Skip to main content
PLOS ONE logoLink to PLOS ONE
. 2014 Sep 12;9(9):e107593. doi: 10.1371/journal.pone.0107593

Comparative Effectiveness of Oral Drug Therapies for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia: A Systematic Review and Network Meta-Analysis

Xinghuan Wang 1,*,#, Xiao Wang 1,#, Sheng Li 1, Zhe Meng 1, Tao Liu 1, Xinhua Zhang 1,*
Editor: Yu-Kang Tu2
PMCID: PMC4162615  PMID: 25216271

Abstract

Introduction

Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are common in elder men and a number of drugs alone or combined are clinically used for this disorder. But available studies investigating the comparative effects of different drug therapies are limited. This study was aimed to compare the efficacy of different drug therapies for LUTS/BPH with network meta-analysis.

Materials and Methods

An electronic search of PubMed, Cochrane Library and Embase was performed to identify randomized controlled trials (RCTs) comparing different drug therapies for LUTS/BPH within 24 weeks. Comparative effects were calculated using Aggregate Data Drug Information System. Consistency models of network meta-analysis were created and cumulative probability was used to rank different therapies.

Results

A total 66 RCTs covering seven different therapies with 29384 participants were included. We found that α-blockers (ABs) plus phosphodiesterase 5 inhibitors (PDE5-Is) ranked highest in the test of IPSS total score, storage subscore and voiding subscore. The combination therapy of ABs plus 5α-reductase inhibitors was the best for increasing maximum urinary flow rate (Qmax) with a mean difference (MD) of 1.98 (95% CI, 1.12 to 2.86) as compared to placebo. ABs plus muscarinic receptor antagonists (MRAs) ranked secondly on the reduction of IPSS storage subscore, although monotherapies including MRAs showed no effect on this aspect. Additionally, PDE5-Is alone showed great effectiveness for LUTS/BPH except Qmax.

Conclusions

Based on our novel findings, combination therapy, especially ABs plus PDE5-Is, is recommended for short-term treatment for LUTS/BPH. There was also evidence that PDE5-Is used alone was efficacious except on Qmax. Additionally, it should be cautious when using MRAs. However, further clinical studies are required for longer duration which considers more treatment outcomes such as disease progression, as well as basic research investigating mechanisms involving PDE5-Is and other pharmacologic agents alleviate the symptoms of LUTS/BPH.

Introduction

Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) are common and interfere with the quality of life (QoL) of elder men [1][3]. LUTS which includes obstructive (voiding) symptoms and irritative (storage) symptoms [4] can be quantitatively evaluated by questionnaires such as the International Prostate Symptom Score (IPSS) [5]. The prevalence of BPH is approximately 40% for men in their fifties and reaches to 90% for men in their nineties [6] and the incidence of LUTS is around 25% for men in their 50 s or older [7], [8]. The drug treatment for bothersome moderate to severe LUTS/BPH aimed to relieve the symptoms and slow the clinical progression of this disease. Current oral therapies recommended by Guidelines include α-adrenoceptor antagonists (α-blockers, ABs), 5α-reductase inhibitors (5ARIs), muscarinic receptor antagonists (MRAs) and a “new emerging treatment” phosphodiesterase 5 inhibitors (PDE5-Is) [9], [10]. ABs and 5ARIs have been widely used for decades. Overactive bladder (OAB) symptoms are commonly reported by LUTS/BPH patients even post-prostatectomy [11][13] and MRAs have been proved efficacious in reducing bladder overactivity and storage symptoms. Recently numerous clinical trials have investigated the efficacy of PDE5-Is for LUTS/BPH, while tadalafil was recently licensed in USA and in European Union for treating LUTS/BPH with or without erectile dysfunction (ED) [9], [10]. Combining drugs from different classes had a positive synergistic effect. Common combinations include ABs plus 5ARIs, ABs plus MRAs and ABs plus PDE5-Is. Both monotherapies and combined therapies have been demonstrated efficacious for LUTS/ BPH by a large number of clinical trials worldwide. However, studies investigating the comparative effects of different types of drug therapies are limited.

The aim of our study was to carry out a systematic review and network meta-analysis comparing the efficacy of different drug therapies for LUTS/BPH based on existing randomized controlled trials (RCTs) and ranking these regimens for practical consideration.

Materials and Methods

Data sources and searches

We performed an electronic search of Cochrane Library, PubMed and Embase till June 2013. The search strings used for electronic searches were based on MeSH terms. Following keywords were used to search both medical subject headings terms and text words: lower urinary tract symptom or benign prostatic hyperplasia/enlargement or bladder outlet obstruction plus α-adrenoceptor antagonists, alfuzosin, tamsulosin, doxazosin, terazosin, naftopidil, prazosin and silodosin or 5α-reductase inhibitors, dutasteride and finasteride or muscarinic receptor antagonists, darifenacin, fesoterodin, oxybutynin, propiverine, solifenacin and tolterodine or phosphodiesterase 5 inhibitors, sildenafil, tadalafil, vardenafil, avanafil plus randomized controlled study. No limitation was placed on publication status or language.

Selection of Studies

We included RCTs that compared different oral therapies or placebo for LUTS/BPH. The treatment duration of most trials was less than 24 weeks, especially for trials with multiple treatment arms. As trials with multiple arms are more important to build comparative loops in network meta-analysis and the consistency model of network meta-analysis required rigorous homogeneity between trials, we excluded trials with treatment duration over 24 weeks.

Exclusion criteria

1) repeated publications; 2) studies with treatment duration longer than 24 weeks; 3) studies were not measured by the aim outcomes of IPSS score and Qmax, or the result were reported incompletely; 4) full text were unavailable or studies reported superficially, such as in the form of an abstract.

Data extraction and quality assessment

Data were extracted independently by three reviewers (SL, ZM and TL) using a standard form. The different dosage or subgroups of one class of treatment from the original studies were pooled into one arm for analysis. Missing information was imputed based on the methods of Cochrane Handbook and when necessary, was requested from the authors of original studies. Discrepancies were resolved by discussion. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool. In particular, the following factors were evaluated: (1) Adequate sequence generation? (2) Allocation concealment? (3) Binding? (4) Incomplete outcome data addressed? (5) Free of selective reporting? (6) Free of other bias? Every question was answered with “yes”, “no” or “unclear” and three reviewers (SL, ZM and TL) assessed each trial. In case of disagreement, judgment was made through open discussion.

