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International Journal of Impotence Research (2008) 20, S33–S43 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir

REVIEW The role of combination medical therapy in benign prostatic hyperplasia

KA Greco and KT McVary

Department of , Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

To review key trials of monotherapy and combination therapy of a1- receptor antagonists (a1-ARAs), 5a-reductase inhibitors (5aRIs) and anti-muscarinic agents in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). To assess the safety and efficacy of combination therapies for LUTS associated with BPH, a search of the MEDLINE and Cochrane databases (1976–2008) was conducted for relevant trials and reviews using the terms benign prostatic hyperplasia, lower urinary tract symptoms, a1- antagonists, 5a-reductase inhibitors, anti-muscarinics, , combination therapy, , , , , , , tolterodine, , , , erectile dysfunction, sildenafil, vardenafil and tadalafil. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study indicated a role for long-term use of a1- ARAs and 5aRIs in combination. In the MTOPS study, combination therapy with the a1-ARA doxazosin and the 5aRI finasteride was significantly more effective than either component alone in reducing symptoms (P ¼ 0.006 vs doxazosin monotherapy; Po0.001 vs finasteride monotherapy) and in lowering the rate of clinical progression (Po0.001 vs either monotherapy). These findings were confirmed by the 2-year preliminary results of the Combination of Avodart and Tamsulosin study. In this study, combination therapy of the a1-ARA tamsulosin and the 5aRI dutasteride resulted in a significantly greater decrease in International Symptom Score (IPSS) when compared with either monotherapy. Several recent trials have studied the efficacy of combining a1-ARAs and anti-muscarinic agents in the treatment of BPH. These studies have found this combination to result in statistically significant benefits in quality of life scores, patient satisfaction, urinary frequency, storage symptoms and IPSS scores. Studies have not shown an increased risk of associated with the use of anti-muscarinics in a highly select cohort of men with BPH. The available data suggest that combination therapy can be beneficial in the treatment of BPH and associated LUTS. The greatest efficacy for the a1-ARA and 5aRI combination was shown in patients with larger prostate size and more severe symptoms. The combination of a1-ARAs and 5aRIs appears to prevent disease progression in these patients. The combination of a1-ARAs with anti-muscarinic agents is useful for relieving symptoms of bladder outlet obstruction and detrusor overactivity. Theoretic concerns regarding the risk of acute urinary retention have been refuted in several recent clinical trials; however, it must be noted that the patients in these trials were a highly select cohort of men. Men with and BPH who are not receiving adequate alleviation of symptoms from the first-line a1-ARAs may benefit from the addition of an anti- muscarinic agent. International Journal of Impotence Research (2008) 20, S33–S43; doi:10.1038/ijir.2008.51

Introduction quality of life (QoL) by interrupting sleep and daily activities.1,2 Owing to availability of effective phar- Benign prostatic hyperplasia (BPH) is a common macological therapies, such as a1-adrenergic recep- disease in older men that can result in bothersome tor antagonists (a1-ARAs), 5a-reductase inhibitors lower urinary tract symptoms (LUTS) that decrease (5aRIs) and antimuscarinic agents, there has been a gradual shift from surgical to medical therapy for LUTS due to BPH.3 Until recently, there has been little data on the benefits of combining these classes Correspondence: Dr KT McVary, Department of Urology, 4 Feinberg School of Medicine, Northwestern University, compared with monotherapy. This article reviews 303 East Chicago Avenue, Tarry Building 16-703, Chicago, key trials of monotherapy and combination therapy IL 60611, USA. of a1-ARAs, 5aRIs and antimuscarinics in the E-mail: [email protected] treatment of LUTS associated with BPH. The role of combination medical therapy in BPH KA Greco and KT McVary S34 Data from the Medical Therapy of Prostatic tamsulosin, terazosin, dutasteride, finasteride, tol- Symptoms (MTOPS) study indicated a role for the terodine, flavoxate, propiverine and oxybutynin. long-term use of a1-ARAs and 5aRIs in combination. The search included clinical trials, meta-analyses, In the MTOPS study, combination therapy with the systematic reviews and major review articles. The a1-ARA doxazosin and the 5aRI finasteride was reference lists of identified articles were then significantly more effective than either component examined for additional publications. alone in reducing symptoms (P ¼ 0.006 vs doxazosin monotherapy; Po0.001 vs finasteride monotherapy) and in lowering the rate of clinical progression Prevalence and pathophysiology of BPH (Po0.001 vs either monotherapy). These findings were confirmed by the 2-year preliminary results of The prevalence of histopathologic BPH is age depen- the Combination of Avodart and Tamsulosin study. dent, with prevalence greater than 50% by 60 years of In this study, combination therapy of the a -ARA 1 age and as high as 90% by 85 years of age.1 It is tamsulosin and the 5aRI dutasteride resulted in a estimated that 50% of men with histopathologic BPH significantly greater decrease in International Pros- have moderate-to-severe LUTS.1 The pathophysiology tate Symptom Score (IPSS) when compared with of BPH involves hyperplasia of the epithelial and either monotherapy. stromal components of the prostate gland. This results Several recent trials have studied the efficacy of in a progressive obstruction of urine flow through the combining a -ARAs and antimuscarinic agents in 1 prostatic urethra.5 This BOO may induce DO through the treatment of BPH. These studies have found this ischemia, denervation, alteration in collagen content combination to result in statistically significant or changes in the electrical properties of detrusor benefits in QoL scores, patient satisfaction, urinary smooth muscle cells.6 Sympathetic overactivity has frequency, storage symptoms and IPSS scores. also been proposed to contribute to LUTS.7 Studies have not shown an increased risk of urinary retention associated with the use of antimuscarinics in a highly select cohort of men with BPH. The available data suggest that combination Diagnosis of BPH therapy can be beneficial in the treatment of BPH and associated LUTS. The greatest efficacy of the The diagnosis of voiding dysfunction due to BPH combination of a1-ARA and 5aRI was shown in can be challenging and complicated. LUTS include patients with larger prostate size and more severe symptoms related to obstruction (weak urine flow, symptoms. The combination of a1-ARAs and 5aRIs hesitancy, straining and incomplete emptying) and appears to prevent disease progression in these bladder storage problems (frequency, urgency and patients. ).8 BPH may progress to produce worsening The combination of a1-ARAs with antimuscarinic of symptoms, as well as other complications such as agents is useful for relieving symptoms of bladder AUR, , recurrent urinary tract outlet obstruction (BOO) and detrusor overactivity infection, renal insufficiency and the need for (DO). Theoretical concerns regarding the risk of surgical intervention.8 History, physical examina- acute urinary retention (AUR) have been refuted in tion, laboratory and urodynamic tests can be several recent clinical trials; however, it must be utilized in the diagnosis and characterization of noted that the patients in these trials were a highly LUTS secondary to BPH.1 History may reveal other select cohort of men. Men with overactive bladder causes for LUTS such as other medical conditions, (OAB) and BPH, who are not receiving an adequate medications or lifestyle factors.9,10 Physical exam- alleviation of symptoms from the first-line a1-ARAs, ination should include both a digital rectal exam- may benefit from the addition of an antimuscarinic ination and a focused neurologic examination.1 agent. Laboratory evaluation may include a urinalysis to screen for hematuria or urinary tract infection and measurement of prostate-specific antigen in select patients.11 Patients seek treatment for BPH because Methods the symptoms alter their QoL. Symptom quantifica- tion is of critical importance in assessing the To assess the safety and efficacy of combination severity of the disease, monitoring response to therapies for LUTS associated with BPH, a search of therapy and in detecting progression of disease.1 English language literature indexed in the MEDLINE Therefore, patients should be assessed with and Cochrane databases (1976–2008) was conducted validated questionnaires. The American Urological for relevant trials and reviews using the terms Association Symptom Index (AUA-SI), which is benign prostatic hyperplasia, lower urinary tract identical to the seven symptom questions of the symptoms, a1-adrenergic receptor antagonists, 5a- IPSS, is regarded as superior to an unstructured reductase inhibitors, antimuscarinics, anticholiner- interview in quantifying symptom frequency and gics, combination therapy, alfuzosin, doxazosin, severity.12

