Abstract
Objectives:
To analyze medications used to treat urinary symptoms in patients before and after prostatic urethral lift (PUL) and determine if there are any significant relationships between several patient factors and onset of overactive bladder (OAB) symptoms requiring treatment.
Methods:
A retrospective chart review of 226 patients who underwent PUL was performed. Data were collected on age, urinary medications, voiding questionnaires, and prostate volume from 6 months before to 6 months after the intervention. Patients were broken up into groups for analysis with age <60 age (group 1), age 60–75 years (group 2), and age >75 years (group 3). A t-test was used to obtain p-values of the changes in questionnaire answers and urinary medication use after the procedure. To look for significant linear correlations between variables, a Pearson correlation was obtained and a randomization test was performed to obtain p-values.
Results:
Significant International Prostate Symptom Score (IPSS) and Quality of Life (QOL) improvements were noted in all groups (p < 0.01). Total medication and Alpha-blocker decrease was significantly correlated with age (p = 0.02 and p < 0.01, respectively). Older groups had a significant increase in Beta 3 agonist usage, with a significant decrease in usage in younger patients preoperatively. However, no significant linear increase was noted with age (p = 0.147). Prostate volume correlated with preoperative alpha-blocker use (p = 0.04).
Conclusions:
Older patients appear to have a higher incidence of medical treatment for de novo OAB symptoms after PUL. Prolonged medical therapy may delay surgical intervention, and intervention at an earlier age, unrelated to prostate volume, is postulated to be preventative of these symptoms. Further studies are needed to delineate long-term effects of medications, obstruction, and environmental factors that may lead to OAB after the obstruction is treated as well as the effect of early intervention on obstruction.
Introduction
Prostatic Urethral Lift (PUL), otherwise known as UroLift (NeoTract, Inc., Pleasanton, CA) is a minimally invasive treatment of benign prostatic hyperplasia (BPH). This was initially approved in 2013 for men >50 years of age and prostates between 30 and 80 g in size, although some surgeons used PUL for glands outside this size range. 1,2 Due to this, PUL is now approved for prostates up to 100 g in size. At 3 months post PUL, International Prostate Symptom Score (IPSS) and Quality of Life (QOL) scores improved 50% and 47%, respectively. 3 Follow-up studies have shown that at 5 years post PUL IPSS and QOL scores maintain improvement of 36% and 50%. 4 PUL has been marketed as a way for men to discontinue urinary medication and potentially avoid associated side effects. The ability to perform the procedure in the office under local anesthesia is attractive to surgeons as older men may not tolerate anesthesia and therefore be less fit for more invasive procedures. 5 Overactive bladder (OAB) symptoms are common after treatment of obstruction and may require treatment. This has been documented in other minimally invasive BPH treatments, with ∼20% to 30% of patients requiring treatment after transurethral resection of the prostate (TURP). 6 This may require medications such as anticholinergics and Beta 3 (B3) Agonists, as well as intradetrusor Botox injections. It is unclear if early intervention on outlet obstruction would have any effect on the need for OAB therapy postintervention.
Objective
The objective of this study is to analyze medications used to treat urinary symptoms in patients before and after PUL and determine if there are any significant relationships between several patient factors and onset of OAB symptoms requiring treatment. Secondary objectives are to analyze the effect of PUL on voiding questionnaires in relation to patient age as well as prostate volume.
Methods
Retrospective chart review was performed of patients who underwent PUL by a single surgeon. Preoperative medications, IPSS and QOL score, age, prostate volume, and number of implants deployed were recorded. Medications for urinary symptoms can be broken into two groups. Obstructive symptoms are treated with alpha-blockers, 5 Alpha-reductase inhibitors, and Phosphodiesterase Inhibitors. Irritative symptoms are treated with anticholinergics, Beta-3 agonists, or vasopressin analogs. In general, 6-month postoperative IPSS and QOL scores, as well as medications were also recorded. The age of patients were categorized into three groups. Group 1 included patients <60 years. Group 2 included patients between 60 and 75 years of age. Group 3 included patients older than 75 years. A t-test was performed to compare medication usage, IPSS, and QOL scores in each of these age groups pre and postoperatively (Using Microsoft Excel).
Additionally, Pearson correlation was performed to correlate medication usage vs age, prostate size, and number of implants placed. This was smoothed with a moving average function before correlation. To determine significance, simulations of permutations around the variable of interest was performed using the randomization test. Our R results were compared with the randomized results to determine significance (Using R).
Results
A total of 226 PULs were performed and their data analyzed. The descriptive information is shown in Table 1. Average age of patients was 71.2 years. Average prostate size was 52.6 cc. Average number of implants implanted was 5.5. Preoperative IPSS and QOL was 18.1 and 4.03, respectively. At 6 months, postop IPSS and QOL were 6.84 and 1.63, respectively. There was a statistically significant improvement in IPSS and QOL scores for all groups (p < 0.01). Five out of 226 patients (2.2%) were reported deceased before 6 months follow-up from causes unrelated to the procedure.
