weeks after intervention
Funding sources	None
Declarations of interest	Vasileos Sfiggas reports grants from the EU (European Social Fund) and Greek national resources under the framework of the "ARISTEIA" project AVLOS code 2130 of the "Education & Lifelong Learning" Operational Program, during the conduct of the study. Apostolos Apostolidis reports grants from the EU (European Social Fund) and Greek national resources under the framework of the "ARISTEIA" project AVLOS code 2130 of the "Education & Lifelong Learning" Operational Program, during the conduct of the study; non‐financial support from Allergan; grants and non‐financial support from Pfizer; grants and non‐financial support from MAVROGENIS (Coloplast GR); grants, personal fees and non‐financial support from ASTELLAS; grants and non‐financial support from Pierre‐Fabre; and grants from Galenica, outside the submitted work. Vasileios Sakalis, Ioannis Vouros, Georgios Salpiggidis and Athanasios Papathanasiou declare no conflict of interest.
Notes	Protocol: ISRCTN11552705 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization process completed using SPSS 19.0 software.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 3/34 (8.8%) randomized participants in group A, and 3/35 (8.5%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events, 3/34 (8.8%) randomized participants in group A, and 3/35 (8.5%) in group B were not included in the analysis. The percentage of missing data was < 10%.
Selective reporting (reporting bias)	Low risk	Study was performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Sener 2013.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: May 2009 to November 2012 Study setting: multi‐center/outpatients/Turkey
Participants	Inclusion criteria: men ages ≥ 40 yr; IPSS > 12; micturition frequency > 8 per 24 h; urgency episodes > 3 per 24 h; PSA < 2.5 ng/mL; having documented detrusor pressure > 10 cm H₂O in urodynamic studies Exclusion criteria: severe BOO (PVR > 200 mL or Qmax < 5 mL/s); suspected prostate cancer; treated with anticholinergics; history of prostatic, urethral, or bladder surgery; history of AUR or chronic urinary retention; acute or chronic UTI, bacterial prostatitis, or history of recurrent UTI; history of interstitial cystitis; treated with concomitant medication that may cause urinary retention (e.g. tricyclic antidepressants, neuroleptic agents, antihistamine drugs, anti‐Parkinson drugs); indwelling catheter or intermittent use of self‐catheterization Total number of participants randomly assigned: 100 Group A Number of participants randomly assigned: 50 Age, yr (mean): 54.1 (SD 5.1) IPSS (mean): 29.2 (SD 1.6) Prostate volume: not reported Qmax, mL/s (mean): 8.0 (SD 0.9) Group B Number of participants randomly assigned: 50 Age, yr (mean): 54.7 (SD 6.0) IPSS (mean): 28.8 (SD 2.4) Prostate volume: not reported Qmax, mL/s (mean): 8.9 (SD 1.1)
Interventions	Group A: placebo + terazosin (2 mg, daily) Group B: propiverine HCl (15 mg, daily) + terazosin (2 mg, daily) Follow‐up/treatment duration: 1 yr
Outcomes	Total IPSS/IPSS4/QoL/OABSS How measured: IPSS questionnaire Time point measured: baseline, 1 yr after intervention Time point reported: baseline, 1 yr after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 1 yr after intervention Time point reported: baseline, 1 yr after intervention Drug adverse effects How measured: record Time point measured: 1 yr after intervention Time point reported: 1 yr after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "They were randomised into two groups" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	As described, it was designed as a double‐blind, placebo controlled, randomized trial.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	As described, it was designed as a double‐blind, placebo controlled, randomized trial.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Shen 2011.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: January 2010 to October 2010 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 8; QoL score ≥ 3; OABSS ≥ 3; Qmax < 15 mL/s; PRV < 60 mL Exclusion criteria: significant BOO (PVR ≥ 200 mL and Qmax < 5 mL/s); UTI, cancer, or stone; organ failure; prostate cancer, neurogenic bladder dysfunction, or bladder neck obstruction; history of prostatic, urethral, or bladder surgery. Total number of participants randomly assigned: 74 Group A Number of participants randomly assigned: 31 Age, yr (mean): 74.10 (SD 5.01) IPSS (mean): 20.97 (SD 5.34) Prostate volume: not reported Qmax, mL/s (mean): 13.87 (SD 2.97) Group B Number of participants randomly assigned: 43 Age, yr (mean): 73.70 (SD 4.97) IPSS (mean): 21.31 (SD 5.50) Prostate volume: not reported Qmax, mL/s (mean): 14.10 (SD 3.84)
Interventions	Group A: terazosin (2 mg, once a day) Group B: terazosin (2 mg, once a day) and tolterodine (2 mg, twice a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscores How measured: IPSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Number of micturition/incontinence episodes/urine volume/nocturia per 24 h How measured: bladder diary Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "Patients were allocated randomly into two groups" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Van Kerrebroeck 2013b.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: January 2010 to March 2011 Study setting: multi‐center/outpatients/Europe
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 13; Qmax 4–12 mL/s with volume ≥ 120 mL; micturition frequency ≥ 8 per 24 h; urgency episodes ≥ 2 per 24 h Exclusion criteria: ultrasound‐estimated prostate weight ≥ 75 g; evidence of symptomatic UTI; history or diagnosis of any other relevant medical condition, including specific urinary conditions; PVR > 150 mL Total number of participants randomly assigned: 1334 Group A Number of participants randomly assigned: 341 Age, yr (mean): 65.6 (SD 8.4) IPSS (mean): 19.0 (SD 4.5) Prostate volume: not reported Qmax, mL/s (mean): 9.1 (SD 1.9) Group B Number of participants randomly assigned: 326 Age, yr (mean): 65.1 (SD 8.0) IPSS (mean): 18.7 (SD 4.6) Prostate volume: not reported Qmax, mL/s (mean): 8.7 (SD 1.9) Group C Number of participants randomly assigned: 337 Age, yr (mean): 65.3 (SD 8.4) IPSS (mean): 18.3 (SD 4.3) Prostate volume: not reported Qmax, mL/s (mean): 8.9 (SD 2.0) Group D Number of participants randomly assigned: 324 Age, yr (mean): 65.5 (SD 7.7) IPSS (mean): 18.6 (SD 4.3) Prostate volume: not reported Qmax, mL/s (mean): 8.9 (SD 2.0)
Interventions	Group A: placebo + placebo Group B: tamsulosin OCAS (0.4 mg, daily) + placebo, daily Group C: tamsulosin OCAS (0.4 mg, daily) and solifenacin (6 mg, daily) Group D: tamsulosin OCAS (0.4 mg, daily) and solifenacin (9 mg, daily) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscores/void subscores/IPSS‐QoL/TUFS/PGI scale/CGI scale How measured: IPSS/TUFS/HRQoL/OABq questionnaire, PGI/CGI scale Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Maximum and mean volume voided per micturition/micturition frequency/urgency episodes/urgency incontinence episodes/incontinence episodes/nocturia episodes/number of pads used per 24 h How measured: bladder diary Time point measured: baseline, 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 4 weeks, 8 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	The NEPTUNE study was conceived and funded by Astellas Pharma Europe B.V.
Declarations of interest	Marcus J Drake certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Philip van Kerrebroeck is a lecturer for Astellas, Ferring, and Medtronic and a member of an advisory board for Allergan, Astellas, Ferring, and Medtronic. Christopher Chapple is a lecturer, consultant, and researcher for Allergan, Astellas, Pfizer, and Recordati; a consultant and researcher for Ono; and a consultant for Takeda and Lilly. Mark Speakman is a lecturer for Allergan, Astellas, Genprobe, GlaxoSmithKline, Neotract, and Pfizer and has undertaken research for the same companies. Roman Sokol is a lecturer for Eli Lilly, MSD, Astellas, Pfizer, and Coloplast and a researcher for Astellas, Pfizer, Millenium Pharma, Active Biotech, Ferring, and GlaxoSmithKline. Marcus J Drake is a lecturer for Allergan, Astellas, Ferring, and Pfizer and a member of an advisory board for Allergan, Astellas, and Ferring. Ted Drogendijk, Monique Klaver, and Klaudia Traudtner are employees of Astellas Pharma Europe B.V.
Notes	Protocol: NCT01018511 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used an interactive response technology.
Allocation concealment (selection bias)	Low risk	Used an interactive response technology.
Blinding of participants and personnel (performance bias)	Low risk	Placebo‐controlled study.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Placebo‐controlled study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 23/341 (6.7%) randomized participants in group A, 29/326 (8.9%) in group B, 26/337 (7.7%) in group C, and 25/324 (7.7%) in group D were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	Study was performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Van Kerrebroeck 2013c.

