Incidence and management of BPH surgery-related urethral stricture: results from a large U.S. database

Introduction and objectives: Urethral stricture (US) is a well-known complication after surgical treatment of benign prostatic hyperplasia (BPH), whose treatment options range from conservative or endoscopic approaches to more invasive ones. This study aimed to evaluate the contemporary incidence of US after different types of BPH surgery, to identify associated risk factors and to assess its management. Methods A retrospective analysis was conducted using the PearlDiver™ Mariner database, containing de-identied patient records compiled between 2011 and 2022. Speci�c International Classi�cation of Diseases (ICD) and Current Procedural Terminology (CPT) codes were employed to identify population characteristics and outcomes. All the most employed surgical procedures for BPH treatment were considered. Multivariable logistic regression was employed to evaluate factors associated with diagnosis of post-operative US.


Introduction
Benign Prostatic Hyperplasia (BPH) is a prevalent condition among aging males, representing the most common etiological factor for lower urinary tract symptoms (LUTS) in this population [1].The management of symptomatic BPH is often multimodal.In selected cases, or when pharmacological treatments lose e cacy, a surgical intervention is indicated [2], [3].For decades, transurethral resection of the prostate (TURP) represented the gold standard.The introduction of new minimally invasive surgical therapies (MIST) with the aim of reducing the incidence of treatment-related morbidity, has signi cantly broadened the spectrum of management options available for BPH treatment [4]- [8].These advances have allowed for a more tailored approach to symptomatic BPH, considering both clinical features and patient preference [9]- [11].
Despite notable improvements in surgical techniques, the incidence of late complications such as urethral stricture (US) has not declined [12].As a matter of fact, BPH surgery still represents the most common cause of iatrogenic stricture disease, accounting for up to 41% of all cases [13].The development of urethral strictures in this setting is attributed to several etiological factors, including the use of wide caliber surgical devices, mechanical or energy induced damage, urinary tract infections, prolonged surgical time, and extended catheterization time [14], [15].
The management of urethral strictures can span from conservative options, such as observation and suprapubic tube placement, to endoscopic treatments, such as direct vision internal urethrotomy (DVIU) and urethral dilatation (UD), to more invasive options, such as urethroplasty procedures.Iatrogenic US can be particularly challenging to manage, since less invasive treatment options carry a considerable risk of recurrence [22], [23].Urethral reconstructive surgery on the other hand, has demonstrated greater long-term success rates.Such evidence has prompted guidelines to consolidate the role of urethroplasty in managing recurrent US and to expand its indication as primary treatment [24].
In this study, our primary endpoint was to assess contemporary incidence of urethral strictures following different BPH surgical treatments.The secondary endpoint was to identify risk factors for urethral strictures development, and to assess their management.

Dataset
We conducted a retrospective analysis using the extensive PearlDiver™ Mariner database (PearlDiver Technologies, Colorado Springs, CO).It is a commercially available, all-payer national claims database, containing over 41 billion Health Insurance Portability and Accountability Act (HIPAA)-compliant patient records collected between 2011 and 2022.The dataset uses unique patient identi er codes which allows for timespeci c research while also keeping patient information de-identi ed.Moreover, this resource catalogs healthcare interactions across inpatient and outpatient settings, facilitating the longitudinal study of patient trajectories.Coverage is comprehensive, extending to all payer models across the entirety of United States territories.Data integrity is ensured via rigorous audits and review processes by independent third parties.
Institutional Review Board provided exemption prior to data collection [25], [26].Speci c International Classi cation of Diseases (ICD), both 9th and 10th editions, and Current Procedural Terminology (CPT) codes were used to identify population and outcomes within the database.

Study Population and procedures
We queried the database from January 1st 2011 to December 31th 2021, for all patients who underwent BHP surgery.The procedures considered for this study were: TURP, Transurethral Incision of the Prostate (TUIP), Holmium/Thulium Laser Enucleation of the Prostate (HoLEP/ThuLEP), Open Simple Prostatectomy (OSP), Laparoscopic-/Robot-Assisted Simple Prostatectomy (Lap/RobSP), Photoselective Vaporization of the Prostate (PVP), Prostatic Urethral Lift (PUL), Robotic Waterjet Treatment (Aquablation ® ), Water Vapor Thermal Therapy (Rezum ® ) and Prostatic Artery Embolization (PAE).The absence of a unique procedural CPT code was considered an exclusion criterion from the study.
We then re ned the cohort to include only those with active insurance claims.Within this patient population, we identi ed individuals who received a rst diagnosis of urethral stricture within 12 months after a BPH procedure.The choice of this time frame aims to minimize the capture of other potential causes of urethral stricture [13].Demographic variables included age, obesity, diabetes mellitus, smoking habit, and Charlson Comorbidity Index (CCI).Subsequently, using appropriate CPT codes, we assessed the utilization rates of different active management strategies for US treatment.

