Professor Christopher Chapple outlines the NICE recommendations on the assessment and treatment options for lower urinary tract symptoms in men


Lower urinary tract symptoms (LUTS) are a common cause of presentation for male patients to see their GP. Their prevalence and severity increase with age. They are traditionally divided into three categories:

  • Voiding symptoms include slow or intermittent stream during micturition, splitting, or spraying of the urine stream, hesitancy when an individual experiences difficulty in initiating micturition, straining to void, and terminal dribble. Such voiding LUTS are generally considered to be indicative of benign prostatic hyperplasia (BPH), but this is an incorrect concept since BPH can only be diagnosed histologically
  • Storage symptoms include increased daytime frequency of micturition, nocturia (when the patient wakes from sleep at night to void), urgency (the sudden compelling desire to pass urine), and urinary incontinence. Overactive bladder (OAB) is the symptom complex including urgency, with or without urgency incontinence, sometimes with frequency or nocturia
  • Post-micurition symptoms such as dribbling.

Voiding LUTS (associated with either bladder outlet obstruction [BOO] due to benign prostatic enlargement [BPE] often resulting from BPH or poor detrusor function) and storage LUTS (OAB) are highly prevalent in older men and frequently occur together.

Lower urinary tract symptoms are associated with reduced health-related quality of life (HRQL) and a negative psychological impact. The symptoms of OAB in particular have a negative impact on quality of life.

Defining lower urinary tract symptoms

The first important milestone in the development of the new NICE guideline was agreement with the Department of Health that the term ‘BPH’ should be replaced by male LUTS.1,2 The term ‘LUTS’ is much broader and was originally introduced in 1994 in order to dissociate male urinary symptoms from any implied site of origin, such as the prostate.3 Formal recognition that BPH is not a clinical entity and that LUTS can arise from many different aetiologies is an important milestone (see Table 1).

Historically, voiding symptoms have been related to obstruction of the bladder outlet; the traditional association in men is with the prostate—the so-called symptoms of ‘prostatism’. However, it is well recognised that voiding symptoms correlate poorly with underlying pathophysiology. Similar symptoms can also be produced by any other form of obstruction, such as a urethral stricture or conversely, by poor function of the lower urinary tract in circumstances where there is impaired detrusor contractility. This has led to the recognition that although LUTS may be commonly related to BOO as a result of benign prostatic obstruction (BPO),4 this is not invariably the case. Failure to empty can be related to an outflow obstruction or to detrusor underactivity of the bladder, or a combination of both.

It is now widely recognised that LUTS encompasses all urinary symptoms, including storage, voiding, and post-micturition symptoms. This terminology links well with the classification proposed by Wein who suggested that disorders of micturition would be more elegantly characterised as ‘failure to store’ or ‘failure to empty.5,6 In this context, it has been known for at least four decades that LUTS does not relate to the underlying pathophysiology in many patients; indeed the phrase ‘the bladder is an unreliable witness’ was aptly coined to acknowledge this.7

An all-encompassing view of LUTS that focuses on the lower urinary tract as an integrated functional unit, but which simultaneously reflects pathophysiology in the body as a whole, is more likely to improve a clinician’s ability to manage the symptoms and therefore benefit patient outcomes. For example, nocturia can be caused by bladder dysfunction, as well as by a number of other pathophysiological processes. This approach will allow us to move beyond a local organocentric view and lead to more appropriate recognition of clinical scenarios. In particular it will allow healthcare professionals to take into account the patient’s expectations and goals more effectively for a successful outcome.

Table 1: Classification of LUTS2
Storage Voiding Post-micturition
  • Frequency
  • Urgency
  • Nocturia
  • Incontinence
  • Slow stream
  • Splitting or spraying
  • Intermittency
  • Hesitancy
  • Straining
  • Terminal dribble
  • Post-micturition dribble
  • Feeling of incomplete emptying
National Clinical Guidelines Centre (2010) CG97. The management of lower urinary tract symptoms. London: NICE. Reproduced with permission. Available from www.nice.org.uk/guidance/CG97/guidance

 