*Study characteristics*
Methods	Study design: double‐blind RCT Study duration: no information Study setting: multi‐center/outpatients/Europe
Participants	Inclusion criteria: men ages ≥ 45 yr; IPSS ≥ 13; Qmax 4–15 mL/s with volume ≥ 120 mL Exclusion criteria: previous surgery of the bladder neck or prostate; evidence of symptomatic UTI; history or diagnosis of any other relevant medical condition, including specific urinary conditions; PVR > 200 mL; any other relevant medical history as determined by the investigator. Total number of participants randomly assigned: 937 Group A Number of participants randomly assigned: 92 (89 were analyzed) Age, yr (mean): 65.0 (SD 7.9) IPSS (mean): 17.4 (SD 3.5) Prostate volume: not reported Qmax: not reported Group B Number of participants randomly assigned: 43 (42 were analyzed) Age, yr (mean): 65.4 (SD 8.2) IPSS (mean): 19.5 (SD 4.9) Prostate volume: not reported Qmax: not reported Group C Number of participants randomly assigned: 43 (42 were analyzed) Age, yr (mean): 65.7 (SD 8.0) IPSS (mean): 18.1 (SD 4.0) Prostate volume: not reported Qmax: not reported Group D Number of participants randomly assigned: 44 (42 were analyzed) Age, yr (mean): 66.0 (SD 6.5) IPSS (mean): 20.2 (SD 5.2) Prostate volume: not reported Qmax: not reported Group E Number of participants randomly assigned: 179 (176 were analyzed) Age, yr (mean): 65.0 (SD 8.3) IPSS (mean): 18.0 (SD 3.8) Prostate volume: not reported Qmax: not reported Group F Number of participants randomly assigned: 180 (179 were analyzed) Age, yr (mean): 65.2 (SD 8.0) IPSS (mean): 18.7 (SD 4.0) Prostate volume: not reported Qmax: not reported Group G Number of participants randomly assigned: 180 (176 were analyzed) Age, yr (mean): 65.2 (SD 8.1) IPSS (mean): 18.1 (SD 4.0) Prostate volume: not reported Qmax: not reported Group H Number of participants randomly assigned: 176 (173 were analyzed) Age, yr (mean): 65.3 (SD 7.7) IPSS (mean): 17.9 (SD 4.0) Prostate volume: not reported Qmax: not reported
Interventions	Group A: placebo + placebo Group B: solifenacin (3 mg, daily) + placebo (daily) Group C: solifenacin (6 mg, daily) + placebo (daily) Group D: solifenacin (9 mg, daily) + placebo (daily) Group E: tamsulosin OCAS (0.4 mg, daily) + placebo (daily) Group F: solifenacin (3 mg, daily) + tamsulosin OCAS (0.4 mg, daily) Group G: solifenacin (6 mg, daily) + tamsulosin OCAS (0.4 mg, daily) Group H: solifenacin (9 mg, daily) + tamsulosin OCAS (0.4 mg, daily) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/storage subscores/void subscores/IPSS‐QoL/PPBC/TUFS How measured: IPSS/PPBC/TUFS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Micturition frequency per 24 h/urgency episodes per 24 h/urgency incontinence episodes per 24 h/mean volume voided per micturition How measured: bladder diary Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention PVR How measured: ultrasound Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	The SATURN study was conceived and funded by Astellas Pharma Europe B.V.
Declarations of interest	Philip Van Kerrebroeck certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Philip van Kerrebroeck is a lecturer for Astellas, Ferring, and Medtronic, and member of an advisory board for Allergan, Astellas, and Ferring. Francois Haab is a consultant, investigator, and lecturer for Allergan, Astellas, and Pfizer. Javier Angulo has received educational grants for research from Astellas and Pfizer and is a lecturer for Astellas, GlaxoSmithKline, and Pfizer. Matthias Oelke has received lecturer or consultant (or both) honoraria from Apogepha, Astellas, GlaxoSmithKline, Eli Lilly and Company, Ethicon, Ferring, Pfizer, Recordati, and Sophiris and received a research grant from Astellas. Alberto‐Garcia Hernandez, Monique Klaver, and Klaudia Traudtner are employees of Astellas. Viktor Vik and Ferenc Katona have nothing to disclose.
Notes	Protocol: NCT00510406 Language of publication: English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were randomised to placebo, tamsulosin OCAS 0.4 mg monotherapy, solifenacin 3, 6, or 9 mg plus tamsulosin OCAS 0.4 mg, or dose‐matched solifenacin monotherapy (2:4:4:4:4:1:1:1 randomisation ratio)" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	Low risk	Quote: "After a 2‐wk placebo run‐in period, eligible patients were randomised (1:1:1:1) using an interactive response technology to 12 wk of double blind treatment with placebo, TOCAS 0.4 mg, solifenacin 6 mg plus TOCAS 0.4 mg, or solifenacin 9 mg plus TOCAS 0.4 mg."
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	As described, it was a randomized double‐blind parallel‐group placebo controlled multi‐center phase 3 trial.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, 3/92 (3.3%) randomized participants in group A, 1/43 (2.3%) in group B, 1/43 (2.3%) in group C, 1/43 (2.3%) in group D, 1/177 (0.5%) in group E, 0/179 (0%) in group F, 2/178 (1.1%) in group G, and 2/175 (1.1%) in group H were not included in the analysis. The percentage of missing data was < 10%.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	The study was performed as planned in the protocol.
Other bias	Low risk	Study appeared free of other sources of bias.

