benign prostatic hyperplasia case study

• Benign prostatic hyperplasia

Citation, DOI, disclosures and case data

At the time the case was submitted for publication Dagnechew Degefu had no financial relationships to ineligible companies to disclose.

Presentation

Difficulty voiding.

Patient Data

Suprapubic ultrasound revealed an enlarged prostate with a hypertrophied median lobe projecting into the bladder lumen.

Case Discussion

On ultrasound imaging, the findings of Benign prostatic hyperplasia can include:

Enlargement of the prostate gland, mainly in the central or transitional zone of the gland.

Increased echogenicity due to an increase in the number and size of both glandular and stromal cells.

Uniform or diffuse appearance of the central zone 1 .

• 1.Mitterberger M, Horninger W, Aigner F et al. Ultrasound of the Prostate. Cancer Imaging. 2010;10(1):40-8. doi:10.1102/1470-7330.2010.0004 -

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• Published: 15 May 2024

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

• Beema T Yoosuf   ORCID: orcid.org/0009-0001-3584-6212 1 ,
• Abhilash Kumar Panda 1 ,
• Muhammed Favas KT   ORCID: orcid.org/0000-0001-8068-6839 1 ,
• Saroj Kundan Bharti   ORCID: orcid.org/0000-0003-4221-0025 1 ,
• Sudheer Kumar Devana 2 &
• Dipika Bansal   ORCID: orcid.org/0000-0003-4520-3293 1  

Scientific Reports volume  14 , Article number:  11116 ( 2024 ) Cite this article

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• Medical research

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.

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Introduction.

Benign prostatic hyperplasia (BPH) is a ubiquitous urological disease that inevitably affects older men, occurring in up to 50% of men over 50 to 60 years, rising to 90% by age 80, and its predominance increases further with age 1 , 2 , 3 . BPH results from the noncancerous prostate gland enlargement induced by cellular hyperplasia of both glandular and stromal components 4 . Numerous sources of evidence reveal that in addition to ageing and family history, modifiable risk factors such as enlarged prostate, dyslipidemia, hypertension, hormonal imbalance, obesity, metabolic syndrome, diet, alcohol use, and smoking can collectively contribute to BPH 5 , 6 . Many individuals with BPH experience lower urinary tract symptoms (LUTS) in the form of irritative (frequency, nocturia and urgency) and obstructive urinary symptoms (hesitancy, intermittency, weak stream, incomplete bladder emptying and acute urinary retention (AUR)) 1 . LUTS correlated with BPH drastically compromises the quality of life (QoL), primarily disrupting sleep and daily activities 7 . Ipso facto, the intent of BPH treatment is to alleviate these troublesome and irritating symptoms 1 .

Pharmacological management of LUTS correlated with BPH has emerged over the last 25 years 6 . Existing medical therapy for BPH includes alpha-adrenergic receptor antagonists (α-blockers), anticholinergics, 5-alpha reductase inhibitors (5-ARIs) and phosphodiesterase inhibitors (PDE5-Is). Medical therapy is generally considered the initial treatment option for patients with moderate to severe LUTS while surgical approaches like transurethral resection of the prostate (TURP) are recommended for patients who had poor response to medical therapy or those with specific indications like refractory urinary retention, recurrent hematuria and those with severe bladder outlet obstruction leading to hydroureteronephrosis 4 . α-blockers are considered as the first-line drugs for treating BPH. Long-acting α-blockers, such as doxazosin, terazosin, tamsulosin, alfuzosin and silodosin, have been approved by the Food and Drug Administration (FDA) for the treatment of BPH 8 . They can mitigate symptoms by blocking endogenously secreted noradrenaline on smooth muscle cells in the prostate gland, thus reducing prostate tone and bladder outlet obstruction 9 .

Despite the fact that a large number of drugs are now available to treat BPH, α-blockers have a significant impact on improvement in International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual (PVR) and QoL 8 , 10 , 11 . Even though several clinical trials have been performed to explore the effectiveness of α-blockers for BPH, direct comparisons among these drugs are still lacking and there is conflicting information coming forward from meta-analysis 12 , 13 , 14 . For instance, a network meta-analysis (NMA) conducted on drug therapies for BPH assessed the effectiveness of multiple drug classes, instead of individual agents 15 . Furthermore, the most recently published NMA demonstrates merely IPSS, peak urine flow rate (PUF), and adverse events (AEs) among mono-drug therapies for LUTs related to BPH 16 . At present, none of the NMA have extensively evaluated the efficacy of these agents within the class in terms of the majority of outcomes as well as treatment-emergent adverse events (TEAEs). Therefore, the aim of the present study is to address the knowledge gap surrounding the comparative effectiveness of α-blockers for BPH based on available randomised controlled trials (RCTs) and rank these agents for clinical consideration.

This network meta-analysis (NMA) was executed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for NMA. We have applied frequentist network meta-analysis for its simplicity associated with the model formulation 17 . The protocol was registered in the Prospective Register of Systematic Reviews (CRD42022365398).

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, allocation concealment, missing outcome data, blinding, selective reporting, and other sources of bias. Each domain has been assigned a score of low, moderate to high.

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 .

Study selection

The literature search of across multiple databases yielded a total of 3019 potentially relevant citations (Table S9). After duplication screening, 2164 articles were found. Of these 2022 articles were removed after the initial title and abstract screening and retrieved 142 articles for full-text review. Finally, 22 RCTs (3271 participants) published from 2000 to 2023 were included (Fig.  1 ) 12 , 13 , 14 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 .

PRISMA flow chart of literature searches and results. ( PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Study characteristics

The included RCTs comprised the currently used six kinds of α-blockers with different dose categories including Naftopidil 25 mg, 50 mg and 75 mg, Silodosin 8 mg, Tamsulosin 0.2 mg and 0.4 mg, Alfuzosin 2.5 mg and 10 mg, Doxazosin 2 mg, 4 mg and 8 mg, Terazosin 0.5 mg with a total 3,371 participants. Among the 22 included studies, 10 were multi-centric 26 , 29 , 31 , 32 , 34 , 36 , 39 , 40 , 41 , 42 , while 12 were single-centric 12 , 13 , 14 , 27 , 28 , 30 , 33 , 35 , 37 , 38 , 43 , 44 . Nine trials were conducted in Japan 26 , 30 , 31 , 32 , 33 , 36 , 39 , 40 , 43 , five in India 12 , 13 , 14 , 37 , 44 , two in Korea 41 , 42 and one each in China 34 , Indonesia 29 , Europe 27 , Philippines 28 , Egypt 35 and Turkey 38 . Most studies (91%) were published after 2005 and, over half of the studies (50%) involved more than 100 patients. A majority of trials (72.73%) had treatment durations of more than 4 weeks. The mean (SD) age of the patients was 65.3 (6.7) years (Table 1 ). According to IPSS, the symptoms of patients in the included trials varied from moderate to severe, with a baseline mean (SD) of 18.1 (4.6). The baseline mean (SD) value of QOL was 4.2 (0.8), Q max (ml/s) 10.2 (3.4), and PVR (ml) 49.0 (34.2).

