Prostate Cancer and Prostatic Diseases (1999) 2 Suppl 4, S9±S15 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pcan 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 hypoten- sion) 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. transure- thral 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 pro- static, 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) improve- ment 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%).