Comparative efficacy and safety of alpha-blockers as monotherapy for benign prostatic hyperplasia: a systematic review and network meta-analysis

Despite the availability of various drugs for benign prostatic hyperplasia (BPH), alpha(α)-blockers are the preferred first-line treatment. However, there remains a scarcity of direct comparisons among various α-blockers. Therefore, this network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of α-blockers in the management of BPH. A comprehensive electronic search covered PubMed, Embase, Ovid MEDLINE, and Cochrane Library until August 2023. The primary endpoints comprised international prostate symptom score (IPSS), maximum flow rate (Qmax), quality of life (QoL), and post-void residual volume (PVR), while treatment-emergent adverse events (TEAEs) were considered as secondary endpoints. This NMA synthesized evidence from 22 studies covering 3371 patients with six kinds of α-blockers with 12 dose categories. IPSS has been considerably improved by tamsulosin 0.4 mg, naftopidil 50 mg and silodosin 8 mg as compared to the placebo. Based on the p-score, tamsulosin 0.4 mg had the highest probability of ranking for IPSS, PVR, and Qmax, whereas doxazosin 8 mg had the highest probability of improving QoL. A total of 297 adverse events were reported among all the α-blockers, silodosin has reported a notable number of TEAEs. Current evidence supports α-blockers are effective in IPSS reduction and are considered safer. Larger sample size with long-term studies are needed to refine estimates of IPSS, QoL, PVR, and Qmax outcomes in α-blocker users.


Literature searches
A comprehensive electronic search of PubMed, Ovid MEDLINE, EMBASE and the Cochrane library, was carried out to identify the eligible studies.Additionally, a manual search in Google Scholar was performed.The initial search strategy was developed in the PubMed database, and the search strings used for electronic searches consist of combinations of keywords and medical subject headings (MeSH) terms like "alpha-blockers", "Alfuzosin", "Tamsulosin", "Doxazosin", "Terazosin", "Silodosin", "Naftopidil", "Benign prostatic hyperplasia" and "Randomised controlled trial".A methodological search filter was adopted to identify RCTs, and the search was limited to English-language publications.This search strategy serves as a template for alternative search algorithms customized to different databases, such as EMBASE, Ovid MEDLINE, and the Cochrane Library.In addition, the reference lists of the selected studies and review articles were hand-searched for additional potentially pertinent studies.

Study eligibility
This systematic review and NMA sought studies that met the PICO (P-population, I-intervention, C-comparator, O-outcome) framework.RCTs that investigated the efficacy and safety of α-blocker in men aged 45 and above with LUTS related to BPH were included.However, monotherapy with α-blockers were eligible, including selective (i.e., terazosin and doxazosin) and uroselective (tamsulosin, silodosin, alfuzosin and naftopidil), with no restrictions on α-blocker dosage 18 .As the research question also explored placebo-controlled trials, therefore the placebo serves to be the comparator.The key outcomes of interest were IPSS, QoL, PVR and Q max.TEAEs are also evaluated in order to provide a comprehensive overview of these drugs.Reviews, editorials, case reports, conference abstracts, studies that deviated from the aimed outcomes or with incomplete results and articles published in non-English were excluded.

Study screening
Two reviewers (BY and AP) worked independently to screen citations and evaluate full-text records for eligibility.Initially, only the title and abstract were screened, and the full texts of presumably pertinent articles were subsequently assessed for ultimate inclusion.A cross-check has been performed at both stages to ensure full compliance with eligibility requirements.Disputes regarding the full-text articles were rectified through discussion with a third reviewer (DB).

Data extraction
Two reviewers (BY and AP) individually extracted the following information into a spreadsheet: study characteristics (Title, first author, publication year, country, duration of treatment), population (study setting, sample size, baseline demographics), characterization of interventions (drug name and dose), and outcomes (reduction in IPSS and PVR, improvement in QOL, Qmax).Disagreements among reviewers were resolved by discussion or, if necessary, communicating with a third reviewer (DB).If any imperative information about study outcomes was missing or unclear in the published studies, the authors were contacted to seek clarification or additional data.

