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NICE Guidance – Prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia

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1 Recommendations

  • 1.1 Current evidence on the safety and efficacy of prostate artery embolisation for benign prostatic hyperplasia is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
  • 1.2 Patient selection should be done by a urologist and an interventional radiologist.
  • 1.3 This technically demanding procedure should only be done by an interventional radiologist with specific training and expertise in prostatic artery embolisation.

2 The Condition, Current Treatments and Procedure

The Condition

  • 2.1 Benign prostatic hyperplasia is common in older men. Stromal and epithelial cells increase in number, causing the prostate to increase in size. It often occurs in the periurethral region of the prostate, with large discrete nodules compressing the urethra. Symptoms include hesitancy during micturition, interrupted or decreased urine stream (volume and flow rate), nocturia, incomplete voiding and urinary retention.

Current Treatments

  • 2.2 Mild symptoms are usually managed conservatively. Drugs may also be used, such as alpha blockers and 5‐alpha‐reductase inhibitors. If other treatments have not worked, then surgical options include transurethral resection of the prostate, transurethral vaporisation of the prostate, holmium laser enucleation of the prostate or prostatectomy (see the NICE guideline on lower urinary tract symptoms in men https://www.nice.org.uk/guidance/cg97). Insertion of prostatic urethral lift implants has been introduced more recently as an alternative treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Potential complications of surgical procedures include bleeding, infection, strictures, incontinence and sexual dysfunction.

The Procedure

  • 2.3 Prostate artery embolisation for benign prostate hyperplasia is usually done using local anaesthesia. Under X‐ray guidance, the prostate is approached through the left or right femoral artery. Super‐selective catheterisation of the small prostatic arteries is done using fine microcatheters through the pelvic arteries. Embolisation involves the introduction of microparticles to completely block the prostatic vessels. Embolisation agents include polyvinyl alcohol (PVA) and other newer synthetic biocompatible materials.
  • 2.4 The aim of prostate artery embolisation is to reduce the prostate’s blood supply, causing some of it to undergo necrosis and shrink. It is common for patients to experience pelvic pain during and after the procedure. This does not usually last more than 1 to 3 days. The potential benefits of prostate artery embolisation compared with surgery include fewer complications, avoiding a general anaesthetic and it may be done as a day case procedure.

3 Committee Considerations

The Evidence

  • 3.1 To inform the committee, NICE did a rapid review of the published literature on the efficacy and safety of this procedure. This comprised a comprehensive literature search and detailed review of the evidence from 10 sources, which was discussed by the committee. The evidence included 1 systematic review, 2 randomised controlled trials (also included in the systematic review), 1 non‐randomised comparative study (also included in the systematic review), 2 case series, 3 case reports, and data provided by the UK‐ROPE register and is presented in table 2 of the interventional procedures overview (https://www.nice.org.uk/guidance/IPG611/evidence). Other relevant literature is in the appendix of the overview.
  • 3.2 The specialist advisers and the committee considered the key efficacy outcomes to be: quality of life, urinary symptoms as measured by the International Prostate Symptom Score, and improvement in urodynamics.
  • 3.3 The specialist advisers and the committee considered the key safety outcomes to be: inadvertent embolisation of other sites, urinary retention, prostatic bleeding (haematuria and haematospermia), groin haematoma, pain, retrograde ejaculation, and no loss of sexual function.
  • 3.4 Four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.

Committee Comments

  • 3.5 The evidence showed a relatively high incidence of urinary retention after the procedure.
  • 3.6 The committee was informed that this procedure involves extensive imaging, which may result in significant radiation exposure.
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Article of the Week: TIND implantation in benign prostatic obstruction

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a podcast discussing the paper.

If you only have time to read one article this week, it should be this one.

3‐Year follow‐up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction

 

Francesco Porpiglia , Cristian Fiori, Riccardo Bertolo, Andrea Giordano, Enrico Checcucci, Diletta Garrou, Giovanni Cattaneo, Stefano De Luca and Daniele Amparore
Division of Urology, Department of Oncology – School of Medicine, San Luigi Hospital, University of Turin, Orbassano (Turin), Italy

 

Read the full article

Abstract

Objectives

To report 3‐year follow‐up results of the first implantations with a temporary implantable nitinol device (TIND®; Medi‐Tate Ltd., Or Akiva, Israel) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).

