Alpha-1 Adrenergic Receptor Blockers for the Treatment of Lower Urinary Tract Symptoms in Women: A Systematic Review and Meta-Analysis

Article information

Int Neurourol J. 2019;23(1):56-68

Publication date (electronic) : 2019 March 31

doi : https://doi.org/10.5213/inj.1836188.094

Do Kyung Kim¹, Joo Yong Lee², Jae Hung Jung³, Jae Heon Kim¹, Yoon Soo Hah⁴, Chang Hee Hong⁵, Kang Su Cho^,5

¹Department of Urology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea

²Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea

³Department of Urology, Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

⁴Department of Urology, Daegu Catholic University Medical Center, Daegu, Korea

⁵Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea

Corresponding author: Kang Su Cho https://orcid.org/0000-0002-3500-8833 Departments of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea E-mail: kscho99@yuhs.ac / Tel: +82-2-2019-3471 / Fax: +82-2-3462-8887

Received 2018 August 16; Accepted 2018 November 5.

Abstract

• HIGHLIGHTS

- Alpha 1-blocker is effective in the treatment of female lower urinary tract symptoms. It showed significant symptom relief compared to placebo, however there was no differences in maximal flow rate and postvoid residual between the α1-blocker and placebo groups.

INTRODUCTION

The European Urological Association guidelines suggest that, relative to placebo, alpha-1 adrenergic receptor blockers (α1-blockers) reduce urinary symptoms and increase maximal flow rate (Qmax) in men with lower urinary tract symptoms (LUTS) [1]. These agents increase smooth muscle relaxation in the prostate and bladder neck. They constitute the first-line drug treatment of male LUTS due to their rapid onset of action, satisfactory efficacy, and acceptable safety profiles.

Voiding dysfunction in women is defined by the International Continence Society and International Urogynecological Association as abnormally slow and/or incomplete urination diagnosed based on symptoms and urodynamic studies [2]. The overall prevalence of female voiding dysfunction is estimated to be between 3% and 39% [3,4]. However, considering the present lack of standardized diagnostic criteria and clinical guidelines, female LUTS is likely overlooked and underestimated. Moreover, the pathophysiological mechanism of female LUTS remains unclear [5].

Although not officially registered for the treatment of female LUTS [6], α1-blockers have been used to alleviate LUTS in women based on their presumed activity in the relief of functional bladder outlet obstruction [7]. In part, the current use of α1-blockers for female LUTS is based on their remarkable effects in the treatment of male LUTS [8]. Published clinical trials evaluating the use of α1-blockers for female LUTS have remained limited in prevalence and participation and have produced contradictory results. The lack of well-designed randomized clinical trials (RCTs) further limits meaningful conclusions. Thus, the authors in the present study conducted a systematic review and meta-analysis assessing the effect of α1-blockers on female LUTS to address some of the current controversies and to obtain additional statistical information.

MATERIALS AND METHODS

This systematic review was registered in PROSPERO (CRD42 018096181).

RESULTS

Systematic Review Process

The authors in the present study used the PRISMA framework to analyze and summarize our systematic analysis and meta-review process (Fig. 1). Only published studies were included to minimize publication bias. The initial database searches identified 482 articles, which were reduced to 406 following duplicate removal. Subsequently, title and abstract review eliminated 377 articles, with only trials published in English included in the present study. An analysis of the remaining full-text articles with respect to the inclusion criteria resulted in the final selection of 14 studies (Table 1) with a total of 1,319 patients [5,6,16-27]. Of these studies, 6 were RCTs and 8 were open-label prospective studies. The α1-blockers used in these studies included alfuzosin, tamsulosin, and terazosin. The duration of treatment ranged from 4 to 12 weeks across all studies. In all publications, urinary symptom scores were assessed using the IPSS or AUASS. These 2 questionnaires consist of the same 9 questions about incomplete emptying, frequency, intermittency, urgency, weak stream, straining, nocturia, and quality of life due to urinary symptoms (Supplementary Figs. 1, 2).

