A Comparison of Varying a-Blockers and Other Pharmacotherapy Options for Lower Urinary Tract Symptoms

TAMSULOSIN FOR THE TREATMENT OF BPH A Comparison of Varying
-Blockers and Other Pharmacotherapy Options for Lower Urinary Tract Symptoms Christopher R. Chapple, MD Department of Urology, Royal Hallamshire Hospital, Sheffield, UK
1-Adrenoceptor antagonists are now well established as the most common treatment for lower urinary tract symptoms (LUTS) suggestive of bladder outflow obstruction associated with benign prostatic hyperplasia. Both
1adrenoceptor antagonists and 5
-reductase inhibitors are accepted treatments for LUTS, but with finasteride this applies only to patients with clinically enlarged prostates, whereas
1-adrenoceptor antagonists are considered to be appropriate treatment for all patients, irrespective of prostate size. Systematic analyses of placebo-controlled studies show that commonly used
1-blockers are significantly superior to placebo in improving urinary flow and reducing symptoms. Efficacy of
-blockers appears to be well maintained over time, and there is no evidence of tolerance or tachyphylaxis to
1-blockade after 6–12 months’ usage. Direct comparative trials show that, in the short term,
1adrenoceptor antagonists are more effective than finasteride in reducing symptom score. For
1-adrenoceptor antagonists, the most commonly reported adverse effects are dizziness, asthenia, postural hypotension, and syncope. Alfuzosin has a more pronounced effect on blood pressure than does tamsulosin, especially in elderly patients. Tamsulosin is well tolerated and has minimal effects on blood pressure; tamsulosin 0.4 mg has the lowest potential to reduce blood pressure and causes less symptomatic orthostatic hypotension than terazosin. [Rev Urol. 2005;7(suppl 4):S22–S30] © 2005 MedReviews, LLC Key words: Benign prostatic hyperplasia • Alpha-blockers • Finasteride • Alfuzosin • Tamsulosin ower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO)—previously referred to as symptomatic benign prostatic hyperplasia (BPH)—are increasingly common in the aging male. Approximately 25% of men over 40 suffer from LUTS, and the prevalence of this condition rises with age.1 Besides surgery and watchful waiting, medical therapies to treat LUTS L S22 VOL. 7 SUPPL. 4 2005 REVIEWS IN UROLOGY 
1-Adrenoceptor Antagonist Therapy for LUTS include
1-adrenoceptor antagonists, finasteride, and phytotherapy. Operative intervention is rather radical from the patient’s perspective; not surprisingly, many patients feel reluctant to undergo surgery and prefer less invasive intervention, such as medical therapy. This trend has been encouraged not only by increased patient awareness of the availability of effective contemporary pharmacotherapy, but also by an
1-Adrenoceptor antagonists are now well established as the most common treatment for LUTS suggestive of BPO, eg, bladder outflow obstruction (BOO) associated with BPH. The best available external evidence for the therapeutic decision to treat an individual patient with
1blockers and for the choice of a given drug within this class (prazosin, indoramin, doxazosin, terazosin, alfuzosin, tamsulosin) is provided by ran- Operative intervention is rather radical from the patient’s perspective. increased awareness of the complications of surgery. In particular, it can be associated with significant morbidity, such as irreversible incontinence and loss of sexual function with subsequent impairment of a patient’s quality of life. Therefore, pharmacotherapy, in particular using
1-adrenoceptor antagonists, has, not surprisingly, become the most common course of therapy for symptomatic patients. Although both
1adrenoceptor antagonists and finasteride, a 5
-reductase inhibitor, are accepted treatments for LUTS, in the case of finasteride, this applies only to patients with clinically enlarged prostates (> 40 g) whereas
1-adrenoceptor antagonists are considered to be appropriate treatment for all patients irrespective of prostate size.2 In some European countries, plant extracts are also registered for the management of LUTS. Despite this, the World Health Organization does not recommend phytotherapy as an appropriate treatment for LUTS suggestive of BPO, mainly because too little information is available from well-designed clinical trials using placebo control, adequate follow-up, and sufficient numbers of patients to define the long-term efficacy and tolerability of plant extracts.2 domized controlled trials (RCTs), an important scientific tool to determine the efficacy and tolerability of a given treatment relative to placebo or other treatment forms. However, due to strict inclusion and exclusion criteria, the patient populations in RCTs may not be fully representative of those routinely consulting the physician. Moreover, participation in a formal study puts physician and patient in a situation where they may react differently from the way they would in real life. In contrast, in real-life practice (RLP) studies cannot determine treatment efficacy or tolerability in absolute terms, because they typically do not include a control group and are purely observational. On the other hand, they tend ence finally to an ongoing study designed to document the use of
