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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 31  |  Issue : 3  |  Page : 99-107

Combination alpha blocker and phosphodiesterase 5 inhibitor versus alpha-blocker monotherapy for lower urinary tract symptoms associated with benign prostate hyperplasia: A systematic review and meta-analysis


1 Department of Urology, En Chu Kong Hospital; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan
2 Department of Urology, En Chu Kong Hospital, Taipei City; Department of Biomedical Engineering, Chung-Yuan Christian University, Chung-Li, Taiwan
3 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan

Date of Submission02-Sep-2019
Date of Decision21-Oct-2019
Date of Acceptance20-Dec-2019
Date of Web Publication26-Jun-2020

Correspondence Address:
Yu-Kang Tu
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, No. 17 Xuzhou Road, Zhongzheng District, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_59_19

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  Abstract 


Purpose: The prevalence of erectile dysfunction (ED) is higher in patients with lower urinary tract symptoms (LUTS). Phosphodiesterase 5 inhibitors (PDE5is) can improve both ED and LUTS and therefore is useful for these patients. Our aim of this study is to evaluate whether combination therapy of alpha blockers and PDE5i is more effective than alpha-blockers monotherapy for the treatment of LUTS. Materials and Methods: A systematic review and meta-analysis were undertaken to assess the difference between the combination therapy and alpha-blockers monotherapy by searching published randomized controlled trials from electronic databases PubMed, Embase, and the Cochrane Library up to April 2018. Results: A total of 13 randomized controlled studies with 1173 patients were included in our meta-analysis. Compared with alpha-blocker monotherapy, the combination therapy obtained a significantly better improvement in International Prostate Symptom Score (IPSS) (1.73, 95% confidence interval [CI]: 1.1–2.35), voiding subscore (0.99, 95% CI: 0.54–1.44), storage subscore (0.57, 95% CI: 0.03–1.1), peak flow rate (0.69 cc/s, 95% CI: 0.27–1.1), and erectile function (EF) symptom score. Meta-regression showed that baseline IPSS, baseline peak flow rate, baseline prostate volume, age, baseline EF symptom score, and dosage of PDE5is were not associated with the difference in IPSS improvement. Conclusion: A combination of alpha blockers and PDE5is has better therapeutic effects than alpha-blocker monotherapy on LUTS related to benign prostate hyperplasia.

Keywords: Alpha blocker, benign prostate hyperplasia, phosphodiesterase 5 inhibitor


How to cite this article:
Chen PC, Wang CC, Tu YK. Combination alpha blocker and phosphodiesterase 5 inhibitor versus alpha-blocker monotherapy for lower urinary tract symptoms associated with benign prostate hyperplasia: A systematic review and meta-analysis. Urol Sci 2020;31:99-107

How to cite this URL:
Chen PC, Wang CC, Tu YK. Combination alpha blocker and phosphodiesterase 5 inhibitor versus alpha-blocker monotherapy for lower urinary tract symptoms associated with benign prostate hyperplasia: A systematic review and meta-analysis. Urol Sci [serial online] 2020 [cited 2020 Jul 12];31:99-107. Available from: http://www.e-urol-sci.com/text.asp?2020/31/3/99/287980




  Introduction Top


Lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH) is a worldwide problem for aging men. Approximate 70% of patients with LUTS/BPH were bothered by erectile dysfunction (ED), although there is still no evidence to support a causal relationship between LUTS/BPH and ED.[1] Many epidemiological studies have demonstrated that there is an age-independent association between these two diseases.[1] The severity of LUTS/BPH is significantly associated with the severity of ED. Therefore, it is important to evaluate patients' ED when patients are treated for LUTS/BPH.