Main outcome measures

The intervention outcomes were the change from baseline to study end in the IPSS (including IPSS total score, IPSS storage subscore and IPSS voiding subscore) and maximum flow rate (Qmax). Compared with pair-wise meta-analysis, network analysis can be applied in the studies with multiple treatment arms and combine both direct and indirect evidence from RCTs in order to obtain a single consistent quantitative synthesis [14][17]. Comparative effects of different drug treatments in the network analysis were calculated using the automated software Aggregate Data Drug Information System (ADDIS) [18]. We created a consistency model by combining the effect of indirect and direct comparison based on Bayesian approach to get an absolute effect and cumulative probability which was used to rank different drug therapies. Node splitting models were conducted to detect inconsistency in a single comparison. Direct evidence was based on pair-wise meta-analysis and indirect evidence based on indirect comparisons through the consistency models of network meta-analysis [19]. Convergence diagnostics were assessed using Brooks-Gelman-Rubin methods to determine whether the modes had converged [20]. Summary effect was calculated as mean difference (MD) for continuous variable, together with its 95% confidence intervals (CIs).

Results

Characteristics of included studies and quality assessment

Using the electronic search strategy, a total of 844 records were retrieved, of which 66 RCTs were finally included [21][86]. Fig.1 shows the flowchart of literature searches and Table S1 provides details of the included trials. The included 66 RCTs covered the currently used seven kinds of drug therapies including ABs, 5ARIs, MRAs, PDE5-Is, ABs plus 5ARIs, ABs plus MRAs and ABs plus PDE5-Is with a total 29,384 participants. Fig.2 shows the overall comparison network. The mean treatment duration of the included trials was 13.3 weeks (ranged 4 to 24 weeks). Table S2 shows summary of the risk of bias. Most studies did not provide detailed randomization and allocation methods, while five studies used inadequate randomization, thus we gave negative judgment. Blinding assessment for most included studies was judged as positive. For the assessment of incomplete outcome data, three studies reported a significant withdrawal of patients, while some others did not report withdrawal information or reasons. We gave positive judgment for all the included studies in the assessment of selective reporting and other bias, as we could not detect any risks for both aspects.

Figure 1. PRISMA flowchart of literature searches and results.

Figure 1

RCT =  randomized controlled trials.

Figure 2. Comparison network of the included studies.

Figure 2

The line linked between two drug therapies means there are direct comparisons from original studies. Numbers on the line mean the count number of studies comparing every pair of treatments, which were also reflected by the width of the lines. The size of every node represents the number of randomized participants. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

Efficacy of treatment on included outcomes

IPSS total score

A total of 48 studies involving all seven kinds of drug therapies contributed to the analysis of IPSS total score. Fig.3 provides the overall effect of different kinds of drugs therapies on IPSS total score. Six kinds of medical therapies had a significant effect on the reduction of IPSS total score as compared with placebo, which were ABs (p<0.01), 5ARIs (p = 0.03), PDE5-Is (p<0.01), ABs plus 5ARIs (p<0.01), ABs plus MRAs (p<0.01) and ABs plus PDE5-Is (p<0.01). Table.1 shows the results of node split models indicating that there was significant difference between direct and indirect effect in the comparisons of placebo vs ABs plus MRAs and ABs plus PDE5-Is vs ABs.

Figure 3. Forest plot for meta-analysis of the overall effect as measured by the IPSS total score.

Figure 3

The difference of IPSS total score between comparisons was calculated as mean difference (MD) and MD below 0 favors the drug therapy on the left header. If the 95% confidence intervals (CI) did not include 0, it means the difference is significant. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

Table 1. Results of node split models for the test of difference between direct and indirect effect in the analysis of primary outcomes of IPSS total score, Qmax, IPSS storage subscore and IPSS voiding subscore.
Comparison Direct Effect Indirect Effect Overall P-Value
IPSS total score
placebo vs ABs 1.89 (1.44, 2.34) 2.76 (1.80, 3.81) 2.01 (1.57, 2.44) 0.09
placebo vs 5ARIs 3.65 (0.35, 6.98) 0.86 (−0.12, 1.75) 1.05 (0.12, 1.95) 0.11
placebo vs MRAs 0.09 (−2.08, 2.23) 1.61 (−0.11, 3.28) 1.15 (−0.51, 2.81) 0.19
placebo vs PDE5-Is 2.38 (1.77, 2.99) 1.31 (0.20, 2.32) 2.12 (1.55, 2.68) 0.06
placebo vs ABs plus MRAs 1.15 (0.17, 2.14) 3.02 (2.36, 3.76) 2.47 (1.83, 3.18) 0.00
ABs vs 5ARIs −1.14 (−2.07, −0.33) 0.71 (−1.55, 2.89) −0.96 (−1.80, −0.14) 0.13
ABs vs PDE5-Is −0.30 (−1.31, 0.63) 0.37 (−0.38, 1.11) 0.11 (−0.53, 0.75) 0.24
ABs plus 5ARIs vs 5ARIs −1.29 (−2.43, −0.14) −2.14 (−5.13, 0.83) −1.36 (−2.40, −0.35) 0.6
ABs plus MRAs vs ABs −0.72 (−1.38, −0.12) 1.26 (−1.00, 3.53) −0.46 (−1.08, 0.08) 0.09
ABs plus PDE5-Is vs ABs −2.15 (−3.52, −0.77) −5.08 (−7.07, −3.10) −3.07 (−4.27, −1.84) 0.02
ABs plus PDE5-Is vs PDE5-Is −3.55 (−4.99, −2.13) −1.79 (−3.86, 0.27) −2.91 (−4.09, −1.69) 0.16
Qmax
placebo vs ABs −1.03 (−1.37, −0.67) −1.35 (−2.10, −0.58) −1.11 (−1.43, −0.79) 0.45
placebo vs 5ARIs −1.63 (−2.68, −0.59) −0.99 (−1.81, −0.13) −1.23 (−1.87, −0.59) 0.34
placebo vs MRAs 0.60 (−1.20, 2.36) 0.01 (−1.48, 1.49) 0.24 (−1.09, 1.56) 0.57
placebo vs PDE5-Is −0.05 (−0.57, 0.46) −1.28 (−2.02, −0.49) −0.40 (−0.94, 0.14) 0.01
placebo vs ABs plus MRAs −1.16 (−2.38, 0.06) −0.81 (−1.60, −0.02) −0.92 (−1.59, −0.18) 0.63
ABs vs 5ARIs 0.15 (−0.62, 0.92) −0.63 (−1.58, 0.33) −0.12 (−0.75, 0.49) 0.21
ABs vs PDE5-Is −0.11 (−0.76, 0.57) 1.24 (0.71, 1.75) 0.71 (0.14, 1.27) 0.00
ABs plus 5ARIs vs 5ARIs 0.66 (−0.36, 1.69) 1.45 (−0.54, 3.46) 0.76 (−0.12, 1.63) 0.48
ABs plus MRAs vs ABs −0.33 (−1.04, 0.41) 0.77 (−0.88, 2.44) −0.20 (−0.86, 0.45) 0.24
ABs plus PDE5-Is vs PDE5-Is 1.94 (0.57, 3.33) 0.95 (−0.36, 2.27) 1.50 (0.51, 2.48) 0.28
IPSS storage subscore
placebo vs ABs 0.33 (−0.41, 1.05) −0.02 (−1.28, 1.29) 0.32 (−0.28, 0.91) 0.62
placebo vs PDE5-Is 0.60 (−0.04, 1.23) 1.09 (−0.13, 2.30) 0.62 (−0.03, 1.26) 0.46
placebo vs ABs plus MRAs 0.79 (−0.76, 2.31) 1.50 (0.54, 2.47) 1.33 (0.50, 2.14) 0.42
ABs vs PDE5-Is 0.51 (−0.55, 1.52) 0.09 (−0.82, 0.99) 0.30 (−0.48, 1.09) 0.53
ABs plus MRAs vs ABs −1.09 (−1.78, −0.41) −0.08 (−2.36, 2.14) −1.00 (−1.66, −0.38) 0.39
ABs plus PDE5-Is vs PDE5-Is −2.09 (−4.67, 0.30) −2.11 (−4.76, 0.57) −1.58 (−3.31, 0.14) 0.99
IPSS voiding subscore
placebo vs ABs 1.16 (0.72, 1.59) 1.18 (0.32, 1.96) 1.17 (0.77, 1.56) 0.98
placebo vs PDE5-Is 1.18 (0.70, 1.63) 0.89 (0.01, 1.74) 1.13 (0.68, 1.55) 0.51
placebo vs ABs plus MRAs 0.39 (−0.53, 1.33) 1.00 (0.37, 1.68) 0.78 (0.23, 1.37) 0.24
ABs vs PDE5-Is −0.24 (−0.97, 0.50) 0.11 (−0.54, 0.71) −0.05 (−0.58, 0.46) 0.44
ABs plus MRAs vs ABs 0.31 (−0.24, 0.83) 0.80 (−0.77, 2.36) 0.39 (−0.10, 0.86) 0.54
ABs plus PDE5-Is vs PDE5-Is −1.66 (−3.55, 0.14) −2.24 (−4.09, −0.33) −1.84 (−3.12, −0.56) 0.65

