Recommended drug treatment of BPH in primary care Claire Taylor MRCS, Charlotte Foley MRCS and Roger Kirby MA, MD, FRCS Urol

Drug review BPH Recommended drug treatment of BPH in primary care Claire Taylor MRCS, Charlotte Foley MRCS and Roger Kirby MA, MD, FRCS Urol Skyline Imaging Ltd The development of safe and effective drugs for the treatment of BPH has allowed many patients to be managed in primary care. Our Drug review considers the efficacy and sideeffects of current treatments, followed by sources of further information and an analysis of prescription data. Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases to afflict older men. Data from a number of autopsy studies have shown histological evidence of BPH in 50 per cent of 51 to 60 year olds, increasing to 90 per cent of 85 year olds. 1 This trend is mirrored by lower urinary tract symptoms (LUTS), suggestive of BPH. Analysis of the UK General Practice Research Database (UK GPRD) reveals LUTS in 3.5 per cent of men in their late 40s and in 35 per cent in their late 80s. 2 Development of safe and effective medical therapies and evidence-based prescribing has meant the role of GPs in BPH treatment has become increasingly important. As a result the British Association of Urological Surgeons (BAUS) has revised guidelines originally devised in 1997 to make them more applicable to the primary care setting (see Figure 1). 3 Presentation and evaluation of the patient Currently, patients will generally consult their GP only when their LUTS are sufficiently bothersome to www.prescriber.co.uk Prescriber 19 November 2008 21

reduce their quality of life (QOL); many men tolerate a high degree of symptoms and impact on daily activities before seeking help. 4 Symptoms of BPH reflect the secondary effects of the disease on the urethra and bladder and are classed into storage or obstructive symptoms (see Table 1). Initial consultation should include assessment of these symptoms; the International Prostate Symptom Score (IPSS) form is a useful tool to quantify symptoms and QOL. Digital rectal examination (DRE) gives an estimation of the prostate gland size and can reveal malignant features such as a palpable dule. Prostatespecific antigen (PSA) measurement, following an explanation of the pros and cons, gives an indication of the size of the gland. Gland size and PSA are among the risk factors for progression to an adverse event such as retention, recurrent infection or stone formation, or the need for surgery for symptom relief (see Table 2). Although obstructive symptoms are often associated with a reduced urinary flow rate, correlation was found between objective flow studies and subjective, patient-reported obstructive symptoms in one study. 5 However, there was a correlation between QOL measures and patient-reported storage symptoms, particularly urgency, frequency and cturia. 5 BPH can present in other ways including sexual dysfunction or recurrent urinary tract infections secondary to a significant postvoid volume. A recent survey, which enrolled 14 254 men aged between 50 and 80 years from seven countries, reported a high prevalence of LUTS associated with sexual problems. Of the 12 815 men who completed a questionnaire, 90 per cent had LUTS, 49 per cent reported erection difficulties, 46 per cent experienced ejaculatory disturbance and 7 per cent felt pain during intercourse. Despite this, 82 per cent of the respondents were sexually active. LUTS was severe in 6 per cent of men, moderate in 25 per cent and mild in 59 per cent, and this was proportional to the severity of their sexual problems; however, only 11 per cent of these men were medically treated for their prostate problems. 6 When to treat and when to refer Patients visiting their GP with BPH symptoms are frequently seeking to improve their QOL through a reduction in symptoms, rather than improving flow rates. They are also keen to avoid hospitalisation and surgery. With this in mind, clinicians have shifted away from immediate surgical approaches, despite their superior efficacy in reducing IPSS scores and 22 Prescriber 19 November 2008

