Comparing effects of alpha-blocker management on acute urinary retention secondary to benign prostatic hyperplasia: A systematic review and network meta-analysis

Abstract

Background

To compare the effects of different alpha-blocker regimes on acute urinary retention (AUR) and the success rate of trial without catheter (TWOC) among patients with AUR secondary to benign prostatic hyperplasia (BPH) to determine the most effective regime.

Methods

A comprehensive literature search was performed using PubMed/Medline, Embase, and Cochrane Library up to June 2021. Studies that compared successful TWOC rates between each alpha-blocker regime in patients with AUR secondary to BPH were included. The outcome was the odds ratio of successful TWOC after AUR between groups (each regime of alpha blocker or placebo). To indirectly compare the effect of each alpha-blocker regime on the outcome (successful TWOC rate), a network meta-analysis was conducted using a Bayesian hierarchical random effects model for dichotomous outcomes.

Results

In total, 13 randomized controlled trials were included in the present study. There were six nodes (five alpha-blocker regimes and placebo) and eight comparisons in the evidence network plot. Compared to placebo, alfuzosin, silodosin, tamsulosin, and alfuzosin plus tamsulosin resulted in significantly higher TWOC success rates, whereas doxazosin did not show a significant difference in TWOC success rate compared to placebo. Alfuzosin plus tamsulosin was ranked first, followed in order by tamsulosin, silodosin, alfuzosin, and doxazosin. There was no significant inconsistency in the results of this analysis.

Conclusions

Alpha blockers may increase the success rate of TWOC. This study evaluated the priority of the effect of several alpha-blocker regimens on AUR related to BPH, which is expected to be helpful in selecting the best medication for patients with AUR.

1. Introduction

Lower urinary tract symptoms (LUTS) are common problems faced by older men. The most common cause of LUTS in older men over 70 is benign prostatic hyperplasia (BPH). BPH typically begins in men in their 50s. It has been reported that 50% of men have histological evidence of BPH by the age of 60 and that 28% of men in their 70s suffer from moderate to severe BPH-related LUTS.¹ Although BPH is rarely life-threatening, acute urological complications such as acute urinary retention (AUR) may occur. AUR is considered the most serious complication involved in the progression of BPH. AUR is characterized by sudden and painful voiding difficulty, which has historically required urgent catheterization followed by prostatic surgery.^2,3

Trial without catheterization (TWOC) is defined as the removal of a catheter that has been inserted through the urethra into the bladder for the purpose of drainage during a trial to determine whether the patient can safely and naturally urinate without further catheterization. TWOC has become a standard practice around the world for male patients with BPH and AUR.⁴ TWOC has seen increased usage in response to the high morbidity and mortality associated with emergency surgery within a few days after AUR, along with the potential morbidity such as bacteriuria, fever, and urosepsis associated with prolonged catheterization.³

The evidence for the use of alpha-1-blockers before a TWOC is based on the fact that BPH-associated AUR may be continual to the sudden stimulation of α1-adrenergic receptors, as was suggested by Caine et al. in 1975.^3,5 Alpha-1-blockers can decrease smooth muscle tone in the prostate. Therefore, alpha-1-blockers are typically prescribed prior to initiating TWOC in an attempt to increase the likelihood of a successful TWOC.⁶

There have been several meta-analyses examining the effects of alpha blockers on AUR, with most studies suggesting that alpha blockers can increase the success rates of TWOC with a low incidence of adverse effects.^3,7, 8, 9, 10 However, Zeif et al.¹¹ reported that there is limited evidence available indicating that alpha blockers can increase the success rate of TWOC. The results of meta-analyses have been inconsistent, and an optimal alpha-blocker regime for patients with AUR has yet to be established. Therefore, the objective of this study was to conduct direct and indirect comparisons of the effects of different alpha-blocker regimes on the success rates of TWOC for patients with AUR secondary to BPH to determine the effects of alpha blockers on AUR and the most effective regime by performing a systematic review and network meta-analysis.

2. Materials And Methods

This systematic review was registered in PROSPERO (CRD42022314726).

2.1. Literature search

A comprehensive literature search was performed using PubMed/Medline, Embase, and Cochrane Library up to June 2021. The search used the following terms: relevant variants of “acute urinary retention” and “alpha blocker”. Two authors (YNG and DKK) independently reviewed the titles and abstracts of the identified studies according to the inclusion and exclusion criteria. Cases of disagreement were resolved through discussions with a third reviewer (JHK).