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S35 Treatment of BPH .15 The older longer-acting a1-ARAs, terazosin and doxazosin have more per- Therapy for BPH is generally directed toward the ipheral effects on as they were origin- alleviation of LUTS. Patients’ symptoms can be ally developed as antihypertensives. They require stratified into mild, moderate and severe groups, dose titration at the initiation of therapy to avoid which allow treatment to be directed accordingly.1 these effects. Tamsulosin and alfuzosin were more The AUA symptom score index discussed pre- recently developed and they are more selective for viously is highly useful for this purpose. Patients the genitourinary tract and do not require the initial with mild tolerable symptoms may be managed dose titration.4 conservatively by watchful waiting with reassurance The a1-ARAs have differing effects on the ejacu- and behavioral interventions. In men with BPH, the latory process. Tamsulosin is associated with a progression of symptoms is not inevitable and some significant incidence of ejaculatory dysfunction men may undergo spontaneous improvement or (EjD), whereas the other a1-ARAs are associated resolution of their symptoms.13 In a randomized with a low incidence of EjD. In one large, multi- comparison of transurethral resection of the center, randomized, double-blind, placebo-controlled prostate to advice alone, one quarter of the men had study, the incidences of abnormal ejaculation attri- disease progression requiring surgical intervention butable to tamsulosin, 0.4 and 0.8 mg daily, were 8.4 in 3 years.14 Men with more bothersome LUTS, which and 18.1%, respectively. No subjects discontinued interfere with their QoL, may be offered drug therapy because of this .18 Conversely, treatment.15 Surgical therapy is usually reserved it appears that alfuzosin does not cause EjD. In fact, for patients with intractable symptoms that are alfuzosin may even have a beneficial effect on EjD. refractory to drug treatment or for those in whom A recent study demonstrated both reduced erectile drug therapy leads to unacceptable side effects. It is dysfunction (ED) and EjD with alfuzosin 10 mg appropriate to proceed directly to surgical therapy daily.19 Doxazosin has not been sufficiently studied in patients with complications due to BPH such as with respect to EjD. These differing effects of the AUR, renal insufficiency, detrusor dysfunction, various a1-ARAs on the ejaculatory process have bladder calculi, urinary incontinence and recurrent been attributed to their relative affinity for the a1A, 4 urinary tract infection. Discussion of surgical a1B, a1D and a1L subtypes in the spinal cord, brain therapies is not in the scope of this review. and pelvic organs. Although the subtypes have not Drug therapy for patients with persistent LUTS yet been fully elucidated, a1-ARAs do appear to play includes a1-ARAs, 5aRIs, antimuscarinic agents, a role in both spinal excitability and in the brain’s phosphodiesterase type 5 inhibitors (PDE5Is) and supraspinal control of ejaculation.20 combination therapies (a1-ARAs plus 5aRIs or a1- The AUA Clinical Practice Guidelines Committee ARAs plus antimuscarinics). Each of these medica- concluded through a meta-analysis that a1-ARAs tion classes has different mechanisms of action, thus provide beneficial effects in treating BOO and DO combining these agents would seem to be beneficial. due to BPH.1 These agents have been found to This rationale has spurred many clinical trials improve BPH-related LUTS by a mean of four to six 4 recently and there have been promising results. points on the AUA-SI. Data on a1-ARA monother- apy in BPH have indicated the efficacy and toler- ability of these agents.21–24 A multicenter, randomized, double-blind, placebo- 21 a1-Adrenergic receptor antagonists controlled study was carried out to evaluate the safety and efficacy of terazosin in the treatment of The a1-ARAs are considered first-line agents for the BPH. The study design resulted for 24 weeks total pharmacologic treatment of LUTS secondary to time on active drug treatment. One-hundred and BPH.1 Available agents include alfuzosin, doxazo- sixty-four patients with a diagnosis of BPH based on sin, tamsulosin and terazosin. The AUA Clinical history, physical examination and digital rectal Guidelines for the management of BPH consider all examination met inclusion criteria for randomiza- four agents to be equally efficacious, although they tion. The trial demonstrated that terazosin signifi- have slightly different adverse-event profiles.1 The cantly increased peak and mean urine flow rates use of a1-ARAs in the treatment of BPH is based (Po0.001 for both) and did not alter voided volume on the hypothesis that LUTS are partially caused by or post-void residual volume. Terazosin also sig- a1-adrenergic-mediated contraction of smooth mus- nificantly improved both obstructive and irritative cle cells that are abundant in the prostate and symptoms, which were assessed using the AUA-SI 16,17 21 bladder neck, resulting in BOO. The a1-ARAs (P ¼ 0.014). function by inhibiting smooth muscle tone and A pooled analysis22 of three double-blind placebo- improving urinary flow. Unfortunately, the a1-ARAs controlled studies of doxazosin for the treatment of can cause peripheral blockade as well, leading to BPH allowed a more robust investigation of the adverse effects such as postural , dizzi- available data with a combined population size of ness, , nasal congestion, drowsiness and 337. The analysis revealed that doxazosin produced