improving flow rates, to the use of pharmacotherapy as the first-line treatment in BPH. Table 3 highlights the circumstances when patients should be referred to a urologist for surgical treatment of their BPH transurethral resection of the prostate (TURP) still being the gold standard or for investigation and treatment of a urological malignancy. Choosing the correct medication Drugs available for the treatment of BPH fall into two main categories: selective alpha-blockers such as terazosin, doxazosin, tamsulosin and alfuzosin (Xatral), and the 5-alpha reductase inhibitors finasteride and dutasteride (Avodart). The choice of the most suitable medication for each patient is further increased by combination therapies. As with any condition, therapeutic goals include long-lasting symptom relief as well as prevention of complications from BPH using a medication the patient can tolerate. There is certainly a place for active surveillance for men with a smaller-volume prostate and few bothersome symptoms. Surveillance should include annual review, lifestyle advice and possibly a PSA test. If the symptoms become bothersome for the patient or the PSA increases by 25 per cent over one year, the possibility of treatment should be reassessed and referral considered. Alpha-blockers The first alpha-blocker to be studied in the treatment of BPH was phexybenzamine, a nselective alpha 1 /alpha 2 adrenergic antagonist. Despite evidence that it improved the symptoms of BPH, the cardiovascular side-effects, mediated predominantly by alpha 2 adrenergic antagonism, led to the development of a number of alpha 1 -selective agents. Although prostate tissue contains both alpha 1 and alpha 2 receptors, prostatic smooth muscle contraction is largely a function of alpha 1. Further work has subclassified the alpha 1 -receptor into three subtypes: alpha 1A, alpha 1B and alpha 1D. Prostates with BPH have a predominance of alpha 1A and, to a lesser extent, alpha 1D -receptors. The alpha 1 -selective agents have a similar efficacy in relieving the symptoms of BPH. Their sideeffect profiles, related to systemic alpha blockade, include dizziness, asthenia, somlence and rarely syncope. 7 The clinical utility of these agents may be limited by the need for multiple titration steps; however, the continued on page 28 24 Prescriber 19 November 2008 www.prescriber.co.uk

LUTS patient GP: history including symptoms assessment (IPSS) examination and DRE urinalysis/msu PSA PSA elevated for age DRE abrmal/of concern haematuria elevated urea/ creatinine palpable bladder recurrent UTI abrmal cytology severe symptoms urinary tract infection treat unresponsive or recurrent UTI cturia? bothersome LUTS? urological referral cturnal polyuria? prostatic obstruction? cturnal polyuria overactive bladder risk factors for progression? large prostate (>30cc) or high PSA (>1.4ng/ml) risk factors for progression? large prostate (>30cc) or high PSA (>1.4ng/ml) lifestyle advice alpha-blocker lifestyle advice 5-alpha reductase inhibitor, alphablocker or combination lifestyle advice 5-alpha reductase inhibitor lifestyle advice LUTS = lower urinary tract symptoms IPSS = International Prostate Symptom Score review at 6-12 weeks review at 3-6 months Figure 1. British Association of Urological Surgeons (BAUS) guidelines for the treatment of BPH in primary care 3 28 Prescriber 19 November 2008 www.prescriber.co.uk

development of modified-release formulations of some of the drugs minimises the need for titration and may improve tolerability. For example, the controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin (Cardura XL) enhances the drug delivery rate and minimises the need for titration. 8 Doxazosin GITS significantly improves LUTS with adverse effect on sexual function and appears to be better tolerated than the standard formulation. 8 Tamsulosin is an alpha 1A and alpha 1D selective antagonist whose efficacy and tolerability have been established in a number of short-term randomised, placebo-controlled trials in both Europe and the USA. In all trials, tamsulosin was well tolerated and associated with significant improvements in symptoms and urinary peak flow rate compared to placebo. 9 Reported frequencies of ejaculation abrmalities, including ejaculatory failure/diminution and retrograde ejaculation, were similar to those in the placebo group. However, two US trials had incidences of ejaculation abrmalities in 8 per cent of men receiving 400µg per day (n=502) and 18 per cent receiving 800µg per day (n=492), indicating that this side-effect is dose dependent. 