2.2. Inclusion and exclusion criteria

The eligibility of a study was evaluated according to the population, intervention, comparator, outcome, and study design (PICOS) approach and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹² Studies that compared successful TWOC rates between alpha blocker and placebo in patients with AUR were included. Studies that compared successful TWOC rates between each alpha-blocker regime in those patients were also included. We only included randomized clinical trial (RCT) research. There was also a language restriction: only English. The exclusion criteria were as follows: 1) non-human study, 2) non-adult study, and 3) inability to extract the data. We also excluded abstracts to avoid publication bias. The outcome was the odds ratio (OR) of successful TWOC after AUR between groups (each regime of alpha blocker or placebo).

2.3. Data extraction

Two authors (YNG and DKK) independently extracted the data using a predesigned form. Conflicts regarding the extracted data between the two authors were resolved through consensus. Extracted data included the author, study year, study design, study population, participant nationality, inclusion and exclusion criteria, participant demographics, definition of treatment success, treatment characteristics, conflict of interest information, and outcome results.

2.4. Study quality assessments and quality of evidence

The risk of bias in the included studies was evaluated using The Cochrane Collaboration's tool for assessing the risk of bias in randomized trials.¹³ The domain of The Cochrane Collaboration's tool consisted of random sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessment, incomplete outcome data, selective reporting, and others.

2.5. Statistical analysis

To indirectly compare the effect of each alpha-blocker regime on the outcome (successful TWOC rate), we conducted a network meta-analysis using a Bayesian hierarchical random effects model for dichotomous outcomes. This model can estimate treatment-specific effects and effect differences. Pooled estimates were obtained using the Markov Chains Monte Carlo method wherein each chain had 20,000 simulations and where the first 5,000 simulations were discarded as burn-in. We modeled dichotomous outcomes for each alpha-blocker regime of all trials and quantified the association between ORs with 95% credible intervals (CrIs) among studies (CrIs can be regarded as similar to conventional CIs). The selection of a random effects model for reported outcomes was based on the deviance information criteria. The node-splitting method was used to compute the inconsistency of the model. The results of the node-splitting analysis were considered to show no significant inconsistency when 95% CIs of inconsistency factors included zero or when there was a large probability value (P-value >0.05) for the comparison between direct and indirect effects. The relative effects were also assessed visually using relative effects table and plots. Probability values were summarized, and they are reported in the form of a rank probabilities plot. Network meta-analyses were conducted using R 3.4.3 (R development Core Team, Vienna, http://www.R-project.org) with the ‘GEMTC’ package.

3. Results

3.1. Systematic review process

The systematic review process that was followed is summarized in a PRISMA flow diagram (Fig. 1). The initial literature search identified a total of 340 studies. After removing duplicates, the titles and abstracts of 331 articles were reviewed in terms of the inclusion and exclusion criteria. After excluding ineligible articles, a full-text review was conducted for the remaining 87 articles and two more RCTs identified by a hand search. Finally, 13 RCTs were ultimately included in the present study. Table 1 presents detailed information on the final included studies.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-analysis flowchart.

Table 1.