Prevalence

The prevalence of LUTS is known to increase with age.8–15 In men, LUTS are often attributed to histological BPH, which also occurs more frequently with ageing, with a reported prevalence of 50% in men aged 51–60 years, increasing to up to 90% in men aged 80 years or older.16 Several studies have attempted, in the view of the Guideline Development Group (GDG), erroneously, to estimate the prevalence of the clinical consequences of histological BPH by determining the presence of LUTS suggestive of BOO associated with BPH. In 2000, approximately 6.5 million of 27 million white men aged 50 to 79 years in the United States met the criteria for discussion of potential treatment for BPH.17 In those aged 40 years and older who were outpatient users of Department of Veteran Affairs healthcare services, the prevalence of BPH/LUTS was 4.8%.18 Using the criteria of international prostate symptom score (IPSS) >7, 42% of men aged 50 years and older visiting their primary care physician for routine care had LUTS suggestive of BPH.19

Improving patient care

There is now clear recognition that LUTS occur commonly, however, the frequency of symptoms does not necessarily correlate with the number of patients who seek treatment. Indeed, many men may not find their symptoms bothersome enough to feel the need to visit their healthcare professional for advice or treatment. However, the impact of LUTS on HRQL and the level of bother are significant drivers for patients to seek treatment. This suggests a clear need for healthcare professionals to know how to assess the frequency and related bother of symptoms effectively, as well as help patients to make informed decisions about their treatment.

The embarrassment and stigma associated with LUTS, especially incontinence, is a significant barrier to treatment seeking.20 Additional public education and improved clinical detection are likely to lessen this stigma and improve the use of NHS resources to diagnose patients effectively and improve HRQL due to LUTS.

Remit of the NICE guideline

Over the past 2 years an independent committee appointed by NICE completed a comprehensive evidence-based review with the objective of developing national recommendations for the appropriate work-up and management of adult male patients who have LUTS. The resulting NICE guideline, Lower urinary tract symptoms: The management of lower urinary tract symptoms in men, is based on an extensive evidence-based analysis of randomised, controlled clinical trials, and Cochrane reviews. It includes studies on adult men (>18 years) with a clinical diagnosis of LUTS or those in high-risk groups (e.g. elderly groups).1,2

The recommendations cover:1,2

  • primary, secondary, and tertiary settings
  • clinical management (including clinical and cost effectiveness), as well as side-effects
  • initial diagnostic assessments
  • monitoring
  • non-pharmacological therapy
  • drugs in licensed indications and other indications supported by compelling evidence
  • surgical interventions or minimally invasive alternatives
  • combinations of the recommendations above.

Box 1 summarises the key recommendations for primary care.

Box 1: Key recommendations for primary care

Providing information

  • Ensure men with LUTS have access to care that can help with:
    • their emotional and physical conditions and
    • relevant physical, emotional, psychological, sexual, and social issues
  • Provide men who have storage LUTS with advice about relevant support groups

Initial assessment

At initial assessment:

  • offer men with LUTS an assessment of their general medical history to identify possible causes of LUTS, and associated co-morbidities:
    • review current medication, including herbal and over-the-counter medicines, to identify drugs that may be contributory to the problem
    • offer men a physical examination guided by urological symptoms and other medical conditions, an examination of the abdomen and external genitalia, and a DRE
    • offer men with LUTS information, advice, and time to decide if they wish to have PSA testing if:
      • their LUTS are suggestive of bladder outlet obstruction secondary to BPE or
      • their prostate feels abnormal on DRE or
      • they are concerned about prostate cancer
    • ask men with bothersome LUTS to complete a urinary frequency volume chart
    • do not routinely offer a flow-rate measurement or a post-void residual volume measurement to men with LUTS
    • only offer men with LUTS a serum creatinine test (plus eGFR calculation) if renal impairment is suspected (for example, if the patient has a palpable bladder, nocturnal enuresis, recurrent urinary tract infections, or a history of renal stones)
    • do not routinely offer cystoscopy or imaging of the upper urinary tract to men with uncomplicated LUTS (that is, without evidence of bladder abnormality)

Conservative management

  • Offer men with storage LUTS (particularly urinary incontinence) temporary containment products (for example, pads or collecting devices) to achieve social continence until a diagnosis and management plan have been discussed
  • Offer men with storage LUTS suggestive of OAB, supervised bladder training, advice on fluid intake, lifestyle advice, and, if needed, containment products