antagonists in real-life practice. Randomized Controlled Trials with
1-Blockers for Lower Urinary Tract Symptoms RCTs evaluate the treatment benefit for LUTS in several ways: improvement of subjective symptoms, (quality of life) and improvement of objective function (flow rate, postvoid residual volume, urodynamics). Taking a longer-term perspective using a pragmatic noninterventional design, issues such as reduction of acute urinary retention rate, other BPH-related morbidity, and the avoidance of surgical intervention can be addressed.3 Placebo-controlled trials are important to identify which part of the overall changes under treatment (“response") is actually attributable to active medication. They differentiate between medication-related and medication-independent changes of the study criteria over time (natural course of disease, improvement by intensified medical care resulting from participation in the trial, etc). Comparison of
1-Blockers to Placebo The placebo response in LUTS is notoriously high: the Agency for Health Care Policy and Research (AHCPR) report estimated a mean
1-Adrenoceptor antagonists are considered to be appropriate treatment for all patients. to be more representative of real treatment outcomes. Thus RCTs have high internal but less external validity, whereas RLP studies have less internal and greater external validity. The present review discusses what we have learned from the many RCTs published in recent years, with refer- probability of symptomatic improvement in open prostatectomy: 98%, transurethral resection of the prostate (TURP): 88%, transurethral incision of the prostate (TUIP): 80%, balloon dilatation: 57%, finasteride: 67%,
1-blockade: 74%, watchful waiting: 42%, and placebo: 45%.4 VOL. 7 SUPPL. 4 2005 REVIEWS IN UROLOGY S23 
1-Adrenoceptor Antagonist Therapy for LUTS continued Systematic analyses of placebocontrolled studies show that commonly used
1-blockers (doxazosin, terazosin, alfuzosin, tamsulosin) are statistically significantly superior to placebo in improving urinary flow and reducing symptoms.5 Active treatment is superior to placebo in terms of improving total symptom scores by about 30%–45%, with an additional benefit of 10%–20% above placebo. Similarly, the overall improvement in flow (Qmax) by 15%–30% is about 10 to 15 times greater than with placebo. Symptom Improvement With
1-Blockers Although usually primarily evaluated in terms of total symptom score, symptomatic improvement can be shown to affect the specific components of filling (irritative) and voiding (obstructive) symptoms. As with other therapies, most would agree that the efficacy of
1-blockade is more pronounced in those patients with more pronounced baseline symptomatology,6 but the subject of the influence of baseline age on efficacy continues to be debated in the literature. On the other hand, it should be emphasized that not all patients Table 1 Symptom Score Reduction From Baseline to Endpoint Study Placebo
1-Antagonist Finasteride Combination VA-COOPa -2.6 -6.1*** -3.2 -6.2*** ALFINb -- -6.3** -5.2 -6.1* -5.7 -8.3* -6.6 -8.5* -4.9 -6.6*** -5.6*** -7.4*** PREDICT MTOPSd c a Mean reduction in AUA symptom score at 52 weeks for placebo, tamsulosin, finasteride, tamsulosin + finasteride b Mean reduction in IPSS score at 6 months for alfuzosin, finasteride, or alfuzosin + finasteride; P values versus finasteride (no placebo group included) c Mean reduction in IPSS score at 52 weeks for placebo, doxazosin, finasteride, or doxazosin + finasteride d Mean reduction in AUA score at 4.5 years for placebo, doxazosin, finasteride, or doxazosin + finasteride *P ≤ .05, **P ≤ .01, ***P ≤ .001 versus placebo, except as noted (ALFIN) and 81% (placebo: 59%) in longerterm studies.11 In contrast, Qmaxresponder rates (≥ 30% increase) are notoriously lower in comparison: for instance, 32% (placebo: 20%)8 and 31% (placebo: 21%).10 The efficacy of
-blockers appears to be well maintained over time, and there is no evidence of tolerance or tachyphylaxis to
1 blockade after 6–12 months’ usage.3 This has been Active treatment is superior to placebo in terms of improving total symptom scores. respond adequately to
1-blockade; responder rates depend on the criteria used to define response and the eligibility criteria of the study sample (including baseline values). For example, with tamsulosin, single doses of 0.4 mg were reported to yield responder rates of 67% (placebo: 44%),7 66% (placebo: 49%),8 55% (placebo: 40%),9 and 70% (placebo: 51%)10 in terms of symptom improvement (≥ 25%) in shorter-term studies S24 VOL. 7 SUPPL. 4 2005 confirmed in open-label extension studies of placebo-controlled RCTs, which confirm maintained efficacy during longer-term use. The durability of tamsulosin, for example, has been maintained up to 6 years. Comparison of
1-Blockers to Finasteride There have been four direct comparative trials between an