Characteristics of eligible studies

Study	Country	Study design	Medication			Regime	Patients number			TWOC success			Definition of successful TWOC	Conflict of Interst
			Group1	Group2	Group3		Group1	Group2	Group3	Group1	Group2	Group3
McNeill et al.38 2005	United Kingdom	RCT	Alfuzosin 10 mg	Placebo		Once daily, 3d	238	122		146/236	58/121		Satisfactory voiding within the first 24 hours	Sanofi-Aventis
Tiong et al.39 2009	Singapore	RCT	Alfuzosin XL 10 mg	Placebo		Once daily, 2d	33	31		21/33	11/31		1. Voiding volume≥100 cc 2. PVR<150 cc	Not mentioned
Patil et al.40 2017	India	RCT	Tamsulosin 0.4 mg	Silodosin 8 mg		Once daily, 3d	80	80		54/80	48/80		1. Voiding volume≥100 cc 2. PVR<150 cc	None
Parikh et al.41 2020	India	RCT	Tamsulosin 0.4 mg	Silodosin 8 mg	Alfuzosin 10 mg	Once daily, 3d	18	17	15	11/18	10/16	9/15	PVR≤150 cc	None
Agrawal et al.42 2009	India	RCT	Alfuzosin 10 mg	Tamsulosin 0.4 mg	Placebo	Once daily, 3d	50	50	50	33/50	35/50	18/50	Satisfactory voiding within the first 24 hours	Not mentioned
Kara et al.14 2014	Turkey	RCT	Tamsulosin 0.4 mg	Alfuzosin 10 mg +Tamsulosin 0.4 mg		Once daily, 3 or 8d	35	35		19/35	27/35		1.Qmax>5 mL/s 2.Voiding volume>100 mL 3.PVR≤200 mL	None
Maldonado-Ávila et al.43 2014	Mexico	RCT	Tamsulosin 0.4 mg	Alfuzosin 10 mg	Placebo	Once daily, 4d	37	34	19	16/37	12/34	5/19	1. Voiding volume>100 cc 2. PVR<200 cc	None
Prieto et al.44 2008	Spain	RCT	Doxazosin 4 mg	No medication		Once daily, 31d	22	24		13/22	13/24		1. Qmax≥5 mL/s 2. Voiding volume≥100 mL 3. PVR≤100 mL	Pfizer
Kumar et al.45 2013	India	RCT	Silodosin 8 mg	Placebo		Once daily, 3d	30	30		23/30	11/30		1. Voiding volume≥100 cc 2. PVR<150 cc	None
McNeill et al.46 1999	United Kingdom	RCT	Alfuzosin SR 5 mg	Placebo		Twice daily, 2d	40	41		22/40	12/41		Satisfactory voiding within the first 24 hours	Lorex Synthelabo
Lucas et al.47 2005	United Kingdom	RCT	Tamsulosin 0.4 mg	Placebo		Once daily, 3 or 8d	71	70		34/71	18/70		1.Qmax>5 mL/s 2.Voiding volume>100 mL 3.PVR≤200 mL	Yamanouchi Pharma Ltd.
Al-Hashimi et al.48 2007	Iraq	RCT	Alfuzosin 10 mg	Placebo		Once daily, 3d	114	110		71/114	36/110		1.Qmax>5 mL/s 2.Voiding volume>100 mL 3.PVR≤200 mL	Not mentioned
Shah et al.49 2002	United Kingdom	RCT	Alfuzosin SR 5 mg	Placebo		Twice daily, 2d	34	28		17/34	16/28		PVR <200 cc	Lorex Synthelabo

COI, conflict of interest; PVR, post-void residual; Qmax, peak flow rate; RCT, randomized controlled trial; SR, sustained release; TWOC, trial without catheterization; XL, extended release.

3.2. Bayesian framework network meta-analysis

The network meta-analysis was performed using 13 studies. As shown in Fig. 2, there are six nodes (five alpha-blocker regimes and placebo) and eight comparisons in the evidence network plot. The width of each line is proportional to the number of trials comparing all treatment pairs, and the size of each node is proportional to the number of randomized participants.

Fig. 2.

Network plot of TWOC success rate. The width of each line is proportional to the number of trials comparing all treatment pairs. The size of each node is proportional to the number of randomized participants.

The network meta-analysis results are presented in Table 2 and Fig. 3. Compared to placebo, alfuzosin, silodosin, tamsulosin, and alfuzosin plus tamsulosin all resulted in significantly higher TWOC success rates, while doxazosin and placebo did not show any significant difference in TWOC success rate. The relative effect plot confirmed this result (Fig. 3).

Table 2.

Relative effect table

Comparison of included interventions: odds ratio (95% CrI). Each cell gives the effect of the column-defining intervention relative to the row-defining intervention.
Placebo	1.189 (0.335, 4.555)	2.120 (1.471, 3.114)	2.977 (1.558, 6.055)	3.205 (2.137, 4.911)	9.711 (2.758, 34.616)
	Doxazosin	1.773 (0.444, 6.610)	2.457 (0.568, 10.650)	2.663 (0.681, 10.298)	8.030 (1.313, 49.051)
		Alfuzosin	1.400 (0.705, 2.960)	1.507 (0.935, 2.435)	4.593 (1.221, 16.529)
			Silodosin	1.078 (0.544, 2.020)	3.226 (0.847, 12.945)
				Tamsulosin	3.027 (0.909, 10.259)
					Alfuzosin + Tamsulosin

Fig. 3.

Relative effect plot of TWOC success rate.

Alfuzosin plus tamsulosin was ranked first, followed in order by tamsulosin, silodosin, alfuzosin, and doxazosin (Fig. 4). There were six node-splitting models. The 95% CrI of inconsistency factors included an OR of one and P-values of >0.05 for the comparison between direct and indirect effects in all node-splitting models. There was no significant inconsistency in the results of this analysis.

Fig. 4.

Rank probabilities plot.