Alpha blockers are traditionally the first-line medication for the treatment of LUTS/BPH, and phosphodiesterase 5 inhibitors (PDE5i) can improve the symptoms of both LUTS/BPH and ED.[2] Some patients do not get satisfactory symptom relief with monotherapy. Concomitant use of alpha blockers with other medications is an alternative for these patients. Combination therapy comprising an alpha blocker with a 5-alpha-reductase inhibitor (5ARI) yields a greater improvement in LUTS, Peak urinary flow rate (Qmax), and BPH progression than alpha-blocker monotherapy.[3] Nevertheless, the combination with 5ARI increased the risk of ED and libido alternation.[4] Concurrent use of an alpha blocker and antimuscarinic agent significantly improved the storage subscore of the International Prostate Symptom Score (IPSS) compared with an alpha-blocker alone.[5] However, an antimuscarinic agent is not suggested for patients with large postvoiding residual urine volumes (PVRs). Recently, several studies have compared the efficacy and safety of alpha blockers in conjunction with PDE5i to alpha-blockers alone in treating patients with LUTS/BPH.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] However, the results of these studies were variable. Thus, we summarize the outcomes to provide a comprehensive assessment of combined alpha blocker and PDE5i therapy for the treatment of LUTS/BPH.

We conducted a systematic review and meta-analysis to compare combination alpha blocker with PDE5i therapy to alpha-blocker monotherapy in patients with LUTS/BPH. We investigated whether the combination therapy yielded a greater beneficial effect on patients' IPSS, Peak urinary flow rate (Qmax), PVR, and International Index of Erectile Function (IIEF) questionnaires than alpha-blocker therapy alone, especially in patients with coexisting ED. In addition, we compared the risk of adverse events of combination therapy to alpha-blocker monotherapy. A meta-regression was performed to investigate the factors related to the differences in IPSS improvement between the combination therapy and alpha-blocker monotherapy.


  Methods Top


Search strategy and study selection

The population, intervention, control, and outcomes statement of our study search is as follows: (1) population: patients with LUTS/BPH; (2) intervention: LUTS/BPH patients who received combination therapy of alpha blocker and PDE5i; (3) comparison: LUTS/BPH patients who received alpha-blocker therapy only; and (4) outcome: Improvement in IPSS, Qmax, PVR, and IIEF.

We conducted a comprehensive search for relevant randomized controlled studies in the electronic databases, including PubMed, Embase, and the Cochrane Library without language restrictions up to April 2018. A combination of following medical terms was searched: (lower urinary tract symptoms OR prostatic hyperplasia) AND (sildenafil OR udenafil OR vardenafil OR tadalafil). We looked for additional studies from the reference lists of related review articles or the papers identified in the search. The inclusion criteria for the analysis are were as follows: (1) patients with LUTS/BPH had to have been randomly assigned to therapy of either alpha-blocker plus PDE5i or alpha blocker alone and (2) the outcome assessment of IPSS or Qmax had to have been reported. We excluded conference abstracts and studies without full text.

Data extraction and quality assessment

One author (PCC) performed the data extraction, and a second author (YKT) checked for its accuracy. The information extracted from the selected studies included authors, year of publication, patient characteristics, study design, inclusion and exclusion criteria, experimental drug strategies (types, duration, and dosage), treatment outcome parameters (IPSS, Qmax, PVR, and IIEF score), and adverse events.

The quality of the included studies was evaluated according to the risk-of-bias method recommended by the Cochrane collaboration.[19] The assessment tool included seven 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), and other bias [Supplementary Figure 1], Cochrane Review Manager, version 5.3, The Nordic Cochrane Centre, Copenhagen].
Figure 1: Forest plot of International Prostate Symptom Score improvement

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Data synthesis and statistical analysis