Fig. 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) flowchart. Chart presenting the flow of information through the different phases of the systematic review, together with the utilized exclusion criteria.

Table 1.

Characteristics of the selected studies

Comparisons of Pretreatment and Posttreatment Outcomes

Subgroup analyses were performed by study design and type of α1-blocker (Fig. 2, Supplementary Fig. 3).

Fig. 2.

Forest plots comparing pre-post study outcomes (subgroup-analysis by study design). The evaluated outcomes included urinary symptom score (A), maximal flow rate (B), and postvoid residual urine volume (C). P, prazosin; T, terazosin; SD, standard deviation; CI, confidence interval; df, degrees of freedom.

Urinary symptom score

Urinary symptoms score was analyzed in 9 studies with 879 patients (Fig. 2A). Posttreatment outcomes demonstrated statistically significant symptom relief relative to pretreatment (MD, -5.85; 95% CI, -7.71 to -3.99, P<0.00001). Heterogeneity was observed among the included studies (I²=89%; P<0.00001).

Qmax

The analysis of Qmax comprised 13 studies with 1,003 patients (Fig. 2B). Qmax significantly increased following treatment (MD, 3.67 mL/sec; 95% CI, 2.76–4.59 mL/sec, P<0.00001). Heterogeneity among the included studies was observed (I²=72%; P<0.0001).

PVR volume

PVR volume was assessed on the basis of 12 studies with 938 patients (Fig. 2C). Posttreatment PVR values significantly decreased relative to pretreatment values (MD, -28.46 mL; 95% CI, -34.99 to -21.93 mL; P<0.00001). Statistical heterogeneity was not observed (I²=47%; P=0.04).

Outcome Comparisons Between Α1-Blocker and Placebo Groups

Urinary symptom score

Urinary symptoms score was analyzed in 4 studies with 396 patients (Fig. 3A). Statistically significant symptom relief was observed following α1-blocker treatment relative to placebo (MD, -1.60; 95% CI, -2.68 to -0.51; P=0.004). Between-study heterogeneity was observed (I²=68%; P=0.03).

Fig. 3.

Forest plots comparing outcomes between α1-blocker and placebo groups. Evaluated outcomes included urinary symptom score (A), maximal flow rate (B), residual urine volume (C), and adverse events (D). SD, standard deviation; CI, confidence interval; df, degrees of freedom.

Qmax

The analysis of Qmax comprised 4 studies with 396 patients (Fig. 3B). Treatment with α1-blockers did not significantly alter Qmax relative to placebo (MD, 0.05 mL/sec; 95% CI, -0.75 to 0.83 mL/sec; P=0.91). Heterogeneity among the included studies was not observed (I²=0%; P=0.50).

PVR volume

PVR volume was analyzed on the basis of 2 studies with 234 patients (Fig. 3C). No significant difference in PVR volume was observed between the α1-blocker and placebo groups (MD, -8.10 mL; 95% CI, -32.32 to 16.12 mL; P=0.51). Between-study heterogeneity was observed (I²=91%; P=0.001).

Adverse events

Adverse events were reported in 4 studies with 403 patients (Fig. 3D). No significant difference in adverse events was observed between the α1-blocker and placebo groups (OR, 1.69; 95% CI, 0.56-5.08, P=0.35). Between-study heterogeneity was observed (I²=68%; P=0.02).

Publication Bias, Quality Assessment, and Qualitative Risk of Bias

The funnel plot analysis of publication bias of the pre-post studies demonstrated a certain degree of symmetry (Fig. 4). The Egger test revealed no statistical evidence of publication bias in the meta-analysis of Qmax and PVR volume (P=0.77 and P=0.18, respectively).

Fig. 4.

Publication bias analysis. Funnel plots for maximal flow rate (A) and postvoid residual urine volume (B).