1-adrenoceptor antagonist, finasteride, and their REVIEWS IN UROLOGY combination. The VA Cooperative study included 1229 patients randomized to placebo, finasteride, terazosin, or a combination of both drugs for 1 year,11 whereas in the ALFIN study, 1051 patients were randomized to finasteride, alfuzosin sustained release, or a combination for 6 months.12 The Prospective European Doxazosin and Combination Therapy (PREDICT) study randomized 1089 patients to placebo, finasteride, doxazosin, or a combination for 1 year.13 The Medical Therapy of Prostatic Symptoms Study (MTOPS) compared the effects of finasteride, doxazosin, and the combination of these two agents versus placebo in 3047 men who were followed for 4.5 years.14 Key results from VA-COOP, ALFIN, PREDICT15,16 and MTOPS are summarized in Table 1. The results show that
1-adrenoceptor antagonists are more effective than finasteride in reducing the symptom score. A retrospective pooled analysis of several placebo-controlled studies 
1-Adrenoceptor Antagonist Therapy for LUTS previously found that finasteride was more effective than placebo in patients with a large prostate volume (> 40 mL).17 However, retrospective analysis of the VA Cooperative study showed that finasteride was no more effective than placebo even in patients with a prostate volume over 40 mL.17 In those patients, finasteride improved Qmax significantly, but no difference was observed in relief of symptoms. Data from the PREDICT study also suggest that finasteride was no more efficacious than placebo when adjusting data for prostate size using surrogate measures such as prostate-specific antigen and digital rectal examination.13 This supports the use of
1-adrenoceptor antagonists as first-line agents in the medical treatment of LUTS. Furthermore, one of the main advantages of
1blockers is that their onset of action is prompt (within the first days of treatment) and the appropriateness of the chosen treatment option can be evaluated without delay, avoiding costly and ineffective long-term treatment, which can occur with finasteride.
1-Blockers as Antihypertensives It has been suggested for a number of years that in patients with a combination of both BPH and hypertension, nonselective adrenoceptor subtype agents would be advantageous because both diseases could be treated with one drug. Although placebo-controlled studies do not indicate differences among the various
1-blockers in terms of efficacy, they do suggest likely differences in terms of tolerability and ancillary cardiovascular effects. For
1-adrenoceptor antagonists, the most commonly reported adverse events are dizziness, asthenia, postural hypotension, and syncope. Doxazosin and terazosin have significant antihypertensive efficacy (vs placebo) and both have been shown to reduce elevated blood pressure more than placebo in hypertensive LUTS patients. In normotensive LUTS patients, their blood pressure–reducing effects are comparably smaller and usually reported as unlikely to be of clinical relevance. In contrast, with tamsulosin, the effects on blood pressure in both hypertensives and normotensives with LUTS are consistently not significantly different from placebo.18 For alfuzosin, the profile is less conclusive: it was initially devel- an extra incidence of about 5% or less with alfuzosin and tamsulosin; the incidence of orthostatic hypotension in the RCTs with alfuzosin and tamsulosin was at placebo level (about 1%), whereas it was larger (2%–8%) under treatment with terazosin or doxazosin. In addition, discontinuation rates (due to adverse events) under treatment with terazosin or doxazosin were higher than in the placebo-control groups, whereas they were about the same as This study has raised a number of questions that cannot be answered at an interim analysis stage. oped as an antihypertensive19 and has been shown to reduce elevated blood pressure in hypertensives; on the other hand, alfuzosin is generally reported to have little effect on blood pressure in LUTS patients compared to placebo. This distinction in terms of associated antihypertensive properties is relevant: antihypertensive
1-blockers are generally not well tolerated and their capacity to reduce pathological blood pressure elevation is likely to result in an impairment of physiological blood pressure control (“homeostasis") in normotensives, resulting in orthostatic hypotension, dizziness, light-headedness, asthenia, etc.20 Comparison of placebo-controlled RCTs endorses this: adverse events likely to relate to their cardiovascular properties were reported more frequently for antihypertensive
