A1-Blocker Therapy in the Nineties: Focus on the Disease

a1-Blocker therapy in the nineties: focus on the disease

KHoÈfner1* 1Department of Urology, Hannover Medical School, Hannover, Germany

Therapy for benign prostatic hyperplasia has evolved rapidly over the last decade, with the introduction in the early 1990s of new agents such as a1-blockers and 5a-reductase inhibitors. The major advantage of a1-blockers over 5a- reductase inhibitors is their rapid onset of action. Maximum ¯ow rate is improved after ®rst administration and optimal symptom relief is usually reached within 2 ± 3 months. In addition, a1-blockers are effective regardless of prostate size and they provide a similar degree of symptom relief in patients with or without bladder outlet obstruction. The main adverse events with the a1- blockers relate to their effects on the cardiovascular system (postural hypotension) and central penetration (asthenia, somnolence). Newer uroselective a1- blockers, such as alfuzosin and tamsulosin, have a better safety pro®le and, as such, do not require initial dose titration. Alfuzosin has also been shown in a six- month study to signi®cantly reduce both residual urine and the incidence of acute urinary retention (AUR) compared with placebo. In addition, alfuzosin is effective in improving the success rate of a trial without catheter in patients with AUR.

Keywords: benign prostatic hyperplasia; prostate; a1-blockers; 5a-reductase inhibitors; acute urinary retention; LUTS

Management of BPH adrenoceptors. Medical management of BPH suddenly exploded at the beginning of the 1990s with the introduc- Therapy for benign prostatic hyperplasia (BPH) has tion of selective a1-blockers and 5a-reductase inhibitors. evolved considerably over the past century. Performance In terms of treatment goals for BPH, the two main of open prostatectomy, routine until 20 ± 25 years ago, has objectives are to reduce symptoms and relieve obstruc- been gradually replaced by transurethral resection of the tion. Obstruction and symptoms are not correlated, how- prostate (TURP), which is now the preferred surgical ever, and patients may present with signi®cant symptoms procedure worldwide. At the start of the 1990s, new but no obstruction. Consequently, it is important to therapies which were less interventional than TURP distinguish between different patient types in order that were introduced, such as thermotherapy, laser therapy the most appropriate treatment be given. and therapies involving radiofrequencies, e.g. transurethral needle ablation. To date, most of these techniques are still regarded as investigational and additional ran- TURP domized studies focusing on costs and durability of symptomatic improvement are needed. Dramatic reduction in the use of TURP for the treatment The development of medical therapy for BPH has been of BPH worldwide have been reported, with perhaps the a long process, beginning with phytotherapy in Egyptian greatest decline in number of procedures being noted in times. In the mid-1970s, the better understanding of the the US (Figure 1).1 TURP constituted 94% of all BPH pathophysiology of BPH led to the ®rst use of phen- surgery in 1995 in the US, but has declined to 52% over oxybenzamine, an irreversible antagonist of both a1/a2 the past decade.2 Only in the UK, where the number of procedures has been consistently low, has the incidence not declined appreciatively. TURP is often referred to as the gold standard treatment for BPH, but in actual fact it *Correspondence: Professor Dr Klaus HoÈfner, Department of Urology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 is not the ®rst treatment choice for the majority of Hannover, Germany. patients. Recent experience in clinical practice has E-mail: [email protected] shown that many patients prefer less aggressive interven- a1-Blocker therapy KHoÈfner S10

Figure 1 Worldwide trends in transurethral resection of the prostate for benign prostatic hyperplasia.1

tions than TURP, even if their symptoms are relatively a1-blockers and 5a-reductase inhibitors have very dif- severe.3 Surgery for BPH remains mandatory, however, ferent modes of action. The former targets the dynamic for a number of conditions, including: refractory urinary component of bladder outlet obstruction (BOO), by retention (after at least one attempt to remove the cathe- decreasing the sympathetically controlled tone of pro- ter), recurrent urinary tract infection due to benign prostatic, urethral and bladder neck smooth muscle, whilst static obstruction (BPO), recurrent gross haematuria due the latter targets the static component, i.e. prostate gland to benign prostatic enlargement (BPE), bladder stones, size. The choice between these two treatment options large bladder diverticula, and renal failure due to BPO.4 implies a critical analysis of various parameters, such as In terms of improvement in symptoms, ¯ow rate and the rapidity of action, the magnitude of the symptom obstruction, TURP is the standard against which other relief, the safety pro®le and also the long-term outcome therapies should be compared. However, it is associated (Table 1). with a low, but signi®cant morbidity, even when per- formed by experienced urologists. In particular, sexual function appears to be a major area of concern, with Rapid onset of action retrograde ejaculation occurring in nearly 75% of patients and about 15% of potent men becoming impotent.5 While the 5a-reductase inhibitor ®nasteride may take three to six months to be effective, there is no doubt that the principal advantage of a1-blockers is their rapid onset of action. Hence, alfuzosin has been shown to increase maximum ¯ow rate (Qmax) by about 30% from Medical therapy

