Topic Nomination: Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia

1.Questions to Consider

1. What is the comparative efficacy and effectiveness of currently available and emerging treatments for lower urinary tract symptoms (LUTS) secondary to Benign Prostatic Hyperplasia (BPH)?
2. What are the necessary tests to determine if BPH or bladder outlet obstruction (BOO) is the cause of LUTS?
3. What are the necessary tests to determine if a patient with a predominant complaint of nocturia has a metabolic, nocturnal polyuria, polydipsia or other non-prostaocentric etiology as the cause of his LUTS? Should these tests be required or recommended to determine if BPH is the cause of LUTS before treatment is initiated?
4. What is the comparative effectiveness of pharmacotherapy treatment options for LUTS secondary to BPH, including alpha-blockers, beta-3 agonists, anticholinergic agents, 5-alpha-reductase inhibitor (5ARI), phosphodiesterase type 5 inhibitor (PDE5) inhibitors, and their combinations?
5. How does active surveillance of LUTS/BPH compare to the pharmacotherapy treatment options including alpha-blockers, beta-3 agonists, anticholinergic agents, 5ARI, PDE5 inhibitors, and their combinations in terms of comparative effectiveness?
6. How do lifestyle modifications of LUTS/BPH risk factors compare to the pharmacotherapy treatment options including alpha-blockers, beta-3 agonists, anticholinergic agents, 5ARI, PDE5 inhibitors, and their combinations in terms of comparative effectiveness?
7. What is the comparative effectiveness of pharmacotherapy treatment, active surveillance, consoling and lifestyle intervention on those men whose predominant complaint is nocturia?
8. What are the adverse effects of pharmacotherapy treatment options for LUTS secondary to BPH, including alpha-blockers, beta-3 agonists, anticholinergic agents, 5ARI, PDE5 inhibitors, and their combinations?
9. What are the effects of pharmacotherapy and surgical treatment options for LUTS secondary to BPH, on sexual health including erection, ejaculation and climax? 10. What are the patient characteristics or test results that can be used to determine the optimal pharmacotherapy treatment options for LUTS secondary to BPH? 11. What are the advantages and disadvantages of minimally-invasive therapies for LUTS secondary to BPH, such as transurethral needle ablation (TUNA), transurethral microwave therapy (TUMT), Urolift, photovaporization of the prostate (PVP), laser enucleation of the prostate, bipolar enucleation of the prostate, monopolar transurethral resection of the prostate (TURP) and bipolar TURP? 12. When is open or laparoscopic/robotic prostatectomy a beneficial alternative to minimally-invasive therapies for LUTS secondary to BPH? Additionally, when is TURP a viable alternative to minimally-invasive therapies? 13. What is the efficacy of alternative and complementary therapies such as beta-sitosterol, saw palmetto, urtica dioica, and other phytotherapeutic agents? 14. How do we define dose ranges for pharmacotherapeutic agents and alternative and complementary therapies? 15. What are the optimal therapies for patients with uncommon or serious complications of BPH? 16. What is the role of 5ARI in the face of the recent REDUCE trial findings about attributed increased risk of prostate cancer in a non-BPH cohort?

Index Patient

The relevant index patient is a male aged 45 or older who is consulting a qualified healthcare provider for his lower urinary tract symptoms (LUTS). This age range is consistent with BPH NIH trials which typically enroll men ? 45 years of age. He does not have a history suggesting non-BPH causes of LUTS and his LUTS may or may not be associated with an enlarged prostate gland, bladder outlet obstruction, or histological BPH. The index patient criterion specifically excludes men who are under 45 years of age and present with voiding dysfunction, polyuria, or underlying neurologic disease.

Health Related Benefits and Harms

There is a potential for subgroups of patients based upon socio-demographics e.g. age, rural versus urban domicile, ethnicity and/or comorbidities to demonstrate varied efficacy of treatment. Obesity and lifestyle also impact LUTS/BPH and an assessment of the linkage between manifestations of obesity related diseases and BPH may differentiate treatment directives.