3.3. Quality assessment and qualitative risk of bias

The summary of the risk of bias assessment and the graph of risk of bias are shown in Fig. 5, Fig. 6, respectively. There were two main sources of bias in the included trials: The first was that the numbers of participants in some included trials were insufficient, which might have made it difficult to demonstrate the effectiveness of the alpha-blocker regime. The second limitation was that some included studies did not perform double blinding or were lacking evidence of assessments of bias.

Fig. 5.

Risk of bias assessment.

Fig. 6.

Risk of bias graph.

4. Discussion

A systematic review and network meta-analysis of male patients with TWOC treatments for AUR secondary to BPH were performed in this study. It was found that alfuzosin, silodosin, tamsulosin, or alfuzosin plus tamsulosin could significantly increase the TWOC success rate compared to placebo. Among various regimens of alpha blockers, alfuzosin plus tamsulosin combination showed the highest (p < 0.05) successful TWOC rate, followed in order by tamsulosin, silodosin, alfuzosin, and doxazosin. The combination therapy may be the most effective for TWOC and there is no difference in side effects with other single alpha-blocker therapy, so it is worth considering as the first or second-line treatment in AUR patients. Moreover, combination therapy of alpha was well tolerated. Three common adverse effects of combination therapy are headache, dizziness, and retrograde ejaculation.¹⁴ However, Kara et al.¹⁴ reported that the differences of incidence rate of adverse effects between single-dose therapy and double-dose therapy were statistically insignificant, and there was no severe adverse effect across the study. Nevertheless, our study included only one study on combination therapy of alpha blocker, so caution is needed in interpreting our results. And further studies on the effectiveness of combination therapy with alpha-blockers are needed to add more evidence.

Alpha-1-adrenergic receptors are abundant in the prostate and bladder neck.⁵ In patients with BPH, AUR might be caused by the sudden stimulation of adrenergic receptors, possibly as a result of infarction, which may increase smooth muscle tone in the prostate and its capsule. The use of alpha-1-adrenalgic receptor antagonists (alpha-1-blockers) can reduce prostate smooth muscle tone, thus reducing resistance to urinary flow.¹⁵ It can therefore be hypothesized that bladder outlet resistance plays an important role in the development of AUR in men with BPH and that alpha blockers may increase the chance of successful TWOC, as was originally suggested by Caine et al. in 1976¹⁶, if there is an adequate detrusor function.¹⁷

According to the American Urological Association (AUA) guidelines for BPH, physicians should prescribe alpha blockers before TWOC to patients with AUR secondary to BPH.¹⁸ These guidelines suggest that alfuzosin and tamsulosin can similarly increase the successful TWOC rate with recommendable evidence, although there is a lack of evidence with which to recommend silodosin and doxazosin. The EAU guidelines for LUTS do not include any detailed recommendations for AUR related to BPH. However, they have strongly recommended the use of alpha blockers for patients with moderate to severe LUTS.¹⁹ Although the European Association of Urology (EAU) guidelines suggest that alpha blockers cannot prevent AUR or reduce prostate size, a recent study has indicated that alpha blockers can especially improve AUR.²⁰ However, neither the AUA nor EAU guidelines mentioned a standardized definition of successful TWOC or the superiority among alpha blockers in increasing TWOC success rate.

There is limited evidence showing that patients with AUR can be managed with pharmacological or non-pharmacological treatments.²⁰ A systematic review on the management of AUR—which includes both pharmacological and nonpharmacological treatment options—has recommended the use of alpha-1 blockers prior to TWOC without recommending emergency surgical management.⁹ Alpha blockers such as alfuzosin, doxazosin, prazosin, tamsulosin, and terazosin, which are some of the more uroselective alpha-1 blockers that have recently been developed, are recommended as the first-line treatment for LUTS with moderate to severe symptoms due to BPH.^11,21 TWOC after treatment with alpha blockers is also the currently recommended treatment option for patients with AUR.²² Several alpha blockers that have been tested in patients with AUR have been shown to increase the rates of successful TWOC.²³ A recent meta-analysis showed that, compared to placebo, most alpha blockers provided significantly higher rates of successful TWOC, including alfuzosin (OR: 2.28, 95% CI: 1.55–3.36), silodosin (OR: 5.68, 95% CI: 1.84–17.5), and tamsulosin (OR: 2.40, 95% CI: 1.29–4.45), but not doxazosin (OR: 1.22, 95% CI: 0.38–3.93).²⁰ The duration of providing alpha blocker before TWOC remains under discussion. In a large retrospective study of 2,188 patients with AUR secondary to BPH, the duration of alpha-blocker therapy was varied from 3 to 7 days before the first voiding attempt.²⁴ The TWOC success rates after 3, 5, and 7 days of alpha-blocker therapy were 33.8, 33, and 33.7%, respectively (p = 0.98). Thus, increasing the duration of alpha blocker prior to TWOC seems to provide no significant benefit, with the level of evidence about this point remaining low.²³