Concurrently with the decline of surgery, the total market Table 1 Main characteristics of a1-blockers and 5a-reductase inhib- for medical therapies for BPH has considerably increased itors over the past nine years worldwide, mainly due to the a1-blockers 5a-reductase inhibitors emergence of two classes of medications, a1-blockers and 5a-reductase inhibitors. These agents have unambigu- Target Dynamic component Static component ously demonstrated their ef®cacy and good safety pro®le Prostate size All Enlarged in well-designed, placebo-controlled studies. Surprisingly, Onset of action Immediate Delayed Ef®cacy LUTS: 30 ± 50% Slightly lower than despite the lack of long-term data con®rming their ef®- improvement a1-blockers, up to one year cacy, sales of phytotherapeutic agents (expressed in mil- Qmax: 30% decrease lions of treatment days) have remained stable for a Effect on PSA None Decrease by 50% number of years and are just starting to decline (Figure Side effects Postural symptoms Sexual disorders 2). While the market for 5a-reductase inhibitors has been Effect on AUR Yes Yes stable since 1995, that of a -blockers is expanding rapidly 1 LUTS lower urinary tract symptoms; Qmax maximum ¯ow rate; worldwide. PSA prostate-speci®c antigen; AUR acute urinary retention. a1-Blocker therapy KHoÈfner S11

Figure 2 Worldwide trends in medical therapy for benign prostatic hyperplasia. From IMS Health Retail Data.

the ®rst administration,6 which represents the bene®t improvement in LUTS and quality of life in those patients 14 expected from an a1-blocker in the medium and long with and without BOO. term. Lower urinary tract symptoms (LUTS) improvement is also rapid and reaches its maximum within two to three months of treatment.7±10 Overall, the magnitude of 11 symptom relief is very similar with different a1-blockers. a1-Blocker plus ®nasteride combination studies

Effect on obstruction In the early 1990s, there was much debate on the potential therapeutic bene®ts of combining two medical therapies Limited studies are available examining the effect of with very different modes of action, i.e. an a1-blocker and a1-blockers on BOO. Two placebo-controlled studies ®nasteride. Both drugs are capable of improving LUTS have been conducted examining the effect of a1-blockers and Qmax and their effect may, in theory, be synergistic. on detrusor pressure at Qmax, the single measurement The value of the combination has now been tested up to most closely associated with the presence and degree of one year in three major studies involving terazosin/ BOO. A study by Martorana et al 12 showed that after four ®nasteride,9 alfuzosin/®nasteride16 and doxazosin/®nas- weeks of treatment with alfuzosin (7.5 mg/day), detrusor teride.17 However, none of these studies demonstrated pressure at Qmax decreased from 78 cmH2O to 54 cmH2O any added bene®t of combining the two types of drug. ( 30%). This difference was signi®cant (P < 0.01) com- In the ®rst combination study, the Veterans' Affairs pared with placebo, where detrusor pressure fell from (VA) Study, the safety and ef®cacy of terazosin (10 mg/ 82 cmH2O to 77 cmH2O( 6.1%). Administration of alfu- day), ®nasteride (5 mg/day), the combination of the two zosin for an additional eight weeks on an open basis was and placebo were compared in 1229 men with BPH over a associated with a further decrease in detrusor pressure at one-year period.9 The mean changes in I-PSS at one year Qmax (from 46 cmH2O to 31 cmH2O; P < 0.05). Similar were of the same order of magnitude with terazosin results have been observed with tamsulosin, 0.4 mg/ ( 6.1) and the combination ( 6.2), both being signi®- day, where a reduction in detrusor pressure from cantly higher than ®nasteride ( 3.2) and placebo ( 2.6). 13 93.6 cmH2O to 67 cmH2O(28%) was recorded. Similarly, mean increases in Qmax at one year were Again, the difference was signi®cant compared with the signi®cantly higher with terazosin ( 2.7 mL/s) and the placebo response of 88.4 cmH2O to 83.5 cmH2O( 6%). combination ( 3.2 mL/s) than with ®nasteride Reductions of 23% and 10% in detrusor pressure at Qmax ( 1.6 mL/s) and placebo ( 1.4 mL/s). have been observed with terazosin14 and doxazosin,15 The second combination study, the ALFIN Study, respectively; however, neither study had a placebo con- compared alfuzosin (10 mg/day), ®nasteride (5 mg/ trol. These results suggest that a1-blockers have a moder- day), and the combination of the two in 1051 patients ate but bene®cial effect on obstruction, although there is with BPH over a six-month period.16 Mean changes in I- increasing evidence that a1-blockers provide a similar PSS were signi®cantly higher with alfuzosin, alone ( 6.3) a1-Blocker therapy KHoÈfner