Statistical Analyses
Categorical variables are reported as frequencies and percentages, while continuous variables are reported as mean and standard deviation (SD).
To identify procedures associated with higher risk of urethral stricture, we performed a multivariable logistic regression analysis adjusting for variables such as age, obesity, smoking habits, and diabetes, and using patients who underwent TURP as reference group.Statistical analyses were performed using the R computing software incorporated into the PearlDiver™ Bellwether user interface.All p values were two-tailed with signi cance de ned as p < 0.05.

Results
We identi ed a total of 274,808 patients undergoing BPH-treatment between 2011 and 2021.Baseline characteristics of the study population are summarized in Supplementary Table 1.
Mean age at surgery was 70.05 (SD 7.7) years, with the oldest patients undergoing PAE (71.55 years SD 7.8) and the youngest undergoing Rezum ® (59.15 years SD 8.5).The PAE group also had the highest mean CCI compared to all the other procedures (4.26 SD 4.4).Of the total cohort, 10,918 patients were diagnosed with post-operative urethral stricture after BPH-treatment, accounting for 3.97% of the patients captured.
Incidence of urethral stricture categorized by treatment group is shown in Table 1.Higher incidence was observed following TURP, PVP, HoLEP/ThuLEP, TUIP and open SP.Lower incidence rates were observed after Laparoscopic/Robotic SP, Aquablation ® , PUL, Rezum ® and PAE.Proportions of application of each treatment and their combination, strati ed by BPH-surgery group, are shown in Table 2. Around 94% of urethral strictures were managed through minimally invasive treatments, with UD and DVIU performed in 76.7% and 14.5% of cases respectively, and a combination of these approaches accounting for 2.8% of the total.Urethroplasty represented the less common primary treatment, performed in only 4.5% of instances.Considering only more representative procedures subgroups (> 10 patients), a higher incidence of DVIU was noted for TUIP (38.71%) and PVP (20.27%) procedures.A very low proportion of patients (0.1%) received a combination of all the three different analyzed treatments (UD, DVIU and urethroplasty).CI 0.92-0.99;p = 0.01) were associated with a reduced likelihood of developing urethral stricture compared to TURP (Table 3).Open SP showed an increased likelihood of urethral stricture (OR 1.23, 95% CI 1.07-1.41;p = 0.002), whereas no signi cant difference was noted for Lap\Rob SP, HoLEP/ThuLEP, and TUIP when compared to TURP.Moreover, multivariable analysis identi ed tobacco use and diabetes as signi cant risk factors for US development (all p-values < 0.001) after BPH-surgery, while age was a protective factor (OR 0.98, 95% CI 0.98-0.99;p < 0.001).

