The Evolution of Alpha-Blockers for the Treatment of Benign Prostatic Hyperplasia
Advances in Alpha-Blocker Therapy in the Management of Urological Disorders
RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S3 ALPHA-BLOCKER THERAPY FOR UROLOGICAL DISORDERS The Evolution of Alpha-Blockers for the Treatment of Benign Prostatic Hyperplasia Herbert Lepor, MD Department of Urology, New York University School of Medicine, New York, NY Alpha-blockers have been evaluated for the treatment of benign prostatic hyperplasia (BPH) for 30 years, from early trials with the nonselective -inhibitor phenoxybenzamine to short-acting (prazosin) then long-acting (terazosin, doxazosin, tamsulosin, alfuzosin) selective 1-antagonists. All of the -blockers evaluated have demonstrated comparable effectiveness, and the evolution of -blocker therapy for BPH has therefore focused primarily on improving convenience and tolerability. Although all of the long-acting 1-blockers are well tolerated, only tamsulosin and alfuzosin SR are administered without the requirement for dose titration. Alfuzosin has the additional advantage over tamsulosin of a lower incidence of ejaculatory dysfunction. Studies of subtype-selective 1-antagonists have not demonstrated superior efficacy or improved tolerability over the existing long-acting 1-blockers. [Rev Urol. 2006;8(suppl 4):S3-S9] © 2006 MedReviews, LLC Key words: Benign prostatic hyperplasia • Selective alpha-blockers • Lower urinary tract symptoms enign prostatic hyperplasia (BPH) describes the benign growth of the prostate resulting from proliferation of both stromal and epithelial elements of the prostate.1 The relative degree of stromal and epithelial hyperplasia is highly variable. Overall, the hyperplastic volume is composed of approximately 80% stromal and 20% epithelial elements.2 Half of the stromal hyperplasia is composed of smooth muscle elements.3 For decades, it was assumed that the enlarged B VOL. 8 SUPPL. 4 2006 REVIEWS IN UROLOGY S3 RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S4 The Evolution of Alpha-Blockers for BPH continued hyperplastic prostate caused bladder outlet obstruction by both dynamic and static mechanisms.4 The dynamic obstruction was the result of smooth muscle hyperplasia causing a functional obstruction, and the static obstruction was attributed to an anatomic obstruction simply from the bulk enlargement of the hyperplastic process encroaching upon the prostatic urethra. Marco Caine and colleagues demonstrated in 1975 that strips of human prostate contracted in response to norepinephrine.5 The norepinephrine-induced contractions were inhibited by pretreatment with phenoxybenzamine, a nonselective inhibitor of -adrenoceptors. These studies implicated the -adrenoceptor as the mediator of prostate smooth muscle contraction. Lepor and associates were the first investigators to characterize both 1- and 2-adrenoceptors in the human prostate using radioligand binding studies.6,7 An abundance of both 1- and 2-adrenoceptors was identified. Functional studies suggested that it was the 1-adrenoceptor subtype that mediated prostate muscle contraction.8 Rationale for Developing Alpha-1 Selective Blockers for BPH Three subtypes of the 1-adrenoceptor (1a, 1b, and 1d) have been cloned and pharmacologically characterized. Lepor and associates demonstrated that 1a is the predominant 1-adrenoceptor subtype in the human prostate.9 Subsequent studies by Lepor and associates using both autoradiography10 and immunohistochemistry11 localized the 1a subtype to the prostatic stroma. Functional studies demonstrated that the 1a subtype mediates human prostate contraction.12 If one assumes that the efficacy of -blockers is mediated by prostate S4 VOL. 8 SUPPL. 