S12 or in combination ( 6.1), than with ®nasteride ( 5.2). Whether the results would have been different in very In those patients likely to be obstructed, increases in Qmax long-term comparative studies needs to be demonstrated. were also signi®cantly higher with alfuzosin ( 2.9 mL/s) and the combination ( 2.9 mL/s) than with ®nasteride alone ( 2.1 mL/s; P < 0.02). Results of a third combination study (PREDICT) comparing doxazosin (8 mg/day), ®nasteride (5 mg/day), the Side effects combination of two and placebo in 1089 BPH patients, further con®rm the VA Study and ALFIN results. Over a Since the research on the ®rst a-adrenoceptor antagonist, one-year treatment period, improvement in LUTS and phenoxybenzamine, in the mid-1970s, more selective Qmax were signi®cantly higher with doxazosin and the antagonists which bind speci®cally to the a1-adrenocep- combination, as compared with ®nasteride alone and tors, the prime determinants of human prostatic smooth placebo, with no additional bene®t of the combination.17 muscle contraction, have been identi®ed.20 However, Unlike ®nasteride, which has been shown to offer none of the a1-blockers speci®cally target the prostate greater bene®ts in prostates greater than 40 mL,18 prostate and potential adverse events with this group of drugs size does not in¯uence the ef®cacy of a-blockers in BPH.19 relate mainly to their effects on the cardiovascular system, For this reason, one criticism of the VA Study was the e.g. dizziness, headache, postural hypotension and syn- inclusion of men with small prostates (mean prostate cope. Blood ± brain barrier penetration can also lead to volumes at baseline ranged from 36 ± 38 mL). However, central events, such as asthenia and somnolence. Ortho- it is interesting to note that in both the ALFIN (Figure 3) static hypotension, occurring mainly at the ®rst adminis- and PREDICT Studies,17 prostate size clearly did not tration of the compound, is a particular cause of concern, in¯uence the results; the a1-blocker was more effective as it may result in substantial morbidity and mortality than ®nasteride even in patients with enlarged prostates. from associated falls and syncope, especially in elderly 21 patients. For this reason, most currently available a1- blockers such as prazosin, terazosin and doxazosin need to be started at low dose in order to avoid a `®rst dose phenomenon' and titrated to obtain maximum ef®cacy and tolerability. Despite initial dose titration precautions, the ®rst dose phenomenon can also occur in those patients with irregular compliance. The risks associated with the use of a1-blockers have been demonstrated in the VA Study:9 postural hypotension was shown to be four times more frequent in patients who received terazosin than in those who received placebo or ®nasteride; dizziness was three times more frequent and asthenia twice as frequent (Figure 4a). By comparison, new uroselective a1-blockers such as alfuzosin and tamsulosin, administered without dose-titration in randomized clinical trials, clearly offer a better safety pro®le. This was demonstrated in the ALFIN Study, where the incidence of postural hypotension, asthenia and dizziness with the sustained-release formulation of alfuzosin, alone or in combination, was low and similar to that observed in patients treated with ®nasteride, which is completely devoid of cardiovascular effects (Figure 4a).16 The safety pro®le of tamsulosin which shows a slight a1A selectivity is, in fact, very similar to that of alfuzosin as shown by a randomized study directly comparing both drugs.22 The decrease in blood pressure was slightly more pronounced with alfuzosin (immediate-release formulation), but this had no in¯uence on the rate of drop-outs for adverse events (alfuzosin 4% vs tamsulosin 8%) or the incidence of postural hypotension (alfuzosin 1% vs tamsulosin 3%). Compared with 5a-reductase inhibitors, a1-blockers also have an advantage with respect to sexual function and this needs to be taken into account in sexually active patients. Hence, in both the VA and ALFIN Studies, Figure 3 Ef®cacy of SR-alfuzosin, ®nasteride and the combination of both erectile dysfunction, ejaculatory abnormality and (ALFIN Study) in patients with prostate size < 40 mL and 40 mL: (a) decreased libido were more frequently reported in Effect on lower urinary tract symptoms (reduction in International Prostate patients treated with ®nasteride or the combination Symptom Score [IPSS]); treatment6volume interaction ns; volume 9,16 effect ns; (b) Effect on Q in patients likely to be obstructed (baseline therapy (Figure 4b). Interestingly, a high rate of abnor- max mal ejaculation has recently been reported with the a - Qmax < 10 mL/s at baseline); prostate6volume interaction ns; volume 1 effect, global P 0.0005.16 blocker, tamsulosin. In a 53-week study conducted in the a1-Blocker therapy KHoÈfner S13

Figure 4 Comparative safety pro®le in ALFIN16 and VA Studies.9 (a) Side effects possibly related to vasodilation. Global P values for VA Study: postural hypotension, P < 0.001; asthenia, P 0.02; dizziness, P < 0.001. Global P values for ALFIN Study: postural hypotension, ns; asthenia, ns; dizziness, ns. (b) Side effects possibly related to sexual function. Global P values for VA Study: ejaculatory abnormality, P < 0.001; decreased libido, P 0.05; impotence, P 0.05. Global P values for ALFIN Study; ejaculatory abnormality, P 0.04; decreased libido, ns; impotence, P < 0.002.