Surgery for voiding symptoms

  • If offering surgery for managing voiding LUTS presumed secondary to BPE, offer monopolar or bipolar TURP, monopolar TUVP, or HoLEP. Perform HoLEP at a centre specialising in the technique or with mentorship arrangements in place
  • Do not offer minimally invasive treatments (including TUNA, TUMT, HIFU, TEAP, and laser coagulation) to men with voiding LUTS presumed secondary to BPE

LUTS=lower urinary tract symptoms; DRE=digitial rectal examination; PSA=prostate specific antigen; BPE=benign prostate enlargement; eGFR=estimated glomerular filtration rate; OAB=overactive bladder; TURP=transurethral resection of the prostate; TUVP=transurethral vaporisation of the prostate; HoLEP=holmium laser enucleation of the prostate; TUNA=transurethral needle ablation; TUMT=transurethral microwave thermotherapy; HIFU=high-intensity focused ultrasound; TEAP=transurethral ethanol ablation of the prostate

 

Assessment

The NICE GDG identified a number of critical issues relating to diagnostic work-up of patients:

  • Since voiding symptoms cannot be considered BPH-specific, this means that an appropriate assessment relies on a comprehensive evaluation2
  • An adequate, internationally accepted and applied definition for BPH is still lacking
  • Robust outcome measures related to LUTS have not been identified and standardised
  • As bladder overactivity is accepted as a major contributor to storage symptoms, its management needs to be routinely addressed
  • Only three out of seven questions from the IPSS deal with storage symptoms, which are now recognised as the most bothersome.2

The guideline section on assessment is subdivided into two sections covering initial and specialist assessment, either of which can be performed in primary or secondary care settings. The initial assessment can be performed in any setting by a healthcare professional who has not been specifically trained to manage LUTS in men.

Initial assessment
There is a general agreement on which investigations should be performed during initial assessment of men with LUTS; this includes:1,2

  • collecting a medical history
  • physical examination including a digital rectal examination (DRE)
  • noting IPSS
  • completing a urinary frequency volume chart
  • urinalyses by dipstick.

Other assessments such as serum creatinine, cystoscopy, imaging, flow-rate measurements, and post-void residual volume measurements, are not required for men with uncomplicated LUTS. Patients should be given reassurance and advice on lifestyle interventions (e.g. fluid intake). Patients with complicated LUTS or who have bothersome symptoms that do not respond to conservative or pharmacological treatment should be referred to a specialist.1,2

Specialist assessment
Specialist assessment should involve a focused physical examination guided by medical history, an examination of the abdomen and external genitalia, and DRE, and a measurement of flow rate and post-void residual volume. The patient should also complete a urinary frequency volume chart and be offered testing for prostate specific antigen (PSA).1,2

Cystoscopy and/or imaging should be offered if the patient has a history of recurrent infection, sterile pyuria, haematuria, profound symptoms, or pain; imaging should also be offered to patients who have a history of chronic retention. Multichannel cystometry may be useful for patients who are considering surgery, and pad tests should only be offered if the degree of urinary incontinence needs to be measured.1,2

Management

Current strategies for treating men with LUTS are watchful waiting, conservative management, pharmacological therapies, minimally invasive therapies, and surgical therapies.

Conservative management
The first approach is conservative therapy, such as urethral milking (to deal with post-micturition dribbling), advice on lifestyle modification (attention to fluid intake both in terms of volume and timing of intake), and bladder training.1,2 Men with storage LUTS should be offered temporary containment products including pads and waterproof underwear. Indwelling urethral, suprapubic catheters, and the use of intermittent catheterisation are also management options.1,2

Pharmacological treatment
Managing a chronic, progressive condition such as LUTS is all about maintaining quality of life by balancing side-effects and the efficacy of treatment in controlling symptoms and if possible slowing down the natural progression of the disease. Decision-making is often controversial, on account of lack of evidence supporting appropriate patient targeting, the natural history of the disease (BPH often does not progress), the high efficacy of placebo, and the lack of long-term safety and efficacy data on pharmacological therapy, as well as on cost effectiveness and cost–benefit.

Drug treatment should only be offered to men with bothersome LUTS when conservative management options have been unsuccessful or are not appropriate. The following classes of drugs are used:1,2

  • alpha1-adrenergic receptor antagonists (alpha blockers)
  • 5-alpha-reductase inhibitors (5-ARIs)
  • anticholinergics for the OAB component of LUTS.