The primary outcome of this study was the difference in total IPSS change between the combination therapy and alpha-blocker monotherapy. In addition, we assessed the differences in IPSS voiding subscore, IPSS storage subscore, Qmax, PVR volume, and IIEF score between the two groups. We conducted a random effects meta-analysis to calculate the pooled mean difference for these continuous outcomes using the DerSimonian-Laird method because the type, duration, and the dosage of an alpha blocker and PDE5i were quite different among the included studies. We reported 95% confidence intervals (CIs) of the pooled results and used the two-tailed t- test. Cochran's Q test and I-square were used to evaluate the heterogeneity. Subgroup analysis was performed according to the types of PDE5i. We conducted a meta-regression to investigate the potential moderators associated with IPSS change using the restricted maximum-likelihood method. The Chi-square test was used to determine the statistical significance of differences in the dropout rate between the combination group and the alpha-blocker monotherapy group. All statistical analyses were performed using statistical software R version 3.3.1. (R Foundation for Statistical Computing, Vienna, Austria; URL https://www.R-project.org/). The statistical significance level was set at 0.05 throughout our meta-analyses.


  Results Top


Study selection and characteristics

We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart to show our literature search [Supplementary Figure 2]. Thirteen randomized controlled studies with 1173 patients were included in the meta-analysis. [Table 1] summarizes the characteristics of eligible studies. Seven studies compared the combination therapy of an alpha blocker and tadalafil to alpha-blocker monotherapy. Five studies investigated the difference between the combination therapy of an alpha blocker plus sildenafil and alpha-blocker monotherapy. One study examined the effect of tamsulosin/vardenafil versus tamsulosin. Four studies included patients with concomitant LUTS/BPH and ED, whereas nine studies included patients with LUTS/BPH, regardless of whether they had ED or not. [Table 2] and [Table 3] summarize the differences in IPSS and Qmax, respectively.
Figure 2: (a) Forest plot of International Prostate Symptom Score voiding subscore improvement. (b) Forest plot of International Prostate Symptom Score storage subscore improvement. (c) Forest plot of International Prostate Symptom Score quality of life improvement

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Table 1: Summary of enrolled studies for meta.analysis

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Table 2: Summary of international prostate symptom score change in enrolled studies

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Table 3: Summary of peak urinary flow rate change in enrolled studies

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International Prostate Symptom Score

Of the 13 eligible studies, 12 studies reported sufficient data for analysis of IPSS. [Figure 1] shows that the combination therapy provided a significantly better improvement in total IPSS (weighted mean difference [WMD] = 1.73, 95% CI: 1.1–2.35) than alpha-blocker monotherapy. The subgroup analysis by PDE5i showed that alpha blockers with either sildenafil or tadalafil yielded greater improvement in IPSS compared with alpha-blocker monotherapy.

Of the 13 eligible studies, five reported IPSS voiding and storage subscores. Tadalafil was the only PDE5i used in these five studies. [Figure 2]a and [Figure 2]b show that the combination therapy resulted in significantly greater improvements in IPSS voiding and storage subscores (WMD = 0.99, 95% CI 0.54–1.44 and WMD = 0.57, 95% CI 0.03–1.1, respectively). Six studies reported IPSS quality of life (QOL), and the meta-analysis showed that the combination therapy attained a significantly greater improvement in the IPSS-QOL (WMD = 0.45, 95% CI: 0.11–0.79) [Figure 2]c.

Qmax and postvoiding residual urine volume

Of the 13 eligible studies, 11 studies reported sufficient data for the analysis of Qmax. The pooled mean difference in Qmax between the combination therapy and alpha-blocker monotherapy group is 0.69 mL/s (95% CI: 0.27–1.1) [Figure 3]a. The subgroup analysis showed that short-acting PDE5is (vardenafil and sildenafil) yielded significantly greater improvement in Qmax (0.92 mL/s, 95% CI: 0.34–1.5; and 2.5 mL/s, 95% CI: 0.32–4.68, respectively) than the use of an alpha blocker alone. However, tadalafil did not provide significant additional benefit to the improvement in Qmax (WMD = 0.31 mL/s, 95% CI: −0.24–0.85) than an alpha blocker alone.
Figure 3: (a) Forest plot of peak flow rate improvement. (b): Forest plot of decreased postvoiding residual urine volume

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Changes in PVR volume were reported in eight studies. The meta-analysis showed that patients on combination therapy attained 8.49 mL (95% CI: 2.5–14.49 mL) greater decrease in PVR volume than patients taking alpha-blocker monotherapy [Figure 3]b.