Patients and Methods

In all, 32 patients with LUTS were enrolled in this prospective study. The study was approved by the local Ethics Committee. Inclusion criteria were: age >50 years, International Prostate Symptom Score (IPSS) ≥10, peak urinary flow (Qmax) <12 mL/s, and prostate volume <60 mL. The TIND was implanted within the bladder neck and the prostatic urethra under light sedation, and removed 5 days later in an outpatient setting. Demographics, perioperative results, complications (according to Clavien–Dindo classification), functional results, and quality of life (QoL) were evaluated. Follow‐up assessments were made at 3 and 6 weeks, and 3, 6, 12, 24 and 36 months after the implantation. The Student’s t‐test, one‐way analysis of variance and Kruskal–Wallis tests were used for statistical analyses.

Results

At baseline, the mean (standard deviation, sd) patient age was 69.4 (8.2) years, prostate volume was 29.5 (7.4) mL, and Qmax was 7.6 (2.2) mL/s. The median (interquartile range, IQR) IPSS was 19 (14–23) and the QoL score was 3 (3–4). All the implantations were successful, with a mean total operative time of 5.8 min. No intraoperative complications were recorded. The change from baseline in IPSS, QoL score and Qmax was significant at every follow‐up time point. After 36 months of follow‐up, a 41% rise in Qmax was achieved (mean 10.1 mL/s), the median (IQR) IPSS was 12 (6–24) and the IPSS QoL was 2 (1–4). Four early complications (12.5%) were recorded, including one case of urinary retention (3.1%), one case of transient incontinence due to device displacement (3.1%), and two cases of infection (6.2%). No further complications were recorded during the 36‐month follow‐up.

Conclusions

The extended follow‐up period corroborated our previous findings and suggests that TIND implantation is safe, effective and well‐tolerated, for at least 36 months after treatment.

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Editorial: The trials of doing trials: will the prostatic stent rise from the dead?

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A further re‐engineering of the prostatic stent (temporary implantable nitinol device [TIND®, Medi‐Tate Ltd., Israel]) is reported by Porpiglia et al. 1 in this edition of the BJUI. Enthusiasm for novel ‘minimally invasive’ treatments for BPH/LUTs has surged recently, with new options supported by strong data becoming available 2, 3. That interest reflects the continuing desire of our patients to seek alternatives to the standard drug or surgical therapies.

The success of UroLift® (Neotract, Pleasanton, CA, USA) in satisfying the rigour of the regulatory bodies (especially the Food and Drug Administration [FDA] in the USA and National Institute for Health and Care Excellence [NICE] in the UK) and the recent merger/acquisition of Neotract by Teleflex Inc. for a sum potentially exceeding 1 billion dollars, indicates the rewards available for a novel treatment with convincing data. Not surprisingly, this has stimulated innovators, so there is a veritable tsunami of new treatments approaching us. The rewards are certainly encouraging, but it is worth remembering that the difficulties and cost of reaching market and the point of sale are now enormous.

The TIND stent is implanted endoscopically and then gradually distends to cause three linear pressure necrosis effects within the prostatic urethra and bladder neck tissues, before it is removed at approximately 5–7 days by a second, minor and office‐based procedure.

However, this report is simply a repeat of the initial case series from 2015 4, just with follow‐up to 36 months. An initial report is legitimate in order to show primarily safety and with effectiveness as a secondary outcome measure. I see limited value in a follow‐up report of a device that has already been superseded by a second version, which is currently being assessed in the more rigorous studies that we, our patients, and regulators require.

Even so, there are some important messages and some inconsistencies. Porpiglia et al. 1 are, firstly, to be commended for successfully following their patients out to 3 years with essentially complete data sets. That is remarkable. Although the TIND seems safe, there was one serious complication (a prostatic abscess associated with arrhythmia, sepsis and hyperglycaemia, which required 10 days of inpatient care). About 10% of men restarted medical therapy, but are not ‘failures’, as failures are defined only as those requiring surgical treatment. The prostate size in this small cohort is also surprisingly small compared to the initial studies of other novel devices (29.5 vs 50 mL for UroLift in the initial report) 5. It is also surprising that even though all were on α‐blockers and a substantial proportion were taking 5α‐reductase inhibitors that there is no sexual or especially ejaculatory dysfunction in any of the 19 sexually active men before or after TIND implantation. They appear to have surprisingly resilient ejaculatory function and one wonders why or how? The population studied may therefore not be representative of men we meet in our clinics. Nevertheless, the safety and effectiveness of the original TIND stent do seem reasonable and many of us will await the definitive ‘pivotal’ randomised controlled studies of the successor device with great interest.