4 2006 smooth muscle relaxation, then there is a compelling reason to develop 1a subtype–selective inhibitors for the treatment of BPH. Presumably, some of the adverse events associated with nonselective 1 blockade are mediated by the 1band 1d-adrenoceptor subtypes. These adverse events would be minimized or eliminated by an 1a subtype–selective antagonist. There is now abundant evidence that 1blockers relieve lower urinary tract symptoms (LUTS) through mechanisms unrelated to prostate smooth muscle relaxation.13 Therefore, it is conceivable that an 1a subtype– selective antagonist would retain its modest impact on relieving bladder outlet obstruction and failing to relieve LUTS if the therapeutic effect on LUTS is mediated by the 1b or 1d subtype. Development of Alpha-Blockers for the Treatment of BPH Nonselective Alpha-Blockers In 1976, phenoxybenzamine was the first -blocker reported to be effective for the treatment of BPH.14 Two years later, the therapeutic benefit of phenoxybenzamine was confirmed by a randomized placebo-controlled study.15 Marco Caine and associates are to be commended for recognizing the importance of conducting randomized clinical trials in order to demonstrate a treatment-related effect in BPH. Validated symptom indices for quantifying changes in LUTS had not been developed at the time Caine and colleagues reported this early study. Phenoxybenzamine was found to be superior to placebo at relieving LUTS and increasing peak flow rate. The primary limitation of phenoxybenzamine was its side effect profile, which includes tiredness, dizziness, impaired ejaculation, nasal stuffiness, and hypotension. REVIEWS IN UROLOGY Short-Acting Selective Alpha-1-Blockers Prazosin was the first selective 1antagonist investigated for BPH. Several small randomized placebocontrolled trials suggested that prazosin exhibits comparable efficacy and better tolerability relative to phenoxybenzamine.16,17 However, prazosin requires multiple daily dosing, and adverse events related to its blood pressure–lowering effect are problematic. Larger multicenter randomized clinical trials were never performed with prazosin, presumably owing to the availability of generic prazosin and the general notion at the time that medical therapy would not be widely accepted by urologists for the treatment of BPH. Long-Acting Selective Alpha-1-Blockers Four long-acting 1-blockers have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic BPH: terazosin, doxazosin, tamsulosin, and alfuzosin SR (sustained release). It is imperative when comparing different 1-blockers to recognize that both efficacy and tolerability are dose dependent, and observed differences in both efficacy and toxicity may simply be due to different degrees of 1 blockade achieved and not inherent advantages or disadvantages of the specific drug. It is therefore important to compare both efficacy and tolerability at various doses of drugs. Terazosin was the first selective long-acting 1-blocker investigated for the treatment of BPH. Lepor and colleagues reported the earliest multicenter randomized placebo-controlled trial of an -blocker that was properly powered to show that statistically significant changes in LUTS were also clinically significant.18 Lower urinary tract symptoms at baseline and throughout the study were RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S5 The Evolution of Alpha-Blockers for BPH efficacy and side effects from these trials are shown in Figure 2 and Table 2, respectively. Both doxazosin studies included a dose titration design to avoid the first-dose effect related to efficacy or tolerability. On the basis of its comparable efficacy and tolerability to terazosin, doxazosin’s longer half life does not seem to confirm any clinical advantage. Both terazosin and doxazosin exhibit lowering of blood pressure only in those men who are hypersensitive at baseline.23,24 The effect on blood pressure was interpreted as desirable because 2 common conditions in the aging male—BPH and hypertension—could be effectively treated with a single agent. However, ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) subsequently demonstrated that -blockers are inferior to other classes of drugs as first-line therapy for the treatment of hypertension.25 This led many to conclude that concomitant BPH and hypertension should be treated independently with the best available agents. ascertained using a quantitative symptom