Medical Management of Lower Urinary Tract Symptoms

Advances in the Pharmacologic Treatment of BPH

7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S19 ADVANCES IN THE PHARMACOLOGIC TREATMENT OF BPH Medical Management of Lower Urinary Tract Symptoms Eric E. Laborde, MD, Kevin T. McVary, MD Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL Lower urinary tract symptoms (LUTS) are a common complaint among aging men and are often caused by benign prostatic hyperplasia (BPH). A number of medical treatments for LUTS/BPH exist, such as -blockers, 5-reductase inhibitors, anticholinergics, phosphodiesterase type 5 (PDE5) inhibitors, and combination therapies. Agonist binding of the 1A-adrenergic receptor (AR), causing prostatic smooth muscle contraction, has been attributed to cause some LUTS. Therefore, medical therapy has aimed to block the 1A-AR and improve LUTS. Determining which therapy to choose must take into account individual patient factors as well as cost and patient choice. [Rev Urol. 2009;11(suppl 1):S19–S25 doi: 10.3909/riu11S1S0004] © 2009 MedReviews®, LLC Key words: 5-reductase inhibitors • -Blockers • Anticholinergics • Benign prostatic hyperplasia • Combination therapy • Lower urinary tract symptoms • Phosphodiesterase type 5 inhibitors ower urinary tract symptoms (LUTS) are a common complaint among aging men. These symptoms are often caused by benign prostatic hyperplasia (BPH), and include nocturia, urinary frequency, urgency, decreased urine flow rates, incomplete bladder emptying, and hesitancy. These symptoms are common, and their prevalence increases as men age. They are present in 8% of men age 31 to 40 years, 50% in those age 51 to 60 years, 70% in those age 61 to 70 years, and 90% in those age 81 to 90 years.1 A number of medical treatments for LUTS/BPH exist, such as -blockers, 5-reductase inhibitors, anticholinergics, phosphodiesterase type 5 (PDE5) inhibitors, and combination therapies. L VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S19 7. RIU0_S0004_12-14.qxd 12/14/09 10:29 PM Page S20 Medical Management of LUTS continued -Blockers There are 2 main groups of adrenergic receptors (ARs),  and , with several subtypes (Figure 1). The different AR subtypes are distributed unequally though the body. 1A-ARs are the predominant subtype in human prostate stroma. 1B-ARs are found in human heart, spleen, kidney, vascular smooth muscle, and lung tissue. 1D-ARs are found in the central nervous system and are the predominant subtype in the bladder.2,3 Agonist binding of the 1A-AR, causing prostatic smooth muscle contraction, has been attributed to cause some LUTS.4 Therefore, are usually attributed to action of the drug at extraurinary receptors; in fact, the main difference among -blockers is their affinity for the specific -AR subtypes. 1-AR Selective Antagonists Agents that are selective 1 antagonists include prazosin, terazosin, doxazosin, and alfuzosin (Table 1).7 These agents bind selectively to 1- versus 2-ARs, but they do not exhibit in vitro selectivity among the different 1-AR subtypes. At prescribed doses they appear to have comparable levels of efficacy.8 Pra- -Blockers are the most commonly used medical therapy for BPH. different 1-AR subtypes. Tamsulosin selectively blocks the 1A- and 1DARs via high-affinity binding.9 Silodosin has a higher affinity for the 1A-AR compared with the 1D- and 1B-ARs.7 Both tamsulosin and silodosin significantly improve LUTS when compared with placebo.10,11 Because of their selectivity for the 1A-AR, vasodilatory side effects are limited. Tamsulosin has been associated with a low incidence of vasodilatory side effects, whereas the incidence of vasodilatory side effects associated with silodosin is no different than placebo.11,12 A summary of all the side effects of the different 1-blockers can be found in Table 2.10,13-15 5-Reductase Inhibitors medical therapy has aimed to block the 1-AR and improve LUTS. A number of 1-blocking agents are currently approved for treating LUTS due to BPH. -Blockers are the most commonly used medical therapy for BPH. They are well tolerated and have been shown to decrease the overall and symptomatic progression of BPH.5 The common side effects reported are dizziness, headache, asthenia, postural hypotension, rhinitis, and sexual dysfunction.6 Side effects zosin is limited by its short half-life (2.5 h), which requires dosing 2 to 3 times daily. Because these agents have affinity for both the 1A-AR and the 1B-AR, vasodilatory side effects are more common. In fact, doxazosin and terazosin have been used to treat essential hypertension. Subtype-Selective 1-AR Antagonists In contrast with the previously mentioned agents, tamsulosin and silodosin exhibit selectivity among the Figure 1.  