Risk of bias
The methodological quality of each included RCT was critically appraised employing the revised Cochrane Risk of Bias Tool (ROB 2.0) 19 .This tool captures six main sources of bias, comprising random sequence generation,

Statistical analysis
To account for certain methodological and clinical heterogeneity across studies, and to acquire the optimal generalizability in the meta-analytical treatment effects, we adopted a random-effects model 20 .As all the efficacy outcomes are continuous data, the effect size was computed as standardised mean difference (SMD) along with 95% confidence intervals (CI), and the outcome data was compiled using direct and indirect evidence employing a frequentist approach.
Statistical analysis was carried out using the "netmeta" package of R Studio and data were analysed following the intention-to-treat approach.A network plot of interventions was used to visualise the evidence gathered and offered a succinct overview of its characteristics.Direct evidence has gathered by pair-wise meta-analysis, while indirect evidence was obtained through indirect comparisons.The treatments were ranked using p-scores derived from the surface under the cumulative ranking curve (SUCRA).Higher p-scores tend to indicate a higher probability of being the most effective treatment 21 .In order to evaluate inconsistency, both global and local approaches were utilized.Under the presumption of a full design-by-treatment interaction random effects model 22 , the Q test and the I 2 statistic are adopted to evaluate consistency 23 .The local approach distinguishes indirect from direct evidence (SIDE) using the back-calculation method.The comparison-adjusted funnel plot was utilized to evaluate small-study effects for each outcome with ≥ 10 studies, where the overall treatment effect for every comparison was estimated employing random-effect meta-analysis model 24 .All eligible drugs have been ordered from oldest to newest according to their international market authorisation dates.Furthermore, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) ratings were deployed to assess the certainty of evidence in networks employing the Confidence In Network Meta-Analysis (CINeMA) framework 25 .
In terms of study quality, 15 trials (68.18%) exhibited a low risk of bias, three trials (13.64%) had a moderate risk of bias, and four trials (18.18%) had a high risk of bias (Table 2).

Quality of life (QoL)
13 RCTs including 6 interventions in 12 dose categories with 2,783 participants contributed to the comparison of the improvement in QoL (Fig. 2b).Fourteen comparisons estimated the treatment effect derived from direct evidence, 58 comparisons with indirect evidence and 7 comparisons with mixed evidence.Compared to the placebo, none of the comparison reached statistical significance in improving QoL (Fig. 3b).Doxazosin 8 mg has the highest probability of improving QoL, although the results were imprecise (Table S3).According to the pairwise comparisons, doxazosin 8 mg (− 1.35 [− 4.68; 1.98]) improves QoL compared to placebo (Table S2).Additionally, the Q consistency test showed a substantial heterogeneity for this evaluation (I 2 , 83.04%) (Appendix S1).
Vol:.( 1234567890 2c).Fifteen comparisons estimated the treatment effect derived from direct evidence, 51 comparisons with indirect evidence and 11 comparisons with mixed evidence.Compared to the placebo, none of the comparisons showed statistical significance in reducing PVR (Fig. 3c).Tamsulosin 0.4 mg and naftopidil 50 mg had the highest probability of improving PVR, with a p-score of 0.89, however, the results were imprecise (Table S5).According to the pairwise comparisons, tamsulosin 0.  S4).Additionally, the Q consistency test showed a no heterogeneity for this evaluation (I 2 , 0%) (Appendix S1).
Maximum urinary flow rate (Qmax) 16 RCTs including 6 interventions in 13 dose categories with 3,114 participants contributed to the comparison of the improvement in Qmax (Fig. 2d).Twenty comparisons estimated the treatment effect derived from direct evidence, 60 comparisons with indirect evidence and 15 comparisons with mixed evidence.Compared to the placebo, none of the comparisons showed statistical significance in improving Qmax (Fig. 3d).Tamsulosin  S8.

Evaluation of evidence quality
The degree of certainty of evidence for each outcome has been depicted in Figure S6, S7, S8, S9.About half of the comparison are moderate to low level confidence rating for IPSS vs placebo.Despite this, it was low for all other comparisons owing to imprecision and incoherence.However, the results of local and global approaches for IPSS showed inconsistent while all the other outcomes were found consistent.The quality scoring of the included studies is illustrated in the Figure S5.Furthermore, visual inspection of the comparison-adjusted funnel plots found the evidence of small-study effects for all outcomes (asymmetrical funnel plot) which indicates presence of potential publication bias (Figs.S1, S2, S3, S4).