1-blockers (such as doxazosin and terazosin) than with placebo. Furthermore, in normotensive patients, meta-analyses of placebocontrolled RCTs indicate an extra 5%–20% incidence of dizziness under treatment with terazosin or doxazosin (in addition to the 3%–10% seen with placebo)21 versus with placebo in the groups treated with alfuzosin and tamsulosin. The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a large, randomized, double-blind study comparing the four antihypertensive drugs chlorthalidone, doxazosin, amlodipine and lisinopril, with a total of 42,448 recruited patients. The patients were men and women aged 55 years and older with hypertension plus an additional risk factor for coronary heart disease. At a median follow-up of 3.3 years in 9067 patients, the doxazosin limb of the study was discontinued because, compared with the chlorthalidone group, there was a 25% higher incidence of significant cardiovascular disease and twice the incidence of congestive heart failure.22 Inevitably this study has raised a number of questions that cannot be answered at an interim analysis stage. Although
1-adrenoceptor antagonists remain the best-validated first-line treatment for BPH, associated hypertension and cardiovascular diseases should be treated independently according to established guidelines. It is reassuring that selective
1-blockers VOL. 7 SUPPL. 4 2005 REVIEWS IN UROLOGY S25 
1-Adrenoceptor Antagonist Therapy for LUTS continued without antihypertensive effects, such as tamsulosin, can be combined safely and efficaciously with suitable first-line antihypertensives.18
1-Blockers and Ejaculation Disorders Disorders of ejaculation have been emphasized in this therapeutic area in recent years, as they are a common complication of the treatment of LUTS. The AHCPR report estimated a mean probability for retrograde ejaculation of 77.2%, 73.4%, 24.9%, and 6.2% for open prostatectomy, TURP, TUIP, and
1-blockade, respectively.23
1-Blockade in general carries a risk of causing retrograde ejaculation as a consequence of its pharmacological properties at the bladder neck and in prostatic smooth muscle and the vas deferens. There is controversy about whether untoward effects on ejaculation are more frequent with tamsulosin. Indeed, tamsulosin has been found to be associated with an increased incidence of readily reversible retrograde ejaculation (“dry ejaculation" and/or cloudy urine on postcoital voiding); in both placebo-controlled RCTs and open extension follow-up studies,24 incidence of retrograde or delayed ejaculation was 4.5%–10% for 0.4 mg tamsulosin versus 0%–1% for placebo. In studies with alfuzosin (either placebo-controlled or vs finasteride and terazosin), lower incidences were reported. However, a direct-comparative RCT between alfuzosin and tamsulosin showed no difference between the two drugs; they were associated with a comparable and only small increase in retrograde ejaculation.25 In addition, abnormal ejaculation was not perceived as a major problem in the placebo-controlled RCTs with tamsulosin because it resulted in very few treatment discontinuations. S26 VOL. 7 SUPPL. 4 2005 Modified-Release Formulations Recently, modified-release formulations have been introduced with the intent to permit less frequent, ie, more convenient, dosing (alfuzosin– slow-release) or to improve overall tolerability (doxazosin). These modified-release formulations achieve a smoother time course of the plasma concentrations. The extent of bioavailability (AUC) of 5 mg and 10 mg modified-release formulations of alfuzosin was shown to be similar compared to the immediate-release 2.5 mg tablets.26 However, there still are distinct pharmacokinetic differ- comparison is needed to test such hypotheses. Such comparisons are often carried out without a simultaneous placebo-control, for instance to evaluate equivalence or superiority versus an already established reference treatment; this is a pitfall in some trials with short treatment courses or finasteride as active control. It should be remembered that parallel-group comparisons of different dose-levels may be confounded by dose-independent group effects. This is demonstrated in the dose-finding studies with tamsulosin: a dose of 0.4 mg administered once daily in the morn- These modified-release formulations achieve a smoother time course of the plasma concentrations. ences, as shown by smoother peakto-trough fluctuations and the lower peak concentrations, that might have therapeutic consequences. For the 10 mg modified-release formulation (administered once daily), a placebo-controlled direct comparison with 2.5 mg t.i.d. has indeed been reported;27 for the 5 mg modifiedrelease formulation (administered twice daily), comparisons to placebo and finasteride but no direct comparisons with the 2.5 mg t.i.d. regimen have been published. With the doxazosin Gastro-Intestinal Therapeutic System (GITS), which has a bioavailability loss of about 40% versus the standard formulation,28 comparative studies between GITS and the standard formulation were published for hypertension but not for LUTS. Optimal Dosing The adequate comparison of data across different studies is difficult when evaluating both tolerability (differences in identifying and recording untoward events, adverse reactions, etc) and efficacy; direct REVIEWS IN UROLOGY ing after breakfast is well established as the optimal dose level; there is little benefit in terms of increased efficacy obtained by increasing the dose above this level, and adverse events are more