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 ).

Efficacy outcome

International prostate symptom score (ipss).

The NMA on IPSS included 22 RCTs with 6 interventions across 13 dose categories and 3271 participants (Fig.  2 a). The base-case estimates of the efficacy of α-blockers regimens on reducing IPSS are listed in Table 2 . Twenty-three comparisons estimated the treatment effect derived from direct evidence, 86 comparisons with indirect evidence and 18 comparisons with mixed evidence. Compared to the placebo, the NMA results found that three drugs had a significant effect on the reduction in IPSS, such as tamsulosin 0.4 mg (SMD: − 6.10; 95% CI: [− 8.74; − 3.47]), followed by naftopidil 50 mg (SMD: − 5.09; 95% CI: [− 8.29; − 1.89]) and silodosin 8 mg (SMD: − 3.63; 95% CI: [− 6.31; − 0.95]) (Fig.  3 a). The relative effectiveness was depicted using the league table (Table S1), all included α-blockers significantly reduce the IPSS compared to the placebo. Based on the p-score the highest-ranked treatment was tamsulosin 0.4 mg (0.89) and the lowest-ranked treatment was doxazosin 2 mg (0.22) (Table 3 ). Furthermore, the Q test of consistency showed substantial heterogeneity for this comparison (I 2 , 85.5%) (Appendix S1).

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.

Forest plot of interventions as measured by the international prostate symptom score (IPSS), quality of life (QoL), post-void residual volume (PVR) and maximum flow rate (Q max). Tam = tamsulosin, Alfu = alfuzosin, Naf = naftopidil, Tera = terazosin, Dox = doxazosin, Sil = silodosin.

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.  2 b). 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.  3 b). 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).

Post-void residual volume (PVR)

15 RCTs including 6 interventions in 10 dose categories with 2,761 participants contributed to the comparison of the reduction in PVR (Fig.  2 c). 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.  3 c). 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 0.4 mg (− 15.99 [− 3.15; 35.12]) reduces the PVR compared to placebo; followed by naftopidil 50 mg (− 15.88 [− 34.73; 2.97]), doxazosin 2 mg (− 12.44[− 36.96; 12.07]) and doxazosin 4 mg (− 6.34 [− 28.27; 15.58]) (Table 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.  2 d). 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.  3 d). Tamsulosin 0.4 mg has the highest probability of improving Qmax, with a p-score of 0.75 (Table S7). According to the pairwise comparisons, tamsulosin 0.4 mg (− 4.30 [− 9.37; 0.76]) reduces the Qmax compared to placebo; followed by terazosin 1 mg (− 3.99 [− 9.86; 1.89]), doxazosin 4 mg (− 3.39 [− 2.08; 8.86]) and naftopidil 75 mg (− 3.53 [− 3.03; 10.09]) (Table S6). Moreover, the Q consistency test showed a considerable heterogeneity for this evaluation (I 2 , 65.87%) (Appendix S1).

Safety outcomes

A total of 297 AEs was reported among the α-blockers (events/participants = 297/3009), silodosin (190/739) dominated with a notable number of AEs followed by tamsulosin (32/966), doxazosin (27/313), naftopidil (25/544), alfuzosin (20/416) and terazosin (3/31). The most prominent AEs included ejaculation dysfunction, dizziness and hypotension. The AEs associated with α-blockers have been listed in Table 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).

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, 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 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 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 short-term 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 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.

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 longer-term 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.

Data availability

The datasets gathered in the present study are considered for sharing upon reasonable requests to the corresponding author.

Park, T. & Choi, J. Y. Efficacy and safety of dutasteride for the treatment of symptomatic benign prostatic hyperplasia (BPH): A systematic review and meta-analysis. World J. Urol. 32 (4), 1093–1105 (2014).

Article   CAS   PubMed   Google Scholar  

Kim, J. H. et al. Efficacy and safety of 5 alpha-reductase inhibitor monotherapy in patients with benign prostatic hyperplasia: A meta-analysis. PLoS ONE. 13 (10), e0203479 (2018).

Article   PubMed   PubMed Central   Google Scholar  

Zitoun, O. A. et al. Management of benign prostate hyperplasia (BPH) by combinatorial approach using alpha-1-adrenergic antagonists and 5-alpha-reductase inhibitors. Eur. J. Pharmacol. 883 , 173301 (2020).

Wu, Y. J., Dong, Q., Liu, L. R. & Wei, Q. A meta-analysis of efficacy and safety of the new α1A-adrenoceptor-selective antagonist silodosin for treating lower urinary tract symptoms associated with BPH. Prostate Cancer Prostatic Dis. 16 (1), 79–84 (2013).

Calogero, A. E., Burgio, G., Condorelli, R. A., Cannarella, R. & La Vignera, S. Epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction. Aging Male. 22 (1), 12–19 (2019).

Article   PubMed   Google Scholar  

MacDonald, R. et al. Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: A systematic review. Aging Male. 22 (1), 1–11 (2019).

Sun, X. et al. Efficacy and safety of PDE5-Is and α-1 blockers for treating lower ureteric stones or LUTS: A meta-analysis of RCTs. BMC Urol. 18 (1), 30 (2018).

Lepor, H., Kazzazi, A. & Djavan, B. α-Blockers for benign prostatic hyperplasia: The new era. Curr. Opin. Urol. 22 (1), 7–15 (2012).

Zhang, J. et al. Alpha-blockers with or without phosphodiesterase type 5 inhibitor for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis. World J. Urol. 37 (1), 143–153 (2019).

Wang, X. H. et al. Systematic review and meta-analysis on phosphodiesterase 5 inhibitors and α-adrenoceptor antagonists used alone or combined for treatment of LUTS due to BPH. Asian J. Androl. 17 (6), 1022–1032 (2015).