and  adrenergic receptor (AR) subdivisions. ARs ␣ ␣2A S20 ␣1B ␤1 ␣2 ␣1 ␣1A ␤ ␣2B ␣2C ␣1D VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY ␤2 5-reductase inhibitors (5ARIs) are compounds that block the conversion of the main male androgenic steroid hormone testosterone (T) to dihydrotestosterone (DHT). This conversion is enabled by the enzyme 5AR, of which there are 2 isoenzymes, known as type I and type II. Both T and DHT bind to the AR, although DHT does so with greater affinity and is thus considered the more potent androgenic steroid hormone.16 The T/DHT-AR complex within the nucleus of the prostate cells initiates transcription and translation, thus promoting cellular growth and ultimately contributing to BPH with an imbalance between growth and apoptosis (cellular death in favor of growth) and subsequent cellular mass or volume increase. Type II 5AR is principally found in the prostate and other genital tissues. Type I is found throughout the body, including the skin, liver, and prostate. Both type I and type II 5AR have been shown as present in all prostate zones (peripheral, transition, and central).17 Currently, 2 5ARIs are used in the treatment of BPH—finasteride and dutasteride. Finasteride is a selective 7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S21 Medical Management of LUTS Terazosin13 (%) Tamsulosin10 (%) 0.4 mg 0.8 mg Alfuzosin14 (%) Silodosin15 (%) Asthenia/fatigue 7.4 7.8 8.5 2.7 Not reported Positive orthostatic test Not reported 16.0 19.0 6.6 2.6 Rhinitis/nasal congestion 3.9 13.1 17.9 0.4 2.1 for men with LUTS/BPH who have demonstrable prostate enlargement. (In different studies different thresholds have been proposed for the definition of prostate enlargement [25, 30, or 40 mL].) Dutasteride is untested in glands smaller than 30 g. There are no data from direct comparator trials or other sources to suggest that the clinical efficacy of the 2 5ARIs in the appropriate indication is different. Comparisons are difficult if not impossible, as inclusion and exclusion criteria do not match for any of the trials performed with finasteride or dutasteride. In the Medical Therapy of Prostatic Symptoms (MTOPS) and Combination Therapy With Avodart and Tamsulosin (CombAT) studies, 5ARIs were shown as useful in preventing progression of LUTS/BPH and reducing the risk of urinary retention and future prostaterelated surgery. However, in this and all settings, 5ARIs should not be used in men with LUTS/BPH if there is no demonstrable prostatic enlargement. Dizziness 9.1 14.9 17.1 5.7 3.2 Anticholinergics Retrograde ejaculation Not reported 8.4 18.1 Not reported 28.1 Table 1 Pharmacologic Selectivity of -Blockers 1-Blocker 1-Receptor Selectivity Doxazosin 1A  1D  1B Terazosin 1A  1D  1B Alfuzosin 1A  1D  1B Tamsulosin 1A  1D  1B Silodosin 1A  1D  1B Data from Schwinn DA and Roehrborn CG.7 Table 2 Treatment-Related Adverse Events of -Blockers Used for Benign Prostatic Hyperplasia inhibitor of type II 5AR. At a dose of 5 mg/d, it reduces plasma DHT by 60% to 70% and prostatic DHT concentrations by approximately 85%.18 Dutasteride differs from finasteride in that it blocks both isoenzymes of 5AR Tolerability improves with prolonged usage (Tables 3 and 4).18,20 At this time there appears to be no clinical benefit of the greater suppression of serum DHT seen with dutasteride as compared with finasteride. 5ARIs are appropriate and effective treatment options for men with LUTS/BPH who have demonstrable prostate enlargement. (type I and type II). This results in a 90% to 95% decrease in circulating DHT.19,20 Side effects of both drugs include decreased libido, erectile dysfunction (ED), decrease in ejaculate volume, and gynecomastia. Both have been shown to decrease prostate volume, improve urinary symptoms, decrease the risk of urinary retention, and decrease the risk of BPH surgery (Table 5).18,21 5ARIs are appropriate and effective treatment options The rationale for the use of anticholinergic medications in treating BPH is based on LUTS including overactive bladder (OAB) symptoms, such as frequency, urgency, and incontinence. OAB symptoms are attributed to detrusor overactivity (DO), which may be induced by bladder outlet obstruction. DO is thought to contribute to symptoms in 40% to 70% of patients with bladder outlet obstruction.22 Bladder contractions are stimulated by the action of acetylcholine on muscarinic receptors in the smooth muscle of the