10 Ejaculation disorders in men treated with tamsulosin are thought to be secondary to impairment of the bladder neck and/or seminal-vesicle contraction. Despite alpha 1A and alpha 1D selectivity, cardiovascular effects are still sometimes seen with tamsulosin. Incidences of orthostatic hypotension and dizziness of 14 per cent on 400µg per day and 17 per cent on 800µg per day, compared to 10 per cent for placebo, have been reported. In addition rhinitis, probably secondary to local vasodilatory effects, was ted. Alfuzosin The efficacy of immediate-release alfuzosin has been established in several trials of up to six months duration in Europe, showing significant improvement in symptom scores and peak urinary flow rates over placebo. There was significant increase in side-effects in those taking alfuzosin vs placebo. A recent large-scale study within the primarycare setting has confirmed the efficacy of immediaterelease alfuzosin in maintaining improved LUTS for up to three years. 11 In addition to the original immediate-release formulation of the drug, a modified-release formulation administered as 10mg once daily (Xatral XL) has been developed with similar efficacy to the immediaterelease formulation. Storage symptoms filling frequency urgency cturia Obstructive symptoms voiding difficulty initiating urination (hesitancy) poor flow terminal dribbling sensation of incomplete emptying Table 1. Storage and obstructive symptoms of BPH Orthostatic events and blood-pressure changes with alfuzosin were only slightly greater than those seen with placebo, even in older patients and those on other antihypertensive treatments, while dizziness was reported in only 5.7 per cent of patients receiving 10mg daily of alfuzosin compared to 2.8 per cent of the placebo patients. The incidence of abrmal ejaculation in alfuzosin recipients was comparable to that observed in placebo patients. 9,12 5-alpha reductase inhibitors The observation that men castrated before puberty or those with metabolic disorders affecting androgen pathways such as 5-alpha reductase deficiency do t develop BPH has led to the conclusion that there is an androgen-dependent mechanism within this multifactorial process. Dihydrotestosterone (DHT) is the primary prostatic androgen and is derived from testosterone by the action of 5-alpha reductase. Two isoenzymes have been identified: type 1 is found in most 5-alpha reductase-producing tissues, including liver, skin and hair, and type 2 is predominant in genital tissues, including the prostate. DHT is more potent than testosterone, with a higher affinity for the receptor, explaining the paradox of high prostatic DHT levels despite falling serum testosterone levels in ageing men. Finasteride The link between prostatic DHT levels and prostate enlargement led to the development of 5-alpha reductase inhibitors. Early human studies using finasteride, which selectively targets the prostate-predominant type-2 enzyme, were found to reduce plasma DHT levels without a significant effect on plasma testosterone levels. Studies have shown that at 12 weeks finasteride confers an 18 per cent decrease in prostate volume, 13 and in a four-year placebo-controlled study a 32 per cent decrease was observed over placebo. 14 www.prescriber.co.uk Prescriber 19 November 2008 31

large gland poor flow large postvoid residual volume increasing age high PSA Table 2. Risk factors for disease progression Meta-analysis has shown that the efficacy of finasteride is related to prostate size, with particular benefit, in terms of symptom control, seen in those patients with prostate volumes of 40mg or above. Clinically, this means that men presenting with LUTS with a prostate larger than a golf ball on DRE are likely to benefit from significant reduction in symptoms and improved flow. Furthermore, it was ted that finasteride can reduce PSA by around 50 per cent; this is thought to be a consequence of a reduction in prostate volume. There is also apoptosis in the glandular cells that produce PSA, 15 but by the simple strategy of doubling the PSA measurement, the utility for prostate cancer screening is maintained. 16 Both two- and four-year studies of finasteride have shown a significantly higher rate of reduced libido (4.8 per cent), ejaculation problems (3.5 per cent) and sexual dysfunction (5.0 per cent) compared to placebo during the first year; 17 however, for the remainder of the study period there was almost difference in the number of new cases in either group. The long-term four- to five-year studies have demonstrated a significant reduction in progression to surgery of 55 to 64 per cent and incidence of acute urinary retention of 57 to 67 per cent. 14,18 Dutasteride was developed on the basis that suppression of both isoforms of 5-alpha reductase will result in better and more consistent suppression of serum DHT. In a phase-ii study in men with BPH, dutasteride 0.5, 2.5 or 5mg per day for 24 weeks was associated with a significantly greater percentage reduction in serum DHT than finasteride 5mg per day or placebo, but the clinical impact of this is still uncertain as inhibition of intraprostatic DHT levels is similar for both drugs. 