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Wang 2015.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: January 2013 to September 2014 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS > 8 and storage IPSS ≥ 6; QoL score ≥ 3; Qmax < 15 mL/s with volume ≥ 200 mL; PRV < 60 mL Exclusion criteria: significant BOO (PVR ≥ 200 mL or Qmax < 5 mL/s); significant cardiac, pulmonic, hepatic, or renal disease; history of transurethral surgery; acute UTI; treated with an alpha‐blocker or anticholinergic within last 2 weeks Total number of participants randomly assigned: 100 Group A Number of participants randomly assigned: 50 Age, yr (mean): 60.5 (SD 6.4) IPSS (mean): 17.6 (SD 2.1) Prostate volume: not reported Qmax, mL/s (mean): 9.4 (SD 1.9) Group B Number of participants randomly assigned: 50 Age, yr (mean): 62.1 (SD 6.0) IPSS (mean): 18.1 (SD 2.0) Prostate volume: not reported Qmax, mL/s (mean): 9.3 (SD 2.0)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + fesoterodine (4 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax How measured: uroflowmetry Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were assigned into two groups randomly" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Wang 2017.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: April 2014 to December 2015 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men; IPSS ≥ 8; OABSS ≥ 3; mean urination frequency ≥ 8 times/day; nocturia episodes ≥ 2; urine volume ≥ 200 mL Exclusion criteria: neurogenic diseases affecting bladder function such as spinal cord injury, prostatic cancer, and urethrostenosis; severe LUT obstruction (PVR ≥ 200 mL); acute infection; underwent transurethral surgery previously; treated with an alpha‐blocker or anticholinergic within last 2 weeks. Total number of participants randomly assigned: 124 Group A Number of participants randomly assigned: 62 Age, yr (mean): 65.4 (SD 5.1) IPSS (mean): 18.5 (SD 2.1) Prostate volume: not reported Qmax, mL/s (mean): 8.5 (SD 1.9) Group B Number of participants randomly assigned: 62 Age, yr (mean): 65.2 (SD 4.7) IPSS (mean): 18.2 (SD 2.3) Prostate volume: not reported Qmax, mL/s (mean): 8.4 (SD 2.2)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + solifenacin (5 mg, once a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL/OABSS How measured: IPSS/OABSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Daytime urination frequency per 24 h/urgency episodes per 24 h/urgency incontinence episodes per 24 h/nocturia episodes How measured: bladder diary Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax/PVR How measured: uroflowmetry/ultrasound Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	None
Declarations of interest	None
Notes	Protocol: not available Language of publication: English Although placebo was mentioned in the article, it did not provide any details about the use of placebo. For example, which group of participants received the placebo. In addition, the blinding method was not mentioned in the article. Therefore, we judged the study as non‐blinded.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were randomly divided into a control group and an observation group" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Wu 2009.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: June 2006 to June 2008 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages > 50 yr; IPSS > 8 and storage IPSS ≥ 6; QoL score ≥ 3; Qmax < 15 mL/s with volume ≥ 200 mL; PRV < 60 mL Exclusion criteria: significant BOO (PVR ≥ 200 mL or Qmax < 5 mL/s); significant cardiac, pulmonic, hepatic, or renal disease; history of transurethral surgery; acute UTI; treated with an alpha‐blocker or anticholinergic within last 2 weeks. Total number of participants randomly assigned: 53 Group A Number of participants randomly assigned: 25 Age, yr (mean): 71.3 (SD 5.8) IPSS (mean): 21.50 (SD 5.42) Prostate volume: not reported Qmax, mL/s (mean): 12.20 (SD 6.60) Group B Number of participants randomly assigned: 28 Age, yr (mean): 72.5 (SD 4.9) IPSS (mean): 20.90 (SD 5.15) Prostate volume: not reported Qmax, mL/s (mean): 13.30 (SD 7.80)
Interventions	Group A: tamsulosin (0.2 mg, once a day) Group B: tamsulosin (0.2 mg, once a day) + tolterodine (2 mg, twice a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Qmax How measured: uroflowmetry Time point measured: baseline, 12 weeks after intervention Time point reported: baseline, 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were assigned into two groups randomly" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events and AUR, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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Yu 2010.