Alpha blockers
NICE recommends offering an alpha blocker (e.g. alfuzosin, doxazosin, tamsulosin, or terazosin) to men with moderate to severe LUTS. The efficacy of alpha blockers in improving LUTS symptoms has been clearly demonstrated in placebo-controlled trials. It has been shown that benefit is not related to prostate size and that it is significantly greater not only versus placebo, but also versus finasteride. Moreover, the onset of action is much faster than with 5-ARIs;2 the effects being recorded within hours. These drugs are effective in aborting acute retention and are likely to reduce its incidence. The efficacy of the various compounds is similar. Alpha blockers also have an excellent safety profile, with tamsulosin and alfuzosin ranging among the most safe and tolerated compounds.2

The Medicines and Healthcare products Regulatory Agency (MHRA) has recently changed the status of tamsulosin, so that pharmacists can supply it to men with LUTS under specific circumstances. This use is outside the scope of the NICE guideline and assessment and management by pharmacists in this context is covered in extensive guidance issued by the MHRA and NICE.21

5-alpha-reductase inhibitors
The two available 5-ARIs—finasteride and dutasteride—are similar in terms of safety and efficacy, with the only difference being that 5-year data are available on finasteride and 4-year data on dutasteride.2 The dual inhibition of both types of alpha-reductase enzymes offered by dutasteride does not appear to result in clinical advantages.2

Both 5-ARIs improve symptoms, shrink prostate volume by 15%–25%, and decrease the risk of acute urinary retention and surgery.2 However, the effect of 5-ARIs is generally greater in patients with larger prostates (>30 g estimated size). Adverse effects are usually sexually related. The drawbacks of the ARIs are slow onset of action (3–6 months); the extent of benefit, which is usually lower than with alpha-blockers; and the halving of PSA, which has to be taken into account.2

Combination of alpha blockers + 5-alpha-reductase inhibitors
The benefits of a combination of alpha blockers and 5-ARIs versus alpha blockers alone were not apparent over a 1-year period (Veteran Affair Cooperative study [VACOOP] and Prospective European Doxazosin and Combination Therapy Study [PREDICT]).22,23 However, in year 4 of the longer-term Medical Therapy of Prostatic Symptoms (MTOPS) study, an improvement in symptoms as well as a reduction in the risk of overall clinical progression, acute urinary retention, and surgery were demonstrated.24 However, the combination therapy also increased costs and certain side-effects.

The CombAT study was designed as a double-blind trial to compare tamsulosin and dutasteride monotherapy and
in combination in a selected group of men (prostate volume >30 g, PSA, 1.5–10 ng/ml) It reached the same conclusions: combination therapy was more effective, but it increased side-effects.25,26 Overall, even though a combination of 5-ARIs and alpha blockers may result in greater efficacy than the agents alone, the clinical usefulness of this therapy is restricted by the difficulty of assessing prostate size in a primary care setting and the increase in cost and adverse events associated with dual therapy.2

Anticholinergic drugs (antimuscarinics) alone or in combination
The limited number of randomised controlled trials evaluating the efficacy and safety of anticholinergics in patients with LUTS secondary to BPH with OAB symptoms (with or without BOO or detrusor overactivity) showed that these drugs are safe, but not always associated with better efficacy in improving symptoms.2,27 Nevertheless, as long as patients with residual urine volumes over 200 ml are excluded, the use of anticholinergic drugs does not seem to cause an increase in acute urinary retention rates.27 According to these data, antimuscarinic monotherapy cannot be recommended for routine use in patients with OAB and BOO. The combination of an antimuscarinic and an alpha-blocker may be safe and effective in these patients, provided that patients with large residual volume are excluded.2

Recommendations for medical intervention
The main NICE recommendations on pharmacological treatment of LUTS are:1,2

  • Offer drug treatment only if conservative management has failed or is inappropriate
  • When offering drug therapy, take into account co-morbidities and current treatment
  • Use an alpha blocker in men with moderate to severe LUTS
  • Offer an anticholinergic agent to men with OAB symptoms
  • Offer a 5-ARI to patients with enlarged prostate (>30 g) and PSA >1.4 ng/ml and at high risk of progression (e.g. older patients)
  • Offer a 5-ARI/alpha blocker combination to men with bothersome or severe symptoms and enlarged prostate who have not responded to an alpha blocker
  • Consider offering a combination of an anticholinergic and an alpha blocker to men who still have storage symptoms after treatment with an alpha blocker alone.