Fusco, F. et al. Alpha-1 adrenergic antagonists, 5-alpha reductase inhibitors, phosphodiesterase type 5 inhibitors, and phytotherapic compounds in men with lower urinary tract symptoms suggestive of benign prostatic obstruction: A systematic review and meta-analysis of urodynamic studies. Neurourol. Urodyn. 37 (6), 1865–1874 (2018).

Perumal, C., Chowdhury, P. S., Ananthakrishnan, N., Nayak, P. & Gurumurthy, S. A comparison of the efficacy of naftopidil and tamsulosin hydrochloride in medical treatment of benign prostatic enlargement. Urol. Ann. 7 (1), 74–78 (2015).

Manohar, C. M. S. et al. Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH—A double-blind randomized trial. Cent. Eur. J. Urol. 70 (2), 148–153 (2017).

CAS   Google Scholar  

Patil, S. B., Ranka, K., Kundargi, V. S. & Guru, N. Comparison of tamsulosin and silodosin in the management of acute urinary retention secondary to benign prostatic hyperplasia in patients planned for trial without catheter. A prospective randomized study. Cent. Eur. J. Urol. 70 (3), 259–263 (2017).

Wang, X. et al. Comparative effectiveness of oral drug therapies for lower urinary tract symptoms due to benign prostatic hyperplasia: A systematic review and network meta-analysis. PLoS ONE. 9 (9), e107593 (2014).

Article   ADS   PubMed   PubMed Central   Google Scholar  

Yuan, J. Q. et al. Comparative effectiveness and safety of monodrug therapies for lower urinary tract symptoms associated with benign prostatic hyperplasia: A network meta-analysis. Medicine 94 (27), e974 (2015).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Shim, S. R., Kim, S. J., Lee, J. & Rücker, G. Network meta-analysis: Application and practice using R software. Epidemiol. Health. 41 , e2019013 (2019).

Capogrosso, P., Salonia, A. & Montorsi, F. Evaluation and Nonsurgical Management of Benign Prostatic Hyperplasia. Campbell-Walsh-Wein Urology 12th edn. (Elsevier, 2021).

Google Scholar  

Higgins, J. P. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343 , d5928 (2011).

Furukawa, T. A., Guyatt, G. H. & Griffith, L. E. Can we individualize the “number needed to treat”? An empirical study of summary effect measures in meta-analyses. Int. J. Epidemiol. 31 (1), 72–76 (2002).

Rücker, G. & Schwarzer, G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med. Res. Methodol. 15 , 58 (2015).

Higgins, J. P. et al. Consistency and inconsistency in network meta-analysis: Concepts and models for multi-arm studies. Res. Synth. Methods. 3 (2), 98–110 (2012).

Higgins, J. P., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. BMJ. 327 (7414), 557–560 (2003).

Chaimani, A., Higgins, J. P., Mavridis, D., Spyridonos, P. & Salanti, G. Graphical tools for network meta-analysis in STATA. PLoS ONE. 8 (10), e76654 (2013).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Papakonstantinou, T., Nikolakopoulou, A., Higgins, J. P., Egger, M. & Salanti, G. Cinema: Software for semiautomated assessment of the confidence in the results of network meta-analysis. Campbell Syst. Rev. 16 (1), e1080 (2020).

Okada, H. et al. A comparative study of terazosin and tamsulosin for symptomatic benign prostatic hyperplasia in Japanese patients. BJU Int. 85 (6), 676–681 (2000).

van Kerrebroeck, P., Jardin, A., Laval, K. U. & van Cangh, P. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 25 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur. Urol. 37 (3), 306–313 (2000).

Lapitan, M. C., Acepcion, V. & Mangubat, J. A comparative study on the safety and efficacy of tamsulosin and alfuzosin in the management of symptomatic benign prostatic hyperplasia: A randomized controlled clinical trial. J. Int. Med. Res. 33 (5), 562–573 (2005).

Rahardjo, D. et al. Efficacy and safety of tamsulosin hydrochloride compared to doxazosin in the treatment of Indonesian patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Int. J. Urol. 13 (11), 1405–1409 (2006).

Yokoyama, T., Kumon, H., Nasu, Y., Takamoto, H. & Watanabe, T. Comparison of 25 and 75 mg/day naftopidil for lower urinary tract symptoms associated with benign prostatic hyperplasia: A prospective, randomized controlled study. Int. J. Urol. 13 (7), 932–938 (2006).

Ukimura, O. et al. Naftopidil versus tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia with special reference to the storage symptom: A prospective randomized controlled study. Int. J. Urol. 15 (12), 1049–1054 (2008).

Masumori, N. et al. Ejaculatory disorders caused by alpha-1 blockers for patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Comparison of naftopidil and tamsulosin in a randomized multicenter study. Urol. Int. 83 (1), 49–54 (2009).

Yokoyama, T. et al. Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract symptoms and sexual function in males with benign prostatic hyperplasia. Int. J. Urol. 18 (3), 225–230 (2011).

Zhang, K. et al. Effect of doxazosin gastrointestinal therapeutic system 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms: A prospective, multicenter, randomized, open, parallel study. Urology. 78 (3), 636–640 (2011).

Shelbaia, A., Elsaied, W. M., Elghamrawy, H., Abdullah, A. & Salaheldin, M. Effect of selective alpha-blocker tamsulosin on erectile function in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Urology. 82 (1), 130–135 (2013).

Yamaguchi, K. et al. Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: A multicenter randomized trial. Int. J. Urol. 20 (12), 1234–1238 (2013).

Kumar, S., Tiwari, D. P., Ganesamoni, R. & Singh, S. K. Prospective randomized placebo-controlled study to assess the safety and efficacy of silodosin in the management of acute urinary retention. Urology. 82 (1), 171–175 (2013).

Keten, T. et al. Determination of the efficiency of 8 mg doxazosin XL treatment in patients with an inadequate response to 4 mg doxazosin XL treatment for benign prostatic hyperplasia. Urology. 85 (1), 189–194 (2015).

Seki, N. et al. Non-inferiority of silodosin 4 mg once daily to twice daily for storage symptoms score evaluated by the International Prostate Symptom Score in Japanese patients with benign prostatic hyperplasia: A multicenter, randomized, parallel-group study. Int. J. Urol. 22 (3), 311–316 (2015).

Matsukawa, Y. et al. Comparison of silodosin and naftopidil for efficacy in the treatment of benign prostatic enlargement complicated by overactive bladder: A randomized, prospective study (SNIPER study). J. Urol. 197 (2), 452–458 (2017).