Investigation of demographic variables may identify treatments which are associated with fewer adverse events across specific populations. In particular what is the incidence of adverse cardiovascular effects during treatment of LUTS/BPH utilizing alpha blockers in patients with hypertension and in patients utilizing erectile dysfunction (ED) drugs? There is also an opportunity to address the sexual side effects of therapies, the relationship of LUTS and ED, and BPH/LUTS risk factors for the ED population. By improving treatment, the panel has an opportunity to significantly impact patients' quality of life and improve adherence to treatment modalities.

Outcomes of interest include change in scores (AUA/IPSS, peak flow rate, QoL question score, BPH impact index), retention, asthenia, breast symptoms, cardiovascular events, dizziness, GI symptoms, headache, hypotension, nasal congestion, sexual side effects (ejaculation, erectile problems, libido), stricture, hematuria, incontinence, infection/UTI, transfusion.

Describe why this topic is important.

LUTS/BPH is a chronic, progressive urologic condition which affects a significant portion of aging males within the United States. However, despite the traditionally elderly characteristic of BPH, signs and symptoms may present themselves in middle age, and are not uncommon amongst men aged 45 years1. The considerable prevalence of LUTS/BPH has positioned the disease as one of the most commonly treated urologic diseases2. In fact, adenomatous prostatic growth can begin at approximately age 30 and yield 50% of men by age 50 and 90% of men by age 90 demonstrating histologic evidence of BPH3. It is estimated that 40-50% of this group will progress to clinically significant BPH4. The prevalence of moderate to severe LUTS ranges from 26% in men aged 40-49 years to 46% in men aged 70 and older2. The reported economic burden varies according to data sets, yet general estimates suggest that the direct and indirect costs of BPH to be nearly $4 billion annually5. On the individual level, the averge employee with BPH missed 7.3 hours of work yearly5. It is projected that population level costs will continue to increase as the positive trajectory of the number of elderly men with treatment eligible BPH in the United States continues.

Along with the economic impact, the impact upon quality of life is tremendous. Some of the common symtoms of LUTS/BPH such as increased and sudden urge to urinate and decreased ability to support urination stream can cause the act of urination to become an agonizing experience 6, 7. As a result men may choose to avoid public urinals and restrict their freedom of movement in order to be near a retroom facility at all times. Moreover, an enlarged prostate can cause a considerable burning sensation upon urination2,8. BPH can lead to a progressive decrease in patient self esteem, disturbance of sleep, disruption of sex life9 , and a fear of prostate cancer and surgery3,5,7.

In 2010, the AUA launched an initiative identifying national research priorities within the field of urology. This National Urology Research Agenda (NURA) taskforce highlighted LUTS/BPH amongst the top priorities for urologic research. Despite an abundance of evidence pertaining to the clinical efficacy and safety of LUTS/BPH treatment, there is a significant lack of real world evidence for pharmacotherapy utilization and trends6. In addition, there are a wide variety of treatments available and, thus, a variety of practice patterns. The ability to develop definitive statements to address these practice variations, such as a statement about phytotherapeutic agents based on more solid data (RCT) than was available in the past would assist in standardizing treatment of BPH10. In addition, the increasing use of minimally-invasive therapies continues to thrive, allowing the panel to address this treatment modality with improved evidence.

The aforementioned pharmacotherapy and surgical treatments should be compared in order to provide patients with adequate information to make an educated decision in selecting appropriate treatment. Additionally, there is a need to evaluate the role of comorbidity conditions such as obesity and diabetes on symptom etiology. Furthermore, patient preferences are critical to the treatment process, and, toward that end, patients must be given information, based on available data, to determine, along with their physician, the treatment that is most appropriate for them. The panel will provide urologists with an evaluation of newer therapies and provide evidence-based judgments on older but current therapies3, 11. The increase in the rate of disease correlates to an increase in age, a particular concern due to the significant population of aging men.

Given the aging population, LUTS/BPH will be a major arena for research. There is a substantial need for a long-range vision to promote a better understanding of the etiology and management of LUTS/BPH. High priority research areas include:

• Obesity and lifestyle interventions
• Preventive strategies aimed at the underlying pathophysiology of LUTS/BPH
• The identification of disease "phenotypes" and lead to better disease definitions
• Study of primary prevention for LUTS/BPH

These topics illustrate the pressing need for improved methods to diagnose LUTS due to BPH and to predict progression; to develop new drug therapies; identify and test prevention strategies; and develop new non- or minimally invasive interventions. Progress in these areas has the potential to advance clinical care for BPH patients beyond symptom management, which in many cases are not uniformly effective across patients classified as having the same disorder.