Chart with Descriptive Information of Retrospective Cohort
These were split into groups based on age with total average on right. IPSS and QOL scores preoperatively and 6 months postoperatively are recorded.
IPSS = International Prostate Symptom Score; QOL = Quality of Life.
All groups had a statistically significant reduction in urinary medications postoperatively. Additionally, all groups had a statistically significant reduction in the use of alpha blockers postoperatively. A reduction of 5-alpha reductase inhibitor (5ARI) use was noted to be statistically significant overall, but on subanalysis, this was only significant for group 3 (Table 2), which also had the largest average prostate size of 58.19 cc. No patients in group 1 were on 5ARI either before or after PUL. All groups had an increase in the use of anticholinergic medications; however, this was not statistically significant. B3 agonist use postoperatively was significantly increased overall, as well as in group 2 and 3. However, group 1 did not have an increase in B3 agonist use.
Changes in Urinary Medications Pre- and Postoperatively
5ARI, 5-alpha reductase inhibitor; B3, beta 3.
Since urinary drug usage was found to differ based on age group, Pearson's correlation (R) was taken between patient age and urinary drug usage to look for a linear correlation between variables. After arranging data in order of the independent variable (age in this instance), this was plotted against the dependent variable (urinary drug usage). To smoothen the data, a moving average was performed before determining Pearson's correlation. To determine the significance of these results, a randomization test was used, where patient ages were decoupled from medication usage and permutated. Correlations in 10,000 randomized tests were used as a background model to determine the significance of the correlation between two variables.
No statistically significant correlation between age and number of preoperative medications was seen (p = 0.266). There was a statistically significant positive correlation between age and number of medications taken postoperatively (p = 0.036). There was also a significant correlation between decrease in total medication usage after PUL and age (p = 0.021). This may indicate that older patients receiving this surgery are less likely to be taken off their medication or be prescribed new medications at 6 months postprocedure.
Similar correlation between specific urinary drugs was performed as well. Preoperatively, there was no correlation between age and alpha blocker use (p = 0.109). Postoperatively, there was a significant positive correlation (p = 0.025) between age and alpha blocker use. Total alpha blocker decrease was significantly negatively correlated (p = 0.002) indicating an increase in alpha blocker use with age postoperatively.
B3 agonist usage was also correlated with age. Preoperatively, there is a significant negative correlation (p = 0.040) between age and B3 agonist usage. Postoperatively, there is no correlation with age (p = 0.444). No significant correlation between age and increase in B3 agonist usage after surgery was noted (p = 0.147). A summary of these data are shown in Table 3.
Pearson Correlation (R) and p-Value of Age Correlated with Medications
A similar analysis was performed based on patient prostate volume. No significant correlation was found between prostate size and total drug usage pre (p = 0.101) or postop (p = 0.339). No significant correlation was noted with prostate volume and decrease in total drug usage (p = 0.338). The only significant correlation between prostate size and urinary medications was preoperative alpha blocker use (p = 0.037). A summary of the R and p-values are shown in Table 4.
Pearson Correlation (R) Between Urinary Drugs and Prostate Volume
The only significant p-value was found between prostate volume and preoperative alpha blocker use (p = 0.037).
To compare prostate volume to the number of implants deployed, these data were sorted by prostate size. The moving average of implants deployed was plotted by prostate size. The Pearson's correlation was obtained and then randomization test performed. A significant positive correlation was found with p < 0.001. Additionally, patient age and prostate volume were correlated, and a this was found to be significant with p < 0.001.
Additional correlations were performed to see if patient questionnaires had any significant correlation with the decrease in total drug usage postoperatively. There was a significant positive correlation between decrease in total drug usage and IPSS (p = 0.046) as well as QOL (p = 0.019). For visual purposes, additional graphs are available in supplementary figures S1, S2, S3, S4, S5, S6, S7.
Discussion
This is a single-surgeon retrospective study of 226 patients. Our study compares favorably with the luminal improvement following prostatic tissue approximation for the treatment of LUTS secondary to BPH (L.I.F.T) study at 5 years in terms of score improvement in IPSS (62% vs 36%) and QOL (60% vs 50%), respectively. 4 However, the L.I.F.T. study shows durability of this score at 5 years, whereas our study only includes up to 6 months. However, this is just the initial study with further data to be collected over time.