Erectile function

Of the 13 eligible studies, 4 studies reported IIEF-5 scores, and 5 studies reported IIEF-EF scores (erectile function [EF] domain of IIEF). Patients taking the combination therapy had significantly higher IIEF-5 and IIEF-EF scores than those taking the alpha-blocker monotherapy, with the mean difference of 3.84 (95% CI: 1.55–6.12) and 3.87 (95% CI: 2.27–5.46), respectively [Supplementary Figure 3].



Meta-regression for total International Prostate Symptom Score improvement

The meta-regression analysis showed that baseline IPSS, Qmax, prostate volume, age, IIEF-EF, and baseline IIEF-5 were not significantly associated with the difference in total IPSS improvement [Supplementary Table 1]. Further meta-regression analyses showed that only the duration, but not the dosage of sildenafil, was significantly associated with the difference in IPSS improvement [Supplementary Table 2]. Neither the duration nor the dosage of tadalafil was associated with the IPSS changes.



Adverse events

The common adverse events reported in each study about tadalafil included headache (14.5%), myalgia (5.8%), and dizziness (3.6%). The total numbers of episodes of adverse events in patients who received combination therapy were significantly higher than that in patients taking alpha-blocker monotherapy (18.9% vs. 7.2%, P < 0.001). However, the dropout rate due to adverse events in the combination group was not significantly different from that of the alpha-blocker group (4.38% vs. 2.63%, P = 0.13). Headache and dizziness were the most frequent adverse events related to dropout in both groups.


  Discussion Top


Our results demonstrated that the combination of an alpha blocker and a PDE5i provided a greater improvement in total IPSS, IPSS voiding subscore, IPSS storage subscore, Qmax, and EF than alpha-blocker monotherapy. Although adverse events in the combination group were significantly higher than those in the monotherapy group, the dropout rates were comparable. The subgroup analysis of various PDE5is showed that the combined alpha blocker and sildenafil or vardenafil, but not tadalafil, provided significantly greater Qmax than alpha-blocker monotherapy. Meta-regression failed to identify baseline patient-related factors that significantly influenced IPSS improvement.

The most common medication for patients with LUTS/BPH consisted of four drug classes: alpha blockers, 5ARIs, antimuscarinic agents, and PDE5is.[20] Among these drugs, 5ARIs not only reduce the IPSS and prostate volume but also decrease the risk of urine retention and BPH-related surgery. However, it has a negative effects on EF and may cause hypoactive sexual desire in patients with LUTS/BPH.[21] Antimuscarinic agents are mainly effective for the relief of storage symptoms, but cognitive function in older men and possible urine retention in those with large PVR volumes are major concerns.[22] Our analysis showed that a combination of an alpha blocker and a PDE5i is an ideal choice for LUTS/BPH patients with ED or those worrying about ED after treating LUTS/BPH. Concurrent alpha blocker and PDE5i use appear to be a better choice for LUTS/BPH patients dissatisfied with alpha-blocker monotherapy, especially in patients for whom 5ARI or an antimuscarinic agent was not suitable.

Our results indicate that PDE5i could provide synergistic effects and have a different mechanism of action for LUTS improvement than alpha-blocker monotherapy. Although the exact mechanisms of PDE5i on LUTS/BPH are not well understood, some studies have demonstrated that PDE5i relaxes the smooth muscle in the prostate and urethra by regulating cyclic guanosine monophosphate and nitric oxide.[23] A recent meta-analysis with 3973 patients revealed that tadalafil 5 mg daily improve total IPSS, with a pooled mean difference of 2.02 (95% CI: 1.53–2.52) compared with placebo.[24] The pooled mean difference of the improved IPSS voiding subscore and improved IPSS storage subscore was 1.20 (95% CI: 0.83–1.57) and 0.72 (95% CI: 0.47–0.98), respectively.[24] Few studies have investigated the effects of sildenafil or vardenafil versus placebo on LUTS/BPH. McVary et al. reported that sildenafil daily use for patients with LUTS and ED had a significantly better effect on total IPSS improvement than placebo.[25] Ko et al. tested different dosages of sildenafil and placebo for 8 weeks and found significant improvement in total IPSS. In addition, the improvement in voiding subscore was better than that of the storage subscore.[26] To the best of our knowledge, there were no previous studies that directly compared different PDE5is. Our results show that there are no statistically significant differences in IPSS improvement between the three types of PDE5is in combination with an alpha blocker versus alpha-blocker monotherapy.