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S36 a significantly greater improvement than placebo in greater response to 5aRI therapy compared with peak urinary flow rates (P ¼ 0.0017), symptom those with smaller .15 severity (Po0.0001) and bother caused by symp- Finasteride is the most extensively studied 5aRI toms (Po0.0001). Doxazosin was well tolerated; and has been found to reduce the risk of AUR and 10% of the patients discontinued use due to adverse the need for surgical intervention.4 In the Proscar effects compared with 4% of patients in the placebo Worldwide Efficacy and Safety Study,26 patients group (Po0.05).22 with BPH were randomized to receive finasteride or The safety and efficacy of alfuzosin (10 or 15 mg placebo for 2 years. This trial revealed significant daily) without initial dose titration was investigated benefits in symptom score, as well as reductions in in a randomized, double-blind, placebo-controlled maximum urinary flow rate and prostate volume. trial23 involving 536 patients. The primary outcome The trial also demonstrated a significant decrease in data were improvement in IPSS and peak urinary the risk of AUR and progression to surgery. flow rates. Alfuzosin was significantly more effec- The Proscar Worldwide Efficacy and Safety tive than placebo in improving symptoms and peak Study was further supported by Prostate Long-term urinary flow rate. The mean change in IPSS from Efficacy and Safety Study, a 4-year, randomized, baseline was significant when compared with double-blind, placebo-controlled trial,27 in which placebo; À3.6 and À3.4 for 10 and 15 mg doses, finasteride (5 mg dÀ1) significantly decreased the respectively, vs À1.6 with placebo (P ¼ 0.001 for risk of urinary retention (Po0.001) and need for alfuzosin 10 mg; P ¼ 0.004 for alfuzosin 15 mg). surgery (Po0.001) compared with placebo in men The mean increase in peak urinary flow was with a larger prostate (455 ml). also significant for both dose groups vs placebo In two 12-month, randomized, double-blind, (P ¼ 0.0006 for both).23 The patients’ QoL also placebo-controlled trials (N ¼ 89525 and 75028), significantly improved with both doses of alfuzosin. finasteride (1–50 mg dÀ1) significantly improved The incidence of was symptom scores (Po0.001 and Po0.015, respec- similar to placebo and there were no clinically tively) and peak urinary flow rates (Po0.001 for relevant ejaculation disorders. The authors con- both).25,28 A meta-analysis revealed more modest cluded that alfuzosin 10 mg daily can be adminis- improvements in men with smaller prostates.29 tered safely without dose titration and is efficacious Another 5aRI, dutasteride, has also been studied in the treatment of BPH.23 significantly for the treatment of BPH. It has also Another randomized, double-blind, placebo-con- been shown to reduce the risks for AUR and need for trolled trial24 investigated the safety and efficacy of surgery. A randomized, double-blind, placebo-con- 30 tamsulosin, the first selective a1-ARA studied in trolled trial investigated the effects of dutasteride clinical trials. The group randomized 756 patients to treatment (0.5 mg dÀ1) for 24 months in 4325 three groups: tamsulosin (0.4 mg daily), tamsulosin patients with BPH. The study reported a 57% (0.8 mg daily) or placebo. There were statistically relative risk for AUR and a 48% relative risk for significant improvements in AUA-SI scores and surgical intervention. Significant reductions in peak urinary flow (Po0.001 for both). The study prostate volume and improvements in AUA-SI demonstrated excellent tolerance to the drug, as the scores were also demonstrated (Po0.001 for both).30 incidence of positive orthostatic test results in Although these agents have been shown to be the tamsulosin groups was comparable with that in effective in reducing the AUA-SI and risk for AUR the placebo group. The group concluded that and surgical intervention, they require long-term tamsulosin is an effective, safe and well-tolerated treatment. The significant reductions in prostate drug at both the 0.4 and 0.8 mg daily doses.24 size occurred after 2 months to 1 year of therapy.4 Other adverse effects include ejaculatory disorder, decreased libido, impotence and gynecomastia.4 5a-Reductase inhibitors

The 5aRIs, dutasteride and finasteride, are compe- Antimuscarinic agents titive inhibitors of the enzyme 5a-reductase. 5a-reductase is responsible for the conversion of The rationale for the use of antimuscarinic medica- testosterone to its active form, dihydroxytestosterone. tions in the treatment of BPH is based on the fact Physiologic levels of dihydroxytestosterone permit that LUTS include OAB symptoms, such as fre- prostate growth, thus the reduction of dihydroxytes- quency, urgency and incontinence. These symptoms tosterone is associated with involution of the are generally the most bothersome to patients and epithelial components of the prostate gland.25 Re- signify a critical target in the management of BPH. gression of overall prostate size is seen over the OAB symptoms are attributed to DO, which may be course of weeks to months.4 Reduction in prostate induced by BOO. Bladder contractions are stimu- size relieves LUTS as well as potentially decreases lated to occur by the action of on the risk of complications of BPH disease, such as muscarinic receptors in the smooth muscles of AUR. Patients with larger prostates typically have a the bladder. Antimuscarinic medications, such as