Discussion
Although there are several therapeutical options for BPH presently, pharmacological therapy has become standard care and is widely recommended by clinical guidelines 7 .American Urological Association (AUA) and Canadian Urological Association (CUA) guidelines recommend α-blockers as the first-line drug for BPH 45,46 .
Despite their rapid onset of action, efficacy and modest frequency and intensity of adverse effects, α-blockers are considered as an excellent choice of therapy for BPH associated LUTS.The underlying mechanism of α-blockers is to inhibit the effect of norepinephrine produced endogenously on smooth muscle cells of the prostate; thereby reducing prostatic tone and consequently, urethral obstruction 47,48 .Several α-blockers have been approved by the FDA for the treatment of BPH, including terazosin, alfuzosin, doxazosin, tamsulosin and silodosin whereas naftopidil is only approved in Japan [49][50][51] .Various clinical trials have been performed to investigate the effectiveness of α-blockers for BPH, however direct comparisons among many drugs are still lacking [12][13][14] .At present, none of the NMA have extensively evaluated the efficacy of these agents within the class in terms of the majority of outcomes (IPSS, QoL, PVR, Qmax) as well as TEAEs.This NMA focused on 22 RCTs, which included 3271 patients randomly assigned to 6 kinds of α-blockers or placebo with 12 dose categories.Our study revealed that among all the α-blocker monotherapy, www.nature.com/scientificreports/tamsulosin 0.4 mg is more effective in improving the IPSS, PVR and Qmax, compared to a placebo, as well as the highest-ranked treatment option for these outcomes based on the rank test.Silodosin is considered to be having the highest selectivity for α1A adrenoreceptors in comparison to other α-blockers.In-vitro studies have shown that the affinity of silodosin and tamsulosin for α1A adrenoreceptors over α1B adrenoreceptors was 580-fold and 55-fold respectively.Based on this several clinical trials have also shown that silodosin has greater or comparable www.nature.com/scientificreports/efficacy to tamsulosin.However, our NMA contradicts the above observations 13,44 and it clearly suggests the so called highly selective α-blocker, silodosin is not superior to tamsulosin in terms of clinical outcomes.This will help urologists in better counselling the BPH patients with regard to efficacy of different α-blockers.All the included α-blockers in our study showed a promising effect in reducing the IPSS.On the other hand, α-blockers www.nature.com/scientificreports/did not significantly improve QoL, although they showed numerically better results.Even though, the pairwise comparison has shown that doxazosin 8 mg considerably improves QoL more than other α-blockers and is the highest-ranked treatment choice in the rank test.
Most guidelines routinely recommended using a symptom questionnaire to evaluate the patient's symptoms.IPSS, is the most ordinarily preferred scoring system, which is based on the American Urological Association Symptom Index (AUA-SI) 15,16 .It comprises eight questions, seven of which explore urinary symptoms and one on the overall quality of life 52 .All of the included α-blockers significantly reduced IPSS within the first 2 weeks of treatment.Controlled studies suggest that α-blockers often lower the IPSS by 30-40% 47 .In addition to their remarkable efficacy, α-blockers are the least expensive and well-tolerated of the drugs used to treat LUTS 16,53 .
The included studies validated the overall safety profile, with the proportion of AEs ranging mild to moderate.The most commonly reported AEs were ejaculation disorder, dizziness, diarrhoea, nasal congestion, drowsiness and postural hypotension.Moreover, for each of the aforementioned α-blockers, dizziness was reported.Wang et al. observed similar findings, stating that the most commonly reported AEs with α-blockers were ejaculation disorders, nasopharyngitis, and vasodilation effects such as asthenia, dizziness, headache and hypotension 15 .As compared to other α-blockers, silodosin elicits a notable number of AEs followed by tamsulosin and doxazosin and the most predominant adverse effects were ejaculation dysfunction, dizziness, and hypotension.In addition to corroborating our findings, investigations on those most recent drug treatments for LUTS also concurred that silodosin have a higher AE profile than the other therapies, exhibiting with a higher rate of ejaculation dysfunction 54,55 .However, α-blockers monotherapies are generally safe with relatively few AEs.This is the first robust network meta-analysis purely focused on α-blockers, considering the majority of outcomes (IPSS, QoL, PVR, Qmax) along with TEAEs.In 2015, Yuan et al. performed a NMA of RCTs for evaluating the comparative effectiveness of monodrug therapies in BPH 16 .However, outcomes such as PVR and QoL were not considered.Moreover, numerous studies were published after 2015 (36.4%), resulting in the up-to-date comparison of interventions.Studies conducted by Lepor et al. found that when comparing different α-blockers, it is imperative to consider that efficacy and safety are dose-dependent.As a result, observed differences in efficacy and toxicity may be related to diverse levels of α1-blockade achieved rather than inherent pharmacological advantages of the specific drug 8 .We compared α-blockers in a dose-dependent way to benefit the comparative efficacy and safety at different dose levels.Furthermore, the selected studies had similar study designs, selection criteria, and patient characteristics with few exception (duration of treatment) thus, supporting exchangeability.Exchangeability across the trials were conceptually considered and the NMA findings were interpreted accordingly.These factors enhance the credibility of the comparisons generated.Besides, the overall quality of the studies selected was found satisfactory.
Although we performed a comprehensive systematic review and NMA of α-blockers, there are still constraints to consider when interpreting the findings.This review focused on four outcomes, but there were limited data available for QoL, PVR, and Qmax as compared to IPSS.The majority of comparisons for outcomes such as PVR and QoL exhibited low certainty of evidence with the CINeMA framework, predominantly implying the risk of bias from the open-label trials and imprecision owing to a relatively small number of trials.Secondly, α-blockers can minimize both storage and voiding LUTS, however, prostate size has no effect in shortterm studies (≤ 1 year) 56,57 .The conventional clinical treatment for larger prostate size requires a prolonged treatment period 15 .Ipso facto, the limited duration in the included RCTs (50% of studies were ≤ 8 weeks and 45% ≤ 12 weeks) impede the estimation of long-term effects of α-blockers.Furthermore, this study assessed the efficacy and safety of six different kinds of α-blockers, including five drugs approved by the US FDA (terazosin, alfuzosin, doxazosin, silodosin, and tamsulosin) for BPH while naftopidil is only approved in Japan.As a result, the findings of naftopidil cannot be generalised.Furthermore, the majority of studies were conducted in Asian countries, which could impact the broader applicability of the results.The safety of different kinds of α-blockers www.nature.com/scientificreports/ was not evaluated using NMA due to a lack of information and the diversity of TEAEs.When interpreting the outcomes of this study, it is imperative to consider the imprecision, heterogeneity and incoherence inherent in the effect estimates.