Results of the node split model to assess the inconsistency by testing the difference between the direct effect and indirect effect. If the P-value is more than 0.05, it indicates that the difference between the direct effect and indirect effect was not significant. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

Qmax

A total of 55 studies having all seven kinds of oral therapies contributed to the analysis of Qmax. Network meta-analysis (Fig.4) demonstrated that with the exception of monotherapy by MRAs (p = 0.73) and PDE5-Is (p = 0.15), all other five therapies significantly improved Qmax as compared with placebo. Node split models (Table.1) showed that there was significant difference between direct and indirect effect in the comparisons of placebo vs PDE5-Is and ABs vs PDE5-Is. The overall effect in the comparison of ABs vs PDE5-Is was not consistent with the direct effect.

Figure 4. Forest plot for meta-analysis of the overall effect as measured by Qmax.

Figure 4

The difference of Qmax between comparisons was calculated as mean difference (MD) and MD above 0 favors the drug therapy on the left header. If the 95% confidence intervals (CI) did not include 0, it means the difference is significant. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

IPSS storage subscore

A total of 32 studies involving seven kinds of drug therapies contributed to the analysis of IPSS storage subscore. Network meta-analysis (Fig.5) indicated that only the combination therapies of ABs plus PDE5-Is and ABs plus MRAs had a significant effect on the reduction of IPSS storage subscore compared to placebo with a MD of −2.20 (95% CI, −3.90 to −0.52) and −1.33 (95% CI, −2.14 to −0.50), respectively. Node split models (Table.1) did not detect any difference between direct and indirect effect.

Figure 5. Forest plot for meta-analysis of the overall effect as measured by IPSS storage subscore.

Figure 5

The difference of IPSS storage subscore between comparisons was calculated as mean difference (MD) and MD below 0 favors the drug therapy on the left header. If the 95% confidence intervals (CI) did not include 0, it means the difference is significant. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

IPSS voiding subscore

A total of 29 studies involving all the seven kinds of medical treatments contributed to the analysis of IPSS voiding subscore. As showed in Fig.6, five kinds of medical therapies had a significant effect on the reduction of IPSS voiding subscore as compared with placebo, which were ABs, PDE5-Is, ABs plus 5ARIs, ABs plus MRAs and ABs plus PDE5-Is with a p-value all less than 0.01. Node split models (Table.1) did not detect any difference between direct and indirect effect.

Figure 6. Forest plot for meta-analysis of the overall effect as measured by IPSS voiding subscore.

Figure 6

The difference of IPSS voiding subscore between comparisons was calculated as mean difference (MD) and MD below 0 favors the drug therapy on the left header. If the 95% confidence intervals (CI) did not include 0, it means the difference is significant. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

Rank test

Fig. 7 showed the cumulative probability of all the seven medical therapies and placebo for rank test on each outcome. Among all the drug treatments, combination therapy with ABs plus PDE5-Is ranked highest on the assessment of IPSS total score, storage subscore and voiding subscore. ABs combined with 5ARIs ranked highest for Qmax, but ABs plus 5ARIs and ABs plus PDE5-Is had adjacent cumulative probabilities indicating that these two combination therapies had similar efficacy on improvement of Qmax. Overall, combination therapies resulted in a relatively better effect than monotherapies.

Figure 7. Cumulative probabilities of different kinds of oral drug therapies as measured by the included outcomes.

Figure 7

The Bayesian approach could apply the rank probabilities of each drug therapy and the cumulative probability sum the rank probabilities to give an overall probability. Larger cumulative probability represents the better effect on the improvement of IPSS total score, Qmax, IPSS storage subscore and IPSS voiding score, which also represent the rank of the drug therapies. ABs  =  α-blockers. 5ARIs  =  5α-reductase inhibitors. MRAs  =  muscarinic receptor antagonists. PDE5-Is  =  phosphodiesterase 5 inhibitors.