questionnaire. Statistically significant improvements were observed relative to placebo for both symptom scores and peak flow rate. Terazosin doses of 2 mg, 5 mg, or 10 mg were administrated once daily, and only 4% and 7% of the participants randomized to placebo and terazosin, respectively, withdrew from the 3-month study because of an adverse event. Two additional studies were part of the new drug application (NDA) submitted for FDA approval of terazosin for the treatment of symptomatic BPH.19,20 All of the terazosin studies included a dose titration study design beginning at 1 mg to avoid the first-dose effect. The treatment-related efficacy and adverse effects of terazosin are shown in Figure 1 and Table 1, respectively. Doxazosin was the second 1blocker approved by the FDA for the treatment of symptomatic BPH. Two pivotal multicenter randomized clinical trials were performed comparing various doses of doxazosin to placebo.21,22 The potential advantage of doxazosin was its longer half-life tolerability. The treatment-related Table 1 Terazosin Adverse Effects Adverse Effect Terazosin Placebo (n 636) (n 360) Asthenia/fatigue 7.4%* 3.3% Postural hypotension 3.9%* 0.8% Dizziness 9.1%* 4.2% Somnolence 3.6%* 1.9% Nasal congestion/ rhinitis 1.9%* 0 Impotence 1.6%* 0.6% Data from Hytrin® prescribing information (Abbott Laboratories, North Chicago, IL). *P .05 vs placebo. Tamsulosin was the third 1blocker to be approved by the FDA for the treatment of BPH. Tamsulosin was brought to market as the first subtypeselective 1-antagonist for the treatment of BPH. Tamsulosin’s 1-subtype selectivity is supported by binding studies showing that tamsulosin is approximately 10 times more 4 3 3.0 * 2.9 * 2.6 * 2 1.4 1 1.0 1.2 0 Mean Change in Symptom Score* Mean Change in Qmax (mL/s) Figure 1. The effect of terazosin on lower urinary tract symptoms and peak flow rate relative to placebo. Data from Hytrin® prescribing information (Abbott Laboratories, North Chicago, IL). *P .05 vs placebo. 0 ⫺1 ⫺1.1 ⫺2 ⫺2.3 ⫺3 ⫺4 ⫺5 ⫺3.8 * ⫺4.5 * ⫺5.3 ⫺6 * ⫺4.6 ⫺7 Study 1 Study 2 Study 3 Study 1 Study 2 Study 3 (12 wk; 10 mg) (24 wk; 2, 5, 10, 20 mg) (24 wk; 1, 2, 5, 10 mg) (12 wk; 10 mg) (24 wk; 2, 5, 10, 20 mg) (24 wk; 1, 2, 5, 10 mg) Terazosin Placebo N ⫽ 1222 VOL. 8 SUPPL. 4 2006 REVIEWS IN UROLOGY S5 RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S6 4 Mean Change in Symptom Score Mean Change in Qmax (mL/s) The Evolution of Alpha-Blockers for BPH continued 3.3 † 3 2.3 * 2 1 0.1 0 0.1 Study 2 Fixed-Dose (14 wk; 4 mg) 0 1 2 4 5 6 Study 2 Fixed-Dose (14 wk; 8 mg) Doxazosin 2.5 2.5 3 † 5.0 4 mg Placebo * 4.2 8 mg N 609 Figure 2. The effect of doxazosin on lower urinary tract symptoms and peak flow rate relative to placebo. Data from Cardura® prescribing information (Pfizer Inc, New York, NY). *P .05 vs placebo; † P .01 vs placebo. selective for the 1a subtype than for the 1b subtype.26,27 There is no demonstrable selectivity of tamsulosin for the 1a versus 1d subtypes. The modest receptor selectivity of tamsulosin, however, is not sufficient to result in a clinically meaningful advantage. Typically, clinical advantages attributed to pharmacological selectivity require receptor selectivity well beyond the 10-fold difference observed with tamsulosin. Table 2 Doxazosin Adverse Effects Adverse Effect Doxazosin (n 665) Placebo (n 300) Dizziness (includes vertigo) 15.6%* 9.0% Fatigue 8.0%* 1.7% Hypotension 1.7%* 0 Edema 2.7%* 0.7% Dyspnea 2.6%* 0.3% Data from Cardura® prescribing information (Pfizer Inc, New York, NY). *P .05 vs placebo. S6 VOL. 8 SUPPL. 