Chung, J. H. et al. Efficacy and safety of tamsulosin 0.4 mg single pills for treatment of Asian patients with symptomatic benign prostatic hyperplasia with lower urinary tract symptoms: A randomized, double-blind, phase 3 trial. Curr. Med. Res. Opin. 34 (10), 1793–1801 (2018).

Kwon, S. Y. et al. Comparison of the effect of naftopidil 75 mg and tamsulosin 0.2 mg on the bladder storage symptom with benign prostatic hyperplasia: Prospective, multi-institutional study. Urology 111 , 145–150 (2018).

Matsumoto, S., Kasamo, S. & Hashizume, K. Influence of alpha-adrenoceptor antagonists therapy on stool form in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Low Urin. Tract. Symptoms. 12 (1), 86–91 (2020).

Pande, S., Hazra, A. & Kundu, A. K. Evaluation of silodosin in comparison to tamsulosin in benign prostatic hyperplasia: A randomized controlled trial. Indian J. Pharmacol. 46 (6), 601–607 (2014).

Lerner, L. B. et al. Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA GUIDELINE PART I-initial work-up and medical management. J. Urol. 206 (4), 806–817 (2021).

Nickel, J. C., Méndez-Probst, C. E., Whelan, T. F., Paterson, R. F. & Razvi, H. 2010 update: Guidelines for the management of benign prostatic hyperplasia. Can. Urol. Assoc. J. 4 (5), 310–316 (2010).

La Vignera, S. et al. Pharmacological treatment of lower urinary tract symptoms in benign prostatic hyperplasia: Consequences on sexual function and possible endocrine effects. Expert Opin. Pharmacother. 22 (2), 179–189 (2021).

Yassin, A. et al. Alpha-adrenoceptors are a common denominator in the pathophysiology of erectile function and BPH/LUTS–implications for clinical practice. Andrologia. 38 (1), 1–12 (2006).

Florent, R., Poulain, L. & N’Diaye, M. Drug repositioning of the α(1)-adrenergic receptor antagonist naftopidil: A potential new anti-cancer drug?. Int. J. Mol. Sci. 21 (15), 5339 (2020).

Masumori, N. Naftopidil for the treatment of urinary symptoms in patients with benign prostatic hyperplasia. Ther. Clin. Risk Manag. 7 , 227–238 (2011).

Yu, Z. J. et al. Efficacy and side effects of drugs commonly used for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. Front. Pharmacol. 11 , 658 (2020).

de la Rosette, J. J. et al. EAU Guidelines on benign prostatic hyperplasia (BPH). Eur. Urol. 40 (3), 256–263 (2001) ( discussion 64 ).

Lepor, H. Alpha-blockers for the treatment of benign prostatic hyperplasia. Urol. Clin. North Am. 43 (3), 311–323 (2016).

Dahm, P. et al. Comparative effectiveness of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: A systematic review and meta-analysis. Eur. Urol. 71 (4), 570–581 (2017).

Hwang, E. C., Gandhi, S. & Jung, J. H. New alpha blockers to treat male lower urinary tract symptoms. Curr. Opin. Urol. 28 (3), 273–276 (2018).

McVary, K. T. et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J. Urol. 185 (5), 1793–1803 (2011).

Oelke, M. et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur. Urol. 64 (1), 118–140 (2013).

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Yoosuf, B.T., Panda, A.K., KT, M.F. et al. Comparative efficacy and safety of alpha-blockers as monotherapy for benign prostatic hyperplasia: a systematic review and network meta-analysis. Sci Rep 14 , 11116 (2024). https://doi.org/10.1038/s41598-024-61977-5

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Benign prostatic hyperplasia (BPH or enlarged prostate) is the most common cause of obstructive lower urinary tract symptoms (LUTS) in men. The walnut-sized prostate gland surrounds the male urethra just below the bladder outlet. As the prostate progressively enlarges with age, it encroaches on the urethra and obstructs the flow of urine from the bladder, leading to urinary straining, frequency, urgency, and nocturia. These symptoms result in significant quality of life issues, including sleep disturbance, psychological burden, and disruption of social life and sexual activity. In the US, an estimated 40% of men over 50 and 90% over 80 have BPH, and the majority of these men will require treatment. An estimated 37 million men in the US and 500 million men worldwide suffer from BPH-related LUTS.

Existing solutions fail to address the clinical need for a large percentage of patients. Drugs often have limited effectiveness and side effects such as loss of libido, and surgical solutions typically involve a painful, invasive procedure and carry a high risk of permanent sexual dysfunction. Minimally invasive attempts have not gained widespread traction due to a difficult user experience, complications, inadequate long-term effectiveness, and/or high cost.

The Zenflow Spring System represents a new paradigm in BPH treatment: a safe, effective, cost-efficient, office-based therapy that provides durable symptom relief in a single procedure without complications. The Spring implant expands the cross-sectional area of the prostatic urethra through a simple five-minute office procedure that does not damage tissue. We designed the Spring to be superior to other minimally invasive therapies in 1) long-term effectiveness, 2) complication rate, 3) cost-effectiveness as enabled by a low cost of goods, 4) ease of placement, and 5) patient comfort. Placement is simple and can be verified with direct visualization and adjusted throughout the procedure. While the device should not require removal except in the case of further surgical treatment, it can be removed easily in an office setting using common urologic tools. The Phase I NSF SBIR objectives involved completing engineering design work in parallel with conducting animal and cadaver studies to confirm the design of the device.

Over the Phase I period, we leveraged bench, cadaver, and animal models to test early prototypes and finalize the design of the Spring System. These studies allowed our team to determine the optimal implant mechanical and morphological parameters and the delivery system components and mechanisms that could accurately place the implant. Upon freezing this design, we performed simulated use validation using a final series of animals and cadavers. These tests verified that the implant could reside safely in a representative animal model for at least 90 days and that deployment could be easily performed by a skilled operator. After completion of the Phase I work, we initiated a first-in-human clinical trial that has further verified the safety and effectiveness of the Spring System.

The broader impact of this project is to improve the lives of many millions of men in the US and beyond. Men who do not experience adequate relief from drugs yet decline to undergo invasive surgery will for the first time have a less painful, lower risk option to restore their quality of life. By easing the burden that BPH-related LUTS has on their sleep and daily activities, the Spring System will restore these men’s ability to live happy, healthy, and productive lives.

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FDA grants Fast Track Designation to RAG-01 in NMIBC

RAG-01 is an saRNA therapy that is delivered via intravesical instillation and is designed to target and activate p21, a tumor suppressor gene.