Review

It is important for a clinician to evaluate any patient who has commenced pharmacological therapy for LUTS. The NICE guideline recommends different intervals at which to review patients depending on indication and treatment. Patient review should include symptom assessment, effect of the drugs on quality of life, and any adverse effects.

Surgery

Surgical interventions should be offered only to men with severe symptoms or those who have not responded to conservative and pharmacological treatment. Surgical options for voiding symptoms presumed secondary to BPE are:1,2

  • monopolar or bipolar transurethral resection of the prostate (TURP)
  • monopolar transurethral vaporisation of the prostate (TUVP)
  • holmium laser enucleation of the prostate (HoLEP) provided that it is performed in a specialised centre.

Transurethral incision of the prostate (TUIP) may be used in men with a small prostate (<30 g) and open prostatectomy in men with a large prostate (>80 g).1,2

Minimally invasive treatments, including transurethral needle ablation (TUNA), transurethral microwave thermotherapy (TUMT), high-intensity focused ultrasound (HIFU), transurethral ethanol ablation of the prostate (TEAP), and laser coagulation should not be offered to men with voiding LUTS presumed secondary to BPE as an alternative to TURP, TUVP, or HoLEP.1,2

Surgical interventions for storage symptoms include cystoplasty, implanted sacral nerve root stimulation, urinary diversion, and implantation of an artificial sphincter to manage stress urinary incontinence.1,2

Implementation

The NICE guidance on male LUTS aims to simplify the management of these patients in primary care. This, coupled with the previous NICE guideline on incontinence in women,28 provides the primary care practitioner with clear recommendations on how to manage LUTS in both sexes. The major implications of this guideline at the primary care level is the emphasis on using frequency volume charts, urinalysis, taking a clear history, and careful examination of the patients. The male LUTS guideline does not recommend the measurement of flow rates and post-voiding residual volumes on first assessment in primary care and suggests these should only be used by healthcare professionals with a specialist interest in this setting.

Further research

The NICE GDG has recommended further areas of research, which include:1,2

  • assessment of the impact on patient-related outcomes and cost effectiveness of pressure-flow studies, and of multichannel cystometry in men being considered for bladder outlet surgery
  • comparison of intermittent versus indwelling catheterisation
  • comparison of absorbent pads versus sheath collectors
  • assessment of clinical and cost effectiveness of green light laser prostatectomy.

Conclusion

This is the first time that NICE has published a clinical guideline for the NHS, which specifically looks at how best to diagnose, treat, and manage LUTS in adult men. It is an important advance as it begins with diagnosis of the symptoms the patient presents with, rather than treatment of an established condition. The guideline acknowledges the importance of LUTS and their appropriate evaluation and management using appropriate diagnostic and therapeutic modalities.

Acknowledgements

This robust evidence-based guideline would not have been possible without the dedication, patience, and hard work of the core development team led by Clare Jones and Jennifer Hill. John Browne, Lee-Yee Chong, Elizabetta Fennu, Kate Homer, Hannah Lewin, Sarah Riley, Carlos Sharpin, and Sarah Willett did all of the primary literature searching and analysis.

Not to forget the devotion, tireless energy, and commitment of the GDG with whom I worked with: Angela Billington, James N’Dow, Paul Joachim, Tom Ladds, Roy Latham, Malcolm Lucas, Jonathan Rees, Mark Speakman, Julian Spinks, William Turner, and Adrian Wagg.

NICE implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 97 on The management of lower urinary tract symptoms in men. They are now available to download from the NICE website: www.nice.org.uk.

Costing tools

National cost reports and local cost templates for the guideline have been produced:

  • Costing reports are estimates of the national cost impact arising from implementation based on assumptions about current practice, and predictions of how it might change following implementation of the guideline
  • Costing templates are spreadsheets that allow individual NHS organisations and local health economies to estimate the costs of implementation taking into account local variation from the national estimates, and they quickly assess the impact the guideline may have on local budgets.

Slide set

The slides are aimed at supporting organisations to raise awareness of the guideline and resulting implementation issues at a local level, and can be edited to cater for local audiences. This information does not supersede or replace the guidance itself.