bladder. Anticholinergic medications such as tolterodine, flavoxate, propiverine, and oxybutynin23 are widely used to treat OAB symptoms, especially in women, but only recently has their role in treating LUTS secondary to BPH been explored.24 VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S21 7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S22 Medical Management of LUTS continued Table 3 Side Effects of Finasteride and Dutasteride from Clinical Trials With Treatment up to 1 Year Finasteride21 Dutasteride19 Treatment (%) Placebo (%) Treatment (%) Placebo (%) Decreased libido 6.4 3.4 3.7 1.9 Erectile dysfunction 8.1 3.7 6.0 3.0 Gynecomastia 0.5 0.1 1.3 0.5 Decreased ejaculate volume 3.7 0.8 1.8 0.7 Table 4 Side Effects of Finasteride and Dutasteride from Clinical Trials With Treatment Longer Than 1 Year Finasteride21 Dutasteride19 Treatment (Patients, %) Placebo (Patients, %) Treatment (Patients, %) Placebo (Patients, %) Decreased libido 2.6 2.6 0.6 0.3 Erectile dysfunction 5.1 5.1 1.7 1.2 Gynecomastia 1.1 1.8 1.3 0.3 Decreased ejaculate volume 1.5 0.5 0.5 0.1 Table 5 Data From Clinical Trials of Finasteride and Dutasteride Finasteride21 Volume change (%) Dutasteride19 Treatment Placebo Treatment Placebo 18 14 26 2 Decrease in IPSS 3.3 1.3 4.5 2.3 Improvement in flow rate (mL/s) 1.9 0.2 2.2 0.6 Patients developing acute urinary retention (%) 3 7 1.8 4.2 Patients requiring BPH surgery (%) 5 10 2.2 4.1 BPH, benign prostatic hyperplasia; IPSS, International Prostate Symptom Score. Complete inhibition of bladder contractions would result in urinary retention, a serious unwanted side effect. However, this occurrence is exceedingly rare with clinically effective dosing of antimuscarinic medica- S22 VOL. 11 SUPPL. 1 2009 tions in a highly select cohort with low baseline postvoid residual volumes.25 This risk was addressed in a study in which 221 men with urodynamically confirmed bladder outlet obstruction and DO were randomized REVIEWS IN UROLOGY to tolterodine compared with placebo for 12 weeks.26 Postvoid residual volume increased to a significantly greater extent in the tolterodine group relative to placebo (25 mL), but this was not accompanied by an 7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S23 Medical Management of LUTS increase in adverse events. Urinary retention was reported by 1 patient treated with placebo. Also demonstrated in this study were significant clinical effects in the bladder outlet obstruction index (a urodynamic measure of the degree of obstruction), volume to first detrusor contraction, and maximum cystometric capacity, favoring tolterodine over placebo.25 Phosphodiesterase Type 5 Inhibitors Newer evidence suggests a role for using phosphodiesterase type 5 (PDE5) inhibitors to treat LUTS due to BPH. A possible mechanism by which PDE5 inhibitors can influence LUTS is through nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The NO/cGMP system generally has an inhibitory effect on the lower urinary tract.27,28 Additionally, men with BPH have been shown to have a decrease in NO-mediated relaxation of prostate smooth muscle.29 PDE5 inhibitors are known to exert their effects by increasing levels of cGMP and NO. A number of isoforms of PDE have been found in the prostate, bladder, and urethra.30 PDE5 inhibitors should improve LUTS by acting at these sites. Studies using daily dosing of both sildenafil and tadalafil have shown improvement in International Prostate Symptom Score (IPSS)31,32; erectile function improved as well, although urinary flow rates did not increase in either study. To date, the exact mechanism and site of action of PDE5 inhibitors on LUTS is unknown. Nonetheless, using PDE5 inhibitors to agent alone.5 Progression of BPH was defined as the first occurrence of an increase over baseline of at least 4 points in the IPSS, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or urinary incontinence. The risk of clinical progression was reduced by 39% in the doxazosin-treated group, 34% in the finasteride-treated group, and 66% in the group on combination therapy. In addition, the risk of acute urinary re- Using PDE5 inhibitors to treat LUTS is especially attractive because LUTS and ED are often found in the same patient populations. treat LUTS is especially attractive because LUTS and ED are often found in the same patient populations.33 Combination Therapy Although the previously mentioned drugs are effective alone, they can also be used in combination. The MTOPS trial is the largest trial to evaluate combination therapy with blockers and 5ARIs. This trial found that combination