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Drugs Aging 2012; 29 (4): 275-284 1170-229X/12/0004-0275/$49.95/0

REVIEW ARTICLE

ª 2012 Adis Data Information BV. All rights reserved.

Combination Pharmacological Therapies for the Management of Benign Prostatic Hyperplasia Seth A. Cohen1 and J. Kellogg Parsons1,2,3 1 Division of Urology, UC San Diego Medical Center, San Diego, CA, USA 2 Urologic Oncology Unit, Moores UCSD Cancer Center, La Jolla, CA, USA 3 Department of Surgery, San Diego VA Medical Center, La Jolla, CA, USA

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Rationale for Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Clinical Trials of Medical Therapy for Benign Prostatic Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Clinical Trials of Bladder-Directed Medications for Lower Urinary Tract Symptoms . . . . . . . . . . . . . . . . 5. Saw Palmetto and Phytotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Phosphodiesterase Type 5 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Current Practice Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Prescription Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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Benign prostatic hyperplasia (BPH) is a highly prevalent condition of older men caused by unregulated growth of the prostate gland. Clinical trials of medical therapy for BPH have consistently demonstrated that combined therapy with an a1-adrenergic receptor (AR) antagonist and a 5a-reductase inhibitor is superior to either agent alone. The addition of anticholinergic therapy to a treatment regimen could effectively improve symptoms in men with persistent storage lower urinary tract symptoms (LUTS) who have not seen a benefit with an a1-AR antagonist or 5a-reductase inhibitor. Among a1-AR antagonists, doxazosin, terazosin, tamsulosin, and alfuzosin, although with slight differences in adverse event profiles, are equivalent in effectiveness and efficacy. No data in the form of direct comparator trials exist to suggest a difference in clinical efficacy of finasteride and dutasteride, the two 5a-reductase inhibitors currently available. Current American Urological Association guidelines do not recommend phytotherapy or dietary supplements in any combination for the medical management of BPH. The current literature supports the safety and efficacy of the combination of an a1-AR antagonist and a 5a-reductase inhibitor in the treatment of symptomatic BPH and, in select patients, the use of an a1-AR antagonist and anticholinergic medication in the treatment of LUTS suggestive of BPH.

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1. Introduction Benign prostatic hyperplasia (BPH) is a highly prevalent condition of older men caused by unregulated growth of the prostate gland. BPH is associated with smooth muscle and epithelial cell proliferation within the transition zone of the prostate.[1,2] The proliferation of these cells can cause lower urinary tract symptoms (LUTS) through increased smooth muscle tone and resistance (dynamic component) and direct, mechanical obstruction of the bladder (static component).[3] LUTS are independently associated with increased risks of mortality, falls, diminished quality of life and impaired activities of daily living.[4-9] Advanced BPH produces urinary infections, acute urinary retention (AUR) and renal failure.[10] BPH has a substantial impact on public health. It is estimated that in the US in the year 2000, 4.5 million visits were made to physician offices for a primary diagnosis of BPH, along with another 8 million visits in which BPH was listed as a diagnosis.[11] BPH affects as many as 75% of US men aged 60–69 years, resulting in up to 38 million hours of lost productivity and, based on data from 1999, over $US4 billion in treatment costs annually.[12] In a prospective evaluation of community-dwelling men, the prevalence of urinary symptoms suggestive of BPH was 70% in those aged 80 years and older.[13] For more than a decade, the age-adjusted incidence and prevalence of BPH in the US have risen steadily.[10,11] 2. Rationale for Combination Therapy In the last 15 years, multiple studies have demonstrated the efficacy and safety of combined pharmacological therapy for BPH. These medications have been shown to improve symptoms, improve quality of life and prevent progression to adverse clinical events.[14] One of the most comprehensively studied combination therapies, as evidenced in large randomized clinical trials, includes an a1-adrenergic receptor (AR) antagonist paired with a 5a-reductase inhibitor.[15,16] The principle behind the effectiveness of this combined therapy is better understood within the ª 2012 Adis Data Information BV. All rights reserved.