frequent at higher doses.10 A small but distinct difference is seen between the doses of 0.4 and 0.8 mg in terms of efficacy after 12 weeks in these studies; this has been cited as proof that the dose level of 0.4 mg might be inappropriately low. Although tempting, this interpretation of the observed difference is erroneous, because it was related mainly to a dose-independent group effect: indeed, most of this difference between the groups was already present at the end of the first week of investigational treatment when both dose groups were still receiving the same dose of 0.4 mg. For all direct comparisons, the selection of the dose is of critical importance: too low a dose might result in a better safety profile but could impair efficacy. Therefore arguments of differential tolerability, ie, clinical selectivity, should be 
1-Adrenoceptor Antagonist Therapy for LUTS based on doses that yield comparable efficacy. A single daily dose of tamsulosin 0.4 mg is the optimal dose level in terms of both efficacy and tolerability. However, these are “average" findings; some patients might benefit from lower doses, others might take further benefit from higher doses without an undue increase in adverse events. Asian patients are most appropriately treated with lower doses of tamsulosin, 0.2 mg rather than 0.4 mg once daily.29 In a Korean study, a fixed dose of 0.2 mg tamsulosin (n = 39) was compared with step-up dosing with 1–5 mg terazosin (n = 33) in a direct, single-blind, parallel-group comparison, with endpoint evaluations after 4 and 8 weeks of treatment. At the endpoint evaluation, 51% and 45% of the patients treated with tamsulosin and terazosin were considered Qmax responders (> 20% improvement) and 74% and 79% were considered International Prostate Symptom Score (IPSS) responders (> 20% decrease); 72% and 67% of the patients were considered by the investigator to have at least moderately improved symptoms with tamsulosin and terazosin, respectively. Although there was no significant difference between endpoint and pretreatment baselines in terms of recumbent and standing blood pressure with tamsulosin, there was a statistically significant and clinically relevant hypotensive effect (relative to baseline) in those normotensive patients with LUTS under treatment with terazosin. Adverse reactions were most frequently dry mouth and dizziness, which, although they were usually mild and transient, were significantly higher in patients on terazosin (18 patients vs 1 on tamsulosin). The changes led to premature discontinuation of two patients on treatment with terazosin.30 Similarly, in Chinese patients, once-daily fixed doses of 0.2 mg tamsulosin (n = 105) and 2 mg terazosin (n = 107) were studied in a direct, single-blind, parallel-group comparison with endpoint evaluations after 4 weeks. The improvements in symptoms (IPSS, tamsulosin: from 21.5 ± 4.7 to 11.8 ± 4.5; terazosin: 21.8 ± 5.6 to 13.3 ± 5.3) and Qmax (tamsulosin: from 9.6 ± 2.8 to 13.2 ± 4.1; terazosin: 10.4 ± 2.6 to 13.6 ± 3.6 mL/sec) were comparable, but there were distinct differences in terms of cardiovascular effects and safety. Indeed, relative to baseline group all were related to hypotension versus only one quarter of the adverse events seen in the alfuzosin group. Alfuzosin (2.5 mg b.i.d. increased to 2.5 mg t.i.d) was also compared directly with tamsulosin (fixed dose of 0.4 mg o.d.) in 256 patients with LUTS treated for 12 weeks according to a double-blind, double-dummy, parallel-group design. Both treatments were equally effective, with responder rates of 34% and 35%, respectively, for alfuzosin and tamsulosin in terms of Qmax (≥ 30% Parallel-group comparisons of different dose-levels may be confounded by dose-independent group effects. there was an average reduction of systolic/diastolic blood pressure of 22/14.7 mm Hg with terazosin versus only 3.8/2.1 mm Hg with tamsulosin. There were 13 and 50 adverse events, respectively, for which a causal relationship to the medication could not be excluded for the treatment with tamsulosin and terazosin; this related mainly to cardiovascular effects: dizziness (tamsulosin: 10; terazosin: 34), headache (tamsulosin: 0; terazosin: 3), palpitation (tamsulosin: 0; terazosin: 2), and severe hypotension requiring the subject’s premature discontinuation (tamsulosin: 1; terazosin: 10).31 In Europe, there is no reason to consider lower doses than those recommended on the basis of extensive regulatory review. Unfortunately there are few studies with a direct larger-scale comparison between the various