Age groups were chosen arbitrarily to categorize the patients into younger, average, and older age groups. There was a statistically significant reduction in urinary medications after PUL in all age groups. Overall, there was a 44% reduction (1.17–0.66) in total urinary medications for the cohort. There was a 64% decrease in prostate medications overall (1.07–0.38) and 87% increase in bladder medications (0.1–0.19). These were both statistically significant (p < 0.01). There was no significant correlation between age and number of medications preoperatively, but there was a significant correlation between age increase in postoperative medications with age (p = 0.02). This is likely due to continued use of alpha blockers and additional OAB medications that appear used in older patients.
There was a significant decrease in prostatic medications overall. Alpha blocker use was significantly decreased in all age groups, from 0.92 to 0.37 medications in total (p < 0.01). There was no significant correlation between age and preoperative alpha blocker use (p = 0.11), but there was significant correlation between postoperative change of alpha blocker use with age (p < 0.01). This may indicate that older patients may still require medications post PUL to improve postvoid residual (PVR) or urinary retention. Similarly, there was a significant decrease in 5ARI use overall, but no significant decrease in group 1 or 2. In fact, no 5ARIs were prescribed to the group 1 pre- or postprocedure, indicating it is not typically considered as a viable treatment option in younger patients. This may be due to smaller prostate size on average (39.97 cc in group one vs 52.6 cc overall), or possibly due to sexual side effects with this class of medications. These include gynecomastia, metabolic syndrome, decreased libido, erectile dysfunction, and even depressive symptoms. 7
Medications typically used for OAB symptoms were also analyzed. Anticholinergic medications (Oxybutynin, Trospium, Solifenacin, Tolterodine, and so on) had an increased use after PUL, but this was not statistically significant. Conversely, B3 agonists (Mirabegron) had a drastic increase overall (200%) that was statistically significant (p < 0.01). Older patients (Group 3) had a 333% increase in B3 agonist use (p = 0.03). The preferential use of B3 agonists over anticholinergics may be due to their side effect profile as efficacy is considered similar. Anticholinergic side effects (dry mouth, constipation, dizziness, confusion) that can be more prominent in older patients and some studies suggest there may be a link with chronic anticholinergic use and dementia in patients with lower urinary tract symptoms (LUTS). 8,9 B3 agonists, however, are only relatively contraindicated in patients with poorly controlled hypertension. 10 Younger patients in group 1 saw no significant increase in B3 agonist use. There was a significant negative correlation between age and preoperative B3 agonist use (p = 0.04). The reason for the lower need for OAB medication-related drugs in the younger group is not clearly delineated, but this is postulated to be due to longstanding obstruction in older patients causing changes in bladder physiology.
The correlation between prostate size and changes in medications was explored as well. No significant correlation was noted for any of the medications other than preoperative alpha blocker use (p = 0.037). This is somewhat surprising as one would suspect that larger prostates would be treated with increased 5ARI use and less OAB medications due to risk of retention. However, many of these patients underwent transrectal ultrasound for size just before PUL. This allows patients to have all procedures done under one anesthetic event. Additionally, most treatment plans were based on symptoms rather than prostate size. Based on chart review, many patients seemed to prefer minimally invasive techniques and avoid hospital stays, making PUL more attractive regardless of prostate size. There was a significant correlation between larger prostate size and more implants deployed (p < 0.001). This is likely due to physical space available to place the implants available in larger prostates. There was also a significant correlation between age and prostate size (p < 0.001), with elderly patients having an expected larger prostate size on average.
Comparison of total urinary drug decrease and IPSS change showed a significant correlation (p = 0.046). Similarly, change in QOL was significantly correlated with total urinary drug decrease (p = 0.019). As a larger improvement in IPSS and QOL score occurred, the patients expressed a subjective improvement in their symptoms. The IPSS has been validated, with patient scores >20 indicating a significant likelihood of bladder outlet obstruction. 11 Additionally, studies have shown that a QOL >5 is associated with patient depression, whereas this correlation was not seen with IPSS. 12 While subjective, the change in these scores, in addition to total scores, can be reflective of patients' overall improvement.
This study has seen a larger increase in OAB medications needed after obstruction is treated in older patients. This symptomatology is hypothesized to be due to changes in the bladder from longstanding obstruction, although it is likely multifactorial. Many factors have been implicated in the development of LUTS, including obstruction, aging, age-related diseases, hormonal changes, nocturnal diuresis, and anoxia. 13 Alpha blockers have been shown to decrease detrusor pressures during maximum flow rate on urodynamics an average of 11.39 cm H2O. 14,15 Chronic ischemia associated with LUTS can also be improved by alpha blocker therapy. 16 Studies suggest that alpha blockade may have a lasting effect on symptoms for up to 6 years. 17 However, surgical procedures have shown greater improvements in detrusor pressures at maximum flow rate compared with medications. On metanalysis, open prostatectomy has shown the greatest improvement, with an average improvement of 40.5 cm H2O. Open prostatectomy shows greater improvements than TURP, which subsequently shows greater improvement than laser and dilation techniques. 18 While there is urodynamic improvement after outlet procedures, there is still some patients with residual OAB symptoms. This is hypothesized to be due to prolonged obstruction effecting long-term bladder health. While medical therapies do not truly relieve obstruction, they have shown effectiveness in treating LUTS.