*Study characteristics*
Methods	Study design: open‐label RCT Study duration: October 2007 to December 2009 Study setting: single‐center/outpatients/China
Participants	Inclusion criteria: men ages ≥ 50 yr; IPSS ≥ 12; QoL score ≥ 3; complain of urgency and frequency with volume < 300 mL Exclusion criteria: significant BOO (PVR ≥ 200 mL and Qmax < 5 mL/s); PSA > 4 ng/mL; UTI; history of prostatic or urethral surgery; treated with an alpha‐blocker or anticholinergic or 5‐alpha‐reductase inhibitor; AUR; history of hypotension or syncope. Total number of participants randomly assigned: 167 Group A Number of participants randomly assigned: 72 Age: not reported IPSS (mean): 23.0 (SD 5.3) Prostate volume: not reported Qmax, mL/s (mean): 9.0 (SD 4.1) Group B Number of participants randomly assigned: 95 Age: not reported IPSS (mean): 24.0 (SD 3.6) Prostate volume: not reported Qmax, mL/s (mean): 10.0 (SD 2.1)
Interventions	Group A: doxazosin (4 mg, once a day) Group B: doxazosin (4 mg, once a day) + tolterodine (2 mg, twice a day) Follow‐up/treatment duration: 12 weeks
Outcomes	Total IPSS/IPSS‐QoL How measured: IPSS questionnaire Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention Qmax How measured: uroflowmetry Time point measured: baseline, 1 week, 6 weeks, and 12 weeks after intervention Time point reported: baseline, 1 week, 6 weeks, and 12 weeks after intervention Drug adverse effects How measured: record Time point measured: 1 week, 6 weeks, and 12 weeks after intervention Time point reported: 12 weeks after intervention
Funding sources	No information
Declarations of interest	None
Notes	Protocol: not available Language of publication: Chinese
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors only stated, "patients were assigned into two groups randomly" and no more information was provided.
Allocation concealment (selection bias)	Unclear risk	Randomization stated but no information on method was available.
Blinding of participants and personnel (performance bias)	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Non‐blinded.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Objective outcomes were likely not affected by lack of blinding.
Incomplete outcome data (attrition bias) IPSS and QoL	Low risk	In terms of IPSS and QoL, all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse events, AUR, and surgical intervention	Low risk	In terms of adverse events, AUR and surgical intervention, all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable.
Other bias	Low risk	Study appeared free of other sources of bias.