1-blockers. One older study compared alfuzosin (2.5 mg t.i.d) with prazosin (2 mg b.i.d) for 3 weeks in a double-blind, randomized, parallel-group fashion. Both treatments had comparable efficacy and were well tolerated. Only eight adverse events were reported: in the prazosin increase) and responder rates of 69% and 68%, respectively, in terms of the Boyarsky symptom score (≥ 25% improvement). Both treatments were well tolerated; alfuzosin had a small but statistically significantly larger effect on recumbent and standing blood pressure in comparison to tamsulosin.32 A double-blind, randomized study compared the potential of tamsulosin and terazosin to induce orthostatic hypotension during earlymorning and nocturnal orthostatic stress testing in 50 normotensive elderly subjects (more than 50% had LUTS).33 Tamsulosin and terazosin were administered for 15 days according to their recommended dosage regimens in daily practice: tamsulosin 0.4 mg once daily after breakfast without dose titration; terazosin dose-titrated from 1 to 5 mg once daily in the evening. The results showed that tamsulosin caused significantly less symptomatic orthostatic hypotension (4% of patients) than terazosin (36% of patients; P = .011). One patient with symptomatic orthostatic hypotension on tamsulosin had prestudy VOL. 7 SUPPL. 4 2005 REVIEWS IN UROLOGY S27 
1-Adrenoceptor Antagonist Therapy for LUTS continued vertigo, which was an exclusion criterion for the study. A subgroup analysis of younger (< 65 years) and older (≥ 65 years) patients enrolled in two European phase III placebo-controlled trials34 revealed that tamsulosin 0.4 mg once daily had comparable effects on blood pressure and was as well tolerated in both younger and older patients, compared with placebo.35 In three clinical interaction studies, tamsulosin was added to hypertensive patients controlled with the -blocker atenolol, the angio- (France, Germany, Italy, the Netherlands, Poland, Spain, and the UK) and Australia and how this condition progresses over time in relation to initial treatment choice. The clinical data will be retrieved from continuous analysis of large computer-based patient files such as the General Practice Research Database (GPRD) in the UK and the Integrated Primary Care Information (IPCI) database in the Netherlands. Results from the GPRD in the UK, including almost 80,000 new patients with LUTS/BPH followed between 7. 8. 9. 10. In Europe, there is no reason to consider lower doses than those recommended on the basis of extensive regulatory review. 11. tensin-converting enzyme inhibitor enalapril, or the calcium channel blocker nifedipine. The results confirmed that tamsulosin has no clinically significant additional effects on blood pressure nor increased potential for orthostatic hypotension in hypertensive patients treated with antihypertensive medication.36 1992 and 1999, show that prostatectomy rates have fallen and continue to fall, with a continuing increase in the use of medical treatments. Medical treatments are also used earlier and delay surgery compared with no treatment. Postponing surgery and low failure rates are most likely with finasteride, alfuzosin, and tamsulosin. The TRIUMPH Project References LUTS due to BPH are likely to become an increasing burden for future health care budgets due to the high prevalence of this condition in the elderly and the aging population. Data on the cost-effectiveness of the available treatment options based on real-life practice will therefore be crucial. This information is currently largely lacking. The European Association of Urology has therefore endorsed the development of the TRIUMPH (Trans-European Research into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare) project.37 This project will evaluate how LUTS/BPH are currently managed in real-life practice in 6 European countries S28 VOL. 7 SUPPL. 4 2005 1. 2. 3. 4. 5. 6. REVIEWS IN UROLOGY Chute CG, Pander LA, Girman CJ, et al. The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol. 1993; 150:85–89. Denis L, McConnell J, Yoshida O, et al. Recommendations of the International Scientific Committee: the evaluation and treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction. In: Denis L, Griffiths K, Khoury S, et al, eds. Proceedings of the 4th International Consultation on BPH. Plymouth, UK: Plymbridge Distributors Ltd; 1998:523–528. Donovan JL. The measurement of symptoms, quality of life and sexual function. BJU Int. 2000;85 (suppl. 1): 10–19. Agency for Health Care Policy and Research. Benign prostatic hyperplasia: diagnosis and treatment. J Am Geriatr Soc. 1998;46:1163–1165. Chapple CR. Pharmacotherapy for benign prostatic hyperplasia—the potential for alpha1adrenoceptor subtype-specific blockade. Br J Urol. 1998;81(suppl 1):34–47. Roehrborn CG, Siegel RL. Safety and efficacy of doxazosin in benign prostatic hyperplasia: a 12. 13. 14. 15. 16. 17. 18. 19. pooled analysis of three double-blind, placebocontrolled studies. Urology. 1996;48:406–415. Abrams P, Schulmann CC, Vaage S, the European Tamsulosin Study Group: Tamsulosin, a selective alpha1c-adrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic obstruction (symptomatic BPH). Br J Urol. 1995;76:325–336. Chapple CR, Wyndaele JJ, Nording J, et al. Tamsulosin, the first prostate-selective