An IND application for RAG-01 in NMIBC was accepted by the FDA earlier this year.

The FDA has granted a Fast Track Designation to RAG-01, a first-in-class small activating RNA (saRNA) therapeutic under review for the treatment of patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC). 1

The FDA’s Fast Track designation is designed to expedite the review and development of novel treatments that will fill an unmet medical need. According to Ractigen Therapeutics, the developer of the therapy, RAG-01 is the first saRNA worldwide to receive a Fast Track Designation.

"We are thrilled to receive Fast Track Designation for RAG-01, marking a significant milestone not only for our program but also for the saRNA field as a whole,” said Long-Cheng Li, MD, co-founder, president, and CEO of Ractigen Therapeutics, in the news release. 1 “This designation underscores the urgency and importance of advancing innovative therapies like RAG-01 to address critical medical needs. We remain dedicated to accelerating the development of innovative saRNA therapies to address a wide range of diseases, including cancer, genetic disorders, and chronic conditions. Through strategic collaborations and pioneering research efforts, the company aims to deliver transformative treatments that improve patient outcomes and quality of life.”

An Investigational New Drug (IND) application for RAG-01 in BCG-unresponsive NMIBC was accepted by the FDA earlier this year, in April 2024. 2 The approval of the IND application initiated the launch of clinical trials of the therapy in the United States.

Ractigen Therapeutics also revealed the launch of a phase 1 trial of RAG-01 in Australia earlier this year by announcing the dosing of the first patient. 3  The trial was initiated in December 2023, and has successfully enrolled and dosed 3 patients in the study to date.

Overall, the multi-center, open-label, first-in-human, phase 1 trial (NCT06351904) of RAG-01 in Australia is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the treatment in patients with NMIBC who have failed prior BCG therapy. 4

The trial is currently enrolling adults aged 18 to 75 years who have pathologically confirmed grade 2 or grade 3 NMIBC, an expected survival time of at least 6 months, and an ECOG performance status of 2 or lower. Patients are not eligible for enrollment if they received anti-tumor treatments other than transurethral resection of bladder tumor within 21 days or 5 half-lives (whichever is shorter) from when they signed their informed consent form.

All patients will receive a starting dose of RAG-01 at 30 mg, but they will be distributed into 4 dose cohorts: 30 mg, 100 mg, 300 mg, and 600 mg.

There are 2 primary outcome measures for the study. The first is safety and tolerability of RAG-01 in patients with NMIBC during the period from screening to 6 months following the initial instillation of RAG-01. Safety and tolerability will be measured through adverse events (AEs), serious AEs, and treatment emergent AEs. The other primary outcome measure is the maximum tolerated dose and/or recommended phase 2 dose of RAG-01. These will be assessed through the evaluation of any dose-limiting toxicities with 21 days of the first instillation of RAG-01.

The estimated enrollment for the trial is 15 patients, and the estimated primary completion date is June 30, 2025.

The study is being conducted through a collaboration between Ractigen Therapeutics and GenesisCare, a leading provider of cancer care services in Australia.

1. Ractigen Therapeutics secures FDA Fast Track Designation for RAG-01, a first-in-class saRNA therapy. News release. Ractigen Therapeutics. Published online and accessed May 21, 2024. https://www.ractigen.com/ractigen-therapeutics-secures-fda-fast-track-designation-for-rag-01-a-first-in-class-sarna-therapy/

2. Ractigen Therapeutics announces FDA approval for RAG-01, a first-in-class saRNA therapy for BCG-unresponsive NMIBC. News release. Ractigen Therapeutics. April 26, 2024. Accessed May 21, 2024. https://www.ractigen.com/ractigen-therapeutics-announces-fda-approval-for-rag-01-a-first-in-class-sarna-therapy-for-bcg-unresponsive-nmibc/

3. Ractigen announces first patient dosed in the phase I clinical trial of RAG-01 for NMIBC. Published online April 3, 2024. Accessed May 21, 2024. https://www.ractigen.com/ractigen-announces-first-patient-dosed-in-the-phase-i-clinical-trial-of-rag-01-for-nmibc/

4. A study of RAG-01 in patients with non-muscle-invasive bladder cancer (NMIBC) who have failed bacillus calmette guérin (BCG) therapy. ClinicalTrials.gov. Last updated April 16, 2024. Accessed May 21, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06351904

Bladder Cancer Awareness Month: Dr. Kamat highlights the state of bladder cancer care

In this episode, Ashish M. Kamat, MD, MBBS, highlights the state of bladder cancer care in recognition of Bladder Cancer Awareness Month.

Dr. Matin discusses early work with FGFR inhibition in localized UTUC

"And [3 out of 5] of those patients who were initially deemed to go on to nephroureterectomy were able to be converted to endoscopic management," says Surena F. Matin, MD.

Speaking of Urology Podcast: Dr. Ritch and Dr. Katz discuss new bladder cancer management app

“It's not a replacement for clinical judgment, obviously. But at the end of the day, the idea is that it shows you what your next steps are based on what the American Urological Association and [Society of Urologic Oncology] guidelines are for non-muscle invasive bladder cancer,” Chad R. Ritch, MD, MBA, FACS.

Clinical trial program of nadofaragene firadenovec in NMIBC expands

The 3 new additional studies are the ABLE-22, ABLE-32, and ABLE-42 clinical trials.

FDA accepts IND application for UGN-103 in NMIBC

The IND will initiate the launch of a phase 3 study to explore the safety and efficacy of UGN-103 in patients with low-grade, intermediate-risk NMIBC.

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Aquablation versus HoLEP in patients with benign prostatic hyperplasia: a comparative prospective non-randomized study

Jakob michaelis.

Department of Urology, Faculty of Medicine, Medical Centre – University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany

Max Träger

Sophie astheimer, moritz von büren, elfi gabele, markus grabbert, jan halbich, marius kamps, jonas klockenbusch, theresa noll, phillippe pohlmann, daniel schlager, august sigle, martin schönthaler, konrad wilhelm, christian gratzke, arkadiusz miernik, dominik stefan schöb, associated data.

The question of best surgical treatment for lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH) remains controversial. We compared the outcomes of aquablation and holmium laser enucleation of the prostate ("HoLEP") in a prospective cohort.