Discussion

This is the first systematic review and network meta-analysis comparing the effectiveness of different oral drug therapies for LUTS/BPH. Our novel data showed that among all the drug treatments, combination therapy by ABs plus PDE5-Is ranked highest in efficacy for decreasing the IPSS total score, storage subscore and voiding subscore. ABs combined with 5ARIs ranked highest in efficacy for increasing of Qmax. ABs plus MRAs showed great effectiveness on improving storage symptoms, but all monotherapy studies showed no effect on the IPSS storage subscore. PDE5-Is alone also showed promising effect, except on Qmax. The results suggest combination therapies, especially ABs plus PDE5-Is, have greatest efficacy for treatment of LUTS/BPH.

Robert and his colleagues published a systematic review in 2011, in which they retrospectively summarized the recent clinical trials on the assessment of medical treatment for LUTS/BPH [87]. New drugs such as PDE5-Is, and combination therapies such as ABs plus 5ARIs or MRAs were suggested for this disorder. But the selection of therapies should be individualized, based on patients' complaints and the characteristics of different drugs.

In the current review, it was intriguing to find that PDE5-Is combined with ABs ranked highest in patients' subjective symptom evaluations including IPSS total score, IPSS storage subscore and voiding subscore. Although ABs plus 5ARIs ranked highest for Qmax in the rank test, the combination showed adjacent cumulative probabilities as ABs plus PDE5-Is (Fig.7) revealing both these combinations actually shared the highest rank. It is also interesting that PDE5-Is alone demonstrated better efficacy on all the aforementioned outcomes, except Qmax, when compared with other monotherapies including guideline recommended first-line treatment drugs, e.g. ABs and 5ARIs. The use of PDE5-Is (tadalafil 5 mg once daily) for the treatment of BPH/LUTS with or without ED was approved in 2011 in the USA and in 2012 in the European Union. Tadalafil or other PDE5-Is may alleviated LUTS/BPH through several key mechanisms independently [88][90]. The effect of PDE5 inhibition leading to increase NO/cGMP concentration in the smooth muscle (SM) of the prostate, urethra, bladder, pelvic neuronal and vascular networks supports lower urinary tract function. Relaxation of the aforementioned SMs results in reduced BPH symptoms including ameliorated detrusor overactivity by increasing blood perfusion and decreasing lower urinary tract tone [91][93], rather than simply reducing prostate and urethral compression and obstruction. Moreover, PDE5 inhibition could activate through L-cysteine/hydrogen sulphide pathway in the human bladder, which was newly found and NO-independently [22] [94] and animal studies also indicated that PDE5 inhibition could modulate the activity of afferent-nerve system in the lower urinary tract, relieving the storage symptoms of bladder [89], [95]. Additionally, PDE5-Is were found in vitro to inhibit prostate stromal cell proliferation through attenuating and reverting fibroblast-to-myofibroblast trans-differentiation [96]. In 2012, Gacci et al. conducted an extensive pair-wise meta-analysis on the use of PDE5-Is alone or in combination with ABs for the treatment of LUTS/BPH. They indicated that PDE5-Is could significantly improve LUTS and be a promising treatment for this disorder, although they were ineffective on Qmax. In our network meta-analysis, we confirmed the efficacy of PDE5-Is on LUTS/BPH and we found that the treatment with PDE5-Is did not increase Qmax, either, which was consistent with Gacci's pair-wise meta-analysis. Gacci explained that PDE5-Is concomitant relaxation of the detrusor muscle may counteract the relaxation of the prostate and bladder neck. But for detrusor SM, the role of PDE5-Is may not just be limited to relaxation and the mechanism remains to be fully clarified [97][99]. But we did not detect significant difference on the increase of Qmax when comparing ABs plus PDE5-Is with ABs alone, which was inconsistent with Gacci's result. This may be due to the methodology difference that we combined direct and indirect comparisons in our meta-analysis. However, the treatment duration of most trials included in current review was less than 24 weeks, especially for trials with multiple treatment arms. The consistency model of network meta-analysis required rigorous homogeneity between trials but long-term treatment could increase heterogeneity and exaggerate the efficacy of some drugs. Thus we excluded trials with treatment duration more than half a year. Therefore, long-term experience with PDE5-Is in patients with LUTS/BPH is limited. There is also limited information about the reduction of prostate size and no information on slowing of disease progression at present.

In our network meta-analysis of IPSS storage subscore, only the combined therapies of ABs plus PDE5-Is and ABs plus MRAs significantly ameliorated OAB/storage symptoms while all monotherapies showed no effect, including the first-line drugs (MRAs), which have been approved worldwide for treatment of OAB and detrusor overactivity. Consistent with guideline recommendation [9], [10], MRAs should be prescribed with caution when BPH/obstruction exists. However, the current study focused on LUTS/BPH and the effect of treatments on OAB may be underestimated. Although MRAs alone showed no effect on storage symptoms, its combination with ABs efficaciously decreased the storage subscore.

The combined therapy of ABs plus 5ARIs ranked second for IPSS voiding subscore but ranked highest in the test of Qmax. This combination is theoretically ideal with ABs relieving dynamic factor related to prostatic SM tone and 5ARIs attenuating static (anatomical) factors associated with prostatic enlargement. In fact, it is the standard clinical treatment for larger prostate size which involves longer treatment duration [9], [10]. As treatment duration of trials included in the present review was less than 24 weeks, long-term studies are required to definitively determine which combination is better, ABs plus 5ARIs or ABs plus PDE5-Is.

The overall safety profile of oral drug therapies has been confirmed in the included studies. Most cases of adverse events (AEs) were mild to moderate, though some studies reported serious AEs (SAEs), but as shown in Table S1, most SAEs were not considered as treatment-related. Table S3 summarized the common treatment-related AEs. As showed in Table S3, the most commonly reported AEs with ABs were nasopharyngitis, ejaculation disorders and vasodilation effects such as asthenia, headache, dizziness and hypotension, while main AEs of 5ARIs were sexual dysfunction including decreased libido. MRAs could lead to some anticholinergic effects, such as dry mouth and constipation and PDE5-Is could cause flushing, headache, dyspepsia and nasopharyngitis. The overall incidence of AEs for combined therapies was higher than for monotherapies. Moreover, though we did not assess the economic factors in current review, combined therapies could increase medical cost. Therefore, the risk of AEs and medical cost should be consulted with patients when prescribing combined therapies for better effect. In the current, the safety of different class of drugs was not evaluated through network meta-analysis, as the mechanism and type of treatment-related AEs were diverse. Thus it is improper to compare the AEs of different class of drugs.