For the TIND to find a place in our range of treatments, we urologists, our patients, and regulators of healthcare, now need to see proper randomised controlled trials, preferably incorporating a sham arm and eventually comparisons with TURP. Ideally, the TIND should also be compared to UroLift and to steam injection (Rezūm®; NxThera, Inc., Maple Grove, MN, USA). But who will pay for these studies, even if the regulators insist on them? Funding the required studies is now a major financial challenge to any new device in development. Those studies cost more than we think. A survey of >200 MedTech companies in 2010 suggested device development costs up to 100 million dollars (the majority spent on FDA‐dependent or related activities) but for UroLift total development spend was nearly 240 million. Unfortunately, even innovative and potentially useful devices will struggle to overcome the double jeopardy of regulatory hurdles and obtaining the finance required to clear them. I wish the developers of TIND well and hope there is adequate funding. Today, developers need deep pockets to perform the proper studies correctly.

 

Tom McNicholas
Pinehill Hospital, Hitchin, Herts, UK

References

 

  • 1 Porpiglia F, Fiori C, Bertolo R et al. 3‐Year follow‐up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction. BJU Int2018; 122: 106–12

 

  • 2 Roehrborn CG, Barkin J, Gange SN et al. Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol 2017; 24: 8802–13

 

  • 3 McVary KT, Roehrborn CG. Three‐year outcomes of the prospective, randomized controlled Rezūm System study: convective radiofrequency thermal therapy for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. Urology 2018; 111: 1–9

 

  • 4 Porpiglia F, Fiori C, Bertolo R, Garrou D, Cattaneo G, Amparore D. Temporary implantable nitinol device (TIND): a novel, minimally invasive treatment for relief of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH): feasibility, safety and functional results at 1 year of follow‐up. BJU Int 2015; 116: 278–87

 

  • 5 Woo HH, Chin PT, McNicholas TA et al. Safety and feasibility of the prostatic urethral lift: a novel, minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2011; 108: 82–8

 

Residents’ Podcast: Follow‐up of TIND implantation for the treatment of benign prostatic obstruction

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Maria Uloko and Guilia Lane are Urology Residents at the University of Minnesota Hospital.

In this podcast they discuss the BJUI Article of the Week, 3‐Year follow‐up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction
Special Guest: Mike Borofsky

 

3‐Year follow‐up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction

 

Francesco Porpiglia , Cristian Fiori, Riccardo Bertolo, Andrea Giordano, Enrico Checcucci, Diletta Garrou, Giovanni Cattaneo, Stefano De Luca and Daniele Amparore

 

Division of Urology, Department of Oncology – School of Medicine, San Luigi Hospital, University of Turin, Orbassano (Turin), Italy

 

Read the full article

Abstract

Objectives

To report 3‐year follow‐up results of the first implantations with a temporary implantable nitinol device (TIND®; Medi‐Tate Ltd., Or Akiva, Israel) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).

Patients and Methods

In all, 32 patients with LUTS were enrolled in this prospective study. The study was approved by the local Ethics Committee. Inclusion criteria were: age >50 years, International Prostate Symptom Score (IPSS) ≥10, peak urinary flow (Qmax) <12 mL/s, and prostate volume <60 mL. The TIND was implanted within the bladder neck and the prostatic urethra under light sedation, and removed 5 days later in an outpatient setting. Demographics, perioperative results, complications (according to Clavien–Dindo classification), functional results, and quality of life (QoL) were evaluated. Follow‐up assessments were made at 3 and 6 weeks, and 3, 6, 12, 24 and 36 months after the implantation. The Student’s t‐test, one‐way analysis of variance and Kruskal–Wallis tests were used for statistical analyses.