4 2006 Two pivotal trials of tamsulosin supported the NDA for the treatment of symptomatic BPH.28,29 Both 0.4 mg and 0.8 mg of tamsulosin achieved clinically significant improvements in symptom scores and peak flow rate (Figure 3). The ability of the 0.4 mg tamsulosin dose to achieve a clinically significant effect without the requirement for dose titration represented a unique advantage over the other approved -blockers. Although a 0.8-mg daily dose is more effective than the 0.4-mg dose, it has not gained popularity as it requires both dose titration and taking 2 0.4-mg tablets (a 0.8-mg tablet is not commercially available). The primary reason tamsulosin was prescribed over terazosin and doxazosin was not greater efficacy or better tolerability, but simply the lack of dose titration. The prescribing community placed a greater value on eliminating the dose response, at the expense of increasing the incidence of ejaculatory dysfunction. Recent studies have demonstrated that tamsulosin causes anejaculation and not retrograde ejaculation (Table 3).30 The mechanism for the increased incidence of ejaculatory REVIEWS IN UROLOGY dysfunction is discussed in the article by Dr. Hellstrom in this supplement.30 Selective -blockers like prazosin offered the advantage of improved tolerability over nonselective blockers like phenoxybenzamine. The long-acting selective 1-blockers like terazosin and doxazosin offered the convenience of once-daily dosing with better tolerability compared with the shorter-acting agents like prazosin. Tamsulosin offered the opportunity to achieve a therapeutic effect without dose titration and with minimal effects on blood pressure; however, the convenience of eliminating dose titration came at the expense of ejaculatory dysfunction. Therefore, there remained an opportunity to develop a long-acting selective 1blocker that eliminated the dose titration with minimal effects on blood pressure and ejaculatory function. Alfuzosin SR is the fourth 1-selective blocker approved by the FDA for the treatment of symptomatic BPH. Radioligand binding studies failed to show any receptor selectivity of alfuzosin for the 1 subtypes.26,27 The ability to eliminate dose titration is most likely due to its RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S7 2 1.78 1.75 * * Mean Change in Symptom Score Mean Change in Qmax (mL/s) The Evolution of Alpha-Blockers for BPH 1.79 * 1.52 0.93 1 0.52 0 Study 1 (13 wk; 0.8 mg, 0.4 mg) 0 2 4 6 * * 5.1 5.8 5.5 8 10 * 9.6 * 8.3 12 Study 2 (13 wk; 0.8 mg, 0.4 mg) Study 1 (13 wk; 0.8 mg, 0.4 mg) Tamsulosin * 3.60 Study 2 (13 wk; 0.8 mg, 0.4 mg) Placebo N 1,486 Figure 3. The effect of tamsulosin on lower urinary tract symptoms and peak flow rate relative to placebo. Data from Flomax® prescribing information (2003) (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT). *P .05 vs placebo. slow release formulation. In vivo studies have shown that alfuzosin exhibits a different threshold for altering blood pressure and bladder outlet obstruction.31 These studies have been interpreted to demonstrate clinical selectivity. Two randomized placebo-controlled trials were conducted as part of the NDA for the approval of alfuzosin SR in the United States for the treatment of symptomatic BPH (Figure 4 and Table 4).32,33 Alfuzosin SR 10 mg achieved a clinically significant improvement in LUTS without dose titration; furthermore, alfuzosin SR showed comparable efficacy to tamsulosin without causing ejaculatory dysfunction. Many consider alfuzosin SR 10 mg to be the superior -blocker currently available for treating BPH because it achieves clinically significant improvements in LUTS without the requirement for dose titration. Although all 4 long-acting 1-blockers are generally well tolerated, alfuzosin has minimal effects on dizziness, asthenia, Table 4 Alfuzosin Adverse Effects Table 3 Tamsulosin Adverse Effects Tamsulosin 0.4 mg (n 502) Tamsulosin 0.8 mg (n 492) Placebo (n 493) 14.9% 17.1% 10.1% Abnormal ejaculation 8.4% 18.1% Asthenia 7.8% Libido decreased 1.0% Amblyopia 0.2% Adverse Effect Dizziness and ejaculatory dysfunction relative to the other available -blockers. All of the -blockers evaluated for the treatment of symptomatic BPH have comparable effectiveness. Over the past 30 years, the evolution of blocker therapy for BPH has focused primarily on improving convenience and tolerability. Although all of the long-acting 1-blockers are well tolerated, only tamsulosin and alfuzosin SR are administered without the requirement for dose titration. The advantage of alfuzosin over tamsulosin Adverse Effect Alfuzosin Placebo (n 473) (n 678) 3.0% 0.6% 0.2% Upper respiratory tract infection 8.5% 5.5% Dizziness 5.7% 2.8% 2.0% 1.2% Headache 3.0% 1.8% 2.0% 0.4% Fatigue 2.7% 1.8% Data from Flomax® prescribing information (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT). Data from Uroxatral® prescribing information (Sanofi-Aventis U.S., Bridgewater, NJ). VOL. 8 SUPPL. 