Patients with BPH underwent aquablation or HoLEP according to their preference between June 2020 and April 2022. Prostate volume (“PV”), laboratory results, postvoid residual volume, uroflowmetry, IPSS, ICIQ-SF, MSHQ-EjD, EES and IIEF were evaluated preoperatively and at three, six and 12 months postoperatively. We also analyzed perioperative characteristics and complications via the Clavien Dindo („CD“) classification.

We included 40 patients, 16 of whom underwent aquablation and 24 HoLEP. Mean age was 67 years (SD 7.4). Baseline characteristics were balanced across groups, except the HoLEP patients’ larger PV. IPSS fell from 20.3 (SD 7.1) at baseline to 6.3 (SD 4.2) at 12 months (p < 0.001) without differences between aquablation and HoLEP. HoLEP was associated with shorter operation time (59.5 (SD 18.6) vs. 87.2 (SD 14.8) minutes, p < 0.001) and led to better PV reduction over all timepoints. At three months, aquablation’s results were better regarding ejaculatory (p = 0.02, MSHQ-EjD) and continence function (p < 0.001, ICIQ-SF). Beyond three months, erectile, ejaculatory, continence function and LUTS reduction did not differ significantly between aquablation and HoLEP. CD ≥ grade 3b complications were noted in six patients in aquablation group while only one in HoLEP group (p =  < 0.01).

Conclusions

While aquablation revealed temporary benefits regarding ejaculation and continence at three months, HoLEP was superior concerning operation time, the safety profile and volumetric results.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00345-024-04997-0.

Introduction

Benign prostatic hyperplasia (BPH) is a highly prevalent condition in older men that triggers lower urinary tract symptoms (LUTS) [ 1 ]. Although medical treatment can alleviate symptoms [ 2 ], a significant proportion of patients needs surgical therapy to enable a lasting resolution of their symptoms [ 3 ]. There is a plethora of operation methods for BPH.

Aquablation is one of the novel options that has rapidly gained in importance. It functions via hydrodissection, by which a high-velocity water jet ablates prostate tissue, thus representing a mechanoablative method in contrast to its widely used thermoablative alternatives.

Aquablation has advantages in terms of morbidity, especially regarding preserving erectile function and prograde ejaculation when compared to TUR-P [ 4 , 5 ]. Another key advantage is the short operative time, outperforming different laser enucleation techniques as well as photovaporization of the prostate [ 6 ]. Recent trials on aquablation reported promising long-term data with low rates (6.0% and 3.7%) of additional BPH therapy required until the fifth year post-therapy [ 7 , 8 ]. Aquablation’s learning curve is also short, achieving a predefined trifecta outcome (operative time < 60 min plus hemoglobin loss limited to under 2g/dl plus avoiding CD > grade 2 complications) in 70% of the first 50 patients [ 9 ]. On the downside, the inability to histologically evaluate the ablated tissue poses a crucial limitation of the aquablation procedure [ 10 ].

Aquablation has so far only been compared in detail to transurethral resection of the prostate (TUR-P) [ 11 ]. TUR-P is associated with a significant range of complications [ 12 , 13 ], i.e., urethral or bladder neck strictures. However, aquablation is also known to cause relevant complications, for example postoperative bleeding complications or—rarely—rectal perforation [ 14 ]. Postoperative bleeding was particularly evident in conjunction with very large prostates [ 15 ] or when cauterization was deliberately omitted [ 16 ]. Bleeding complications were significantly reduced in subsequent trials by focal cauterizing of the bladder neck at the end of the procedure [ 17 , 18 ]. Multi-pass aquablation appears to be more effective than single-pass aquablation with regard to volume reduction [ 19 ].

Comparisons between aquablation and techniques other than TUR-P are scarce. Holmium laser enucleation of the prostate (HoLEP) is one of the most frequent surgical treatments [ 20 ] for BPH. HoLEP yields favorable outcomes in comparison to TUR-P in uroflowmetric results, retreatment rates, and in patient-reported outcomes [ 21 ]. Comparative analyses between HoLEP and aquablation are lacking except for assessments of perioperative bleeding complications [ 22 ]. We devised/planned this project to address the knowledge gap concerning objective and patient-reported outcomes, perioperative characteristics, and safety when comparing HoLEP and aquablation.

Materials and methods

Patients with BPH were either scheduled for aquablation or HoLEP according to patient preference following urological consultation providing information on therapy options. During their preoperative work-up, all patients were offered extended follow-up as part of this prospective study. Exclusion criteria were a history of prostate cancer, indwelling urinary catheterization for longer than 3 months (to ensure reliable information on preoperative continence and prostate-related symptoms), urethral strictures, bladder stones, chronic pelvic pain syndrome, antimuscarinergic therapy due to overactive bladder, and anticoagulation unable to be discontinued.

Aquablation was performed in a standardized fashion, resembling the approach described by Zorn et al. [ 23 ]. After resection, patients regularly underwent hemostasis via monopolar diathermy for focal bladder neck cauterization. HoLEP was conducted using the three horse shoe-like incision technique [ 24 ]. A group of three surgeons (A.M., M.S. and K.W.) with at least 5 years of HoLEP experience and each having conducted over 100 procedures performed HoLEP. Aquablation was executed by a fixed team of two surgeons (A.M. and D.S.S.) with one year of experience each and 9 cases performed together prior to the first patient included in this analysis.

Baseline evaluation and follow-up at three, six and 12 months after surgery incorporated the five questionnaires IPSS, International Index of Erectile Function (IIEF), International Consultation on Incontinence Questionnaire – short form (ICIQ-SF), Male Sexual Health Questionnaire—ejaculatory dysfunction (MSHQ-EJD) and Ejaculation, Erection and Satisfaction Scale (EES). Besides those, we carried out uroflowmetry and transrectal ultrasound (TRUS) volumetry (calculated by [height x length x width x π/6]) and monitored PSA values and creatinine. Operation time was measured from the surgeon’s first preparation step at the operating table until the final catheter insertion for both interventions. We recorded the maximum perioperative daily pain level via a numerical rating scale (verbal NRS-11). Time to catheter removal, sonographic post-void residual volume and time to discharge were also documented.

We conducted statistical analyses using Pearson's chi-squared test for categorical, two sample t-test for normally distributed continuous and Wilcoxon signed-rank test for non-normally distributed continuous variables. We decided against applying methods for imputation of missing values. Analyses were done with R language and environment for statistical computing (version 4.3.0, R Foundation for Statistical Computing, Vienna, Austria). Significance level was set at 0.05.

