The Long-Term Outcome of Medical Therapy for BPH

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1 european urology 51 (2007) available at journal homepage: Review Benign Prostatic Hyperplasia The Long-Term Outcome of Medical Therapy for BPH Stephan Madersbacher a, *, Martin Marszalek a, Jakob Lackner b, Peter Berger c, Georg Schatzl b a Departments of Urology and Andrology, Danube Hospital, Vienna, Austria b Medical University of Vienna, Vienna, Austria c Institute for Biomedical Ageing Research, Austrian Academy of Sciences, Innsbruck, Austria Article info Article history: Accepted March 17, 2007 Published online ahead of print on March 28, 2007 Keywords: Benign prostatic hyperplasia Efficacy Long-term outcome Medical management Natural history Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: The lack of cure with medical therapy implies life-long treatment emphasising the need for a thorough understanding of the longterm outcome. We review the natural history, markers for progression, placebo effect, efficacy, pharmacoeconomic aspects, and preventive measures. Methods: Literature review with particular reference to long-term controlled studies using plant extracts, a 1 -blockers, 5a-reductase inhibitors (5-ARIs), and combination therapy. Results: There is a long-lasting (12 mo) placebo response of symptoms (20% decrease) and maximum flow rate (10% rise). The five long-term controlled trials of plant extracts are inconclusive and therefore their role in contemporary medical management is still controversial. The a 1 -blockers provide fast amelioration of symptoms yet have no relevant impact on the risk of acute urinary retention or surgery. Combination therapy should be reserved for moderately or severely symptomatic patients with a high risk of progression; in the majority of patients the a 1 -blocker can be safely stopped after 6 12 mo. The preventive use of 5-ARIs in men with no or mild symptoms at risk of progression is scientifically sound yet not generally accepted mainly for economic reasons. Conclusions: A sharp contrast exists between the duration of the longest controlled trial (4.5 yr) and the situation in real life with treatment periods up to one or two decades of life. Real-life and registry data will be the only source of this important information in the future. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology and Andrology, Donauspital, Langobardenstrasse 122, A-1220 Vienna, Austria. Tel ; Fax: address: stephan.madersbacher@wienkav.at (S. Madersbacher) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 51 (2007) Introduction Medical management has become the standard of care for men with bothersome lower urinary tract symptoms (LUTS) suggestive of benign prostatic enlargement (BPE)/benign prostatic obstruction (BPO) in the absence of a strong indication for surgery [1 3]. The World Health Organization-Benign Prostatic Hyperplasia (WHO-BPH) Consensus Conference has defined standards regarding the evaluation of medical therapies for LUTS due to BPE/BPO: prospective, randomised against placebo/standard therapy and with a minimum study period of 12 mo [4]. The lack of cure with drugs implies life-long treatment unless severe complications, lack of efficacy, or side-effects necessitate termination. Given the current life expectancy, this means that a man in his sixties will have to take these drugs over one to two decades of life. Therefore, a detailed knowledge on the long-term outcome is of paramount interest. The high prevalence of this disorder and demographic changes further underline the socioeconomic relevance of this disease [5 8]. This review highlights a number of important aspects regarding the long-term medical management of LUTS, such as the natural history, markers for progression, placebo effect, long-term efficacy, pharmacoeconomic aspects, and preventive measures. 2. Methods A MedLine-based research covering was performed (abstracts were not considered). Regarding efficacy and tolerability we concentrated on controlled trials with a minimum follow-up of 12 mo, and small-sized studies were excluded (Table 1). Table 1 Overview of randomised controlled trials with a minimum follow-up of 12 mo Reference No. of patients Active Comparator Duration, mo Plant extracts Bach, 2000 [36] 476 Pumpkin extract Placebo 12 Schneider, 2005 [35] 246 Stinging nettle roots Placebo 12 Bent, 2006 [34] 225 Saw Palmetto Placebo 12 Debruyne, 2002 [38] 704 Saw Palmetto Tamsulosin 12 Sökeland, 1997 [37] 543 Sabal/Stinging nettle roots Finasteride a 1 -Blocker Roehrborn, 1996 [47] 2084 Terazosin Placebo 12 Lepor, 1996 [48] 710 Terazosin Placebo 12 Lepor, 1998 [49] 418 Tamsulosin Placebo 12 Kirby, 2003 [50] 503 Doxazosin Placebo 12 McConnell, 2003 [27] 1493 Doxazosin Placebo 54 Roehrborn, 2006 [28] 1522 Alfuzosin Placebo ARIs Andersen, 1995 [56] 707 Finasteride Placebo 12 Nickel, 1996 [57] 613 Finasteride Placebo 12 Lepor, 1996 [48] 615 Finasteride Placebo 12 Kirby, 2003 [50] 492 Finasteride Placebo 12 Lowe, 2003 [58] 487 Finasteride Placebo 12 Marberger, 1998 [59] 2902 Finasteride Placebo 24 McConnell, 1998 [60] 3040 Finasteride Placebo 48 McConnell, 2003 [27] 1505 Finasteride Placebo 54 Roehrborn, 2002 [61] 4325 Dutasteride Placebo 24 14,686 Combination therapy Lepor, 1996 [48] 614 Terazosin/Finasteride Placebo 12 McConnell, 2003 [27] 1523 Doxazosin/Finasteride Placebo 54 Kirby, 2003 [50] 518 Doxazosin/Finasteride Placebo All published series on plant extracts, a 1 -blockers, and combination therapy were added; for finasteride a few older studies were not considered (see Methods). 5-ARIs = 5a-reductase inhibitors.