This symptomatic improvement has led to medical therapy becoming the first-line treatment of BPH, with TURP and other surgical procedures reserved for patients who fail medical therapy. 19 There has been an increase in patients undergoing TURP who were on medical therapy, from 2% in 1990 to 43% in 2010. 20 This increase mirrors the trend seen with men presenting with high pressure chronic retention, with an increase from 1% in 1990 to 18% in 2010. 20 Studies have suggested that earlier surgical treatment compared with watchful waiting will reduce the rate of treatment failure 21 and that a delay in surgical treatment by using medical therapy may have long-term effects on the detrusor muscle that may not be able to be reversed with prolonged obstruction. 22,23 This is postulated to be due to decreased outflow resistance with TURP that therefore decreases detrusor pressure and preserves bladder integrity. 24 While earlier surgical intervention with PUL, rather than medical therapy with delayed intervention is hypothesized by the authors to be responsible for reduced OAB symptoms postoperatively in younger patients, additional studies are needed to make any definitive statements on the effect of PUL on bladder preservation over time.
There are several limitations to this study. Although significant correlations were found, its retrospective nature makes it difficult to draw definite conclusions from the data. Around 2.2% of patients were unable to follow-up due to death from unrelated causes before 6 months postoperatively. Six months was chosen as the time period to examine as many patients did not follow-up longer as they were either improved and no longer followed up, or were referred from a different urologist for the procedure and therefore did not have longer data available. Some patients received their urinary medications from their primary care physician, which can make prescriptions difficult to confirm. Additionally, some patients were provided with drug samples rather than prescriptions initially. This was to ensure the medication was effective before purchasing, however it did make exact start and stop dates difficult to track precisely. Desmopressin and tadalafil were also included in the study. While not typically thought of as urinary medications, in this instance they were prescribed for urinary symptom treatment and therefore included in the study. These were rarely used and while considered for overall urinary medications, further analysis was not performed as the infrequent use would make it difficult to gain any insight into their significance. The study is only a preliminary study with 6 months follow-up. Continued postoperative data will need to be collected to see if our results are maintained over time.
Future studies are still needed to focus on many areas of the PUL. Long-term data to compare the longevity to the gold standard of TURP still needs to be determined, although 5-year data in the L.I.F.T. study show continued improvement in IPSS (36%) and QOL (50%). 4 Preservation of erectile and ejaculatory function, a major advantage of PUL for patients who wish to maintain fertility, is also noted in that timeframe. 4 Additionally, more studies on the effect of early intervention for obstruction are needed to determine the optimal time for surgical intervention to maintain integrity of the bladder in patients with BPH. While elements not included in this study would likely be helpful, such as PVR and urodynamics, these are more costly and invasive than questionnaires. With an estimated $1.1 billion in direct health care costs related to BPH treatment in the United States in 2000, an investment by national health agencies for a long-term longitudinal study to determine optimal intervention time is warranted. 25
Conclusions
PUL may represent a minimally invasive intervention to reduce medication usage in all patients, maintain normal sexual function, and possibly reduce the long-term risk of bladder damage. QOL and IPSS scores were significantly improved at 6 months, with the greater change in score appearing more important than postoperative scores themselves, with larger decrease in urinary medications overall. Preoperative alpha blocker use was correlated with larger prostate size, but post PUL urinary medication use was independent of prostate size. Older age correlates with increased alpha blocker and OAB medication use postoperatively, with B3 agonists utilized more significantly than anticholinergics. This positive correlation between age and OAB medication use is hypothesized to be due to bladder changes from prolonged obstruction rather than age itself. Future studies should look at preoperative storage symptoms and effect of early PUL vs medical treatment of BPH to determine if patients who develop OAB after intervention can be determined preoperatively. Additionally, determining if there is an optimal time to intervene surgically on outlet obstruction and if delaying surgical treatment by using medication to improve LUTS has an adverse effect on bladder health long term is essential.
Footnotes
Author Disclosure Statement
T.M. has a financial relationship with NeoTract, Inc. All other authors have no competing financial interests.
Funding Information
No funding was received for this article.
Supplementary Material
Supplementary Figure S1
Supplementary Figure S2
Supplementary Figure S3
Supplementary Figure S4
Supplementary Figure S5
Supplementary Figure S6
Supplementary Figure S7
Abbreviations Used
References
Supplementary Material
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