The Downs and Black scale was utilized to assess the quality of 8 prospective trials using the reporting, external validity, bias, confounding, and power assessment categories (Table 2). The Downs and Black scores of the evaluated studies ranged from 12 to 15. The risk of bias graph and assessment of RCTs are summarized in Figs. 5 and 6. One study did demonstrate a statistically high risk of other biases (early stop due to low recruitment and enrollment rate).

Table 2.

Downs and black scale for quality assessment of non-RCT and single-arm studies

Fig. 5.

Risk of bias assessment graph. Risk of bias was assessed using the Cochrane Risk of Bias Tool.

Fig. 6.

Study-specific bias risk. Risk of bias was assessed using the Cochrane Risk of Bias Tool. A green plus sign indicates a low risk of bias, a yellow question mark indicates an unclear risk of bias, and a red minus sign indicates a high risk of bias.

The results of the GRADE quality assessment for direct evidence of each comparison are shown in Tables 3-5. Of the 10 comparisons, certainty was moderate in 5 and low in 5.

Table 3.

Results of the GRADE quality assessment for evidence of comparisons between pretreatment and posttreatment outcomes

Table 4.

Results of the GRADE quality assessment for evidence of comparisons between alpha-1 blocker and placebo groups (treatment outcomes)

Table 5.

Results of the GRADE quality assessment for evidence of comparison between alpha-1 blocker and placebo groups (adverse events)

DISCUSSION

Large-population studies have indicated that LUTS are highly prevalent in women and men over 40 years of age [28]. Storage LUTS, including urinary incontinence, are more prevalent in women. Conversely, voiding LUTS are more common in men. However, women also suffer from voiding LUTS despite the absence of obvious anatomic obstructions, such as benign prostatic obstructions seen in men. In men with benign prostatic hyperplasia, α1-blockers relieve LUTS via smooth muscle relaxation in the prostate and the bladder neck. Thus, many clinicians have prescribed similar treatments to women with LUTS based on the assumption that α1-blockers will similarly affect the female bladder neck. Some open-label prospective trials [16-19,21,23,24,27] and RCTs [5,6,20,22,25,26] have examined the effect of α1-blockers on female voiding dysfunction. However, the outcomes of these studies have not been consistent. The lack of well-designed RCTs with large study populations further prevents the establishment of a consensus on the use of α1-blockers for LUTS in women. Therefore, the authors in the present study performed a systematic review and meta-analysis to assess the evidence and to provide more information regarding the efficacy of α1-blockers in the treatment of female LUTS.

Our meta-analysis demonstrated that α1-blockers have beneficial effects on female LUTS. Our study comprised 2 analyses: a comparison of urinary symptom scores and urodynamic parameters before and after α1-blocker treatment in 8 prospective, open-label studies and 5 RCTs, and the comparison of the same variables following α1-blocker and placebo treatments in 4 RCTs. The first analysis indicated that α1-blockers are effective in reducing urinary symptom scores (-5.85 points), increasing Qmax (+3.67 mL/sec), and decreasing PVR urine volume (-28.46 mL). Recent studies have suggested that α1-blockers may provide an effective treatment effect for female functional bladder outlet obstruction. Kumar et al. [29] reported that 50% of women with functional bladder outlet obstruction experienced improvements in urinary symptoms, Qmax, and PVR after treatment with α1-blocker therapy alone. Yamanish et al. [30] also reported that female patients with detrusor underactivity showed improvements in the total IPSS (-6.3 points) and PVR volume (48 mL) after 4 weeks of α1-blocker treatment, and that storage and voiding symptom scores were reduced.

The second analysis demonstrated that α1-blockers are more effective in reducing urinary symptoms than placebo, but with an MD of only 1.6 points. Furthermore, no significant differences in Qmax and PVR volume between the α1-blocker and the placebo groups were observed. Zhang et al. [31] previously performed a meta-analysis comparing the effects of tamsulosin and various controls (placebo, anticholinergics, or combination therapy) in female LUTS patients. Our meta-analysis included studies using not only tamsulosin, but also other α1-blockers, such as alfuzosin and terazosin. In addition, only placebo control arms were included in our analysis. Furthermore, in contrast to Zhang and colleagues, the authors in the present study also added prospective open-label studies to compare pre- and posttreatment clinical variables in our analysis of the effects of α1-blockers on female LUTS.