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AUR: acute urinary retention; BCI: Bladder Contractile Index; BOO: bladder outlet obstruction; BPH: benign prostatic hyperplasia; BVE: bladder voiding efficiency; CGI: Clinical Global Impression; ER: extended release; GITS: gastrointestinal therapeutic system; h: hour; HRQoL; health‐related quality of life; ICIQ‐LUTSqol: International Consultation on Incontinence Questionnaire – Lower Urinary Tract Symptoms Quality of Life; ICIQMaleLUTS: International Consultation on Incontinence Questionnaire – Male Lower Urinary Tract Symptoms; IPSS: International Prostate Symptom Score; IPSS‐QoL: International Prostate Symptom Score – Quality of Life; LUT: lower urinary tract; OAB: overactive bladder; OABq: Overactive Bladder Questionnaire; OABSS: Overactive Bladder Symptom Score; OCAS: oral controlled absorption system; PGI: Patient Global Impression; PPBC: Patient Perception of Bladder Condition; PPIUS: Patient Perception of Intensity of Urgency Scale; PSA: prostatic specific antigen: PVR: postvoid residual; Qmax: maximum flow rate; QoL: quality of life; RCT: randomized controlled trial; s: second; SD: standard deviation; TPV: total prostate volume; TUFS: Total Urgency and Frequency Score; UPS: Urgency Perception Scale; UTI: urinary tract infection; yr: year.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aldemir 2010	Wrong intervention (without control group).
Ali 2020	No available data (the reported data could not be used for our review).
Chen 2018	Wrong patient population (our review focused on men with IPSS ≥ 8 based on our published protocol, but this study was aimed at men with BPH and OAB, no matter whether IPSS was ≥ 8).
Deva 2017	Wrong study design (non‐randomized study).
Du 2015	Wrong intervention (participants in both groups received combination therapy).
Fang 2012	Wrong study design (quasi‐randomized study).
Fujihara 2010	Wrong intervention (participants in both groups received alpha‐blockers monotherapy).
Gan 2011	Wrong study design (quasi‐randomized study).
Gao 2014	Wrong study design (quasi‐randomized study).
He 2019	Wrong intervention (only with a follow‐up of 8 weeks, which did not meet the criteria of our review).
Kosilov 2018	Wrong intervention (only with a follow‐up of 8 weeks, which did not meet the criteria of our review).
Lee 2014	Wrong intervention (participants in both groups received combination therapy).
Malkoç 2012	Wrong patient population (the baseline IPSS of participants varied from 3 to 35, which did not meet our inclusion criteria).
Maruyama 2006	Wrong study design (quasi‐randomized study).
NCT02972268	No available data (no study results posted on ClinicalTrials.gov).
Qin 2019	Wrong intervention (only with a follow‐up of 10 weeks, which did not meet the criteria of our review).
Rovner 2008	Wrong outcomes (outcomes did not meet the criteria of our review).
Sakalis 2016	Wrong patient population (our review focused on men with IPSS ≥ 8 based on our published protocol, but this study aimed at men with predominately storage LUTS, no matter whether IPSS was ≥ 8).
Takahashi 2013	Wrong patient population (our review focused on the participants with a IPSS of ≥ 8 based on our published protocol, but this study aims at the participants with BPH and OAB, no matter whether IPSS is ≥ 8).
Wang 2013	Wrong study design (non‐randomized study).
Xin 2016	Wrong study design (non‐randomized study).
Xu 2015	Wrong intervention (only with a follow‐up of 4 weeks, which did not meet the criteria of our review).
Yan 2018	Wrong patient population (our review focused on men with IPSS ≥ 8 based on our published protocol, but this study aimed at men with BPH and OAB, no matter whether IPSS was ≥ 8).
Yang 2014	Wrong intervention (only with a follow‐up of 4 weeks, which did not meet the criteria of our review).
Zhao 2011	Wrong intervention (only with a follow‐up of 4 weeks, which did not meet the criteria of our review).