4 2006 REVIEWS IN UROLOGY S7 RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S8 3 P .03 2.3 P .0004 2 Mean Change in Symptom Score Mean Change in Qmax (mL/s) The Evolution of Alpha-Blockers for BPH continued 1.7 1.4 1 0.2 0 Study 1 N 337 0 1.6 2 4 3.6 6.9 8 Study 2 N 283 Study 1 N 337 Alfuzosin 4.9 P .001 6 P .002 Study 2 N 289 Placebo Figure 4. The effect of alfuzosin SR on lower urinary tract symptoms and peak flow rate relative to placebo. Dosage: 10 mg/d. Data from Uroxatral® prescribing information (2004) (Sanofi-Aventis U.S., Bridgewater, NJ). is the lower incidence of ejaculatory dysfunction. Ejaculatory dysfunction is generally well tolerated by men in the BPH age range. Without a doubt, minimizing the effect on ejaculatory dysfunction represents a step forward in the development of -blockers. Alpha-1a Subtype–Selective Agents As previously discussed, there is increasing evidence that -blockers relieve LUTS through mechanisms other than prostate smooth muscle relaxation.13 Although it is universally agreed that prostate smooth muscle contraction is mediated by the 1a subtype,12 the specific 1 subtype mediating LUTS is unknown. There is also increasing evidence that adverse events associated with -blocker therapy, including asthenia and dizziness, are not due to blood pressure lowering.34 Therefore, developing a drug that prefer- entially relaxes prostate smooth muscle without affecting vascular smooth muscle will not necessarily yield a more effective drug with fewer side effects. Several 1a subtype–selective drugs entered the developmental phase at various pharmaceutical companies. All of these drug development programs were discontinued because of failure to relieve LUTS despite increasing peak urinary flow Main Points • All of the -blockers evaluated for the treatment of symptomatic benign prostatic hyperplasia (BPH) have comparable effectiveness. Over the past 30 years, the evolution of -blocker therapy for BPH has focused primarily on improving convenience and tolerability. • In the 1970s, phenoxybenzamine, a nonselective -blocker, was the first drug in its class shown to be effective for the treatment of BPH; its primary limitation was its side-effect profile, which includes tiredness, dizziness, impaired ejaculation, nasal stuffiness, and hypotension. Prazosin was the first selective 1-antagonist investigated for BPH; however, because of the need for multiple daily dosing and its hypotensive effects, large multicenter randomized trials were never conducted for its use in BPH. • Subsequently, 4 long-acting 1-blockers have been approved by the US Food and Drug Administration for the treatment of symptomatic BPH: terazosin, doxazosin, tamsulosin, and alfuzosin SR (sustained release). They all show similar efficacy versus placebo. • Although all of the long-acting 1-blockers are well tolerated, only tamsulosin and alfuzosin SR are administered without the requirement for dose titration. In addition, alfuzosin SR has a lower incidence of ejaculatory dysfunction than tamsulosin. • Although a number of companies have sought to develop 1a subtype–selective drugs, all of these development programs were subsequently discontinued because of a failure to relieve lower urinary tract symptoms despite increasing peak urinary flow rate, indicating that improvement in lower urinary tract symptoms is not related to relief of bladder outlet obstruction. S8 VOL. 8 SUPPL. 4 2006 REVIEWS IN UROLOGY RIUS0001(Sanofi)_12-05.qxd 12/5/06 6:12 PM Page S9 The Evolution of Alpha-Blockers for BPH rate. The clinical outcomes seen with these 1a subtype–selective drugs provide compelling evidence that improvement in LUTS is not related to relief of bladder outlet obstruction. 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