Discussion
Through the analysis of this extensive national database, encompassing data collected over a 10-year period, we can offer a broad picture on BPH surgery-related development of urethral strictures, including their management.
We identi ed 274,808 patients who underwent various BPH treatment modalities, including recently introduced ones.The observed rates of postoperative incidence of urethral strictures varied from 0.65-4.48%(Table 1).PAE, Rezum ® , PUL and Aquablation ® showed the lowest rates (0.65-1.59%) of US development.This nding could be explained by the reduced operative time and consequent reduced urethral manipulation usually required during MIST such as PUL, Rezum ® and Aquablation ® , as well as the absence of a potentially harmful energy source [27]- [29].Similarly, since PAE may requires only the positioning of a urethral catheter as a reference point for the interventional radiologist [30], if not already present before, is it not surprising that this procedure is the one associated with the lowest rate of US (0.65%).An interesting observation is the lower US incidence rate in patients undergoing Lap/Rob SP (1.76%), compared to the 3.21% for those undergoing the open SP procedure.This disparity may be attributed to the laparoscopic system's advantages, which include superior visualization and precision during bladder neck reconstruction [31]- [33].Such enhancements not only help in minimizing undue stress and traction from stitches on urethral tissues, but may also contribute to better bleeding control, ultimately leading to a shorter catheterization time [34], [35].
The overall rate of post-operative strictures observed in our study (3.97%) aligns with the lower limits of ranges reported in literature [13], [39].This evidence may be attributable to several factors.Firstly, a retrospective analysis might underestimate the actual incidence, especially if we consider patients with mild symptomatic strictures that did not seek evaluation or treatment, ultimately leading to a potential selective reporting of outcomes.This could be further affected by the variability in complication reporting across different healthcare settings, with some institutions possibly having more comprehensive follow-up and reporting protocols that identify more cases.In fact, it is not surprising that higher incidences come from prospective single center study designs [21].Moreover, the advancements in established surgical techniques over the years, and the growing awareness of possible complications, might have contributed to their rates reduction.
Finally, it is important to acknowledge the possibility that some clinical entities reported as bladder neck contractures (BNC) may fall under the diagnosis of urethral stricture.These two conditions can cause similar urinary symptoms at presentation, and there is a possibility that the respective ICD codes could sometimes be erroneously used interchangeably [40], [41].Despite this potential for diagnostic overlap, the likelihood of it affecting all groups we have analyzed is uniform, and the robust sample size at our disposal ensures the reliability of the incidence ranges we have observed.
Insightful observations also arise from our adjusted multivariable analysis (Table 3).This analysis con rms the incidence rates previously discussed, highlighting a statistically signi cant reduced risk of urethral stricture for some MISTs (being between 5% and 76% lower compared to TURP).The only procedure signi cantly associated with an increased risk of stricture, by 23%, is open SP.
Moreover, we observed that diabetes (1.07 [1.03-1.11],p < 0.001) and tobacco use (1.08 [1.05-1.12],p < 0.001) were statistically signi cant risk factors for the development of a urethral stricture.These results are consistent with what is known about the etiology of urethral stricture, which appears connected to impaired angiogenesis, excessive formation of brous tissue, and in ammation [42].Interestingly, age was found to be a protective factor (0.98 [0.98-0.99],p < 0.001).This could be attributed to a tendency for reduced postoperative follow-up and diagnosis as age advances.Additionally, healing process in older individuals may vary compared to younger patients, potentially resulting in less aggressive scar formation.
We also examined the rates and treatment strategies employed among the different BPH procedures (Table 2 and Fig. 1).UD and DVIU were the most employed treatment in our cohort.Current literature shows wide and inconsistent ranges of patency rates after UD and DVIU, varying from 35.5-92.3% and 8-77% respectively [43].Moreover, these procedures carry a well-known inherent risk of potentially worsening the stricture, thereby signi cantly increasing treatment failure and recurrence rate [19].Only a minority of patients in our cohort (4.5%) underwent open urethral reconstruction.These data are of interest considering that urethroplasty has proven to be a durable and de nitive treatment with lifetime success rates between 75-100% [44].A possible explanation for this phenomenon is the concern about iatrogenic urinary incontinence.Because endoscopic BPH treatments disrupt the internal urethral sphincter, continence relies on the external sphincter muscle.
Therefore, it is plausible that to preserve sphincter control, some urologists recommend repeated endoluminal treatments in place of open repair [19].Moreover, such procedure is technically demanding and thus predominantly performed in specialized centers by dedicated surgeons [19], [45].This expertise requirement is a further point that might explain why, despite its high success rates, urethroplasty was the least frequently performed intervention in our study population.
Nevertheless, it is essential to acknowledge the limitations of this retrospective study, particularly those associated with the PearlDiver™ Mariner database.ICD codes do not allow for differentiation between procedure types like monopolar versus bipolar TURP or HoLEP versus ThuLEP.Moreover, since it was not made for this purpose, the database does not provide speci c clinical information that could further characterize the diagnosis of interest.Our reliance on diagnosis codes, without details on the anatomical location and length of the stricture, therefore, limits our capacity to draw de nitive conclusions about urethral strictures treatment strategies.
The study provides valuable information on the United States population; however, these ndings may not be generalizable to other countries with different medical practices and patient demographics.
Finally, it is crucial to recognize that while statistics of medical needs in public health are shaped by the system's regulatory framework, there may be a difference from the scienti c reality [46].However, if we are aware of the nature and limits of this kind of database, these data still provide a valuable representation of the medical practice's reality.

Conclusions
The present from a contemporary large dataset suggests that the incidence of urethral stricture after BPH surgery is relatively low (< 5%) and varies among procedures.Around 94% of cases are managed using minimally invasive (UD and DVIU) treatment approaches.

Declarations
Con icts Interest: The authors declare no con ict of interest. Figures

Table 1
Incidence of urethral strictures diagnosis and treatment in the total sample and strati ed by procedure.

Table 2
Urethral stricture treatment type in the total sample and strati ed by procedures.

Table 3
Multivariate logistic regression analysis for predictors of US after BPH surgery.