3 1524 european urology 51 (2007) Natural history and the concept of progression A thorough understanding of the natural history is of paramount importance in interpreting long-term medical trials. The natural history is best studied from longitudinal, ideally population-based studies, such as the Olmsted County Study, Health Professional Follow-up Study or Krimpen Study, the largest European longitudinal study on this issue [9 14]. Useful information can also be derived from registries and the placebo arms of controlled trials [15]. All approaches have their advantages and limitations, such as the Hawthorne effect or the natural regression to the mean [16]. Furthermore BPH-related outcomes tend to be underestimated in the placebo arm of clinical trials compared with community-dwelling men [17]. All aspects of BPE/LUTS/BPO progress with age [10,18 20]. The median annual prostate growth in the Olmsted County Study was 1.9%. In parallel, LUTS deteriorate with age as moderate-to-severe LUTS are present in about 25% of men in their sixties, 30% of men in their seventies, and up to 40% in those older than 70 yr [21]. Although LUTS tend to worsen over time, 20 30% of patients experience a prolonged remission [22]. Little is known regarding the natural history of BPO because there is only one long-term urodynamic-based longitudinal study suggesting that untreated BPO does not significantly deteriorate in the long term [23]. The maximum flow rate (Q max ) declines around 2%/yr depending on the baseline flow rate, age, prostate volume, and symptom severity [24]. Serious complications such as acute urinary retention (AUR) or the need for surgery are rather rare events, in the range of 0.2 1%/yr [10,25,26]. The impact of medical therapy on BPH progression was first studied in detail in the Medical Trial of Prostatic Symptoms (MTOPS) [27]. In this study, progression was defined as symptomatic worsening (American Urological Association [AUA] score 4), occurrence of AUR/prostate surgery, incontinence, renal failure, or recurrent urinary tract infection [27]. Over 4.5 yr only 17% within a typical LUTS population developed a progression event in the placebo arm, with symptomatic worsening by far most frequent event (78%), followed by AUR (12%), and urinary incontinence (9%) [27]. The recently published 2-yr placebo-controlled trial with alfuzosin applied a similar definition of progression [28]. The rate of progression was twice as high (20% in 2 yr) than in the MTOPS, most likely due to the inclusion of patients at higher risk of progression [28]. This trial confirmed that symptomatic worsening is by far the most frequent progression event (65%) [28]. 4. Risk factors for progression Age, severe LUTS, low Q max, high postvoid residual (PVR), enlarged prostate, and high serum prostatespecific antigen (PSA) are risk factors for AUR and BPH-related surgery [16 20]. Slawin et al presented the first nomogram to predict AUR by modelling 4294 men treated in phase 3 dutasteride trials [29]. This nomogram included the AUA score, bother index, prior a 1 -blocker therapy, prostate volume, PSA and Q max. Such nomograms may enable an in individualised, risk-adapted, and economical medical management in the future [29]. 5. Long-term outcome of medical therapy 5.1. Placebo effect There is considerable evidence of a long-lasting placebo effect [30,31]. This placebo effect is demonstrable for subjective and objective parameters (Fig. 1). The mean improvement of symptom score after 12 mo was 21.4% (range: %), after 24 mo 10.9% (range: %), and after 4.5 yr 15.9% (range: %; Fig. 1). Q max improved for a mean of 12.4% after 12 mo (0 27%), 5.3% after 24 mo Fig. 1 Placebo response in long-term medical trials. The data of all trials listed in Table 1 were analysed; some trials contained no detailed information regarding maximum flow rate (Q max ). Each dot indicates the placebo arm of one study, the horizontal bars the respective mean values.