context of a brief explanation of the pathophysiology of BPH. In BPH, unregulated cellular proliferation leads to increased stromal smooth muscle tone and prostate volume; increased stromal smooth muscle tone and prostate volume lead to physical compression of the urethra and mechanical obstruction of the bladder outlet. Combined medical therapy is directed at relieving both the smooth muscle (dynamic) component and mechanical (static) component. With respect to the dynamic component, the bladder neck and prostate are densely innervated by a1-ARs, the majority of which are a1A receptors.[14] a1-AR antagonists are effective at blocking these receptors, allowing smooth muscle tissue at the bladder neck and prostate to relax, improving urine flow and diminishing LUTS.[15] With respect to the static component, 5a-reductase inhibitors block the conversion of testosterone to dihydrotestosterone (DHT). DHT is a potent androgen that promotes prostate growth and is an essential component of BPH pathogenesis. Within 6 months, inhibition of 5a-reductase leads to a 25% reduction in prostate volume, a 50% reduction in total serum prostate-specific antigen (PSA) level and improvements in urinary flow rate and LUTS.[16] There are several a1-AR antagonists and two 5a-reductase inhibitors currently available (table I). 3. Clinical Trials of Medical Therapy for Benign Prostatic Hyperplasia Because the mechanisms of action of the two classes of agents are complementary, clinical trials of medical therapy for BPH have consistently demonstrated that combined therapy with an a1-AR antagonist and a 5a-reductase inhibitor is superior to either agent alone. This principle is particularly true with respect to monotherapy with a1-AR antagonists, which tends to be inferior over the long term to monotherapy with 5a-reductase inhibitors. A retrospective analysis of 316 patients with LUTS treated with a1-AR antagonist monotherapy found many patients were at high risk of requiring retreatment within 3 years.[20] Retreatment rates for patients were as follows for specific treatments: terazosin 49%, alfuzosin 37% and tamsulosin 27%. Drugs Aging 2012; 29 (4)

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Table I. a1-AR antagonists and 5a-reductase inhibitors[1,17-19] Generic

Mechanism of action

Receptor/enzyme selectivity

Dosing (mg)

Side effects

Doxazosin

a1-AR antagonist

a1A = a1B = a1D

1–8

Hypotension (1–2%), dizziness (10–15%), headache (9–10%), sexual dysfunction (NR), fatigue (1–2%), nasal congestion (NR)

Terazosin

a1-AR antagonist

a1B = a1D > a1A

1–10

Hypotension (2–8%), dizziness (7–14%), headache (4–10%), sexual dysfunction (2–7%), fatigue (4–8%), nasal congestion (2%)

Alfuzosin

a1-AR antagonist

a1A = a1B = a1D

10

Hypotension ( a1B

0.4–0.8

Hypotension ( a1D >> a1B

4–8

Hypotension ( indicates greater than; >> indicates much greater than.

Unlike 5a-reductase inhibitors, a1-AR antagonists do not hamper prostate growth and do not reduce the risks of progression to AUR or the need for surgery.[21] Of historical significance, in 1996, the VACS (see table II for full trial names and details) was one of the first multicentre, randomized, doubleblind, placebo-controlled trials examining the combination of an a1-AR antagonist and a 5areductase inhibitor in the treatment of LUTS in men with BPH.[22] Over the course of 1 year, 1229 men received either placebo, terazosin (10 mg daily), finasteride (5 mg daily), or a combination of terazosin and finasteride. Using reductions in American Urological Association (AUA) symptom score and increases in maximal urinary flow (Qmax) rates, terazosin was found to be effective therapy, while finasteride was not. It was also determined that combined terazosin/finasteride therapy was no more effective than terazosin monotherapy. A multicentre, randomized, double-blind, parallel-group study, conducted between 1994 and 1996 by the ALFIN Study Group examined the combined use of sustained-release (SR) alfuzosin, an a1-AR antagonist, and finasteride in the treatment of patients with LUTS related to BPH.[23] 1051 patients received either SR alfuzosin 5 mg twice daily, finasteride 5 mg daily, or both drugs, for 6 months. Symptomatic improvement in Inª 2012 Adis Data Information BV. All rights reserved.