1Aadrenoceptor antagonist: a meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). Eur Urol. 1996;29:155–167. Narayan P, Tewari A, members of the United States 93-01 Study Group. A second phase III multicenter placebo controlled study of 2 dosages of modified release tamsulosin in patients with symptoms of benign prostatic hyperplasia. J Urol. 1998;160:1701–1706. Lepor H, for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology. 1998;51:892–902. Lepor H, for the Tamsulosin Investigator Group. Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Urology. 1998;51:901–906. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med. 1996: 335(8):533–539. Debruyne FMJ, Jardin A, Colloi D, et al, on behalf of the European ALFIN Study Group. Sustainedrelease alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol. 1998;34:169–175. 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. Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003;61:119-126. Kirby R, Jens EA, Bartsch G, et al, for the PREDICT Investigators. Results of the PREDICT (prospective European doxazosin and combination therapy) trial. J Urol. 1999;16(suppl 4):266. Abstract 1027. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: metaanalysis of randomized clinical trials. Urology. 1996;48:398–405. Tewari A, Narayan P. Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. Urology. 1999;53(3 suppl 3a): 14–20. Reid JL, Vincent J. Clinical pharmacology and therapeutic role of prazosin and related alpha- 
1-Adrenoceptor Antagonist Therapy for LUTS 20. 21. 22. 23. 24. 25. 26. adrenoceptor antagonists. Cardiology. 1986; 73:164–174. de Mey C. Alpha1-blockers for BPH: are there differences? Eur Urol. 1999;36(suppl 3):52–63. McKiernan JM, Lowe FC. Side effects of terazosin in the treatment of symptomatic benign prostatic hyperplasia. South Med J. 1997;90:509–513. ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA. 2000;283:1967–1975. Roehrborn CG. The Agency for Health Care Policy and Research. Clinical guidelines for the diagnosis and treatment of benign prostatic hyperplasia. Urol Clin North Am. 1995; 22:445–453. Schulman CC, Cortvriend J, Jonas U, et al. Tamsulosin: 3-year long-term efficacy and safety in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction: analysis of a European, multinational, multicenter, open-label study. Eur Urol. 1999;36:609–620. Hofner K, Claes H, De Reijke TM, et al. Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36:335–341. Rauch-Desanti C, Fraisse J, Dubruc C, et al. Pharmacokinetic and metabolic profiles of alfuzosin. In: Debruyne FMJ, Jardin A, Roehrborn CG, Langer SZ, eds. Benign Prostatic 27. 28. 29. 30. 31. Hyperplasia—The Place of Alfuzosin (From Basic Pharmacology to Clinical Practice). Tatenhall, UK: Adis Press; 1998:63–73. van Kerrebroeck P, Jardin A, Laval KU, van Cangh P, and the ALFORTI Study Group. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. Eur Urol. 2000;37:306–313. Chung M, Vashi V, Puente J, et al. Clinical pharmacokinetics of doxazosin in a controlledrelease gastrointestinal therapeutic system (GITS) formulation. Br J Clin Pharmacol. 1999;48:678–687. Okada H, Kamidono S, Yoshioka T, et al. A comparative study of terazosin and tamsulosin for symptomatic benign prostatic hyperplasia in Japanese patients. BJU Int. 2000;85: 676–681. Lee E, Lee C. Clinical comparison of selective and non-selective alpha 1A-adrenoreceptor antagonists in benign prostatic hyperplasia: studies on tamsulosin in a fixed dose and terazosin in increasing doses. Br J Urol. 1997; 80:606–611. Na YJ, Guo YL, Gu FL. Clinical comparison of selective and non-selective alpha 1A-adrenoceptor antagonists for bladder outlet obstruction associated with benign prostatic hyperplasia: studies on tamsulosin and terazosin in Chinese patients. The Chinese Tamsulosin Study Group. J Med. 1998;29:289–304. 32. 33. 34. 35. 36. 37. Buzelin JM, Fonteyne E, Kontturi M, et al. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). The European Tamsulosin Study Group. Br J Urol. 1997;80:597–605. Erratum Br J Urol. 1998;81:510. 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. Chapple CR, Baert L, Thind P, et al, on behalf of the European Tamsulosin Study Group: Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of benign prostatic obstruction (symptomatic BPH). Eur Urol. 1997;32:462–470. Michel MC, Mehlburger L, Bressel H-U, et al. Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does co-morbidity alter tolerability? J Urol. 1998;160:784–791. Lowe FC. Coadministration of tamsulosin and three antihypertensive agents in patients with benign prostatic hyperplasia: pharmacodynamic effect. Clin Ther. 1997;19:730–742. Chapple CR, on behalf of the Pan-European Expert Panel. Lower urinary tract symptoms suggestive of benign prostatic obstruction— Triumph: design and implementation. Eur Urol. 2001;39(suppl.3):31–36. Main Points • The efficacy of
1-blockers in relieving symptoms, improving quality of life and augmenting urinary flow in patients with lower urinary tract symptoms is clear from currently reported studies. • Improvement involves both filling (irritative) and voiding (obstructive) symptoms, occurs promptly, is well maintained over time, and is independent of prostate size and baseline prostate-specific antigen. • There is no evidence of relevant differences between the different