In all, 58 patients declared their initial interest in participating, of whom 18/58 were excluded (14 aquablation, four HoLEP). 8/58 (6/8 aquablation, 2/8 HoLEP) were excluded preoperatively because of failing to complete the baseline questionnaires. Ten of the remaining 50 (8/10 aquablation, 2/10 HoLEP) patients withdrew their consent either preoperatively or by the first follow-up appointment. This was mainly due to Covid-19 pandemic restrictions or because patients were no longer willing to comply with extended follow-up. Our final evaluation included 40 patients.

We included these patients between June 2020 and April 2022; 16 subjects underwent aquablation and 24 the HoLEP procedure. Mean age was 67 years (range 52 – 82; SD 7.4), patients presented with a prostate volume (PV) of 66.3 cm 3 (range 33 to 118 cm 3 , SD 20.9) and mean PSA value of 4.87 (SD 4.18) ng/ml. Mean IPSS of 20.3 (median 22) at baseline reflected the severity of BPH-related symptoms. Baseline characteristics were adequately balanced across groups, except that HoLEP patients presented a larger PV (73.8 cm 3  ± 18.1 SD vs. 55.0 cm 3  ± 19.2 for aquablation, p = 0.005). Participation in the three, six, and 12-month follow-ups ranged from 85 to 95 percent (further baseline characteristics are summarized in Table  1 ).

Table 1

Patient baseline parameters. Note: Anticoagulation had to be paused preoperatively

Significant values are printed in bold

Average operation time for aquablation was significantly longer than for HoLEP (87.2 ± 14.8 vs. 59.5 ± 18.6 min, respectively; p < 0.001). Aquablation’s maximum pain intensity was also higher than HoLEP’s, with the pain maximum on numeric rating scale of 2.6 ± 1.6 vs. 1.3 ± 1.5 (p = 0.01), 1.8 ± 1.8 vs. 0.7 ± 1.2 (p = 0.03) and 0.9 ± 1.3 vs. 0.2 ± 0.6 (p = 0.02) on the day of surgery, and first and second postoperative day, respectively. Nevertheless, pain intensity was generally low with no patient requiring escalating analgesics to opioids (see Fig.  1 ). We found no significant differences in time to catheter removal (median two days) or time to discharge (median three days) between the groups.

Perioperative characteristics

At all follow-up timepoints, HoLEP’s relative PSA-reduction was significantly greater than aquablation’s ( – 78%/ – 72%/ – 75% vs.  – 16%/ – 27%/ – 36% at 3, 6 and 12 months, respectively). We observed no significant changes in creatinine levels over time. Differences in post-void residual volume never reached statistical significance at any follow-up timepoint with 21.0 ± 43.6 ml for aquablation and 22.4 ± 54.1 ml for HoLEP mean post-void residual volume across all follow-up examinations (p = 0.86) compiled. PV reduction in our HoLEP patients, was markedly larger at all follow-up timepoints when compared to aquablation patients. Residual volume at 12 months was 15.0 ± 5.1 cm 3 ( – 79.6% compared to preoperative volumetry) for HoLEP, while aquablation-treated patients had glands of 33.1 ± 11.9 cm 3 ( – 39.2%) (p < 0.001). Uroflowmetric outcomes favored HoLEP, reaching statistical significance at six months postoperative (maximum urinary flow rate 28.1 ± 11.3 ml/s for HoLEP vs. 20.6 ± 6.7 ml/s for aquablation, p = 0.03). Detailed results are illustrated in Fig.  2 .

Objective outcomes at baseline (BL) and at follow-up examinations at three months postoperative (3M_p), six months postoperative (6M_p) and 12 months postoperative (12M_p), respectively. PV was measured via transrectal sonography ( a ), uroflowmetric outcomes are reported as maximum urinary flow rate ( b ) with sonographic evaluation of post-void residual volume afterwards ( d ). PSA values are measured as serum levels by chemiluminescence immunoassay ( c )

IPSS improved significantly over time, dropping from 21.3 ± 7.9 (median 23) vs. 19.8 ± 6.5 (median 21) at baseline to 9.1 ± 4.8 (median 10) vs. 10.5 ± 4.5 (median 12), 8.1 ± 5.8 (median 6) vs. 7.9 ± 4.5 (median 6) and 6.5 ± 4.4 (median 5) vs. 6.2 ± 4.1 (median 5.5) at three, six and 12 months for aquablation vs. HoLEP without differences across treatment groups. Concerning quality of life regarding prostate symptoms obtained in IPSS, both groups improved from 4.1 ± 1.5 vs. 3.8 ± 1.3 (median 4 each) at baseline to 1.6 ± 1.5 vs. 1.2 ± 0.7 (median 1 each) for aquablation vs. HoLEP, also without significant differences between groups. Postoperative ejaculative function showed significant deterioration for HoLEP, but not aquablation. That difference favoring aquablation was significant at three months after surgery and remained a non-significant trend at later timepoints. At three months, continence was significantly worse for HoLEP than aquablation, but continence status recovered by the six-month post-operative follow-up. Both groups reported similar erectile function outcomes with no statistically significant difference. For more details about functional outcomes, see supplementary Fig. 3.

We observed a significant higher number of severe complications in association with aquablation compared to HoLEP, with Clavien-Dindo ≥ grade 3 complications in six (37.5%) vs. one (4.2%) patient (p < 0.01). This was mainly driven by their higher rate of postoperative bleeding requiring revision. (One case of iatrogenic rectal perforation occurred, which was managed by intraluminal vacuum therapy and protective ileostomy on postoperative days 5 and 6, respectively. That patient underwent an ileostomy reversal and ileoileostomy four months postoperatively. Surgical retreatment due to persistent/recurrent bladder outlet obstruction was necessary in one patient in each group. No blood transfusions were necessary in either group. Minor complications (Clavien-Dindo grade 1–2) were more frequent for HoLEP without reaching statistical significance (8/24 for HoLEP vs. 2/16 for aquablation, p = 0.14), particularly attributable to their higher rates of urinary retention. Supplementary Fig. 4 shows details about each group’s complications and their severity over time group.

In this clinical study, we compared the efficacy and safety of aquablation and HoLEP as treatment modalities for benign prostatic hyperplasia (BPH). The study included a one-year follow-up period to assess the long-term outcomes of these procedures.