Results

At baseline, the mean (standard deviation, sd) patient age was 69.4 (8.2) years, prostate volume was 29.5 (7.4) mL, and Qmax was 7.6 (2.2) mL/s. The median (interquartile range, IQR) IPSS was 19 (14–23) and the QoL score was 3 (3–4). All the implantations were successful, with a mean total operative time of 5.8 min. No intraoperative complications were recorded. The change from baseline in IPSS, QoL score and Qmax was significant at every follow‐up time point. After 36 months of follow‐up, a 41% rise in Qmax was achieved (mean 10.1 mL/s), the median (IQR) IPSS was 12 (6–24) and the IPSS QoL was 2 (1–4). Four early complications (12.5%) were recorded, including one case of urinary retention (3.1%), one case of transient incontinence due to device displacement (3.1%), and two cases of infection (6.2%). No further complications were recorded during the 36‐month follow‐up.

Conclusions

The extended follow‐up period corroborated our previous findings and suggests that TIND implantation is safe, effective and well‐tolerated, for at least 36 months after treatment.

Read more articles of the week

 

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Infographic: Impact of dutasteride/tamsulosin combination therapy on sexual function in men with LUTS secondary to BPH

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Infographic: Impact of dutasteride/tamsulosin combination therapy on sexual function in men with LUTS secondary to BPH

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Article of the Month: Nocturia Increases Depressive Symptoms

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Nocturia increases the incidence of depressive symptoms: a longitudinal study of the HEIJO-KYO cohort

Kenji Obayashi*, Keigo Saeki*, Hiromitsu Negoro† and Norio Kurumatani*

 

*Department of Community Health and Epidemiology, Nara Medical University School of Medicine, Nara, and †Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan

 

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How to Cite

Obayashi, K., Saeki, K., Negoro, H. and Kurumatani, N. (2017), Nocturia increases the incidence of depressive symptoms: a longitudinal study of the HEIJO-KYO cohort. BJU International, 120: 280–285. doi: 10.1111/bju.13791

Abstract

Objectives

To evaluate the association between nocturia and the incidence of depressive symptoms.

Participants and Methods

Of 1 127 participants in the HEIJO-KYO population-based cohort, 866 elderly individuals (mean age 71.5 years) without depressive symptoms at baseline were followed for a median period of 23 months. Nocturnal voiding frequency was logged using a standardized urination diary and nocturia was defined as a frequency of ≥2 voids per night. Depressive symptoms were assessed using the Geriatric Depression Scale.

aotw-aug-2017-1

Results

During the follow-up period, 75 participants reported the development of depressive symptoms (score ≥6). The nocturia group (n = 239) exhibited a significantly higher hazard ratio (HR) for incident depressive symptoms than the non-nocturia group (n = 627) in the Cox proportional hazard model, which was adjusted for age, gender, alcohol consumption, day length and presence of hypertension and chronic kidney disease (HR 1.69, 95% confidence interval [CI] 1.05–2.72; P = 0.032]. The significance remained after adjustment for sleep disturbances (HR 1.68, 95% CI 1.02–2.75; P = 0.040). Analysis stratified by gender showed that the association between nocturia and the incidence of depressive symptoms was significant in men (HR 2.51, 95% CI 1.27–4.97; P = 0.008) but not in women (HR 1.12, 95% CI 0.53–2.44; P = 0.74).

Conclusions

Nocturia is significantly associated with a higher incidence of depressive symptoms in the general elderly population, and gender differences may underlie this association.

Read more articles of the week

Article of the Week: Prostatic urethral lift vs transurethral resection of the prostate

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Every week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Prostatic urethral lift vs transurethral resection of the prostate: 2-year results of the BPH6 prospective, multicentre, randomized study

Christian Gratzke*, Neil Barber†, Mark J. Speakman‡, Richard Berges§, Ulrich Wetterauer, Damien Greene**, Karl-Dietrich Sievert††, Christopher R. Chapple‡‡, Jacob M. Patterson‡‡, Lasse Fahrenkrug§§, Martin Schoenthaler¶ and Jens Sonksen

 

§§*Department of Urology, Ludwig-Maximilians University, Munich, Germany, † Frimley Park Hospital NHS Foundation Trust, Surrey, UK, ‡Department of Urology, Taunton and Somerset NHS Trust, Taunton, UK, §PAN Klinik Koln, Koln, Germany, Department of Urology, University Hospital Freiburg, Freiburg, Germany, **City Hospitals Sunderland, Sunderland, UK, ††University Clinic of Lubeck, Lubeck, Germany, ‡‡Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK, and §§Department of Urology, Herlev Hospital, Herlev, Denmark

 

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Abstract

Objectives

To compare prostatic urethral lift (PUL) with transurethral resection of the prostate (TURP) with regard to symptoms, recovery experience, sexual function, continence, safety, quality of life, sleep and overall patient perception.