Significant predictors of TWOC failure include age, AUA symptom score, prostate volume, intravesical prostatic protrusion (IPP), and bladder volume during AUR.²⁴ Several studies have commonly reported that older patients have a higher risk of TWOC failure than younger patients despite the different age criteria.24, 25, 26, 27 A decrease in the contractility of the detrusor muscle with increasing age is expected to be the reason behind the association between age and TWOC success rate.²⁸ Bhomi et al.²⁹ have shown that patients with lower AUA scores are significantly more likely to succeed in TWOC. However, Djavan et al.³⁰ have demonstrated that there is no significant correlation between AUA score and success rate of TWOC. Several studies have reported that a larger prostate volume is associated with the failure of TWOC whereas a smaller prostate volume is associated with the success of TWOC.^29,31,32 IPP refers to protruding median lobe of prostate into bladder. It can cause a ball-valve effect.²⁴ It has been urodynamically demonstrated that IPP is correlated with bladder outlet obstruction, and that the greater the protrusion, the more severe the obstruction.³³ Various studies have consistently shown that IPP is the most accurate parameter predicting the outcome of TWOC.^29,34,35 Prolonged bladder distention can lead to increased intravesical pressure accompanied with ischemia of bladder muscle. Prolonged intramural ischemia can cause nerve damage. It is believed that bladder over-distention may lead to loss of bladder tone.³⁶ However, bladder volume during AUR is a controversial predictor of TWOC.

There have been several PRISMA examining the effectiveness of using alpha blockers before TWOC for patients with spontaneous AUR secondary to BPH.^3,7, 8, 9^,11,20 Although many studies have reported that using alpha blockers before TWOC could increase the success rate of TWOC compared to placebo, Karavitakis et al.²⁰ and Fisher et al.⁷ have shown that doxazosin has no benefit in increasing the success rate of TWOC compared to placebo. However, because the numbers of patients and studies with doxazosin have been small and as the evidence level of studies with doxazosin has been low, there is a lack of evidence with which to assess the effectiveness of doxazosin on successful TWOC. Also, the ineffectiveness of doxazosin might be affected by its dose. Keten et al.³⁷ reported that treatment of 8 mg doxazosin XL is an effective choice for patients who do not respond to treatment with 4 mg doxazosin XL with no changes in side effects. In our study, only the study that evaluated the effect of doxazosin 4 mg group was included, so further evaluation is required for the effect of doxazosin.

Our study showed similar results to those PRISMA. We also showed a ranking of alpha blockers through a network meta-analysis.

The present study has several strengths. Unlike the meta-analyses that have been performed thus far, we conducted a network meta-analysis for the first time, where we directly and indirectly compared various alpha blockers to analyze their relative effectiveness. Therefore, this study is expected to help in selecting the appropriate medication for patients with AUR secondary to BPH, thus reducing the economic cost and complications that were previously associated with this surgery.

However, this study also has several limitations. First, the numbers of trials and participants were relatively small. Because previous studies were mainly focused on alfuzosin or tamsulosin, there was a lack of information on some alpha blockers such as doxazosin. Moreover, because only one RCT about a combination regime—alfuzosin plus tamsulosin—was included, it is possible that the effect of this group was maximized. Therefore, the results of this study should be interpreted with caution. Thus, there is a need for more randomized controlled studies. Secondly, the results of this study might have been affected by inconsistencies in the duration and dosage of alpha-blocker therapy. Although there was no significant difference shown in the duration of alpha-blocker therapy, the level of evidence has remained low, as described previously, and there have been limited studies comparing the dosage of alpha blockers.²³ Finally, and most importantly, definitions of successful TWOC were not established in the included studies, which showed significant heterogenicity, thus decreasing the reliability of the results. There is therefore a need for a standardized definition of successful TWOC.

5. Conclusion

There is some evidence that alpha blockers may increase the success rate of TWOC. Thus, alpha blockers are recommended as the first-line treatment in patients with AUR secondary to BPH. However, there have been no studies showing which alpha blockers are more effective for AUR. Our study revealed the ranking of alpha blockers for AUR related to BPH, which is expected to aid in the selection of appropriate medication for patients with AUR. Further research studies with standardized definitions of TWOC and durations of prescribing alpha blockers are needed.

Conflicts of interest

The authors declare no conflict of interest.