therapy (finasteride and doxazosin) reduced the overall progression of BPH more than either tention and the need for BPH-related surgery was decreased by both the finasteride-treated group and the combination therapy group (but not by the doxazosin only group). Combination therapy with anticholinergics and -blockers has also been studied. Although the length of follow-up in each of the studies is short, there appears to be consensus that combination therapy is more effective than either -blockers or anticholinergics alone in the treatment of LUTS due to BPH (Table 6)34-37 Table 6 A Summary of Trials With -Blockers/Anticholinergic Combination Therapy Study Agents N Duration Primary Outcome Combination Therapy Efficacy vs 1-ARA Alone Athanasopoulos et al.36 Tamsulosin and tolterodine 50 3 mo QoL questionnaire, urodynamic studies Improved QoL scores, some urodynamic variables Lee et al.37 Doxazosin CR and propiverine CR 211 8 wk Urinary frequency, urodynamic studies, patient satisfaction rates Improved urinary frequency, average micturition volume, storage symptoms, urgency severity Kaplan et al.35 Tamsulosin and tolterodine ER 879 12 wk Bladder diaries Improved urgency incontinence Yang et al.34 Terazosin and tolterodine 191 6 wk IPSS score, peak urinary flow rate, postvoid residual volume Reduced IPSS score ARA, adrenergic agent; CR, controlled release; ER, extended release; IPSS, International Prostate Symptom Score; QoL, quality of life. VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S23 7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S24 Medical Management of LUTS continued More recently, combining both PDE5 inhibitors and -blockers has been evaluated. A study by Kaplan and colleagues38 compared the impact of alfuzosin, sildenafil, or the combination of alfuzosin and sildenafil on LUTS. The results indicated that combination therapy (24.1% improvement) improved LUTS more than treatment with alfuzosin (15.6% improvement) or sildenafil (11.8% improvement) alone. treatment, is a new area and requires further study. Conclusions 4. Currently, multiple treatment modalities exist for the treatment of LUTS due to BPH. At this time -blockers, 5ARIs, and PDE5 inhibitors appear effective. Determining which therapy to choose must take into account individual patient factors as well as cost and patient choice. No single medical therapy available appears to be superior to the others. The role of PDE5 inhibitors, both alone and in combination with other forms of LUTS References 1. 2. 3. 5. 6. 7. 8. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol. 1984;132:474-479. Price DT, Lefkowitz RJ, Caron MG, et al. Localization of mRNA for three distinct alpha 1-adrenergic receptor subtypes in human tissues: implications for human alpha-adrenergic physiology. Mol Pharmacol. 1994;45:171-175. Malloy BJ, Price DT, Price RR, et al. Alpha1adrenergic receptor subtypes in human detrusor. J Urol. 1998;160:937-943. Lepor H, Tang R, Shapiro E. The alphaadrenoceptor subtype mediating the tension of human prostatic smooth muscle. Prostate. 1993; 22:301-307. 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;349:2387-2398. Debruyne FM. Alpha blockers: are all created equal? Urology. 2000;56(5 suppl 1):20-22. Schwinn DA, Roehrborn CG. Alpha1adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-199. Akduman B, Crawford ED. Terazosin, doxazosin, and prazosin: current clinical experience. Urology. 2001;58:49-54. 9. Noble AJ, Chess-Williams R, Couldwell C, et al. The effects of tamsulosin, a high affinity antagonist at functional alpha 1A- and alpha 1Dadrenoceptor subtypes. Br J Pharmacol. 1997; 120:231-238. 10. Tamsulosin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2006. 11. Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective alpha1Aadrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2009;181:2634-2640. 12. de Mey C, Michel MC, McEwen J, Moreland T. A double-blind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol. 1998;33: 481-488. 13. Terazosin [package insert]. Abbott Park, IL: Abbott Laboratories; 2003. 14. Alfuzosin [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2004. 15. Silodosin [package insert]. Morristown, NJ: Watson Pharmaceuticals; 2009. 16. Wilson JD. The role of 5alpha-reduction in steroid hormone physiology. Reprod Fertil Dev. 2001;13:673-678. 