4 european urology 51 (2007) et al have reported such an analysis based on a 25-mo placebo-controlled trial [32]. Total symptom score improved by 2.3 points (16%) and the Q max by 1.0 ml/s (+10%) at 25 mo [32]. These changes were indeed slightly higher than the respective placebo responses reported traditionally (excluding the runin phase). The mechanisms leading to this prolonged placebo response remain poorly understood, yet condition-specific factors and self-management, patient-specific factors, and trial-specific factors are likely to be involved [30,33] Efficacy Fig. 2 Impact of long-term medical therapy on lower urinary tract symptoms. All trials listed in Table 1 are included. Light-orange bar = active substance; Darkorange bar = comparator, with the exception of two plant extract trials (see asterisk) always placebo. ( %), and 7.5% ( %) after 4.5 yr (Fig. 1). The placebo response shows remarkable differences in the various trials (Figs. 1 3). These differences are most likely caused by different inclusion/exclusion criteria, study designs, dosing, etc. In fact, the highest placebo response (eg, Fig. 2, Lepor 1998 [49]) exceeds the active drug of many other trials. These data, despite being impressive, do not describe the real placebo effect because this is partly dissipated in the placebo-run in phase. Nickel Fig. 3 Impact of long-term medical therapy on maximum flow rate (Q max ). All trials listed in Table 1 are included. Light-orange bar = active substance; Dark-orange bar = comparator, with the exception of two plant extract trials (see asterisk) always placebo Plant extracts In countries with a long tradition in phytotherapy (Austria, Germany, France) plant extracts still reach market shares up to 30% [6,7]. Only five randomised, controlled studies with a follow-up of 12 mo are available; longer controlled studies have not been reported [34 38] (Table 1). Due to different extraction techniques each extract needs to be analysed separately [39,40]. Bent et al randomised 225 patients 1:1 between saw palmetto and placebo [34]. This highly published and probably best designed phytotherapy trial was negative, leading to the conclusion that this extract was identical to placebo (Figs. 2 and 3) [34]. Schneider and Rübben randomised 226 patients 1:1 into a placebo or a stinging nettle roots arm [35]. After 12 mo, the symptom score decreased by 4.7 points ( 25%) with placebo and by 5.7 points ( 30.5%) with the stinging nettle root extract (Fig. 2). Changes of Q max and PVR volume were identical in both arms, yet not described in detail [30]. Finally, Bach et al randomised 476 men 1:1 to placebo or a pumpkin extract [36]. After 12 mo, the International Prostate Symptom Score (IPSS) decreased by 5.5 ( 30.6%) in the placebo arm and by 6.7 ( 25.4%) in the plant extract arm (Fig. 2). Data of Q max and prostate volume were not available [36]. Two extracts have been tested against standard therapy: saw palmetto against tamsulosin and a combination product (saw palmetto/stinging nettle root) against finasteride [37,38] (Table 1 and Figs. 2 and 3). Both trials revealed similar outcomes regarding symptoms, Q max, and PVR between the plant extract and standard therapy; unfortunately, these two trials contained no placebo arms (Figs. 2 and 3). Based on these limited data, it is not surprising that the statement of various BPH guidelines for plant extracts range from negative to only tentatively positive [2,41,42]. The large numbers of meta-analyses cannot supplement prospective studies according to WHO standards, which should ideally contain a placebo arm [43 45].