Although our meta-analysis indicated positive effects of α1-blockers on both subjective and objective variables in the treatment of LUTS, we recommend caution in the interpretation of the results. Bias is likely in simple pre-post comparisons in clinical studies of voiding dysfunction. For example, as participants become accustomed to the test method (i.e., uroflowmetry), the results of the subsequent tests can improve. A strong behavioral factor has been observed in the placebo response of LUTS patients, as revealed by voiding diaries that make patients aware of their voiding habits, as well as of the timing and quantity of fluid intake [32]. In addition, significant placebo effects cannot be avoided in open-label studies. Thus, the clinical implications of our pre-post study meta-analysis are limited.

In contrast, the second meta-analysis, targeting placebo-controlled RCTs, has more important clinical implications. This meta-analysis, which demonstrated a significant effect of α1-blockers on urinary symptom relief, suggests that α1-blockers should be considered for the treatment of women suffering from LUTS. However, a <2-point MD in urinary symptom scores and an absence of significant differences in objective measurements were observed between the α1-blocker and placebo groups. These findings may be partly explained by the placebo effect. The involvement of neurotransmitters in the urination process can account for the LUTS placebo response, at least with respect to the subjective outcome. A placebo-induced dopamine release in LUTS patients has been hypothesized to improve bladder function [33]. Several studies have examined the specific factors influencing the placebo response in LUTS patients. Placebo therapy rapidly produces a significant improvement in Qmax and relieves the symptoms of benign prostatic hyperplasia, with fading beneficial effects remaining even after 2 years [34]. Another study also suggested that the placebo effect is often rapid, but declines over time [35]. In the present meta-analysis, the treatment periods in the RCTs ranged from 4 to 12 weeks. Thus, it is possible that the peak placebo effect was observed in the urinary symptom score and Qmax measurements due to the short follow-up period. Nickel [34] also demonstrated that placebo responses were higher in patients with small or normal prostates. Assuming that female LUTS are more similar to LUTS in men with smaller prostates, a stronger placebo effect in women may further explain the observed limited effect of α1-blockers on female LUTS.

The authors in the present study compared adverse event rates between α1-blockers and placebo in the studies that reported safety outcomes for the α1-blockers and found no statistically significant difference in the adverse event rate of the α1-blockers compared to placebo [5,6,25,26]. The side effects of α1-blockers reported in the studies were dizziness, headache, asthenia, GI discomfort, and edema. The most common adverse events were dizziness and headache. Although the results of this study showed no difference in adverse events between α1-blockers and placebo, clinicians should always use caution regarding side effects while assessing a patient’s condition.

Among the RCTs analyzed, Lee et al. [5] applied relatively strict inclusion criteria (AUASS ≥15 and Qmax <15 mL/sec and/or PVR volume >150 mL). However, the other 3 RCTs used very simple selection criteria (IPSS>8), with no specific cutoffs for Qmax or PVR volume [6,25,26]. Such broad criteria may not select for α1-blocker-responsive candidates. The meta-analysis was further limited by the small sample sizes and the methodological quality of the included RCTs. Moreover, between-trial differences in α1-blockers and treatment periods also likely affected the results. Thus, high-quality RCTs, with large sample sizes, adequately defined study participants, and long-term treatment and follow-up, are required to overcome these limitations and to draw more reliable conclusions.

In conclusion, our results suggest that α1-blockers may be effective in the treatment of female LUTS. However, certain limitations of the study, which could have led to inevitable bias, may have masked the effects of α1-blockers in the treatment of female LUTS. Thus, the results of this study should be interpreted with caution. Although α1-blockers are effective for treating female LUTS patients, the effect of α1-blockers on female LUTS should be assessed according to the underlying cause. In addition, the role of α1-blockers in combination therapy with other drugs should also be investigated.

SUPPLEMENTARY MATERIALS

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