Patients and Methods

A total of 80 patients with lower urinary tract symptoms attributable to benign prostatic hyperplasia (BPH) were enrolled in a prospective, randomized, controlled, non-blinded study conducted at 10 European centres. The BPH6 responder endpoint assessed symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation and safety. Additional evaluations of patient perspective, quality of life and sleep were prospectively collected, analysed and presented for the first time.

aotw-may-3-results

Results

Significant improvements in International Prostate Symptom Score (IPSS), IPSS quality of life (QoL), BPH Impact Index (BPHII), and maximum urinary flow rate (Qmax) were observed in both arms throughout the 2-year follow up. Change in IPSS and Qmax in the TURP arm were superior to the PUL arm. Improvements in IPSS QoL and BPHII score were not statistically different between the study arms. PUL resulted in superior quality of recovery, ejaculatory function preservation and performance on the composite BPH6 index. Ejaculatory function bother scores did not change significantly in either treatment arm. TURP significantly compromised continence function at 2 weeks and 3 months. Only PUL resulted in statistically significant improvement in sleep.

Conclusion

PUL was compared to TURP in a randomised, controlled study which further characterized both modalities so that care providers and patients can better understand the net benefit when selecting a treatment option.

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Editorial: The BPH6 study raises the bar on how we should conduct BPH surgical trials

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We have all done it. We’ve all shaken our heads with bemusement when men have severe symptoms, as would be defined by the IPSS, yet their response to the quality-of-life question would either be ‘delighted’ or ‘satisfied’. Likewise, we may see men who have objective multiple-fold improvement in their urinary flow rates after a BPH surgical procedure but are more unhappy about their urinary function than they were with their preoperative state. Such mismatches in clinician and patient expectation are not uncommon in clinical practice and are likely, in part, to be a reflection of what measurements clinicians and patients consider to be of importance.

The BPH6 study has challenged the traditional way in which the success of a surgical treatment has been assessed [1]. When prostatic urethral lift (PUL) was compared with TURP in the setting of a randomized controlled trial, there was clearly superior performance of the former as highlighted by a patient-centred outcome metric referred to as the BPH6. It could be argued on the one hand that the combined metric games the outcome in favour of PUL, given that known shortfalls in TURP outcomes, such as recovery, sexual dysfunction and morbidity, could not see it fairly compete with a minimally invasive surgical treatment, but, on the other hand, perhaps the BPH6 metric is just measuring what matters to our patients. The BPH6 is made up of variables that are not in any way new and have all either been established or validated ways of measuring outcomes. A valid criticism, however, is that the combined BPH6 metric is yet to be validated.

Gratze et al. [2] report the 2-year results of the BPH6 study, in a paper that is a great deal more than just a progress report. It represents the most comprehensive patient-centred outcome and quality-of-life assessment ever performed on BPH surgical procedures. Their study also introduces several patient-centred outcome measures that were not reported in the 1-year publication. Additional to the now already well-described BPH6 variables, the study includes the Patient Global Impression of Improvement (PGI-I), the Short-Form Health Survey (SF-12) with its derivative SF-6D utility score, the minimal clinical important difference (MCID) and the Jenkins Sleep Questionnaire.

The PGI-I is perhaps the true test as to what a patient thinks about the effectiveness of a surgical procedure. There is no ambiguity about a response to a direct question as to whether a patient perceives a treatment to have improved or worsened their condition. Whilst the origins of the PGI-I are in the non-urological literature, it has recently been making its way into BPH clinical studies [3, 4]. This should be encouraged and we should indeed dare to ask our patients whether they consider our treatment has lead to improvement or otherwise.

The MCID has been used extensively in the medical literature since its introduction in 1989 [5]. The BPH6 study is the first clinical trial on BPH surgical treatment to use this metric. The MCID is exactly as the term is defined, and is assessed across a range of measures in the paper by Gratze et al. in the context of quality of life. A literature search will reveal that urologists have been very late to the party, but this study will probably have a role-modelling effect with regard to the future use of the MCID in health-related quality of life assessments in BPH studies.