The overall quality of the included studies was considered acceptable. All included studies had no severe imbalanced baseline, early withdrawal, or other recognizable risk of bias. Moreover, as there was no unified heterogeneity assessment for network meta-analysis, we conducted the node split models to detect the inconsistency between direct and indirect effect and some inconsistency was found, especially in the comparison of ABs vs PDE5-Is on Qmax that the overall effect was not consistent with the direct effect. Thus the conclusion comparing intervention by ABs with PDE5-Is on Qmax should be treated with some caution.

The overall value of the present systematic review and network meta-analysis is lessened by several limitations as follows. Firstly, network meta-analysis was conducted with combining direct and indirect evidences and the overall effect could be influenced by the indirect evidences when the direct comparison was limited. Secondly, as aforementioned, the treatment duration of most trials included in current review was less than 24 weeks and long-term efficacy of different drug therapies for patients with LUTS/BPH was limited. Thirdly, current study aimed on LUTS/BPH and the effect of MRAs for OAB may be underestimated.

Conclusions

Our novel data demonstrates that ABs plus PDE5-Is was the best combination for treatment for LUTS/BPH in terms of improving outcomes of IPSS total score, IPSS storage subscore and IPSS voiding subscore. ABs plus 5ARIs was the best treatment for increasing Qmax. ABs plus MRAs showed great efficacy on improving storage symptoms. As a newly emerging treatment, there is growing evidence confirming the efficacy of PDE5-Is for the treatment LUTS/BPH, although they consistently exhibited no effect on Qmax. Additionally, all monotherapies including first-line drugs (MRAs) for OAB showed no effect on IPSS storage subscore. Based on our findings, combined therapy, especially ABs plus PDE5-Is, is recommended for short-term treatment for LUTS/BPH. However, further studies are required for longer duration which consider more treatment outcomes, such as disease progression, as well as studies which lead to a greater understanding of the mechanism by which pharmacologic agents, particularly PDE5-Is, are efficacious in treating for BPH/LUTS.

Supporting Information

Table S1

Characteristics of included studies.

(DOCX)

Table S2

Risk of bias summary. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool. In particular, the following factors were evaluated: (1) Adequate sequence generation? (2) Allocation concealment? (3) Binding? (4) Incomplete outcome data addressed? (5) Free of selective reporting? (6) Free of other bias?

(DOCX)

Table S3

Most common reported treatment-related adverse events. We reported the incidence of each common adverse event in the treatment arms and an overall rate summed the incidence.

(DOC)

Checklist S1

(DOC)

Acknowledgments

The authors thank Dr. Kelvin P. Davies, associate Professor and director of Department of Urology & Institute of Smooth Muscle Biology, Albert Einstein College of Medicine, for manuscript revision.