1-blockers in terms of efficacy, and all
1-blockers can be accepted as appropriately efficacious at the presently recommended doses. • All
1-adrenoceptor antagonists have similar efficacy in the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction, but they differ in their potential to lower blood pressure and induce related adverse events such as symptomatic orthostatic hypotension. • Most
1-adrenoceptor antagonists affect blood pressure by design; sustained release alfuzosin and tamsulosin have the lowest propensity to cause side effects. • Tamsulosin is easy to use as it does not require dose titration and can be taken once a day. • Alfuzosin has a more pronounced effect on blood pressure than does tamsulosin, especially in elderly patients, and it is more often discontinued because of adverse vasodilatory events in patients over 75 years with lower urinary tract symptoms, who are receiving therapy for concomitant cardiovascular disease(s). • In elderly patients and the majority of patients with cardiovascular comorbidity or comedication, tamsulosin is well tolerated and has minimal effects on blood pressure; tamsulosin 0.4 mg has the lowest potential to reduce blood pressure and causes less symptomatic orthostatic hypotension than terazosin. VOL. 7 SUPPL. 4 2005 REVIEWS IN UROLOGY S29 
1-Adrenoceptor Antagonist Therapy for LUTS continued Editor’s Summary of Meeting Presentation Dr. Lepor opened the discussion stating that all
-blockers appear very similar in terms of efficacy as measured by symptom scores and flow rates, whereas there are differences regarding the adverse event (AE) profiles. The development of slow release formulation of alfuzosin and doxazosin both administered now without dose titration as a once-aday formulation, in fact, may suggest that the formulation of the drug and pharmacokinetics play a more significant role in terms of safety profiles than the chemical compounds themselves. This provocative assumption would imply that selectivity to the
1A receptor versus the (vascular)
1B receptor may be less important than the way in which the drug is administered. Dr. Lowe agreed with the basic statement and suggested tolerability of the older, titratable
-blockers might even be better when taken postprandial without dose titration. Although it is unlikely that such a trial will be carried out using the traditionally titratable
-blockers, it is clear that the future and the market place belong to the once-a-day and the slow release formulations, which do not require titration. Dr. Lepor suggested that the ideal S30 VOL. 7 SUPPL. 4 2005 tamsulosin formulation might be a slow release 0.8 mg tablet that could be taken without the need of titration and satisfy the need and desire for optimized efficacy. This remark was triggered by a brief discussion of the most commonly used tamsulosin dosage. According to market information, no more than 20% of prescribing physicians offer their patients tamsulosin 0.8 mg in the form of 0.4 mg b.i.d. One reason clearly is the doubling of the cost associated with such regimen, as Dr. Lepor pointed out. The absence of well-designed and -executed direct comparator trials was noted by the panel, as all trials comparing two or more
-blockers with each other suffer from small patient numbers, inappropriate dosing schemes, poor randomization or blinding, and all are very short in duration. To truly compare both efficacy and (more importantly) safety of different
blockers, appropriately powered direct comparator trials are needed to assure that all patients are enrolled under the same inclusion and exclusion criteria, follow the same trial design, and have the same intensity of follow-up. The justification for such a trial becomes more urgent when different drugs for the same indication have seemingly similar efficacy but different REVIEWS IN UROLOGY AE profiles, which may be real or just the result of different trial design and follow-up. The last discussion topic was brought up by Dr. Lepor, regarding the various “superselective"
1A receptor blockers and their failure in early clinical studies. Such drugs were developed by Roche Pharmaceuticals, Merck Sharp and Dohme, as well as Abbott Laboratories. The Roche compound apparently induced improvements in flow rate—consistent with the
1A-blockade—but had no impact on symptoms. This dataset was never published, but suggest that other mechanisms than smooth muscle relaxation via
1A receptors must be involved in symptom improvement. The Abbott drug, fiduxosin, had both
1A and
1D activity, but liver toxicity prevented its clinical development. Finally, the Merck Sharp and Dohme compound was found inferior or at least not superior to tamsulosin in a direct comparator trial, despite a 1000-fold increase in selectivity, also suggesting that increased selectivity does not necessarily increase efficacy in terms of symptoms or flow rate. The desire to publish such negative trials was expressed by the entire faculty, as the knowledge gained would greatly increase our understanding of the mechanisms of action of
-blockers overall.