The BPH6 study raises the bar for how we should measure the full impact of the surgical treatment of BPH. There has never been a clinical study that has explored patient-centred outcome measures and quality of life after surgical treatment of BPH to an extent that is even remotely close to that reported here. Whether the combined BPH6 metric becomes popularized or not is less important than the fact that future clinical trials will undoubtedly see an adoption of patient-measured outcomes. Such measures could play an increasingly important role in the decision process for health funders to support a new or existing treatment as well as assist patients in understanding the trade-off between the negative and positive impacts of treatment. We can expect to see plenty of future work that will attempt to verify these assertions.

Read the full article

How to Cite

Woo, H. H. (2017), The BPH6 study raises the bar on how we should conduct BPH surgical trials. BJU International, 119: 654–655. doi: 10.1111/bju.13815

Henry H. Woo
Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, NSW, Australia

 

References

 

1 Sonksen J, Barber N, Speakman M et al. Prospective, Randomized, Multinational Study of Prostatic Urethral Lift Versus Transurethral Resection of the Prostate: 12-month Results from the BPH6 Study. Eur Urol 2015; 68: 643–52

 

2 Gratzke C, Barber N, Speakman M et al. Prostatic urethral lift vs transurethral resection of the prostate: 2-year results of the BPH6 prospective, multicentre, randomized study. BJU Int 2017; 119: 767–75

 

3 Viktrup L, Hayes R, Wang P, Shen W. Construct validation of patientglobal impression of severity (PGI-S) and improvement (PGI-I) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. BMC Urol 2012; 12: 30

 

4 Hossack T, Woo H. Validation of a patient reported outcome questionnaire for assessing success of endoscopic prostatectomy. Prostate Int 2014; 2: 182–7

 

5 Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10: 407–15

 

Article of the Week: eNOS G894T gene polymorphism and responsiveness to a selective α1-blocker in BPH/LUTS

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

The association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective α1-blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms

Yung-Chin Lee*,†, Yung-Shun Juan*,†,‡, Chia-Chu Liu*,†,§, Bo-Ying Bao,**,††, Chii-Jye
Wang*,†, Wen-Jeng Wu*,†, Chun-Nung Huang*,† and Shu-Pin Huang*,†,‡‡
*Department of Urology, †Department of Urology, Faculty of Medicine, Kaohsiung Medical University, ‡Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, §Department of Health, Executive Yuan, Pingtung Hospital, Pingtung,

 

Department of Pharmacy, **Sex Hormone Research Center, China Medical University Hospital, ††Department of Nursing, Asia University, Taichung, and ‡‡Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Read the full article

Objective

To prospectively investigate the association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective α1-blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms (BPH/LUTS), as nitric oxide has recently gained increasing recognition as an important neurotransmitter of functions in the lower urinary tract.

Patients and Methods

In all, 136 men with BPH/LUTS were recruited from urology outpatient clinics in a university hospital. Oral therapy with doxazosin gastrointestinal therapeutic system (GITS) 4 mg once-daily was given for 12 weeks. The drug efficacy was assessed by the changes from baseline in the total International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax) and post-void residual urine volume (PVR) at 12 weeks of treatment. The ‘responders’ to doxazosin GITS were defined as those who had a total IPSS decrease of >4 points from baseline. eNOS G894T polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method.

AugAOTW2

Results

Patients had statistically significant improvements in total IPSS, quality of life score, and Qmax (P < 0.01) after a 12-week period of treatment. Using multiple logistic regression analysis adjusted for age and IPSS, our results showed that being a eNOS 894T allele carrier was an independent risk factor for being a drug non-responder (P = 0.03, odds ratio 4.19). Moreover, a decreased responder rate (P = 0.01), as well as the lower improvements in IPSS (P = 0.02) and Qmax (P = 0.03) were significantly associated with increment in the T allele number.

Conclusions

The presence of the eNOS 894T allele had a significantly negative impact on responsiveness to a selective α1-blocker in BPH/LUTS treatment, suggesting that eNOS G894T gene polymorphism may be a genetic susceptibility factor for α1-blocker efficacy in men with BPH/LUTS.

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Editorial: Responsiveness to Medical BPH Therapy – Is There a Genetic Factor?

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In this issue, Lee et al. [1] from Taiwan demonstrate that the endothelial nitric oxide synthase (eNOS) G894T gene polymorphism predicts responsiveness to α1-blocker therapy in men with BPH/LUTS.