Funding Statement

X.H.Z. is supported by National Natural Science Foundation of China (N.81270843 and N.81160086). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1. Sexton CC, Coyne KS, Kopp ZS, Irwin DE, Milsom I, et al. (2009) The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU Int 103 Suppl 3 12–23. [DOI] [PubMed] [Google Scholar]
  • 2. Barry MJ, Cantor A, Roehrborn CG (2013) Relationships among participant international prostate symptom score, benign prostatic hyperplasia impact index changes and global ratings of change in a trial of phytotherapy in men with lower urinary tract symptoms. J Urol 189: 987–992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Kupelian V, McVary KT, Kaplan SA, Hall SA, Link CL, et al. (2013) Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston area community health survey. J Urol 189: S107–S114. [DOI] [PubMed] [Google Scholar]
  • 4. Roehrborn CG (2005) Benign prostatic hyperplasia: an overview. Rev Urol 7 Suppl 9 S3–S14. [PMC free article] [PubMed] [Google Scholar]
  • 5. Barry MJ, Fowler FJ Jr, O'Leary MP, Bruskewitz RC, Holtgrewe HL, et al. (1992) The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148: 1549–1557. [DOI] [PubMed] [Google Scholar]
  • 6. Berry SJ, Isaacs JT (1984) Comparative aspects of prostatic growth and androgen metabolism with aging in the dog versus the rat. Endocrinology 114: 511–520. [DOI] [PubMed] [Google Scholar]
  • 7. Garraway WM, Collins GN, Lee RJ (1991) High prevalence of benign prostatic hypertrophy in the community. Lancet 338: 469–471. [DOI] [PubMed] [Google Scholar]
  • 8. Chute CG, Panser LA, Girman CJ, Oesterling JE, Guess HA, et al. (1993) The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol 150: 85–89. [DOI] [PubMed] [Google Scholar]
  • 9. Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, et al. (2013) EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 64: 118–140. [DOI] [PubMed] [Google Scholar]
  • 10. McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, et al. (2011) Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 185: 1793–1803. [DOI] [PubMed] [Google Scholar]
  • 11. Roehrborn CG, Van KP, Nordling J (2003) Safety and efficacy of alfuzosin 10 mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. BJU Int 92: 257–261. [DOI] [PubMed] [Google Scholar]
  • 12. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, et al. (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50: 1306–1314. [DOI] [PubMed] [Google Scholar]
  • 13. Chapple CR, Smith D (1994) The pathophysiological changes in the bladder obstructed by benign prostatic hyperplasia. Br J Urol 73: 117–123. [DOI] [PubMed] [Google Scholar]
  • 14. Lumley T (2002) Network meta-analysis for indirect treatment comparisons. Stat Med 21: 2313–2324. [DOI] [PubMed] [Google Scholar]
  • 15. Caldwell DM, Ades AE, Higgins JP (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331: 897–900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23: 3105–3124. [DOI] [PubMed] [Google Scholar]
  • 17. Salanti G, Higgins JP, Ades AE, Ioannidis JP (2008) Evaluation of networks of randomized trials. Stat Methods Med Res 17: 279–301. [DOI] [PubMed] [Google Scholar]
  • 18. van Valkenhoef G, Tervonen T, Zwinkels T, de Brock B, Hillege H (2013) ADDIS: A decision support system for evidence-based medicine. Decision Support Systems 55: 459–475. [Google Scholar]
  • 19. Dias S, Welton NJ, Caldwell DM, Ades AE (2010) Checking consistency in mixed treatment comparison meta-analysis. Statistics in Medicine 29: 932–944. [DOI] [PubMed] [Google Scholar]
  • 20. Brooks SP, Gelman A (1998) General Methods for Monitoring Convergence of Iterative Simulations. Journal of Computational and Graphical Statistics 7: 434–455. [Google Scholar]
  • 21. Brock G, Broderick G, Roehrborn CG, Xu L, Wong D, et al. (2013) Tadalafil once daily in the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in men without erectile dysfunction. BJU Int 112: 990–997. [DOI] [PubMed] [Google Scholar]
  • 22. Barkin J, Roehrborn CG, Siami P, Haillot O, Morrill B, et al. (2009) Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial. BJU Int 103: 919–926. [DOI] [PubMed] [Google Scholar]
  • 23. Bae JH, Kim SO, Yoo ES, Moon KH, Kyung YS, et al. (2011) Efficacy and safety of low-dose propiverine in patients with lower urinary tract symptoms/benign prostatic hyperplasia with storage symptoms: a prospective, randomized, single-blinded and multicenter clinical trial. Korean J Urol 52: 274–278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Debruyne FM, Jardin A, Colloi D, Resel L, Witjes WP, et al. (1998) Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 34: 169–175. [DOI] [PubMed] [Google Scholar]
  • 25. Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, et al. (2010) Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J Urol 183: 1092–1097. [DOI] [PubMed] [Google Scholar]
  • 26.Fabricius PG, Weizert P, Dunzendorfer U, Hannaford JM, Maurath C (1990) Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial. Prostate Suppl 3: 85–93. [DOI] [PubMed]
  • 27. Jardin A, Bensadoun H, Delauche-Cavallier MC, Attali P (1991) Alfuzosin for benign prostatic hypertrophy. Lancet 338: 947. [DOI] [PubMed] [Google Scholar]
  • 28. Jin Z, Zhang ZC, Liu JH, Lu J, Tang YX, et al. (2011) An open, comparative, multicentre clinical study of combined oral therapy with sildenafil and doxazosin GITS for treating Chinese patients with erectile dysfunction and lower urinary tract symptoms secondary to benign prostatic hyperplasia. Asian J Androl 13: 630–635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Lloyd SN, Buckley JF, Chilton CP, Ibrahim I, Kaisary AV, et al. (1992) Terazosin in the treatment of benign prostatic hyperplasia: a multicentre, placebo-controlled trial. Br J Urol 70 Suppl 1 17–21. [DOI] [PubMed] [Google Scholar]
  • 30. Lepor H (1998) Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 51: 892–900. [DOI] [PubMed] [Google Scholar]
  • 31. Lee E (2002) Comparison of tamsulosin and finasteride for lower urinary tract symptoms associated with benign prostatic hyperplasia in Korean patients. J Int Med Res 30: 584–590. [DOI] [PubMed] [Google Scholar]
  • 32. Lee KS, Choo MS, Kim DY, Kim JC, Kim HJ, et al. (2005) Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol 174: 1334–1338. [DOI] [PubMed] [Google Scholar]
  • 33. Lee SH, Chung BH, Kim SJ, Kim JH, Kim JC, et al. (2011) Initial combined treatment with anticholinergics and alpha-blockers for men with lower urinary tract symptoms related to BPH and overactive bladder: a prospective, randomized, multi-center, double-blind, placebo-controlled study. Prostate Cancer Prostatic Dis 14: 320–325. [DOI] [PubMed] [Google Scholar]
  • 34. Liguori G, Trombetta C, De GG, Pomara G, Maio G, et al. (2009) Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med 6: 544–552. [DOI] [PubMed] [Google Scholar]
  • 35. Na Y, Ye Z, Zhang S (2012) Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia: a randomized, double-blind, parallel-group, placebo-controlled study with an open-label extension. Clin Drug Investig 32: 29–39. [DOI] [PubMed] [Google Scholar]
  • 36. Narayan P, Tewari A (1998) A second phase III multicenter placebo controlled study of 2 dosages of modified release tamsulosin in patients with symptoms of benign prostatic hyperplasia. United States 93-01 Study Group. J Urol 160: 1701–1706. [PubMed] [Google Scholar]