Audit support

Audit support has been developed to support the implementation of the NICE guideline on the management of lower urinary tract symptoms in men. The aim is to help NHS organisations with a baseline assessment and to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. The audit support is based on the key recommendations of the guidance and includes criteria and data collection tools.

Implementation briefing

This document provides further information to help put the guideline into practice. It includes details about the tools provided by NICE and indicates other support available.

Baseline assessment tool

The baseline assessment is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

Implementation advice

This advice tool will consider implementation issues that are specific to the guideline on the management of lower urinary tract symptoms in men. It will provide practical suggestions for action to help those responsible for planning and implementing the guideline.


References

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  2. National Clinical Guidelines Centre. The management of lower urinary tract symptoms in men. London: National Clinical Guidelines Centre for Acute Care, 2009. Available at: www.nice.org.uk/guidance/CG97/Guidance
  3. Abrams P. New words for old: lower urinary tract symptoms for "prostatism”. BMJ 1994; 308 (6934): 929–930.
  4. Eckhardt M, van Venrooij G, Boon T. Symptoms, prostate volume, and urodynamic findings in elderly male volunteers without and with LUTS and in patients with LUTS suggestive of benign prostatic hyperplasia. Urology 2001; 58 (6): 966–971.
  5. Wein A. Classification of neurogenic voiding dysfunction. J Urol 1981; 125 (5): 605–609.
  6. Wein A. Pathophysiology and classification of voiding dysfunction. In: Wein A, Kavoussi L, Novick A et al, editors. Campbell-Walsh urology, ed 9. Philadelphia: Saunders/Elsevier; 2007.
  7. Turner-Warwick R, Whiteside C, Worth P et al. A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and trans-trigonal posterior prostatectomy. Br J Urol 1973; 45 (1):44–59.
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  10. Stewart W, Van Rooyen J, Cundiff G et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003; 20 (6): 327–336.
  11. Chapple C. Lower urinary tract symptoms suggestive of benign prostatic obstruction—Triumph: design and implementation. Eur Urol 2001; 39 (suppl 3): 31–36.
  12. Garraway W, Collins G, Lee R. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338 (8765): 469–471.
  13. Verhamme K, Dieleman J, Bleumink G et al. Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care—the Triumph project. Eur Urol 2002; 42 (4): 323–328.
  14. Engstrom G, Walker-Engstrom M, Loof L, Leppert J. Prevalence of three lower urinary tract
    symptoms in men—a population-based study. Fam Pract 2003; 20 (1): 7–10.
  15. Malmsten U, Milsom I, Molander U, Norlen L. Urinary incontinence and lower urinary tract symptoms: an epidemiological study of men aged 45 to 99 years. J Urol 1997; 158 (5): 1733–1777.
  16. Berry S, Coffey D, Walsh P, Ewing L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132 (3): 474–479.
  17. Wei J, Calhoun E, Jacobsen S. Urologic diseases in America project: benign prostatic hyperplasia. J Urol 2005; 173:1256–1261.
  18. Anger J, Saigal C, Wang M, Yano E. Urologic disease burden in the United States: veteran users of Department of Veterans Affairs healthcare. Urology 2008; 72: 37–41.
  19. Naslund M, Issa M, Grogg A et al. Clinical and economic outcomes in patients treated for enlarged prostate. Am J Manag Care 2006; 12 (4 Suppl): S111–116.
  20. Landefeld C, Bowers B, Feld A et al. National Institutes of Health State-of-the-Science Conference Statement: Prevention of fecal and urinary incontinence in adults. Ann Intern Med 2008; 148 (6): 449–458.
  21. National Institute for Health and Care Excellence. Lower urinary tract symptoms: implementation briefing for pharmacists. London: NICE, 2010.
  22. Lepor H, Williford W, Barry M et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335 (8): 533–539.
  23. Kirby R, Roehrborn C, Boyle P et al; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003; 61 (1): 119–126.
  24. McConnell J, Roehrborn C, Bautista O et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign
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  25. Barkin J, Roehrborn C, Siami P et al; CombAT Study Group. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial. BJU Int 2009; 103 (7): 919–926.
  26. Montorsi F, Henkel T, Geboers A et al. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 4-year data from the CombAT study. Int J Clin Pract 2010; 7 May (Epub ahead of print).
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