5 1526 european urology 51 (2007) The a 1 -blockers Efficacy of a 1 -blockers is well documented with an improvement of symptoms of 30 40% (10 20% over placebo) and Q max around 15 30% (10 15% over placebo) [46]. To date, six long-term placebo-controlled a 1 -blocker trials (including the three combination trials) with a duration of 12 mo are available; only two were >12 mo (Table 1) [27,28,47 50]. These six trials document the long-term efficacy of a 1 - blockers in ameliorating symptoms [27,28,47 50]. The mean symptom score decrease after 12 mo was 41.6% (range: %) versus 25.2% (range: %) for placebo. As shown in Fig. 2, symptom improvements after 12 mo were fairly constant. The two studies with the longest duration (2 yr and 4.5 yr) suggest a slight decrease of efficacy. After 2 yr, alfuzosin induced a symptom score decline of 31% versus 25% for placebo; the difference in the 4.5-yr trial was also modest at 11% (35% for doxazosin vs. 24% for placebo) [27,28]. Improvement of Q max was remarkably similar in the long-term trials. After 12 mo, Q max improved by 27% (range: 22 35%) in the six trials compared to 10% for placebo (range: 4 14%) [27,28,47 50]. Again, efficacy seems to decrease slightly over time; after 24 mo the difference in Q max was only 8% (alfuzosin 23% vs. placebo 15%) and after 5 yr 11% (doxazosin 24% vs. placebo 13%) [27,28]. A number of long-term open-label studies with study periods up to 6 yr support the sustained efficacy yet have to be interpreted with caution because of the high drop-out rates [51 55] The 5-a reductase inhibitors Dutasteride and, particularly, finasteride are the most intensively studied drugs for BPH (Table 1 and Figs. 2 and 3) [27,48,50,56 61]. To date no comparative trial between the two 5-a reductase inhibitors (5-ARIs) has been published in the peer-reviewed literature and a comparison based on the existing data is flawed due to different inclusion/exclusion criteria. The 5-ARIs are the only drugs for BPH that reduce prostate volume by 20 25% [27,48,50,56 61]. LUTS improve in about 20 30%, and this improvement is maintained for 4.5 yr in controlled settings [27,48,50,56 61]. The three long-term combination trials suggest a superiority of a 1 -blockers in improving LUTS [27,48,50]: Prospective European Doxazosin and Combination Therapy (PREDICT, 12 mo): symptom score reduction 49% (doxazosin) versus 36% (finasteride); VA Cooperative Study (12 mo): 38% (terazosin) versus 20% (finasteride); and MTOPS (4.5 yr): 35% (doxazosin) versus 29% (finasteride) (Fig. 2) [27,48,50]. Uroflow improves less impressively by 10 20%; again a 1 -blockers are slightly superior in this respect (Fig. 3) [27,48,50] Combination therapy The rationale for combining a 1 -blockers and 5-ARIs is their differential mode of action in managing LUTS secondary to BPE/BPO (Table 1) [27,48,50]. The VA Cooperative Study and the PREDICT trial failed to demonstrate a benefit for combination therapy over a 1 -blocker monotherapy (Figs. 2 and 3). The 12-mo duration of these two trials, however, was too short to demonstrate a benefit of combination therapy on the natural history [62]. Hence, MTOPS is the only combination trial with a sufficient duration to provide sufficient answers in this respect [27,62]. Combination therapy reduced the risk of progression by 68% compared to placebo, 39% versus finasteride and 42% versus doxazosin. In terms of individual secondary end points within the study, combination therapy resulted in benefits over both a-blocker (doxazosin) and 5-ARI (finasteride) for median improvement in AUA score 7.0 ( 44%) verus 6.0 ( 35%) and 5.0 ( 29%) points and Q max +3.7 (+35%) versus +2.5 (+24%) versus +2.2 [21%] ml/s [27,62]. In general, there was a strong correlation (correlation coefficient: 0.86, p < ) between the symptomatic and objective improvement in the long-term trials analysed herein (Figs. 2 and 3). These data demonstrate that patients with a more significant improvement in uroflow exhibit also a more profound symptom improvement. Interestingly, a similar trend that did not reach statistical significance ( p = 0.8) was also observed for the placebo arm. Further data from the MTOPS study suggest that combination therapy has the greatest benefit in reducing symptoms and the risk of AUR in men with higher baseline prostate volume or PSA [63]. These findings are confirmed by real-life data [64]. For several reasons the duration of combination therapy is relevant: (1) economic aspects (although generics reduce costs), (2) side-effects, (3) the fact that combination therapy provides no relevant advantage over 5-ARI monotherapy regarding the impact on the natural history, and (4) the 5-ARI exerts the full clinical efficacy after 6 mo. The Symptom Management After Reducing Therapy (SMART-1) demonstrates that withdrawal of the a 1 -blocker is possible in men with moderate LUTS after 6 mo; those with severe LUTS may require a longer combined treatment time (9 12 months) [65] Side-effects and drop-out rates Plant extracts Plant extracts exhibit a good tolerability that has been emphasised as one of the pros of this approach that renders plant extracts particularly attractive for sexually active men who want to avoid the sexual