US, a dose ± response effect was recorded; abnormal Bene®ts of a -blockers on acute urinary ejaculation occurred in 26% of patients treated with 1 0.8 mg tamsulosin and 10% of patients treated with a retention 0.4 mg dose of the drug.8 This compares with 0% of patients in the placebo group. Incidence of abnormal Acute urinary retention (AUR) is one of the main complica- ejaculation in a European study published by Chapple tions of BPH and represents a mandatory indication for and co-workers23 was lower at 4.5% with tamsulosin surgery in case of recurrence. Large community-based stu- (0.4 mg), compared with a 1% incidence in the placebo dies have contributed to identifying risk factors for AUR, group, but the duration of this study was only 12 weeks. such as increasing age, severity of symptoms, low Qmax, As none of the 1544 patients treated with alfuzosin in enlarged prostate and abnormal residual urine.25 ± 27 randomized controlled studies reported abnormal ejacu- Recent data suggest that 5a-reductase inhibitors are asso- lation,24 it has been suggested that this effect may be due ciated with a lower incidence of AUR compared with 28 to the speci®c selectivity of tamsulosin for the a1A-adreno- placebo in the long-term. a1-Blockers, by reducing sym- ceptor subtype. However, this needs to be con®rmed. pathetic overstimulation, i.e. the main pathophysiologic a1-Blocker therapy KHoÈfner

S14 mechanism of AUR,29 have also shown a bene®cial 7 Buzelin JM, Roth S, Geffriaud-Ricouard C, Delauche-Cavallier impact on this complication. Hence, alfuzosin has been MC and the ALGEBI Study Group. Ef®cacy and safety of demonstrated in a large placebo-controlled study invol- sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. Eur Urol 1997; 31: 190 ± 198. ving 518 patients, to reduce signi®cantly post-void resi- 8 Lepor H. Long-term evaluation of tamsulosin in benign prostatic dual urine as well as the incidence of AUR: over a six- hyperplasia: placebo-controlled, double-blind extension of phase month period, AUR occurred in one patient (0.4%) in the III trial. Urology 1998; 51: 901 ± 906. alfuzosin group and seven patients (2.6%; P 0.04) in the 9 Lepor H et al. The ef®cacy of terazosin, ®nasteride or both in placebo group.30 This bene®t has been con®rmed in the benign prostatic hyperplasia. N Engl J Med 1996; 335: 533 ± 539. three-year open study in 3228 patients in general practice, 10 Fawzy A et al. Doxazosin in the treatment of benign prostatic in which the incidence of AUR was only 0.3%.31 Although hyperplasia in normotensive patients: a multicenter study. J Urol 1995; 154: 105 ± 109. there was no placebo arm, the incidence of AUR in this 11 Chapple CR, Andersson KE. a-Blocker clinical results. In: Denis L study was lower than the 2 ± 3% incidence reported in the et al (eds). 4th International Consultation of Benign Prostatic Hyper- literature for watchful waiting.32 plasia. Paris, July 2 ± 5, 1997. Health Publications Ltd, 1998, pp Alfuzosin has also been shown to favour return to a 610 ± 632. normal voiding pattern in a trial without catheter 12 Martorana G et al. Effects of short-term treatment with alpha-1 (TWOC) conducted in BPH patients with AUR.33 Alfuzo- blocker alfuzosin on urodynamic pressure/¯ow parameters in patients with benign prostatic hyperplasia. Eur Urol 1997; 32:47± sin was given at a dose of 5 mg twice daily in the 24-h 53. period before catheter removal and for 24 h following 13 Abrams P et al. A dose-ranging study of the ef®cacy and safety of removal. A failed TWOC was de®ned as recatheterisation tamsulosin, the ®rst prostate-speci®c a1-Adrenoceptor antagonist, within 24 h of removal due to a further episode of AUR or in patients with benign prostatic obstruction (symptomatic because the patient was passing small urine volumes. benign prostatic hyperplasia). Br J Urol 1997; 80: 587 ± 596. Results showed that 55% of patients treated with alfuzo- 14 Witjes WPJ et al. Urodynamic and clinical effects of terazosin therapy in symptomatic patients with and without bladder outlet sin voided successfully after catheter removal compared obstruction: a strati®ed analysis. Urology 1997; 49: 197 ± 206. with 29% of patients receiving placebo (P 0.03). 15 Gerber GS et al. 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