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S37 tolterodine, flavoxate, propiverine and oxybutynin,15 Phosphodiesterase type 5 inhibitors are widely used to treat OAB symptoms especially in women, but only recently has their role in treating Lower urinary tract symptoms and sexual dysfunc- LUTS secondary to BPH been explored.31 tion are highly prevalent in aging men, and both A complete inhibition of bladder contractions conditions have a significant impact on overall QoL. would result in urinary retention, a serious un- Male sexual dysfunction may manifest as hypoac- wanted side effect. However, this occurrence is tive sexual disorder, EjD, ED or a combination of all exceedingly rare with clinically effective dosing of these conditions. LUTS is an independent risk factor antimuscarinic medications in a highly select cohort for and significant predictor of ED after controlling with low baseline post-void residual volumes.32 for other risks (for example, age, diabetes, hyperten- This risk was addressed in a study in which 221 sion, cardiac disease, hypercholesterolemia, stroke, men with urodynamically confirmed BOO and DO physical activity, smoking and depression).36 In were randomized to tolterodine compared with addition, many currently available therapies for placebo for 12 weeks.33 Post-void residual volume LUTS due to BPH affect sexual function as dis- increased to a significantly greater extent in the cussed earlier. Recently, PDE5Is, traditionally used tolterodine group relative to the placebo group to treat ED, have demonstrated the ability to ( þ 25 ml), but this was not accompanied by an improve LUTS in multiple studies. increase in adverse events. Urinary retention was Four randomized placebo-controlled studies reported by one patient treated with placebo. Also sought to elucidate the relationship between PDE5Is demonstrated in this study were significant clinical and LUTS, utilizing sildenafil, vardenafil and effects in the BOO index (a urodynamic measure of tadalafil twice, respectively. The study37 investigat- the degree of obstruction), volume to first detrusor ing sildenafil utilized a 12-week, double-blind, contraction and maximum cystometric capacity, placebo-controlled approach in 369 men, 45 years favoring tolterodine over placebo.33 or older, who had International Index of Erectile In a multicenter, double-blind, randomized, placebo- Function (IIEF) scores o26 (on EF domain) and controlled trial,34 tolterodine extended release (ER) IPSS scores 411. The 189 men receiving sildenafil was studied relative to placebo and to the immedi- had significant improvement of IPSS when com- ate-release formulation for the treatment of OAB. pared with the 180 men on placebo (À6.32 vs À1.93, The group randomized 1529 patients (81% women) Po0.0001).37 with urinary frequency to the three groups. Efficacy The vardenafil study38 included 222 men aged was assessed using micturition diary variables. Both 45–64 years who had an IPSS 411 at the time of of the tolterodine formulations significantly reduced randomization. They underwent 8 weeks treatment the mean number of urge incontinence episodes per of vardenafil 10 mg twice daily or placebo. No week when compared with placebo (P ¼ 0.00001 and history of ED was required for inclusion in the P ¼ 0.0005, for ER and immediate release, respec- study. Vardenafil treatment resulted in a signifi- tively). The ER formulation was more effective than cantly lower IPSS score when compared with the immediate-release formulation (Po0.05). The placebo with a decrease in IPSS of 2.2 greater than most frequent adverse effect was dry mouth, but placebo (16.8–11 in treatment arm and 16.8–13.2 in rates of withdrawal were comparable for the two the placebo arm, P ¼ 0.0013). A significant improve- active treatment groups and the placebo group. It ment was noted in QoL, irritative and obstructive was concluded that tolterodine ER 4 mg daily is IPSS subscores, as well as IIEF scores in the effective and well tolerated in the treatment of OAB treatment group.38 with no safety concerns.34 The study performed utilizing tadalafil likely Another group studied the efficacy of yields more reliable findings, given its trial design.39 in a multicenter, randomized, double-blind, Following a 4-week, single-blind, placebo run-in, placebo-controlled trial35 involving 911 patients 281 men were randomly assigned to tadalafil 5 mg with OAB. Micturitions per 24 h were statistically daily for 6 weeks, followed by dose escalation to significantly decreased with solifenacin 5 mg 20 mg for 6 weeks or 12 weeks of placebo. Subjects (À2.37, P ¼ 0.0018) and solifenacin 10 mg (À2.81, were aged 45 years or older and had IPSS scores P ¼ 0.0001), as compared with placebo (À1.59). X12 secondary to BPH for at least 6 months. Episodes of urgency were also statistically signifi- Tadalafil significantly improved the mean change cantly reduced, and reduction of nocturia was of IPSS scores at 6 weeks over placebo (À2.8 vs À1.2 significant with the 10 mg dose. Dry mouth was for placebo), at 12 weeks (À3.8 vs À1.8 for placebo) reported in 7.7% of patients receiving solifenacin and with inclusion of the placebo run-in at 12 weeks 5 mg and 23% of patient receiving solifenacin 10 mg (À7.1 vs À4.5 for placebo). Significant improve- (vs 2.3% with placebo). In this study, solifenacin ments were seen in obstructive and irritative IPSS 5 mg daily significantly improved all of the major domains, QoL index and IIEF scores.39 symptoms of OAB including frequency, urgency and A recent well-designed and powered study was incontinence. Solifenacin was associated with a low published that demonstrated a profound impact of adverse effect profile, especially at the 5 mg dose.35 tadalafil on LUTS using a dose-ranging design.40 In