Our meta-analysis revealed that combination therapy with an alpha blocker and a PDE5i significantly increased Qmax compared to alpha-blocker monotherapy. However, the subgroup analysis found the effect was only statistically significant with sildenafil or vardenafil but not tadalafil. A previous meta-analysis showed that PDE5is had superior effects than placebo on IPSS but not on Qmax.[2] A randomized controlled trial conducted by McVary et al. revealed that daily sildenafil use improved IPSS compared to placebo but not Qmax.[25] Ko et al. also reported similar results, which showed sildenafil exhibited significant IPSS improvements but no change in Qmax.[26] Most previous studies comparing PDE5is and placebo showed that PDE5is improves IPSS but not Qmax. However, our result showed sildenafil or vardenafil combined with an alpha blocker provided better Qmax than alpha-blocker monotherapy. Choi et al. reported similar results in their meta-analysis and hypothesized that the difference could be attributable to the extent of relaxation of the bladder neck and prostate.[27] Further studies are needed to investigate the differences in Qmax change among the different types of PDE5is and the combination PDE5i plus alpha blocker therapies with different types of alpha blockers.

Our meta-regression showed that baseline IPSS, Qmax, prostate volume, age, IIEF, and drug dosage were not predictive of IPSS improvement. This finding was different from that of a previous meta-analysis of 12 studies (7 for PDE5i versus placebo, 5 for the combination of PDE5i and alpha blocker versus alpha blocker alone) showed that the effects of PDE5i on IPSS improvements were larger in patients with lower body mass index and higher baseline IPSS and in younger patients.[28] Sun et al. conducted a meta-regression including 28 studies of PDE5i versus placebo and found that poor baseline IPSS and a higher dosage of PDE5i were associated with greater IPSS improvement.[2] This discrepancy might be explained by the large difference in mean IPSS improvement between alpha blocker versus placebo and combination therapy versus monotherapy (6.11 vs. 1.73). Alpha blockers could mask the contribution of IPSS improvement from PDE5is. Further studies are needed to evaluate which patients would benefit most from combination therapy.

There are some limitations to our study. First, most randomized controlled trials included in our meta-analysis were head-to-head comparisons of combination therapy (PDE5i+alpha blocker) and alpha-blocker monotherapy. One study was designed to compare add-on PDE5i versus placebo for patients who already received alpha-blocker therapy. There is little difference between starting on combination therapy and adding PDE5i to existing alpha-blocker therapy. Second, some researchers could be interested in whether combination therapy provided better therapeutic efficacy in patients with a poor response to alpha-blocker monotherapy. However, this subgroup analysis was not available in the studies we analyzed. Third, we did not conduct a meta-analysis of adverse events because not all studies reported adverse events.


  Conclusion Top


The combination of a PDE5i and an alpha blocker was superior to alpha-blocker monotherapy for treating LUTS/BPH.

The combination therapy improved total IPSS, IPSS voiding subscore, IPSS storage subscore, IPSS QOL, and Qmax. Although the combination therapy increased the risk of adverse events, they were well tolerated, without decreasing the drug compliance. Combination therapy provided a significant benefit for EF. Combination therapy seems to be a good option for LUTS/BPH patients, especially for those with co-existing ED.

Acknowledgments

The authors would like to thank Formosa Medical Editors for assistance with manuscript preparation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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