References

1. Emberton M, Cornel EB, Bassi PF, Fourcade RO, Gómez JM, Castro R. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. Int J Clin Pract. Jul 2008;62(7):1076-86.

2. Scher HI. Benign and malignant diseases of the prostate. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008. Chapter 91.

3. McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12(suppl 5):S122-S128

4. Chapter 1: AUA guideline on the management of benign prostatic hyperplasia: diagnosis and treatment recommendations. American Urological Association. www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/bph-management/chapt_1_appendix.pdf. Accessed October 2, 2013.

5. Nickel JC. BPH: costs and treatment outcomes. Am J Manag Care. 2006;12(suppl 5):S141-S148.

6. Madersbacher S, Marszalek M, Lackner J, Berger P, Schatzl G. The long-term outcome of medical therapy for BPH. Eur Urol. Jun 2007;51(6):1522-33.

7. Montorsi F, Roehrborn C, Garcia-Penit J, Borre M, Roeleveld TA, Alimi JC, et al. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study. BJU Int. Feb 2011.

8. Burnett AL, Wein AJ. Benign prostatic hyperplasia in primary care: what you need to know. J Urol. 2006;175:S19-S24.

9. Seftel AD, Rosen RC, Rosenberg MT, Sadovsky R. Benign prostatic hyperplasia evaluation, treatment and association with sexual dysfunction: practice patterns according to physician specialty. Int J Clin Pract. Apr 2008;62(4):614-22.

10. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. Aug 2011;108(3):388-94.

11. Roehrborn CG, Gange SN, Shore ND, Giddens JL, Bolton DM, Cowan BE, et al. Multi-Center Randomized Controlled Blinded Study of the Prostatic Urethral Lift for the Treatment of LUTS Associated with Prostate Enlargement Due to BPH: The L.I.F.T. Study. J Urol. Jun 2013.

The AUA has a rigorous, evidence based, high quality guideline development and dissemination process. The AUA Board of Directors has mandated that the AUA increase its number of guidelines as well as periodically assess existing guidelines on a regular basis; as such, the AUA Guidelines team develops and /or revises a minimum of three new guidelines per year and assesses existing guidelines every one to three years. The AUA publishes guidelines on its website as well as on the NGC and G-I-N websites, and these are accompanied by pocket guides and smartphone APPs for physicians. Following a guideline's publication, a summary manuscript is published in the Journal of Urology, which has extensive readership spanning both national and international clinical communities. Additionally, the AUA widely disseminates information about its guidelines through its annual meeting, the AUA Health Policy Brief, AUA News, social media and through its Board of Directors and members. The AUA also provides extensive education for its members and other participants on guideline topics via in person courses, and enduring materials such as toolkits. In addition, AUA is utilizing informaticists to help make guideline statements more actionable and relevant for electronic health records (EHRs). The creation of an AHRQ evidence report on Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia will enhance physician knowledge and reduce treatment inequalities among both the urologic and primary care medical communities. The AUA Guidelines Department works closely with the Urology Care Foundation, committed to patient education and advocacy, to develop patient education materials from its clinical practice guidelines. The AUA is dedicated to providing quality, evidence-based education through the dissemination of pocket guides to both urologic specialists and primary care physicians in addition to patients. The development of a newly-updated clinical practice guideline on LUTS/BPH would enable the AUA to develop additional material with a strong focus on the importance of patient counseling and education. This goal is further assisted via the AUA's new initiative including patient advocates on clinical practice guidelines. Given the substantial role patient preference plays in the treatment of BPH, the patient perspective will be an integral component of developing treatment statements. In addition, the AUA's Quality Department is committed to the development of quality measures from its guidelines. To date, the AUA has worked with the American Medical Association's Physician Consortium for Performance Improvement on its prostate cancer measures as well as partnered with the American College of Obstetricians and Gynecologists to develop measures on stress urinary incontinence in females. The AUA is committed to quality initiatives aimed at measuring urologists and improving patient care in accordance with AUA evidence-based guidelines.

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