Conclusion
All the included α-blockers showed reduction in IPSS whereas tamsulosin 0.4 mg outperforms the other α-blocker monotherapies in terms of improving IPSS, PVR, and Qmax.Moreover, larger sample sizes along with longerterm studies are required to refine our estimates of IPSS, QoL, PVR, and Qmax among α-blocker users.Silodosin elicits a notable number of AEs however, dizziness was a common AE observed for all α-blockers.Despite the advancing volume of evidence on the α-blocker, there remains a paucity of evidence demonstrating comparative safety in terms of serious and unexpected outcomes.Even though results provide a pragmatic evaluation of six different types of α-blockers that can aid in treatment decisions, direct head-to-head comparisons are required to validate these findings.

Figure 3 .
Figure 3. Network plot comparing individual α-blockers on international prostate symptom score (IPSS), quality of life (QoL), post-void residual volume (PVR) and maximum flow rate (Q max).The width of the edge is proportional to the number of trials comparing the two drugs, and the node represents the type of treatment.Tam = tamsulosin, Alfu = alfuzosin, Naf = naftopidil, Tera = terazosin, Dox = doxazosin, Sil = silodosin.

Table 1 .
Study characteristics in brief.a As some studies report more than one outcome, the values in this category do not match the totals.IPSS, International prostate symptom score; Q max, maximum flow rate; QoL, quality of life; PVR, post-void residual.

Table 2 .
Study characteristics in detail.

Table 3 .
Ranking probability based on p-score for IPSS reduction.The higher scores reflected a higher probability of being the most effective treatment.