  • 37. Nishizawa O, Yamaguchi O, Takeda M, Yokoyama O (2011) Randomized Controlled Trial to Treat Benign Prostatic Hyperplasia with Overactive Bladder Using an Alpha-blocker Combined with Anticholinergics. LUTS: Lower Urinary Tract Symptoms 3: 29–35. [DOI] [PubMed] [Google Scholar]
  • 38. Nordling J (2005) Efficacy and safety of two doses (10 and 15 mg) of alfuzosin or tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia. BJU Int 95: 1006–1012. [DOI] [PubMed] [Google Scholar]
  • 39. Porst H, Kim ED, Casabe AR, Mirone V, Secrest RJ, et al. (2011) Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 60: 1105–1113. [DOI] [PubMed] [Google Scholar]
  • 40. Regadas RP, Reges R, Cerqueira JB, Sucupira DG, Josino IR, et al. (2013) Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial. Int Urol Nephrol 45: 39–43. [DOI] [PubMed] [Google Scholar]
  • 41. Rigatti P, Brausi M, Scarpa RM, Porru D, Schumacher H, et al. (2003) A comparison of the efficacy and tolerability of tamsulosin and finasteride in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 6: 315–323. [DOI] [PubMed] [Google Scholar]
  • 42. Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, et al. (2008) The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 179: 616–621. [DOI] [PubMed] [Google Scholar]
  • 43. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L (2008) Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 180: 1228–1234. [DOI] [PubMed] [Google Scholar]
  • 44. Roehrborn CG (2001) Efficacy and safety of once-daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized, placebo-controlled trial. Urology 58: 953–959. [DOI] [PubMed] [Google Scholar]
  • 45. Roehrborn CG, Kaplan SA, Jones JS, Wang JT, Bavendam T, et al. (2009) Tolterodine extended release with or without tamsulosin in men with lower urinary tract symptoms including overactive bladder symptoms: effects of prostate size. Eur Urol 55: 472–479. [DOI] [PubMed] [Google Scholar]
  • 46. Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, et al. (2010) Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int 105: 502–507. [DOI] [PubMed] [Google Scholar]
  • 47. Roehrborn CG, Siegel RL (1996) Safety and efficacy of doxazosin in benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. Urology 48: 406–415. [DOI] [PubMed] [Google Scholar]
  • 48. Tammela TL, Kontturi MJ (1993) Urodynamic effects of finasteride in the treatment of bladder outlet obstruction due to benign prostatic hyperplasia. J Urol 149: 342–344. [DOI] [PubMed] [Google Scholar]
  • 49. Tuncel A, Nalcacioglu V, Ener K, Aslan Y, Aydin O, et al. (2010) Sildenafil citrate and tamsulosin combination is not superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. World J Urol 28: 17–22. [DOI] [PubMed] [Google Scholar]
  • 50. Van KP, Haab F, Angulo JC, Vik V, Katona F, et al. (2013) Efficacy and safety of solifenacin plus tamsulosin OCAS in men with voiding and storage lower urinary tract symptoms: results from a phase 2, dose-finding study (SATURN). Eur Urol 64: 398–407. [DOI] [PubMed] [Google Scholar]
  • 51. van Kerrebroeck P, Jardin A, Laval KU, van CP (2000) Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol 37: 306–313. [DOI] [PubMed] [Google Scholar]
  • 52.van Kerrebroeck P, Chapple C, Drogendijk T, Klaver M, Sokol R, et al. (2013) Combination Therapy with Solifenacin and Tamsulosin Oral Controlled Absorption System in a Single Tablet for Lower Urinary Tract Symptoms in Men: Efficacy and Safety Results from the Randomised Controlled NEPTUNE Trial. Eur Urol. [DOI] [PubMed]
  • 53. Abrams P, Speakman M, Stott M, Arkell D, Pocock R (1997) A dose-ranging study of the efficacy and safety of tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist, in patients with benign prostatic obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 80: 587–596. [DOI] [PubMed] [Google Scholar]
  • 54. Andersen M, Dahlstrand C, Hoye K (2000) Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia. Eur Urol 38: 400–409. [DOI] [PubMed] [Google Scholar]
  • 55. Arora S, Khajuria V, Gupta S, Tandon VR, Kohli K (2012) Efficacy and tolerability of tamsulosin alone and in combination with dutasteride in patients of benign prostatic hyperplasia. JK Science 14: 134–138. [Google Scholar]
  • 56. Elhilali MM, Ramsey EW, Barkin J, Casey RW, Boake RC, et al. (1996) A multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of terazosin in the treatment of benign prostatic hyperplasia. Urology 47: 335–342. [DOI] [PubMed] [Google Scholar]
  • 57. Madani AH, Afsharimoghaddam A, Roushani A, Farzan A, Asadollahzade A, et al. (2012) Evaluation of Tadalafil effect on lower urinary tract symptoms of benign prostatic hyperplasia in patients treated with standard medication. Int Braz J Urol 38: 33–39. [DOI] [PubMed] [Google Scholar]
  • 58. Maruyama O, Kawachi Y, Hanazawa K, Koizumi K, Yamashita R, et al. (2006) Naftopidil monotherapy vs naftopidil and an anticholinergic agent combined therapy for storage symptoms associated with benign prostatic hyperplasia: A prospective randomized controlled study. Int J Urol 13: 1280–1285. [DOI] [PubMed] [Google Scholar]
  • 59. MacDiarmid SA, Peters KM, Chen A, Armstrong RB, Orman C, et al. (2008) Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc 83: 1002–1010. [DOI] [PubMed] [Google Scholar]
  • 60. McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, et al. (2007) Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 177: 1071–1077. [DOI] [PubMed] [Google Scholar]
  • 61. McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, et al. (2007) Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 177: 1401–1407. [DOI] [PubMed] [Google Scholar]
  • 62. Yang Y, Zhao XF, Li HZ, Wang W, Zhang Y, et al. (2007) Efficacy and safety of combined therapy with terazosin and tolteradine for patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective study. Chin Med J (Engl) 120: 370–374. [PubMed] [Google Scholar]
  • 63. Yamaguchi O, Kakizaki H, Homma Y, Takeda M, Nishizawa O, et al. (2011) Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms–ASSIST, randomized controlled study. Urology 78: 126–133. [DOI] [PubMed] [Google Scholar]
  • 64. Yu HJ, Chiu TY, Lai MK (1995) Therapeutic effects of finasteride in benign prostatic hyperplasia: a randomized double-blind controlled trial. J Formos Med Assoc 94: 37–41. [PubMed] [Google Scholar]
  • 65. Yokoyama T, Uematsu K, Watanabe T, Sasaki K, Kumon H, et al. (2009) Naftopidil and propiverine hydrochloride for treatment of male lower urinary tract symptoms suggestive of benign prostatic hyperplasia and concomitant overactive bladder: a prospective randomized controlled study. Scand J Urol Nephrol 43: 307–314. [DOI] [PubMed] [Google Scholar]
  • 66. Yokoyama O, Yoshida M, Kim SC, Wang CJ, Imaoka T, et al. (2013) Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosin-controlled 12-week study in Asian men. Int J Urol 20: 193–201. [DOI] [PubMed] [Google Scholar]
  • 67. Christensen MM, Bendix HJ, Rasmussen PC, Jacobsen F, Nielsen J, et al. (1993) Doxazosin treatment in patients with prostatic obstruction. A double-blind placebo-controlled study. Scand J Urol Nephrol 27: 39–44. [DOI] [PubMed] [Google Scholar]
  • 68. Chapple CR, Carter P, Christmas TJ, Kirby RS, Bryan J, et al. (1994) A three month double-blind study of doxazosin as treatment for benign prostatic bladder outlet obstruction. Br J Urol 74: 50–56. [DOI] [PubMed] [Google Scholar]
  • 69. Chapple CR, Wyndaele JJ, Nordling J, Boeminghaus F, Ypma AF, et al. (1996) Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group. Eur Urol 29: 155–167. [PubMed] [Google Scholar]