15 Probably both dutasteride and finasteride have similar efficacy and side-effect profiles. Dutasteride, like finasteride, reduces acute urinary retention and the need for surgery and has primarily sexual side-effects. Similarly, dutasteride can lower PSA concentrations, and this fact should be taken into account when patients are monitored for prostate cancer, again by doubling the PSA value in treated patients. history of haematuria or haematuria on testing recurrent UTI positive urinary cytology acute or chronic retention suspicious DRE or PSA above age-adjusted range Table 3. Indications for referral to a urologist Combination therapy The Medical Therapy of Prostatic Symptoms (MTOPS) study was conducted to determine whether combined treatment with an alpha-blocker (doxazosin) and a selective 5-alpha reductase inhibitor (finasteride) would be more effective than either drug alone. 18 Men with BPH (n=3047) were randomised to treatment with doxazosin, finasteride, combination therapy or placebo and followed for an average of four years and six months. The results of this study revealed a greater delay in clinical progression of BPH with a combination of doxazosin and finasteride than with either drug alone (risk reduction relative to placebo: doxazosin 39 per cent, finasteride 34 per cent, combination therapy 67 per cent). Progression was defined as the occurrence of one of the following end-points: greater than 4-point increase in AUA (American Urological Association) symptom score, acute urinary retention, incontinence, renal insufficiency or recurrent urinary tract infection. In contrast to finasteride motherapy, doxazosin conferred benefit over placebo in terms of reducing the risk of acute urinary retention or surgery. The greatest benefit seen in combination therapy was in preventing the progression of symptoms. More recently the CombAT study of dutasteride and tamsulosin has also confirmed that a 5-alpha reductase inhibitor plus an alpha-blocker is more effective than either drug alone. 19 The use of two drugs rather than one, of course, increases the cost of treatment and also slightly increases the risk of side-effects. 5-alpha reductase inhibitors reduced libido decreased ejaculatory volume impotence (reports between 3 and 19 per cent) Alpha 1 -blockers headache postural hypotension asthenia dizziness Table 4. Common side-effects of drug treatments www.prescriber.co.uk Prescriber 19 November 2008 33

5-alpha reductase inhibitors gradual shrinkage of the prostate alpha 1 -blockers relaxation of smooth muscle in prostate and bladder neck reduced bladder outflow obstruction reduced lower urinary tract symptoms Figure 2. Mode of action of 5-alpha reductase inhibitors and alpha 1 -blockers Conclusion The increasing availability of medical treatments for BPH has meant that this common condition is w frequently and safely managed in the primary-care setting in the long term. The most cost-effective selection of the most suitable medication for each patient is influenced by their symptom profile and prostate size. 20 The BAUS guidelines, 3 grounded in evidencebased medicine, indicate which treatment is most likely to improve patients QOL and prevent progression to surgery. Furthermore, the guidelines will help busy GPs to decide which patients to refer for specialist management and at what stage of their disease process. References 1. Guess HA, Arrighi HM, Metter EJ, et al. Cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia. Prostate 1990;17:241-6. 2. Logie JW, Clifford GM, Farmer RDT, et al. Lower urinary tract symptoms suggestive of benign prostatic obstruction - Triumph: the role of general practice databases. Eur Urol 2001;39:42-7. 3. Speakman M, Kirby R, Joyce A, et al. BAUS guidelines. BJU International 2004;93:985-90. 4. Medina JJ, Parra RO, Moore RG. Benign prostatic hyperplasia (the aging prostate). Med Clin North Am 1999;83: 1213-29. 5. The Department of Veterans Affairs Cooperative Study of transurethral resection for benign prostatic hyperplasia. A comparison of quality of life with patient reported symptoms and objective findings in men with benign prostatic hyperplasia. J Urol 1993;150:1696-700. 