ternational Prostate Symptom Score (IPSS) and increase in Qmax were assessed. Results determined that SR alfuzosin was more effective that finasteride, with no additional benefit of combining both drugs. In 2003, the PREDICT trial examined the combined use of doxazosin, an a1-AR antagonist, and finasteride in the treatment of LUTS secondary to BPH.[24] This multicentre, randomized, double-blind, placebo-controlled trial enrolled 1007 patients, who were given doxazosin 8 mg/day, finasteride 5 mg/day, a combination of doxazosin/finasteride, or placebo. Patients were followed for 52 weeks, during which time changes in IPSS and Qmax were recorded. Doxazosin was more effective than finasteride and placebo in improving urinary symptoms and Qmax; the addition of finasteride to doxazosin did not provide further benefit than that achieved with doxazosin monotherapy. The National Institutes of Health (NIH) sponsored the MTOPS trial, a long-term, multicentre, randomized, double-blind, placebo-controlled study involving 3047 men aged ‡50 years with moderate to severe LUTS and a Qmax of 4–15 mL/s.[17] MTOPS compared the effects of placebo, an a1-AR antagonist (doxazosin 8 mg/day), a 5a-reductase inhibitor (finasteride 5 mg/day), and combination therapy (doxazosin and finasteride) on measures of Drugs Aging 2012; 29 (4)

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the clinical progression of BPH. A clinical progression event was defined as an increase above baseline of at least 4 points on the AUA symptom score, AUR, urinary incontinence, renal insufficiency or recurrent urinary tract infection. There was a 66% reduction in risk of clinical progression associated with combination therapy versus placebo, with a median follow-up of 4.5 years. This result was a significantly greater reduction than that associated with doxazosin (p < 0.001) or finasteride (p < 0.001) alone. The risk of AUR and need for invasive therapy was significantly reduced by combination therapy (p < 0.001) and finasteride (p < 0.001) but not by doxazosin monotherapy. Combination therapy was superior to doxazosin and finasteride monotherapies with respect to improvement of symptom scores (p < 0.001) as well. The CombAT study, a multicentre, randomized, double-blind, parallel-group trial, investigated the effectiveness of a combined therapy, a 5a-reductase inhibitor (dutasteride 0.5 mg) and a1-AR antagonist (tamsulosin 0.4 mg), versus these medications as monotherapies, with respect to its ability to reduce

the relative risk for AUR, BPH-related surgery and BPH clinical progression over 4 years, in more than 4800 at-risk men.[25] Analysis after 4 years found time to first AUR or BPH-related surgery was significantly longer with combination therapy versus tamsulosin (p < 0.001), but there was no significant difference between combination therapy and dutasteride (p = 0.18). Combination therapy was significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression (p < 0.001 for both comparisons). Thus, MTOPS and CombAT both serve as excellent examples of well-designed trials, with longer follow-up than VACS, ALFIN and PREDICT, which demonstrate the benefit of combining a 5a-reductase inhibitor and an a1-AR antagonist in reducing the risk of BPH progression. 4. Clinical Trials of Bladder-Directed Medications for Lower Urinary Tract Symptoms In addition to a1-AR antagonists and 5areductase inhibitors, anticholinergic medications

Table II. Sampling of key trials investigating the use of combined pharmacotherapy in the management of lower urinary tract symptoms Study

Year of publication

Design

Combined therapy

Outcome of combined therapy

CombAT (Combination of Avodart and Tamsulosin) study

2010

Multicentre, randomized, double-blind, parallel-group

a1-AR antagonist and 5a-reductase inhibitor

Benefit

TIMES (Tolterodine and tamsulosin In Men with LUTS including OAB: evaluation of Efficacy and Safety) study

2006

Multicentre, randomized, double-blind, placebo-controlled

a1-AR antagonist and anticholinergic agent

Benefit

Combination Treatment with Propiverine Hydrochloride Plus Doxazosin Controlled Release Gastrointestinal Therapeutic System Formulation for Overactive Bladder and Coexisting Benign Prostatic Obstruction

2005



Benefit

Combination Treatment with an a-Blocker Plus an Anticholinergic for Bladder Outlet Obstruction

2003

Single-centre, randomized


Benefit

MTOPS (Medical Therapy of Prostatic Symptoms) trial

2003



Benefit

PREDICT (Prospective European Doxazosin and Combination Therapy) trial

2003



No benefit

ALFIN (European Alfuzosin and Finasteride) study

1998



No benefit

VACS (Veterans Affairs Cooperative Study)

1996



No benefit

AR = adrenergic receptor; LUTS = lower urinary tract symptoms; OAB = overactive bladder.