  • 70. Kaplan SA, Gonzalez RR, Te AE (2007) Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 51: 1717–1723. [DOI] [PubMed] [Google Scholar]
  • 71. Kaplan SA, He W, Koltun WD, Cummings J, Schneider T, et al. (2013) Solifenacin plus tamsulosin combination treatment in men with lower urinary tract symptoms and bladder outlet obstruction: a randomized controlled trial. Eur Urol 63: 158–165. [DOI] [PubMed] [Google Scholar]
  • 72. Kirby RS, Andersen M, Gratzke P, Dahlstrand C, Hoye K (2001) A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int 87: 192–200. [DOI] [PubMed] [Google Scholar]
  • 73. Kirby RS, Bryan J, Eardley I, Christmas TJ, Liu S, et al. (1992) Finasteride in the treatment of benign prostatic hyperplasia. A urodynamic evaluation. Br J Urol 70: 65–72. [DOI] [PubMed] [Google Scholar]
  • 74. Kirby RS, Chapple CR, Sethia K, Flannigan M, Milroy EJ, et al. (1998) Morning vs evening dosing with doxazosin in benign prostatic hyperplasia: efficacy and safety. Prostate Cancer Prostatic Dis 1: 163–171. [DOI] [PubMed] [Google Scholar]
  • 75. Kim SC, Park JK, Kim SW, Lee SW, Ahn TY, et al. (2011) Tadalafil Administered Once Daily for Treatment of Lower Urinary Tract Symptoms in Korean men with Benign Prostatic Hyperplasia: Results from a Placebo-Controlled Pilot Study Using Tamsulosin as an Active Control. LUTS: Lower Urinary Tract Symptoms 3: 86–93. [DOI] [PubMed] [Google Scholar]
  • 76. Shen J, Chen JH, Yu QW, Shen J, Sun P (2011) Effectiveness of combined therapy with terazosin and tolterodine for patients with benign prostatic hyperplasia. Journal of Shanghai Jiaotong University 31: 809–812. [Google Scholar]
  • 77. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E (2008) A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 53: 1236–1244. [DOI] [PubMed] [Google Scholar]
  • 78. Stoner E (1992) The clinical effects of a 5 alpha-reductase inhibitor, finasteride, on benign prostatic hyperplasia. The Finasteride Study Group. J Urol 147: 1298–1302. [DOI] [PubMed] [Google Scholar]
  • 79. Seo DH, Kam SC, Hyun JS (2011) Impact of lower urinary tract symptoms/benign prostatic hyperplasia treatment with tamsulosin and solifenacin combination therapy on erectile function. Korean J Urol 52: 49–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Singh P, Indurkar M, Singh A, Indurkar P (2013) Comparison of the efficacy and safety of tamsulosin (0.4 mg) v/s (and)finasteride for short-term treatment of patients with symptomatic benign prostatic hyperplasia. International Journal of Current Pharmaceutical Research 5: 24–28. [Google Scholar]
  • 81. Gacci M, Vittori G, Tosi N, Siena G, Rossetti MA, et al. (2012) A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 9: 1624–1633. [DOI] [PubMed] [Google Scholar]
  • 82. Ozbey I, Aksoy Y, Polat O, Bicgi O, Demirel A, et al. (1999) Effects of doxazosin in men with benign prostatic hyperplasia: urodynamic assessment. Int Urol Nephrol 31: 471–479. [DOI] [PubMed] [Google Scholar]
  • 83. Ozturk MI, Kalkan S, Koca O, Gunes M, Akyuz M, et al. (2012) Efficacy of alfuzosin and sildenafil combination in male patients with lower urinary tract symptoms. Andrologia 44 Suppl 1 791–795. [DOI] [PubMed] [Google Scholar]
  • 84. Oelke M, Giuliano F, Mirone V, Xu L, Cox D, et al. (2012) Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 61: 917–925. [DOI] [PubMed] [Google Scholar]
  • 85. Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G (2009) Rapid efficacy of the highly selective alpha1A-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol 181: 2634–2640. [DOI] [PubMed] [Google Scholar]
  • 86. Kawabe K, Yoshida M, Homma Y (2006) Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int 98: 1019–1024. [DOI] [PubMed] [Google Scholar]
  • 87. Robert G, Descazeaud A, Delongchamps NB, Cornu JN, Azzouzi AR, et al. (2012) [Benign prostatic hyperplasia medical treatment: systematic review of the literature by the CTMH/AFU]. Prog Urol 22: 7–12. [DOI] [PubMed] [Google Scholar]
  • 88. Andersson KE, de Groat WC, McVary KT, Lue TF, Maggi M, et al. (2011) Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol Urodyn 30: 292–301. [DOI] [PubMed] [Google Scholar]
  • 89. Giuliano F, Uckert S, Maggi M, Birder L, Kissel J, et al. (2013) The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol 63: 506–516. [DOI] [PubMed] [Google Scholar]
  • 90. Brock GB, McVary KT, Roehrborn CG, Watts S, Ni X, et al. (2014) Direct Effects of Tadalafil on Lower Urinary Tract Symptoms versus Indirect Effects Mediated through Erectile Dysfunction Symptom Improvement: Integrated Data Analyses from 4 Placebo Controlled Clinical Studies. J Urol 191: 405–411. [DOI] [PubMed] [Google Scholar]
  • 91. Morelli A, Filippi S, Comeglio P, Sarchielli E, Chavalmane AK, et al. (2010) Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med 7: 107–120. [DOI] [PubMed] [Google Scholar]
  • 92. Morelli A, Sarchielli E, Comeglio P, Filippi S, Mancina R, et al. (2011) Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. J Sex Med 8: 2746–2760. [DOI] [PubMed] [Google Scholar]
  • 93. Zhang X, Zang N, Wei Y, Yin J, Teng R, et al. (2012) Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling. Am J Physiol Endocrinol Metab 302: E243–E253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Fusco F, di Villa BR, Mitidieri E, Cirino G, Sorrentino R, et al. (2012) Sildenafil effect on the human bladder involves the L-cysteine/hydrogen sulfide pathway: a novel mechanism of action of phosphodiesterase type 5 inhibitors. Eur Urol 62: 1174–1180. [DOI] [PubMed] [Google Scholar]
  • 95. Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ (2012) Inhibitory effects of phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder afferent nerve activities of the rat, and on acrolein-induced hyperactivity of these nerves. BJU Int 110: E259–E266. [DOI] [PubMed] [Google Scholar]
  • 96. Zenzmaier C, Kern J, Sampson N, Heitz M, Plas E, et al. (2012) Phosphodiesterase type 5 inhibition reverts prostate fibroblast-to-myofibroblast trans-differentiation. Endocrinology 153: 5546–5555. [DOI] [PubMed] [Google Scholar]
  • 97. Truss MC, Uckert S, Stief CG, Forssmann WG, Jonas U (1996) Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res 24: 129–134. [DOI] [PubMed] [Google Scholar]
  • 98. Fujiwara M, Andersson K, Persson K (2000) Nitric oxide-induced cGMP accumulation in the mouse bladder is not related to smooth muscle relaxation. Eur J Pharmacol 401: 241–250. [DOI] [PubMed] [Google Scholar]
  • 99. Kajioka S, Nakayama S, Seki N, Naito S, Brading AF (2008) Oscillatory membrane currents paradoxically induced via NO-activated pathways in detrusor cells. Cell Calcium 44: 202–209. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1

Characteristics of included studies.

(DOCX)

Table S2

Risk of bias summary. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool. In particular, the following factors were evaluated: (1) Adequate sequence generation? (2) Allocation concealment? (3) Binding? (4) Incomplete outcome data addressed? (5) Free of selective reporting? (6) Free of other bias?

(DOCX)

Table S3

Most common reported treatment-related adverse events. We reported the incidence of each common adverse event in the treatment arms and an overall rate summed the incidence.

(DOC)

Checklist S1

(DOC)


Articles from PLoS ONE are provided here courtesy of PLOS

RESOURCES