6. Rosen R, Altwein J, Boyle P, et al. LUTS and male sexual dysfunction: the Multinational Survey of the Aging Male (MSAM-7). Eur Urol 2003;44:637-49. 7. Roehrborn CG. Are all alpha-blockers created equal? An update. Urology 2002;59(2 Suppl 1):3-6. 8. Andersen M, Dahlstrand C, Høye K. Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia. Eur Urol 2000;38:400-9. 9. Michel MC, Flannery MT, Narayan P. Worldwide experience with alfuzosin and tamsulosin. Urology 2001;58:508-16. 10. Physicians desk reference. Montvale, NJ: Medical Ecomics Co, 2002;974-7. 11. Lukacs B, Grange JC, Comet D, et al. Prospective followup of 3228 patients suffering from clinical benign prostatic hyperplasia (BPH) treated for 3 years with alfuzosin in general practice. BPH Group in General Practice. Prog Urol 1999;9:271-80. 12. Van Kerrebroeck PE. The efficacy and safety of a new once-a-day formulation of an alpha-blocker. Eur Urol 2001;39(suppl 6):19-26. 13. Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. J Steroid Biochem Mol Bio 1990; 37:375-8. 14. McConnell JD, Bruskewitz R, Walsh P, et al. The effect on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyper- 34 Prescriber 19 November 2008 www.prescriber.co.uk

plasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998;338:557-63. 15. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5 alpha-reductase inhibition in human benign prostatic hyperplasia. Eur Urol 2000; 37:367-80. 16. Andriole GL, Guess HA, Epstein JL, et al. Treatment with finasteride preserves usefulness of prostatic-specific antigen in the detection of prostate cancer: results of a randomised, double-blind, placebo-controlled clinical trial. PLESS study group. Urology 1998;52:195-202. 17. Stoner E. Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology 1994;43:284-94. 18. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-98. 19. Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2- year results from the CombAT study. J Urol 2008;179(2): 616-21. 20. Foley CL, Taylor C, Kirby RS. Counting the cost of treating benign prostatic hyperplasia. BJU International 2004; 93:250-2. Dr Taylor and Dr Foley are higher surgical trainees and Professor Kirby is director of the Prostate Centre, London Resources Groups and organisations Men s Health Forum is a registered charity tackling men s health issues, including prostate disorders, for health professionals. The Men s Health Forum, 32-36 Loman Street, London SE1 0EH. Tel: 020 7922 7908; website: www.menshealthforum.co.uk. Runs the Malehealth website, www.malehealth.co.uk, for the general public. Prostate Help Association (PHA). www.prostate help.me.uk. Provides an information service on the treatment of all types of prostate disease. Men s Health Matters, Blythe Hall, 100 Blythe Road, London W14 0HB. The Adviceline (020 8995 4448) is open from 7pm to 9pm on Mondays and is staffed by specialist nurses. Factsheets on health issues affecting men are also available. Prostate UK (formerly Prostate Research Campaign UK), 10 Northfields Prospect, Putney Bridge Road, London SW18 1PE. Tel: 020 8877 5840, info@prostate uk.org; www.prostateuk.org. Funds medical research and training of healthcare professionals and provides information on all prostate diseases. Prescription review Despite an increase of 16 per cent in prescription numbers since 2005, total spending on drugs for BPH declined by 16 per cent to 110.4 million in 2007. Alpha-blockers still accounted for the majority of scrips (though these figures include their use for hypertension) but prescribing of indoramin and prazosin (Hypovase) declined and costs have fallen overall. Spending on tamsulosin (the only alpha-blocker licensed exclusively for BPH symptoms) has fallen by 46 per cent since 2005 and prescribing has increased by one-third. Use of the 5-alpha reductase inhibitors has also risen substantially up by 61 per cent for dutasteride and 35 per cent for finasteride, with cost growth of 58 and 27 per cent respectively over two years. alfuzosin 618 10 625 doxazosin * 5 209 41 604 indoramin 156 3 404 prazosin 111 702 terazosin 170 1 925 tamsulosin 2 221 22 790 dutasteride 259 7 595 finasteride 1 264 21 788 *Cardura and generic doxazosin all brands Hytrin, Hytrin BPH and generic terazosin Items (000) Cost ( 000) Table 5. Number of prescriptions and costs for drugs used in BPH in England, 2007 36 Prescriber 19 November 2008 www.prescriber.co.uk