Drugs Aging 2012; 29 (4)


have also emerged as an effective component of combined medical therapy, specifically for storage LUTS. Storage LUTS by definition includes frequency, urgency, nocturia and urgency incontinence.[26] Although LUTS have traditionally been associated with BPH, storage LUTS may not be prostate related, and aetiologies for these symptoms may be in the bladder or at other extra-prostatic sites.[27] It is estimated that up to two-thirds of men with LUTS have a mixture of storage and voiding symptoms.[28] Overactive bladder (OAB) is defined as urgency, with or without urgency incontinence, usually with frequency and nocturia.[26] Thus, OAB is a syndrome of storage LUTS.[29] There is an ongoing investigation into how often these symptoms are secondary to BPH, versus other aetiologies, including detrusor overactivity.[30] From a pathophysiological perspective, there is an abundance of cholinergic muscarinic receptors within the human bladder whose activation causes contractions. Anticholinergic medications inhibiting these muscarinic receptors have been used to successfully treat unstable bladder contractions, such as in OAB.[31] Studies have confirmed anticholinergic therapies appear to benefit patients with storage LUTS, which may be associated with OAB and/or BPH.[32,33] The use of combination therapy in the form of an a1-AR antagonist and a 5a-reductase inhibitor in men mainly treats symptoms related to the prostate and does not address persistent storage LUTS secondary to OAB.[34] The addition of anticholinergic therapy to a treatment regimen could effectively improve symptoms in men with persistent storage LUTS who have not seen a benefit with an a1-AR antagonist or 5a-reductase inhibitor.[35,36] Athanasopoulos et al.[33] conducted one of the first trials examining the combination of an a1-AR antagonist and anticholinergic therapy in 2003. This randomized trial enrolled 50 men with urodynamically proven mild or moderate bladder outlet obstruction (BOO) and concomitant detrusor instability; half received tamsulosin 0.4 mg daily monotherapy and the other half received tamsulosin 0.4 mg daily combined with tolterodine 2 mg twice daily. Those patients using the combined therapy had significant improvements in quality of ª 2012 Adis Data Information BV. All rights reserved.

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life, as documented on questionnaires used in the study. In 2005, Lee et al.[37] conducted a multicentre, randomized, double-blind study comparing doxazosin monotherapy with combined doxazosin/ propiverine hydrochloride therapy. The study enrolled 211 men, 50 years or older, with OAB symptoms and urodynamically proven BOO; 69 men were given a doxazosin controlled-release gastrointestinal therapeutic system formulation (4 mg daily) and 198 men received doxazosin plus propiverine hydrochloride (20 mg daily), over 8 weeks. Significant improvements were noted in urinary frequency, average micturition volume and IPSS. Patient satisfaction rates were significantly higher in the combined therapy cohort. Between 2004 and 2006, Kaplan et al.[32] conducted the TIMES study, a multicentre, randomized, double-blind, placebo-controlled trial, to evaluate the efficacy and safety of an anticholinergic (tolterodine extended release [ER]), an a1-AR antagonist (tamsulosin) and a combination of the two in men who met research criteria for both OAB and BPH. Participants were ‡40 years of age and were randomly assigned to receive placebo (n = 222), 4 mg of tolterodine ER (n = 217), tamsulosin 0.4 mg (n = 215), or both (n = 225) for 12 weeks. The combination of tolterodine ER plus tamsulosin showed a significant symptomatic benefit over placebo (p < 0.001), as opposed to tolterodine ER (p = 0.48) and tamsulosin (p = 0.06) monotherapies, which did not provide a statistically significant benefit over placebo. The patients on combination therapy also saw significant reductions in urgency urinary incontinence, urgency episodes without incontinence, micturitions per 24 hours and micturitions per night. The incidence of AUR requiring catheterization was low in all groups: combination therapy 0.4%, tolterodine ER 0.5%, tamsulosin 0% and placebo 0%. Within the last 5 years, interest in b3-adrenoreceptor agonists in the management of storage LUTS has grown.[27] The detrusor muscle of the bladder has been found to express b3-adrenoreceptors, which when stimulated with b3-adrenoreceptor selective agonists may increase bladder capacity and reduce frequency, urgency and incontinence.[38] Drugs Aging 2012; 29 (4)