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BPH: benign prostatic hyperplasia; IPSS: International Prostatic Symptom Score; LUTS: lower urinary symptom score; OAB: overactive bladder.

Differences between protocol and review

This review was based on a published protocol (Pang 2016), with differences as described here.

We added JHJ as an author in the review since he took part in appraising the risk of bias, the certainty of evidence, drafting the review, and final approval, as a methodological expert in the Cochrane Urology Group.
We made explicit that we would excluded cross‐over studies, and cluster‐randomized studies as not relevant to the question to be addressed.
We added detailed methods and defined minimal clinically important difference for each outcome in the Methods section since MCID can interpret the implication of the results on clinical practice.
We removed the unimportant outcomes (maximum urine flow (Qmax), post void residual (PVR)) and only focused on the patient‐important outcomes (urologic symptom score, quality of life, adverse events, acute urinary retention, surgical intervention) in the current review, because Qmax and PVR are surrogate outcomes that are likely to be meaningful to the intended users and recipients of the reviewed evidence.
We performed sensitivity analysis by exclusion of the studies with non‐blinded design since these studies were a potential source of the heterogeneity.

Contributions of authors

ZXY and WB: developing the search strategy, undertaking the searches, and obtaining copies of trials.

YXL, BH, and WXL: screening records against the eligibility criteria, and appraising risk of bias and certainty of the evidence.

YXL and BH: extracting data.

PR and ZYX: conducting the analysis.

PR, ZYX and WXL: interpreting the analysis, and drafting and updating the final review.

JHJ: appraising risk of bias and certainty of the evidence, drafting the review, and final approval.

Sources of support

Internal sources

Guang An Men Hospital, China Academy of Chinese Medical Sciences, China

This work was funded by grant 2019S443.

External sources

Beijing Municipal Science & Technology Commission, China

This work was funded partly by Beijing Municipal Science & Technology Commission No. Z161100000516156.

Declarations of interest

PR: none.

ZXY: none.

WXL: none.

WB: none.

YXL: none.

BH: none.

JHJ: none.

New

References

References to studies included in this review

Cai 2016 {published data only}

Cai JL, Zhou Z, Yang Y, Yan YF, Jing S, Na YQ. Efficacy and safety of medium-to-long-term use of tolterodine extended release with or without tamsulosin in patients with benign prostate hyperplasia and larger prostate size: a double-blind, placebo-controlled, randomized clinical trial. Chinese Medical Journal 2016;129(24):2899-906. [DOI: 10.4103/0366-6999.195461] [DOI] [PMC free article] [PubMed] [Google Scholar]

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Kaplan 2006 {published data only}

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MacDiarmid 2008 {published data only}

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Matsukawa 2016 {published data only}