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S38 this randomized, double-blind, placebo-controlled, not for doxazosin. Doxazosin (Po0.001), finasteride parallel-group, global study,4 1058 men were ran- (P ¼ 0.001) and combination therapy all resulted in a domly assigned to placebo or one of four tadalafil significant improvement in symptom scores, with daily dosing regimens (2.5, 5, 10 and 20 mg) for combination therapy being superior to either agent 12 weeks. Subjects were aged 45 þ , had IPSS 412 alone. Adverse effects including dizziness, postural from BPH for 6 months and a Qmax of 4–15 ml sÀ1. hypotension, asthenia and ED were significantly After a 4-week, single-blind, placebo run-in, men more common in the combination group when were stratified by baseline IPSS (o20 vs X20), compared with the placebo group (Po0.05).41 baseline uroflow parameters, ED history (o3 The randomized, double-blind, placebo-controlled months vs X3 months) and geographic region. The Symptom Management After Reducing Therapy main end point of the studies revealed a significant (SMART) trial42 investigated how the combination improvement in IPSS in the 5 mg group with a of an a1-ARA (tamsulosin) with a 5aRI (dutasteride), change of 4.9 vs 1.8 (Po0.05). Increase in tadalafil followed by withdrawal of tamsulosin, would affect dose to greater than 5 mg showed similar improve- LUTS due to BPH. The two classes differ greatly in ments in IPSS scores, but had a higher incidence of terms of the onset of action; 5aRIs require several 40 adverse side effects. months to achieve clinical efficacy, whereas a1- All four studies consistently demonstrated that ARAs have a relatively rapid onset of action.4 In PDE5Is significantly improve IPSS scores when addition, the two classes differ in their area of compared with placebo. The magnitude of IPSS effectiveness; a1-ARAs provide symptomatic relief improvement observed was comparable with results and 5aRIs have been found to reduce prostate reported in previous a–blocker studies. However, a volume and risk of complications.4 These two head-to-head randomized controlled trial is required differences were the basis for the study rationale. to definitively state that treatment effects are truly In the SMART study, 327 patients with BPH were comparable. randomized to receive either the combination of tamsulosin (0.4 mg dÀ1) and dutasteride (0.5 mg dÀ1) for 36 weeks (DT36) or the combination therapy for 24 weeks, followed by 12 weeks of dutasteride 42 Combination therapy: a1-ARAs with 5aRIs monotherapy plus placebo (DT24 þ D12). The efficacy of the treatment was assessed between Combining the available pharmacologic classes in weeks 24 and 30 by asking the patients the following the treatment of LUTS due to BPH allows the patient question: ‘Over the past 2 weeks, on average have to derive the benefits from each class, thus poten- you felt better, worse or the same with respect to tially maximizing treatment response. The AUA your urinary symptoms than at your last visit?’ In currently recommends the use of 5aRIs in combina- the DT36 group, 91% of patients reported feeling the tion with a1-ARAs for patients with moderate-to- same or better between weeks 24 and 30, whereas severe symptoms and enlarged prostates.1 Early 77% of the DT24 þ D12 group reported feeling the 42 short-term trials comparing combination a1-ARA/ same or better (P ¼ 0.001). 42 5aRI therapy with a1-ARA alone found no signifi- The group concluded from the SMART study cant benefits, and as a result combination therapy that it is possible to discontinue the a1-ARA from was not utilized until recently.4 therapy in a majority of the patients, but patients The MTOPS study41 was a long-term double-blind with severe symptoms may benefit from longer term study of 3047 men that was undertaken to determine combination therapy. Although the data from this whether monotherapy with the a1-ARA doxazosin study suggest that withdrawal of a1-ARA may be 4–8 mg dÀ1 or the 5aRI finasteride 5 mg dÀ1,or possible, it is evident from data from the MTOPS 41 therapy with the two agents combined, could delay trial that 5aRI and a1-ARA combination therapy or prevent the progression of symptomatic BPH. may take 2–3 years to reach full clinical efficacy in The study found that the risk of overall clinical preventing AUR and progression of disease. The progression, defined as an increase of at least four short duration of the SMART trial was not sufficient points in the AUA-SI, AUR, urinary incontinence, for evaluating the true efficacy of combination renal insufficiency or recurrent urinary tract infec- therapy. tion, was significantly reduced by doxazosin (39% The Prospective European Doxazosin and Combi- risk reduction, Po0.001) and by finasteride (34% risk nation Therapy (PREDICT) trial43 was a 1-year, reduction, P ¼ 0.002) as compared with placebo.41 randomized, double-blind, placebo-controlled trial À1 Importantly, the reduction in risk associated with evaluating the a1-ARA doxazosin (1–8 mg d ), the combination therapy (66% compared with placebo, 5aRI finasteride (5 mg dÀ1) and their combination in Po0.001) was significantly greater than that asso- 1095 men with BPH. Primary end points were ciated with doxazosin (Po0.001) or finasteride the changes in IPSS and peak urinary flow rates. (Po0.001) alone.41 Combination therapy and finas- The groups receiving doxazosin monotherapy teride also significantly reduced the risk of AUR and and the doxazosin plus finasteride combination the need for invasive therapy (Po0.001 for both), but therapy saw significant improvements in IPSS when

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S39 compared with finasteride monotherapy and place- these events. Adverse events that were more bo (Po0.001 for both).43 The results for peak urinary common in the combination group than in either flow were similar: doxazosin and combination monotherapy group were ED, altered libido, ejacu- therapy were both superior to finasteride monother- latory disorders and nipple pain.45 apy (Po0.01 for both) and to placebo (Pp0.001 for both), but did not differ significantly from each other. Finasteride and placebo did not differ Combination therapy: a1-ARAs with significantly in their effects on peak urinary flow antimuscarinic agents rates.43 Similar to the SMART trial,42 the PREDICT trial43 was restricted by the short duration of Antimuscarinic medications have also recently been therapy, which was likely not adequate to demon- studied in combination with a1-ARAs. Again, combi- strate the advantages of combination therapy. nation therapy allows the beneficial effects of each The PREDICT trial43 was also similar in design to class to work together in alleviating LUTS.15 Anti- an earlier critical trial conducted by the Veterans muscarinics work primarily on DO, thus preventing Affairs Cooperative Studies Benign Prostatic Hyper- uninhibited bladder contractions. As DO is thought to plasia Study Group.44 This randomized placebo- contribute to symptoms in 40–70% of patients with 6 controlled trial examined the efficacy of the a1-ARA BOO, it is rational to expect that combination terazosin and the 5aRI finasteride individually and therapy with an a1-ARA and an antimuscarinic would in combination in patients with LUTS due to BPH. alleviate LUTS and improve QoL.46 The group concluded that terazosin was an effective A study46 of 50 men with urodynamically proven therapy for BPH, but finasteride was not, and the mild or moderate BOO and DO investigated the use combination of terazosin and finasteride was not of an a1-ARA (tamsulosin) in combination with an more effective than terazosin alone. The trial was antimuscarinic (tolterodine). Patients were initially similar to the PREDICT trial43 in its population size treated with tamsulosin (0.4 mg dÀ1) for 1 week. (N ¼ 1229) and its short duration of 1 year. Again, 1 Patients were then randomized to either continue year is not a sufficient duration of time to show tamsulosin alone or to continue tamsulosin with significant 5aRI efficacy. In addition, the Veterans tolterodine (2 mg dÀ1). Patients were evaluated with Affairs trial did not stratify patients by prostate size a QoL questionnaire and urodynamic studies after nor did they require a threshold level of prostatic 3 months of therapy. The study identified a enlargement. As discussed earlier, 5aRIs appear to statistically significant improvement in QoL scores be more efficacious in men with larger prostates. only in the combination therapy group. There were The mean baseline prostatic volume in the finaster- significant differences in both groups after treatment ide group of the Veterans Affairs trial was only for maximum flow rate and volume at first contrac- 36.2 cc.44 The Prostate Long-term Efficacy and tion. Statistically significant differences in max- Safety Study trial27 showed that finasteride signifi- imum detrusor pressure and maximum unstable cantly decreased the risk of AUR and the need for contraction pressure were present only in the surgery in men with a prostate volume larger than combination therapy group.46 55 cc. Symptom relief was the main focus of the Another group randomly assigned 211 men with Veterans Affairs trial; thus, it was not designed to OAB and urodynamically proven BOO to receive demonstrate the key benefits of 5aRIs in the doxazosin controlled release 4 mg dÀ1 or doxazosin prevention of disease progression. controlled release 4 mg dÀ1 plus propiverine The Combination of Avodart and Tamsulosin hydrochloride controlled release 20 mg dÀ1 for a study45 is an ongoing, randomized, double-blind duration of 8 weeks.47 Improvement was signifi- (non-placebo-controlled) clinical trial investigating cantly greater in the combination group compared the long-term outcomes of the use of the a1-ARA with the doxazosin controlled-release only group for tamsulosin and the 5aRI dutasteride alone and in urinary frequency (P ¼ 0.004), average micturition combination for the treatment of LUTS. In all, 4844 volume (P ¼ 0.004), storage symptoms (P ¼ 0.029) men with moderate-to-severe LUTS and prostate and urgency severity (P ¼ 0.019). Post-void residual enlargement 30 cc or greater were randomized to volume was also increased significantly in the receive tamsulosin alone (0.4 mg dÀ1), dutasteride combination group ( þ 20.7 ml), but there were no alone (0.5 mg dÀ1) or combination therapy for reports of AUR.47 Patient satisfaction rates were 4 years. The results at 2 years have been significantly higher in the combination group than published.45 The primary end point was the change in the doxazosin monotherapy group (P ¼ 0.002). in IPSS score from baseline. Combination therapy The odds of a patient reporting a treatment benefit resulted in a significantly greater decrease in IPSS were 2.34 times higher in patients receiving propi- score when compared with either dutasteride alone verine hydrochloride and doxazosin than in those or tamsulosin alone. There was also a significant receiving doxazosin alone (95% CI, 1.21–4.52).47 increase in drug-related adverse events with combi- A randomized, double-blind, placebo-controlled nation therapy vs monotherapies, but 5% or less of trial48 involving men with both OAB and BPH was the men in each treatment group withdrew due to executed to evaluate the efficacy and safety of