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More randomized, placebo-controlled trials are needed to examine the potential benefits of this medication class. It may eventually play a role in combined pharmacotherapy in the management of LUTS. 5. Saw Palmetto and Phytotherapy Current AUA guidelines do not recommend phytotherapy or dietary supplements in any combination for the medical management of BPH.[3] In 2006, results from the STEP (Saw palmetto Treatment for Enlarged Prostates) study were reported.[39] This 12-month single institution, randomized, double-blind, placebo-controlled trial of saw palmetto (Serenoa repens) did not find any significant improvement in LUTS, Qmax, prostate size, post-void residual (PVR) urine volume, quality of life or serum PSA levels for saw palmetto compared with placebo. In 2009, a Cochrane Review came to similar conclusions, determining that saw palmetto was not superior to placebo, finasteride or tamsulosin in improving LUTS or urine flow or reducing prostate size.[40] Most recently, a multicentre, randomized, double-blind, placebo-controlled trial, conducted by the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) Study Group between 2008 and 2010, examined the potential benefit of up to 3 times the standard dose of saw palmetto extract (standard dose defined as 320 mg daily).[41] The study enrolled 369 men, 45 years of age and older, with a Qmax of at least 4 mL/s and an AUA symptom score between 8 and 24 at two screening visits. After 72 weeks, change in AUA symptom score, along with measures of urinary bother, nocturia, peak uroflow, PVR urine volume and indices of sexual function, continence, sleep quality and prostatitis symptoms were assessed. There was no benefit of saw palmetto extract over placebo. To date, there is a lack of randomized, double-blind, placebo-controlled trials for phytotherapies, other than saw palmetto, including African plum (Pygeum africanum), b-sitosterol and pollen extracts; there are virtually no studies examining the use of these substances in combined therapy with current pharmacotherapies. This remains an area for future study. ª 2012 Adis Data Information BV. All rights reserved.

6. Phosphodiesterase Type 5 Inhibitors Multiple studies within the last 3–4 years have begun investigating the use of phosphodiesterase 5 (PDE5) inhibitors in the management of LUTS. An 8-week randomized controlled trial examined the use of vardenafil 10 mg twice daily versus placebo.[42] Those in the vardenafil group had significant improvements in mean IPSS total score compared with participants receiving placebo (-5.9 vs -3.6, p = 0.0013), but urine flow and PVR urine volume did not change significantly. Studies using tadalafil, of which the longest followup was 12 months, reported similar findings.[43-45] There were significant improvements in IPSS and quality of life index; however, there were no changes in uroflowmetry parameters or PVR urine volume. The US Food and Drug Administration (FDA) recently approved the use of tadalafil for the treatment of LUTS secondary to BPH. Further long-term studies will be needed to investigate the role of PDE5 inhibitors in combined pharmacotherapy management. 7. Current Practice Patterns Using the BPH Registry and Patient Survey, Wei et al.[46] examined physician practice patterns in the management of LUTS in 402 urologist and primary care physician practices throughout the US. Men being treated by urologists were twice as likely as men being treated by primary care physicians to be treated with BPH medical therapy versus watchful waiting. Among men on BPH medical therapy, the use of a1-AR antagonist plus 5a-reductase inhibitor combination therapy was significantly greater in the patients seeing urologists when compared with those seeing primary care physicians. 8. Prescription Recommendations There are multiple options for a1-AR antagonists currently available in the US (table I). These medications differ in their selectivity. a1-ARs have three subtypes: a1A, a1B and a1D.[47-49] a1A-ARs are predominant in the stromal smooth muscle cells of the prostate, while a1B-ARs are found in the Drugs Aging 2012; 29 (4)


smooth muscle of arteries and veins, and a1DARs are found in the bladder.[49-51] a1D-ARs are also found in the spinal cord, where they seem to have a role in the sympathetic modulation of parasympathetic activity.[1,52] Blockade of these a1D-ARs in animal models has been shown to reduce irritative voiding symptoms.[51] Thus, by antagonizing the a1A and a1D receptors, and limiting such activity at a1B receptors (which may cause cardiovascular side effects), selective a1AR blockers could provide optimum therapy for the symptoms of BPH.[1] The AUA clinical guidelines for the management of BPH note that doxazosin, terazosin, tamsulosin and alfuzosin, although with slight differences in adverse event profiles, are equivalent in effectiveness and efficacy.[3] Of note, silodosin, approved relatively recently by the US FDA, was not included in this efficacy statement, because of a relative lack of published articles at the time of the analysis. Patients on doxazosin and terazosin, the older, nonselective a1-AR antagonists, have a higher incidence of dizziness and orthostasis and require dose titration and blood pressure monitoring. Patients on the more specific a1A-AR antagonists, tamsulosin and silodosin, have a higher incidence of absence of ejaculation.[16] Floppy iris syndrome is a condition that may occur with any of the a1-AR antagonists; patients scheduled to undergo cataract surgery should inform their ophthalmologists and should discontinue this medication prior to surgery.[53] There are two 5a-reductase inhibitors currently available (table I): finasteride and dutasteride.[16] Finasteride inhibits the type II 5a-reductase enzyme; dutasteride inhibits both type I and II enzymes, leading to a larger reduction in DHT; dutasteride inhibits >90% of serum DHT and approximately 95% of intraprostatic DHT, compared with finasteride, which inhibits approximately 70% of serum DHT and approximately 85% of intraprostatic DHT.[54] The serum half-life of dutasteride is 5 weeks, while the serum half-life of finasteride is less than 1 day. The recent update of the AUA guidelines for the management of BPH reaffirmed that no data in the form of direct comparator trials exist to suggest a difference in clinical efficacy between these two medications.[3] ª 2012 Adis Data Information BV. All rights reserved.