There is a long-standing interest in the establishment of a genetic marker for BPH/LUTS predicting clinical status, the natural history and – ideally – also responsiveness to for example medical therapy. The high prevalence of disease, the socioeconomic impact of diagnosis, medical and surgical treatment, and the availability of drugs (5α-reductase inhibitors) that alter the natural course of the disease justify the intensive search for a genetic marker for BPH/LUTS.

The few familial and twin studies suggest a (moderate) genetic background for this disease to an extent similar to other chronic diseases such as hypertension or diabetes mellitus type II [2, 3]. However, BPH/LUTS is a complex disorder and it is very unlikely that the pathogenesis can be reduced to a single gene or gene defect. Most likely, genetic alterations – besides inflammation, endocrine, myogenic, neurogenic, and morphological factors – act as co-factors.

Within the past decade numerous polymorphisms in the steroid-metabolism pathway, in cytokine genes, in the vitamin D receptor gene, the α-adrenoceptor gene, in homeobox genes, in the angiotensin converting enzyme, the glutathione S-transferase gene, and in the nitric oxide system (just to mention the most frequently studied ones) have been correlated to several clinical parameters of BPH/LUTS, such as symptom status, prostate volume, maximum urinary flow rate and the natural history of the disease [4, 5]. None of these studies provided compelling evidence that one of these polymorphisms (or combinations thereof) could serve as a clinically relevant marker [4, 5]. As indicated by Cartwright et al. [5], many of these genetic studies are hampered by a small sample size, lack of genotyping quality control, inadequate adjustment for populations from heterogeneous descent groups, and poorly defined/inhomogeneous study endpoints.

There is increasing evidence that the nitric oxide (NO)/cGMP pathway plays an important role in controlling the smooth muscle tone of the lower urinary tract. Decreases in the NO/cGMP pathway with age would result in decreased levels of intracellular cGMP and calcium, leading to less smooth muscle relaxation of the bladder and the prostate, thus worsening LUTS. NO is synthesised by at least three isoenzymes of NOS, inducible NOS (iNOS), neuronal NOS (nNOS) and eNOS [1]. The close relationship between NOS/NO pathway and the pathophysiology of BPH/LUTS was the rationale for the study by Lee et al. [1]. Using multiple logistic regression analysis adjusted for age and IPSS, the data showed that the eNOS 894T allele carrier was an independent factor for drug non-responders [1]. However, responsiveness to α1-blocker therapy was also strongly dependent on diabetes mellitus and hypertension, suggesting that the metabolic syndrome plays an important role in the pathogenesis of BPH/LUTS [1]. This is indeed the first study showing that a genetic factor is predictive of the responsiveness to medical BPH/LUTS therapy, therefore this study is significant.

Further studies in populations with other genetic backgrounds (e.g. Caucasian) are required to confirm and to generalise these data. Phosphodiesterase type 5 inhibitors have been proposed to act in BPH/LUTS via the NO systems; therefore, it would be interesting to test this genetic marker also in men treated with tadalafil 5 mg/day. Finally, one has to be aware of the fact that the authors have tested α-blocker monotherapy. All major guidelines recommend a combination of α-blocker and 5α-reductase inhibitor for men with larger prostates (e.g. prostate volume >30–40 mL) [6]. The mean prostate volume in this cohort was 35 mL suggesting that, according to guideline recommendations, these men would have required combined therapy [6].

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Stephan Madersbacher, Professor and Chairman
Department of Urology, Kaiser-Franz-Josef Spital, Vienna, Austria

 

References

 

1 Lee Y-C, Juan Y-S, Liu C-C et al. The association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective a 1-blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms. BJU Int 2016; 118: 313–19

 

2 Partin AW, Page WF, Lee BR, Sanda MG, Miller RN, Walsh PC. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urology 1994; 44: 646–50

 

3 Rohrmann S, Fallin MD, Page WF et al. Concordance rates and modifiable risk factors for lower urinary tract symptoms in twins. Epidemiology 2006; 17: 419–27

 

4 Konwar R, Chattopadhyay N, Bid HK. Genetic polymorphism and pathogenesis of benign prostatic hyperplasia. BJU Int 2008; 102: 536–43

 

5 Cartwright R, Mangera A, Tikkinen KA et al. Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men. Eur Urol 2014; 66: 752–68

 

6 Gravas S, Bach T, Bachmann A et al. Treatment of Non-Neurogenic Male LUTS. Available at: www.uroweb.org. Accessed March 2016.

 

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