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S40 tolterodine ER alone, tamsulosin alone or both significantly different in the terazosin group and together. In all, 879 men were randomly assigned was interestingly reduced in the combination group to one of four groups: placebo, tolterodine ER (À3.9 ml, P ¼ 0.016), but did not differ significantly (4 mg dÀ1), tamsulosin (0.4 mg dÀ1) or both toltero- between groups. The frequency of adverse effects dine and tamsulosin.48 After 12 weeks of treatment, was higher in the combination group, with the most significantly more men receiving combination ther- common effect being dry mouth.49 apy reported treatment benefits compared with placebo (Po0.001). Combination therapy was also more effective than tolterodine alone (P ¼ 0.001), but the comparison with tamsulosin alone was not The role of combination therapy in statistically significant (80.0 vs 70.5%, P ¼ 0.064). patients with BPH Treatment efficacy for OAB symptoms was assessed using data from bladder diaries. Combination ther- The available data suggest that combination apy significantly reduced all bladder diary variables therapy can be beneficial in the treatment of BPH at week 12 when compared with placebo. Patients in and associated LUTS. The a1-ARA and 5aRI the tolterodine ER group compared with placebo combination was shown to be significantly experienced significant reductions in only urgency effective in several trials; however, only the MTOPS incontinence episodes at week 12 (P ¼ 0.008). There and Combination of Avodart and Tamsulosin were no significant differences between tamsulosin trials demonstrated that combination therapy was monotherapy and placebo for any of the bladder more effective than either monotherapy.41,45 In spite diary variables.48 of this, MTOPS and Combination of Avodart and In another study,49 191 men with LUTS associated Tamsulosin were also the only trials with durations with BPH were treated with terazosin (2 mg dÀ1)for1 and designs to reasonably evaluate a significant week. All subjects then underwent urodynamic long-term efficacy. The SMART trial42 was designed testing and were excluded from the study if they to answer whether an a1-ARA could be removed had a post-void residual volume greater than 50 ml or from combination therapy and was only 36 weeks in a peak urinary flow rate less than 10 ml sÀ1.The duration. The PREDICT trial43 was restricted by patients who met the inclusion criteria and also had small population size and by short duration, which continued LUTS were randomized to receive either may have prevented recognition of the full efficacy terazosin alone or terazosin in combination with of the 5aRI. It has also been shown that the 5aRIs are tolterodine (2 mg twice daily).49 After 6 weeks of beneficial in preventing the progression of BPH. treatment, there was a significant reduction in Patients with larger prostate size and more severe symptoms as measured by IPSS in both the groups, symptoms appear to derive additional benefit from 4 with the combination group’s reduction significantly the combination of a1-ARAs and 5aRIs. Currently, greater than the terazosin alone group (Po0.01). The the AUA Practice Guidelines recommend combina- peak urinary flow rate was increased from baseline in tion therapy for patients with LUTS associated with both groups, but did not differ significantly between demonstrable prostatic enlargement to reduce the groups. The post-void residual volume was not risk of disease progression (Figure 1).1

Figure 1 Choosing treatment options for lower urinary tract symptoms.

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S41 The combination of a1-ARAs with antimuscarinic more beneficial than monotherapy in the prevention agents appears to be useful for relieving symptoms of progression and complications of BPH, especially of BOO and DO in a highly select group.15 Theoretic in men with larger prostate size, more severe concerns regarding the risk of AUR have been symptoms and higher prostate-specific antigen refuted in several recent clinical trials, but given levels. In addition, the combination of a1-ARAs the exclusion criteria, the application to the LUTS/ with antimuscarinic agents may also be useful in the BPH population at large may be doubtful.46–49 treatment of LUTS associated with BPH. Although Although the post-void residual urine volume trials suggest that AUR is an exceedingly rare appears to increase with the use of antimuscarinics, complication, the drugs were assessed in a highly this has not been shown to be clinically significant. select cohort of patients and the true safety of Significant reductions in IPSS scores as well as more antimuscarinics in the general population of subjective treatment benefits were demonstrated in patients with BPH is unknown. Combination ther- several trials. Men with OAB and BPH who are not apy with a1-ARAs and antimuscarinics may be receiving adequate alleviation of symptoms from the useful in patients without baseline urinary retention first-line a1-ARAs may benefit from the addition of who have symptoms that are not alleviated by an antimuscarinic agent. Before beginning therapy, a traditional therapy. Further research must be per- post-void residual volume should be measured to formed to determine the long-term benefits and risks exclude baseline urinary retention, as the clinical of combination therapy with antimuscarinics in the trials excluded men with post-void residual vo- general population of men with BPH. Recently, lumes greater than 30–40% of cystometric max- studies have brought attention to a link between imum or 50–200 ml.15 Thus, the safety in patients LUTS due to BPH and sexual function. PDE5Is may with baseline urinary retention is not known. have a place in the treatment of LUTS in the future.