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Large long-term trials have demonstrated that the adverse event profiles of both medications are similar.[55] There is now a US FDA approved combined formulation of dutasteride and tamsulosin, which administers 0.5 mg of dutasteride and 0.4 mg of tamsulosin in a single pill daily. This may be of use to patients who find it cumbersome to take multiple medications. Of note, it is the expectation that a man initiated on a 5a-reductase inhibitor would have a 50% decline in PSA within 6–12 months of treatment; after the initial 6 months, physicians should multiply the serum PSA by 2 and compare it with either age-independent or the age-specific upper limits of normal.[56] If the PSA is elevated, one should consider referral to a urologist to rule out underlying prostatic malignancy. Data collected previously by the PLESS (Proscar Long-term Efficacy and Safety Study) Group determined that in the setting of treatment with finasteride, multiplying the PSA by 2 preserves its usefulness in screening for prostate cancer.[57] Recently the FDA issued a Drug Safety Communication warning that 5a-reductase inhibitors may slightly increase the risk of diagnosis of a more serious form of prostate cancer. This risk should be enumerated in an informed discussion with the patient, prior to initiating a 5a-reductase inhibitor; an outline of appropriate information to discuss can be found in the joint American Society of Clinical Oncology/AUA 2008 practice guidelines.[58] There remains a multitude of choices of anticholinergic medications for the treatment of LUTS: oxybutynin, tolterodine, darifenacin, solifenacin and trospium chloride. The AUA guidelines for BPH noted three randomized trials examining the use of an anticholinergic as monotherapy or in combination with an a1-AR antagonist in men with LUTS; all of these studies used tolterodine.[3] Thus, the most rigorous data at this time on combined therapy for the management of LUTS appear to reference tolterodine. Of note, there had been initial concern that anticholinergic therapy may put men with LUTS at increased risk for urinary retention. Work by Abrams et al.[59] examined the alteration in pressure flow urodynamics in men with OAB and BOO, treated Drugs Aging 2012; 29 (4)

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with anticholinergic therapy. Qmax and detrusor pressure at Qmax were compared in those men treated with tolterodine 2 mg twice daily and placebo over 12 weeks. Tolterodine did not alter urinary flow; there were no clinically meaningful changes in voiding pressure, PVR urine volume or urinary retention. A meta-analysis of five randomized controlled trials and 15 observational studies found that anticholinergic medications did not significantly alter Qmax or rates of AUR.[60] These results provide objective data that appear to support the safe use of anticholinergic medications in men with BOO. However, after an assessment of the current literature, the recent update of the AUA guidelines for the management of BPH reaffirmed that prior to the initiation of anticholinergic therapy, baseline PVR urine volume should be assessed, and anticholinergics should be used with caution in patients with a PVR volume >250–300 mL.[3]

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9. Conclusion The current literature supports the safety and efficacy of the combination of an a1-AR antagonist and a 5a-reductase inhibitor in the treatment of symptomatic BPH and, in select patients, the use of an a1-AR antagonist and anticholinergic medication in the treatment of LUTS suggestive of BPH. Acknowledgements J.K.P received compensation as a consultant for American Medical Systems (AMS). S.A.C received an honorarium as a Medscape Reference author. No sources of funding were used to assist in the preparation of this article.

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Correspondence: Dr J. Kellogg Parsons, UC San Diego Medical Center, Division of Urology, 200 W Arbor Dr. #8897, San Diego, CA 92103-8897, USA. E-mail: [email protected]

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