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Haab F, Van Kerrebroeck P, Klecka J, Vik V, Angulo J, Garcia-Hernandez A, et al. Safety of tamsulosin OCAS™ plus solifenacin in men with LUTS associated with BPH in the SATURN trial. Urology 2011;78(3):S264-5. [Google Scholar]
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Study	Intervention(s) (route, frequency, total dose/day)	Intervention(s) appropriate as applied in a clinical practice setting^a	Comparator(s) (route, frequency, total dose/day)	Comparator(s) appropriate as applied in a clinical practice setting^a
Cai 2016	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + tolterodine ER (orally, once a day, total 4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; tolterodine ER 4 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; tolterodine ER, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
			C2: tolterodine ER (orally, once a day, total 4 mg/day) + placebo	Dosing scheme: tolterodine ER 4 mg, orally, once a day Provision for contraindications: tolterodine ER, closed‐angle glaucoma
			C3: placebo + placebo	N/CPS
Cho 2017	I1: alfuzosin (orally, once a day, total 10 mg/day) + imidafenacin (orally, twice a day, total 0.2 mg/day)	Dosing scheme: alfuzosin 10 mg, orally, once a day; imidafenacin 0.1 mg, orally, twice a day, Provision for contraindications: alfuzosin, postural hypotension; imidafenacin, closed‐angle glaucoma	C1: alfuzosin (orally, once a day, total 10 mg/day) + placebo	Dosing scheme: alfuzosin 10 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
He 2012	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Kang 2009	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + propiverine (orally, once a day, total 10 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; propiverine 20 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; propiverine, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Kaplan 2006	I1: tamsulosin (orally, once a day, total 0.4 mg/day) + tolterodine ER (orally, once a day, total 4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; tolterodine ER 4 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; tolterodine ER, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.4 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
			C2: tolterodine ER (orally, once a day, total 4 mg/day) + placebo	Dosing scheme: tolterodine ER 4 mg, orally, once a day Provision for contraindications: tolterodine ER, closed‐angle glaucoma
			C3: placebo + placebo	N/CPS
Kaplan 2009	I1: tamsulosin (orally, once a day, total 0.4 mg/day) + solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.5 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Kaplan 2013	I1: tamsulosin OCAS and solifenacin 6 mg (orally, once a day, total tamsulosin 0.4 mg/day and solifenacin 6 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: placebo	N/CPS
Kaplan 2013	I2: tamsulosin OCAS and solifenacin 6 mg (orally, once a day, total tamsulosin 0.4 mg/day and solifenacin 9 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: placebo	N/CPS
Lee 2011	I1: doxazosin GITS (orally, once a day, total doxazosin 4 mg/day) + tolterodine ER (orally, once a day, total 4 mg/day)	Dosing scheme: doxazosin 4 mg, orally, once a day; tolterodine ER 4 mg, orally, once a day Provision for contraindications: doxazosin, postural hypotension; tolterodine ER, closed‐angle glaucoma	C1: doxazosin gastrointestinal therapeutic system (GITS) (orally, once a day, total doxazosin 4 mg/day) + placebo	Dosing scheme: doxazosin 4 mg, orally, once a day Provision for contraindications: doxazosin, postural hypotension
Lee 2016	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Lee 2016	I2: tamsulosin (orally, once a day, total 0.2 mg/day) + solifenacin (orally, once a day, total 10 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)
Liu 2013	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
MacDiarmid 2008	I1: tamsulosin (orally, once a day, total 0.4 mg/day) + oxybutynin ER (orally, once a day, total 10 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; oxybutynin ER 10 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; oxybutynin, closed‐angle glaucoma	C1: tamsulosin (0.4 mg, once a day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Matsukawa 2016	I1: silodosin (orally, once a day, total 8 mg/day) + propiverine (orally, once a day, total 20 mg/day)	Dosing scheme: silodosin 8 mg, orally, once a day; propiverine 20 mg, orally, once a day Provision for contraindications: silodosin, postural hypotension; propiverine, closed‐angle glaucoma	C1: silodosin (orally, once a day, total 8 mg/day) + placebo	Dosing scheme: silodosin 8 mg, orally, once a day Provision for contraindications: silodosin, postural hypotension
Memon 2014	I1: alfuzosin (orally, once a day, total 10 mg/day) + tolterodine (orally, 2 mg twice a day, total 4 mg/day)	Dosing scheme: alfuzosin 10 mg, orally, once a day; tolterodine 2 mg, orally, twice a day Provision for contraindications: alfuzosin, postural hypotension; tolterodine, closed‐angle glaucoma	C1: alfuzosin 10 mg, once a day	Dosing scheme: alfuzosin 10 mg, orally, once a day Provision for contraindications: alfuzosin, postural hypotension
Nishizawa 2011	I1: tamsulosin 0.2 mg (orally, once a day, total 0.2 mg/day) + propiverine (orally, once a day, total 10 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; propiverine 20 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; propiverine, closed‐angle glaucoma	C1: tamsulosin 0.2 mg	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Nishizawa 2011	I2: tamsulosin 0.2 mg (orally, once a day, total 0.2 mg/day) + propiverine (orally, once a day, total 20 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; propiverine 20 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; propiverine, closed‐angle glaucoma	C1: tamsulosin 0.2 mg