Overall paradigm of LUTS and sexual Disclosure function Kristin Greco has declared no financial interests. Kevin McVary has received consulting fees from Lower urinary tract symptoms and sexual dysfunc- Pfizer and Eli Lilly as well as lecturing fees from Eli tion are highly prevalent in aging men. It is well Lilly, GSK and -aventis. Kevin McVary also established that both LUTS and ED independently received grant support from GSK and Eli Lilly. reduce QoL. Four explanations that partially overlap each other with a variable amount of supporting data have been proposed to explain the LUTS and ED relationship that has been demonstrated in References multiple studies. The four theories are (1) decreased or altered nitric oxide synthase/nitric oxide levels in 1 American Urological Association. Guideline on the Manage- ment of Benign Prostatic Hyperplasia (BPH). www.auanet.org/ the prostate and penile smooth muscle; (2) auto- guidelines/bph.cfm (updated 2006). nomic hyperactivity effects on LUTS, prostate 2 Welch G, Weinger K, Barry MJ. Quality-of-life impact of lower growth and ED; (3) increased Rho-kinase activa- urinary tract symptom severity: results from the health tion/endothelin activity; and (4) prostate and penile professionals follow-up study. Urology 2002; 59: 245–250. 20 3 Sung JC, Curtis LH, Schulman KA, Albala DM. Geographic atherosclerosis. Sexual problems related to LUTS variations in the use of medical and surgical therapies for are not limited to ED and may include decreased benign prostatic hyperplasia. J Urol 2006; 175: 1023–1027. libido and EjD as well. In addition, many currently 4 McVary KT. A review of combination therapy in patients with available treatments (medical and surgical) for one benign prostatic hyperplasia. Clin Ther 2007; 29: 387–398. disease affect the other. PDE5Is seem to exert their 5 Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human prostatic hyperplasia with age. J Urol 1984; 132: positive effect to a greater degree on detrusor 474–479. 20 activity rather than directly on the prostate. The 6 Kaplan SA, Walmsley K, Te AE. Tolterodine extended release future use of PDE5Is as prophylaxis for LUTS or attenuates lower urinary tract symptoms in men with benign as a primary treatment for LUTS or OAB is emerging prostatic hyperplasia. J Urol 2005; 174: 2273–2276. 7 McVary KT, Rademaker A, Lloyd GL, Gann P. Autonomic as a possibility, especially in patients with con- nervous system overactivity in men with lower urinary tract current ED. symptoms secondary to benign prostatic hyperplasia. J Urol 2005; 174: 1327–1433. 8 Wilt TJ, N’Dow J. Benign prostatic hyperplasia. Part 1— diagnosis. BMJ 2008; 336: 146–149. Conclusions 9 Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I. Incidence rates and risk factors for acute urinary The available data suggest that there is a place for retention: the health professionals follow-up study. J Urol 1999; 162: 376–382. combination medical therapy in the treatment of 10 Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, men with LUTS due to BPH. Evidence suggests that Guess HA et al. Natural history or prostatism; risk factors for the combination of a1-ARAs with 5aRIs may be acute urinary retention. J Urol 1997; 158: 481–487.