We found no significant differences in IPSS, uroflowmetric results and postvoid residual volume at the final one-year follow-up. However, PV reduction was significantly better in the HoLEP group, which, at least at 6 months, also translated into significantly better uroflowmetric results. Concerning PV reduction, HoLEP as a procedure guided by the anatomical limits of the surgical capsule appears to have advantages over a TRUS controlled procedure like aquablation, even when the latter is combined with “fluffy tissue” resection and focal bladder neck cauterization. As decision about single vs. multi-pass aquablation was not specified by our study protocol and evidence for the beneficial effects of multi-pass aquablation arised recently [ 19 ], it will be interesting to see if the PV reduction continue to differ significantly with mandatory multi-pass aquablation in other cohorts. Our cohort’s PV reduction, IPSS improvement and improvement in maximum urinary flow rate of aquablation were similar to other studies: Whiting et al. reported a residual PV of 33.2 cm 3 , IPSS of 6.1 and maximum urinary flow rate of 23.9 ml/s at 12 months [ 25 ], which is well in line with our results (33.1 cm 3 , 6.5 points and 21.0 ml/s, respectively).

As reported previously, the aquablation group showed an advantage regarding preservation of ejaculative function (difference in MSHQ-EjD 4.2 points at three months favoring aquablation (p = 0.021) vs. HoLEP in our study compared to 3.1 points difference favoring aquablation vs. TUR-P at 3 months (p = 0.002) in Gilling et al. 2019 [ 26 ]). Nevertheless, these differences in MSHQ-EjD did not maintain significance beyond the three-month time point. Postoperative erectile function was also similar in both groups. Regarding patient safety: our HoLEP results were favorable, with a significantly higher number of severe complications in the aquablation group, especially their higher rate of postoperative bleeding. This finding is supported by other studies, showing a significant higher loss of hemoglobin and transfusion rates for aquablation compared to transurethral resection [ 27 ] and as a non-significant trend for transurethral enucleation [ 22 ]. Despite that, none of our patients required a blood transfusion (compare to the 5,9% transfusion rate in the WATER-II trial) [ 28 ]. We guess that our surgical therapy of postoperative bleeding to avoid blood transfusion was more aggressive, which may explain these different results. However, we observed no differences in the occurrence of complications up to 12 months.

Aquablation’s significantly longer operation time in our study differs from previous reports, as e.g., 45, 38, and 37 min, respectively [ 11 , 22 , 29 ]. We defined operation time as the surgeon’s start of intervention preparations at the operating table up to catheter insertion. We found various definitions of operation times in other studies, e.g. handpiece placement to final urinary catheter placement [ 29 ], pre- to post treatment cystoscopy [ 11 ] or TRUS insertion to urinary catheter placement [ 28 ]. As none of these definitions consider all the preparation steps, they may fail to accurately measure total procedure time. We believe our definition reflects more accurately the genuine amount of time these procedures take. Our definition should at least partially account for our prolonged mean operation times for aquablation in our study. Another reason for our longer durations per patient might be partly that we had performed very few (nine aquablations) in our institution before initiating this study, while we had extensive experience (> 750 cases) with HoLEP. This may have also affected other outcomes variables and should be taken into account, even if previous studies proved the short learning curve for aquablation [ 9 ] concerning safety and operative time. Shorter procedure times are obviously a medical advantage for patients, and there is also a potential benefit for health care providers (since one can do more procedures within the same time span), as well as for the healthcare system (as more patients being treated by one center may reduce time to surgery and thus improve regional medical care). We can conclude that both procedures have their specific strengths and that to offer a broad range of different procedures might give clinicians the opportunity to offer each patient the procedure which suits best their individual priorities and objectives.

There are several limiting factors to our study to be considered: Above all, the relatively small number of participants limits our results ‘ generalizability. The non-randomized study design can lead to selection bias. This may be reflected in the difference in baseline volume between the groups, even if TRUS volumetry has known inaccuracies. Different baseline volumes might also have affected other parameters such as operating time, bleeding rate, PSA values or uroflowmetric outcomes. Moreover, patients’ compliance with aftercare appointments was impaired due to the Covid-19 pandemic, which led to a 15% loss of follow-up data, which might detract from the robustness of our findings. Distinct levels of experience with the two procedures could also have influenced our results. Long-term follow-ups beyond one year are necessary to assess the durability of outcomes and potential late complications associated with both aquablation and HoLEP. Further studies with a higher case load are necessary to provide more data on the benefits and disadvantages of both procedures. Prospective trials comparing HoLEP and aquablation are already recruiting ( {"type":"clinical-trial","attrs":{"text":"NCT04801381","term_id":"NCT04801381"}} NCT04801381 , {"type":"clinical-trial","attrs":{"text":"NCT04560907","term_id":"NCT04560907"}} NCT04560907 [ 30 ]).

Both HoLEP and aquablation are effective treatment options for patients with LUTS due to BPH. The choice between these techniques should be individualized, considering each patient's specific needs and preferences, as well as the surgeon's expertise. Our study data suggest no functional advantage for either of these procedures beyond three months. However, HoLEP’s safety profile and volumetric results proved to be superior. The generalizability of our study findings is restricted by several limitations. Long-term follow-up and patient-reported outcomes assessments will further enhance our understanding of the outcomes and patient satisfaction associated with these interventions to better advise our patients.

Below is the link to the electronic supplementary material.

Author contribution

Michaelis: Data collection; data management; data analysis; visualization; manuscript writing; manuscript editing. Träger: Data collection; data management; manuscript editing. Astheimer: Data collection; manuscript editing. Von Büren: Data collection; manuscript editing. Gabele: Data collection; manuscript editing. Grabbert: Data collection; visualization; manuscript editing. Halbich: Data collection; manuscript editing. Kamps: Data collection; manuscript editing. Klockenbusch: Data collection; manuscript editing. Noll: Data collection; manuscript editing. Pohlmann: Data collection; manuscript editing. Schlager: Data collection; manuscript editing. Sigle: Data collection; manuscript editing. Schönthaler: Funding acquisition; validation; manuscript editing. Wilhelm: Validation; manuscript editing. Gratzke: Protocol/project development; funding acquisition; project administration; supervision; validation; manuscript editing. Miernik: Protocol/project development; funding acquisition; project administration; supervision; validation; manuscript editing. Schöb: Protocol/project development; data management; data analysis; visualization; manuscript writing; manuscript editing.

Open Access funding enabled and organized by Projekt DEAL.

Declarations

All authors declare that there is no conflict of interest and gave their consent for publication.

The study was approved by our local ethics committee (IRB approved protocol number ETK FR 479/17; leading ethics committee: Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Germany) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave their consent prior to their inclusion in the study.

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