17. Iehle C, Radvanyi F, Gil Diez de Medina S, et al. Differences in steroid 5alpha-reductase isoenzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol. 1999;68:189-195. Main Points • Lower urinary tract symptoms (LUTS) are a common complaint among aging men and are often caused by benign prostatic hyperplasia (BPH). A number of medical treatments for LUTS/BPH exist, including -blockers, 5-reductase inhibitors, anticholinergics, phosphodiesterase type 5 (PDE5) inhibitors, and combination therapies. • There are 2 main groups of adrenergic receptors (ARs),  and , with several subtypes. The different AR subtypes are distributed unequally through the body; 1A-ARs are the predominant subtype in human prostate stroma. Agonist binding of the 1A-AR, causing prostatic smooth muscle contraction, has been attributed to cause some LUTS; therefore, medical therapy has aimed to block the 1-AR and improve LUTS. • 5-reductase inhibitors are compounds that block the conversion of the main male androgenic steroid hormone testosterone to dihydrotestosterone. Both dutasteride and finasteride have been shown to decrease prostate volume, improve urinary symptoms, decrease the risk of urinary retention, and decrease the risk of BPH surgery. • The rationale for the use of anticholinergic medications in treating BPH is based on LUTS including overactive bladder (OAB) symptoms. OAB symptoms are attributed to detrusor overactivity, which may be induced by bladder outlet obstruction. Anticholinergic medications are widely used to treat OAB symptoms, and recently their role in treating LUTS secondary to BPH has been explored. • A possible mechanism by which phosphodiesterase type 5 (PDE5) inhibitors can influence LUTS is through nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The NO/cGMP system generally has an inhibitory effect on the lower urinary tract. Studies using daily dosing of both sildenafil and tadalafil have shown improvement in International Prostate Symptom Score and erectile function, but not urinary flow rates. • Several large trials have proven that combination therapy reduced the overall progression of BPH more than one agent alone. S24 VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY 7. RIU0_S0004_12-14.qxd 12/14/09 4:12 PM Page S25 Medical Management of LUTS 18. 19. 20. 21. 22. 23. 24. McConnell JD, Wilson JD, George FW, et al. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74:505-508. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alphareductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60: 434-441. Clark RV, Hermann DJ, Cunningham GR, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab. 2004;89:2179-2184. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 1998;338:557-563. Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol. 2005;174:2273-2275. Gallegos PJ, Frazee LA. Anticholinergic therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia. Pharmacotherapy. 2008;28:356-365. Blake-James BT, Rashidian A, Ikeda Y, Emberton M. The role of anticholinergics in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. BJU Int. 2007;99:85-96. 25. 26. 27. 28. 29. 30. 31. 32. Ruggieri MR Sr, Braverman AS, Pontari MA. Combined use of alpha-adrenergic and muscarinic antagonists for the treatment of voiding dysfunction. J Urol. 2005;174:1743-1748. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol. 2006;175:999-1004. Andersson KE, Persson K. Nitric oxide synthase and nitric oxide–mediated effects in lower urinary tract smooth muscles. World J Urol. 1994;12:274-280. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev. 2004;56:581-631. Klotz T, Mathers MJ, Bloch W, et al. Nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia. Int Urol Nephrol. 1999;31:335-341. Uckert S, Kuthe A, Jonas U, Stief CG. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol. 2001;166: 2484-2490. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177:1401-1407. McVary KT, Monnig W, Camps JL Jr, et al. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007;177: 1071-1077. 33. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44:637-649. 34. Yang Y, Zhao XF, Li HZ, et al. Efficacy and safety of combined therapy with terazosin and tolterodine for patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective study. Chin Med J (Engl). 2007;120:370-374. 35. Kaplan SA, Roehrborn CG, Rovner ES, et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296:2319-2328. 36. Athanasopoulos A, Gyftopoulos K, Giannitsas K, et al. Combination treatment with an alphablocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol. 2003;169:2253-2256. 37. Lee KS, Choo MS, Kim DY, et al. Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol. 2005;174:1334-1338. 38. Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol. 2007;51: 1717-1723. 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