Sakalis 2018	I1: tamsulosin OCAS (orally, once a day, total 0.4 mg/day) and solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin oral controlled absorption system (TOCAS) (orally, once a day, total 0.4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Sener 2013	I1: terazosin 2 mg (orally, once a day, total 2 mg/day) + propiverine (orally, once a day, total 15 mg/day)	Dosing scheme: terazosin 2 mg, orally, once a day; propiverine 20 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; propiverine, closed‐angle glaucoma	C1: terazosin (orally, once a day, total 2 mg/day)	Dosing scheme: terazosin 2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Shen 2011	I1: terazosin 2 mg (orally, once a day, total 2 mg/day) + tolterodine (orally, 2 mg twice a day, total 4 mg/day)	Dosing scheme: terazosin 2 mg, orally, once a day; tolterodine 2 mg, orally, twice a day Provision for contraindications: terazosin, postural hypotension; tolterodine, closed‐angle glaucoma	C1: terazosin (orally, once a day, total 2 mg/day)	Dosing scheme: terazosin 2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Van Kerrebroeck 2013b	I1: tamsulosin OCAS (orally, once a day, total 0.4 mg/day) and solifenacin (orally, once a day, total 6 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin oral controlled absorption system (TOCAS) (orally, once a day, total 0.4 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Van Kerrebroeck 2013b	I2: tamsulosin OCAS (orally, once a day, total 0.4 mg/day) and solifenacin (orally, once a day, total 9 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C2: placebo + placebo	N/CPS
Van Kerrebroeck 2013c	I1: solifenacin (orally, once a day, total 3 mg/day) + tamsulosin OCAS (orally, once a day, total 0.4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: placebo + placebo	N/CPS
	I2: solifenacin (orally, once a day, total 6 mg/day) + tamsulosin OCAS (orally, once a day, total 0.4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C2: solifenacin (orally, once a day, total 3 mg/day) + placebo	Dosing scheme: solifenacin 5 mg, orally, once a day Provision for contraindications: solifenacin, closed‐angle glaucoma
	I3: solifenacin (orally, once a day, total 9 mg/day) + tamsulosin OCAS (orally, once a day, total 0.4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C3: solifenacin (orally, once a day, total 6 mg/day) + placebo	Dosing scheme: solifenacin 5 mg, orally, once a day Provision for contraindications: solifenacin, closed‐angle glaucoma
			C4: solifenacin (orally, once a day, total 9 mg/day) + placebo	Dosing scheme: solifenacin 5 mg, orally, once a day Provision for contraindications: solifenacin, closed‐angle glaucoma
			C5: tamsulosin OCAS (orally, once a day, total 0.4 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Wang 2015	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + fesoterodine (orally, once a day, total 4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; fesoterodine 4 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; fesoterodine, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Wang 2017	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + solifenacin (orally, once a day, total 5 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; solifenacin 5 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension; solifenacin, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Wu 2009	I1: tamsulosin (orally, once a day, total 0.2 mg/day) + tolterodine (orally, 2 mg once a day, total 4 mg/day)	Dosing scheme: tamsulosin 0.2 mg, orally, once a day; tolterodine 2 mg, orally, twice a day Provision for contraindications: tamsulosin, postural hypotension; tolterodine, closed‐angle glaucoma	C1: tamsulosin (orally, once a day, total 0.2 mg/day) + placebo	Dosing scheme: tamsulosin 0.2 mg, orally, once a day Provision for contraindications: tamsulosin, postural hypotension
Yu 2010	I1: doxazosin (orally, once a day, total doxazosin 4 mg/day) + tolterodine (orally, 2 mg twice a day, total 4 mg/day)	Dosing scheme: doxazosin 4 mg, orally, once a day; tolterodine 2 mg, orally, twice a day Provision for contraindications: doxazosin, postural hypotension; tolterodine, closed‐angle glaucoma	C1: doxazosin (orally, once a day, total doxazosin 4 mg/day)	Dosing scheme: doxazosin 4 mg, orally, once a day Provision for contraindications: doxazosin, postural hypotension

PERMALINK

Anticholinergics combined with alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction

Ran Pang

Xin-Yao Zhou

Xiangling Wang

Bin Wang

Xue-Lai Yin

Hai Bo

Jae Hung Jung

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Combination therapy versus placebo for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Summary of findings 2. Combination therapy versus alpha‐blockers for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Summary of findings 3. Combination therapy versus anticholinergics for treating lower urinary tract symptoms related to benign prostatic obstruction (short term).

Background

Description of the condition

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

Types of outcome measures

Primary outcomes

Secondary outcomes

Main outcomes for 'Summary of findings' table

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 and assessment of the certainty of the evidence

Results

Description of studies

1.

Results of the search

Included studies

1. Baseline characteristics.

Design

Participants

Interventions

2. Description of Interventions.

Comparisons

Outcomes

Funding and conflicts of interest

Excluded studies

Studies awaiting classification

Ongoing trials

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data