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S42 11 Brown CT, O’Rynn E, van der Meulen J, Newman S, with finasteride: meta-analysis of randomized clinical trials. Mundy AR, Emberton M. The fear of in men Urology 1996; 48: 398–405. with lower urinary tract symptoms: should symptomatic men 30 Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G, for be screened? BJU Int 2003; 91: 30–32. the ARIA3001, ARIA3002, and ARIA3003 Study Investigators. 12 Barry MJ, Fowler Jr FJ, O’Leary MP, Bruskewitz RC, Holtgrewe Efficacy and safety of a dual inhibitor of 5--reductase HL, Mebust WK et al. The American Urological Association types 1 and 2 (dutasteride) in men with benign prostatic symptom index for benign prostatic hyperplasia. The Mea- hyperplasia. Urology 2002; 60: 434–441. surement Committee of the American Urological Association. 31 Blake-James BT, Rashidian A, Ikeda Y, Emberton M. The role J Urol 1992; 148: 1549–1557. of anticholinergics in men with lower urinary tract symptoms 13 Lepor H. Natural history, evaluation, and nonsurgical manage- suggestive of benign prostatic hyperplasia: a systematic review ment of benign prostatic hyperplasia. In: Walsh PC, Retik AB, and meta-analysis. BJU Int 2006; 99: 85–96. Vaughan Jr ED and Wein AJ (eds). Campbell’s Urology. 32 Ruggieri MR, Braverman AS, Pontari MA. Combined use of W.B. Saunders Company: Philadelphia, PA, 1998, chapter 47 a-adrenergic and muscarinic antagonists for the treatment pp 1453–1477. of voiding dysfunction. J Urol 2005; 174: 1743–1748. 14 Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, 33 Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and Henderson WG. A comparison of transurethral surgery with tolerability of tolterodine for the treatment of overactive watchful waiting for moderate symptoms of benign prostatic bladder in men with bladder outlet obstruction. J Urol 2006; hyperplasia. The Veterans Affairs Cooperative Study Group on 175: 999–1004. Transurethral Resection of the Prostate. N Engl J Med 1995; 34 Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, for 332: 75–79. the Tolterodine Study Group. Tolterodine once-daily: superior 15 Gallegos PJ, Frazee LA. therapy for lower efficacy and tolerability in the treatment of overactive bladder. urinary tract symptoms associated with benign prostatic Urology 2001; 57: 414–421. hyperplasia. Pharmacotherapy 2008; 28: 356–365. 35 Cardozo L, Lisec M, Millard R, Van Vierssen Trip O, Kuzmin I, 16 Caine M, Raz S, Zeigler M. Adrenergic and Drogendijk TE et al. Randomized, double-blind placebo receptors in the human prostate, prostatic capsule and bladder controlled trial of the once daily antimuscarinic agent neck. Br J Urol 1975; 47: 193. solifenacin succinate in patients with overactive bladder. 17 Marshall I, Burt RP, Chapple CR. Noradrenaline contractions J Urol 2004; 172: 1919–1924. of human prostate mediated by alpha 1-A(alpha 1c-) adreno- 36 Galee BJ, Galee MA. Phosphodiesterase-5 inhibitors for lower receptor subtype. Br J Pharmacol 1995; 115: 781. urinary tract symptoms in men. Ann Pharmacother 2008; 42: 18 Tamsulosin [package insert]. Boehringer Ingelheim: Ridge- 111–115. field, Conn, 2002. 37 McVary KT, Monnig W, Camps Jr JL, Young JM, Tseng LJ, 19 Van Moorselaar RJ, Hartung R, Emberton M, Harving N, Mazkin van den Ende G. Sildenafil citrate improves erectile function H, Elhilali M et al. Alfuzosin 10 mg once daily improves sexual and urinary symptoms in men with erectile dysfunction and function in men with lower urinary tract symptoms and lower urinary tract symptoms associated with benign prostatic concomitant sexual dysfunction. BJU Int 2005; 95: 603–608. hyperplasia: a randomized, double-blind trial. J Urol 2007; 20 McVary KT. Sexual function and a-blockers. Rev Urol 2005; 7: 177: 1071–1077. S3–S11. 38 Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A 21 Elhilali MM, Ramsey EW, Barkin J, Casey RW, Boake RC, randomized placebo controlled study to assess the efficacy Beland G et al. A multicenter, randomized, double-blind, of twice daily Vardenafil in the treatment of LUTS secondary placebo-controlled study to evaluate the safety and efficacy of to BPH. Eur Urol 2008; 53: 1236–1244. terazosin in the treatment of benign prostatic hyperplasia. 39 McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Urology 1996; 47: 335–342. Wachs B, Young JM et al. Tadalafil relieves lower urinary tract 22 Roehrborn CG, Siegel RL. Safety and efficacy of doxazosin in symptoms secondary to benign prostatic hyperplasia. J Urol benign prostatic hyperplasia: a pooled analysis of three 2007; 177: 1401–1407. double-blind, placebo-controlled studies. Urology 1996; 48: 40 Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. 406–415. Tadalafil administered once a day in the treatment of men 23 Roehrborn CG, for the ALFUS Study Group. Efficacy and with LUTS secondary to BPH; a dose-finding study. J Urol safety of once-daily alfuzosin in the treatment of lower urinary 2008; 180: 1228–1234. tract symptoms and clinical benign prostatic hyperplasia: 41 McConnell JD, Roehrborn CG, Bautista OM, Andriole Jr GL, a randomized, placebo-controlled trial. Urology 2001; 58: Dixon CM, Kusek JW, et al., for the Medical Therapy of 953–959. Prostatic Symptoms (MTOPS) Research Group. The long-term 24 Lepor H, for the Tamsulosin Investigator Group. Phase III effect of doxazosin, finasteride, and combination therapy multicenter placebo-controlled study of tamsulosin in benign on the clinical progression of benign prostatic hyperplasia. prostatic hyperplasia. Urology 1998; 51: 892–900. N Engl J Med 2003; 349: 2387–2398. 25 Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, 42 Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, Walsh PC, McConnell JD et al. The effect of finasteride in men van Vierssen Trip OB et al. Alpha-blocker therapy can be with benign prostatic hyperplasia. N Engl J Med 1992; 327: withdrawn in the majority of men following initial combina- 1185–1191. tion therapy with the dual 5alpha-reductase inhibitor dutaste- 26 Marberger MJ, for the PROWESS Study Group. Long-term ride. Eur Urol 2003; 44: 461–466. effects of finasteride in patients with benign prostatic 43 Kirby RS, Roehrborn C, Boyle P, Bartsch G, Jardin A, Cary MM, hyperplasia: L a double-blind, placebo-controlled, multicenter et al., for the Prospective European Doxazosin and Combina- study. Urology 1998; 51: 677–686. tion Therapy Study Investigators. Efficacy and tolerability of 27 McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, doxazosin and finasteride, alone or in combination, in Holtgrewe HL, et al., for the Finasteride Long-Term Efficacy treatment of symptomatic benign prostatic hyperplasia: the and Safety Study Group. The effect of finasteride on the risk of Prospective European Doxazosin and Combination Therapy acute urinary retention and the need for surgical treatment (PREDICT) trial. Urology 2003; 61: 119–126. among men with benign prostatic hyperplasia. N Engl J Med 44 Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, 1998; 338: 557–563. Gormley G et al. for the Veterans Affairs Cooperative Studies 28 The Finasteride Study Group. Finasteride (MK-906) in the Benign Prostatic Hyperplasia Study Group. The efficacy of treatment of benign prostatic hyperplasia. Prostate 1993; 22: terazosin, finasteride, or both in benign prostatic hyperplasia. 291–299. NEJM 1996; 335: 533–539. 29 Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts 45 Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, outcome of treatment of benign prostatic hyperplasia Morrill B, et al., for the Combination of Avodart and

International Journal of Impotence Research The role of combination medical therapy in BPH KA Greco and KT McVary S43 Tamsulosin (CombAT) Study Group. The effects of dutaste- system formulation for overactive bladder and coexisting ride, tamsulosin and combination therapy on lower urinary benign prostatic obstruction: a prospective, randomized, tract symptoms in men with benign prostatic hyperplasia and controlled multicenter study. J Urol 2005; 174: 1334–1338. prostatic enlargement: 2-year results from the CombAT study. 48 Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, J Urol 2008; 179: 616–621. Bavendam T, Guam Z. Tolterodine and tamsulosin for 46 Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, treatment of men with lower urinary tract symptoms and Perimenis P, Barbalias G. Combination treatment with an overactive bladder: a randomized controlled trial. JAMA 2006; alpha-blocker plus an anticholinergic for bladder outlet 296: 2319–2328. obstruction: a prospective, randomized controlled trial. J Urol 49 Yang Y, Zhao XF, Li HZ, Wang W, Zhang Y, Xiao H et al. 2003; 169: 2253–2256. Efficacy and safety of combined therapy with terazosin and 47 Lee KS, Choo MS, Kim DY, Kim JC, Min KS, Lee JB et al. tolterodine for patients with lower urinary tract symptoms Combination treatment with propiverine hydrochloride plus associated with benign prostatic hyperplasia: a prospective doxazosin controlled release gastrointestinal therapeutic study. Chin Med J (Engl) 2007; 120: 370–374.

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