6 european urology 51 (2007) small-pupil syndrome, called intraoperative floppy iris syndrome (IFIS), was recently described in patients undergoing cataract surgery and taking a 1 -blockers [72,73]. Urologists must be aware of this rare complication and should inform patients and ophthalmologists accordingly [73]. Drop-out rates in the majority of a 1 -blocker trials were higher than those with 5-ARIs (Fig. 4) [31]. When interpreting these data one has to be aware that the majority of these trials were performed with older a-blockers (doxazosin/terazosin) known to have a higher rate of AEs [46]. The only long-term trial with a modern a 1 -blocker (eg, alfuzosin) suggests a lower drop-out rate (30% after 2 yr) [28]. Fig. 4 Drop-out rates in long-term medical trials. Black = plant extracts; orange = a 1 -blocker; green = 5a-reductase inhibitors; blue = combination therapy. side-effects of a 1 -blockers and 5-ARIs [34 38,66]. Claus Roehrborn was among the first to highlight the importance of reporting discontinuation rates when comparing clinical trials [31]. Fig. 4 (in analogy to Roehrborn s original graph [31]) presents discontinuation rates of all randomised controlled trials analysed herein (Table 1). Discontinuation rates of the four plant extract trials that provide information on this aspect were low at 0% [37], 8.9% [34], 14.4% [38], and 14.6% [36] The a 1 -blockers Safety and tolerability of a 1 -blockers, 5-ARIs, and combination therapy have been recently described in great detail in European Urology and we largely refer to this article [67]. The main adverse events (AEs) are vasodilatory effects and ejaculatory dysfunction. Cardiovascular AEs occur more frequently in patients aged 70 yr or older than in younger patients. Alfuzosin and tamsulosin are generally better tolerated than terazosin and doxazosin. Tamsulosin causes fewer vasodilatory AEs than alfuzosin, but more ejaculatory abnormalities in the range of 5% to 10% [46]. Preliminary data suggest that alfuzosin may even improve various aspects of sexual function [68,69]. The phosphodiesterase type 5 inhibitors (PDE5-Is) in patients receiving a 1 -blockers should be prescribed with care due to the potential risk of a synergistic lowering of blood pressure, although recent short-term controlled trials suggest that a clinically significant hypotension is unlikely to be induced [70,71]. A new The 5-ARIs The only AEs that occurred more often with the 5-ARIs than with placebo were sexual AEs (<10%) and gynaecomastia (2%) [67]. Sexual AEs tend to occur during the first 6 12 mo and there is no evidence of increased AEs compared with placebo thereafter. Both 5-ARIs reduce serum PSA by approximately 50% yet maintain its role as a serum tumour marker for prostate cancer by doubling the value [74]. Recent data from the Prostate Cancer Prevention Trial (PCPT) suggest that PSA performance is even improved in patients receiving finasteride [74]. Serum testosterone levels increase by approximately 20% due to reduction of serum dihydrotestosterone (DHT) [75]. 5-ARIs do not interact with cardiovascular drugs and use of PDE5-Is is unrestricted [67]. Discontinuation rates in the 5-ARIs trials were lower than in the a 1 -blocker trials; 10 20% of patients discontinued after 2 yr (Fig. 4) [31] Combination therapy MTOPS revealed that patients on combination therapy experienced AEs similar to those for each drug alone and that these were typical for patients receiving these classes of drugs, that is, dizziness, erectile dysfunction, postural hypotension, and asthenia [27]. There was a higher incidence of AEs in the combination arm compared with either monotherapy. Nevertheless, discontinuation rates were lower with combination therapy (18%) compared to finasteride (24%) and doxazosin (27%) monotherapy [27] Impact on the natural history Given the fact that the concept of medical therapy is a lifelong strategy, the impact of any medical approach on the natural history of the disease (AUR/ surgery) is of importance. Although open-label and post-marketing studies can provide some evidence

7 1528 european urology 51 (2007) in this respect, randomised, controlled trials (RCTs) remain the gold standard to reliably assess this issue. The low incidence of AUR and of surgical intervention emphasise the need for long-term placebo trials. The substantial costs of such trials explain the paucity of long-term data Plant extracts Three 12-mo trials provide information regarding the impact on AUR [34,37,38]. In two studies, the rate of AUR was identical between the plant extract and the respective comparator; in the third study the plant extract was even superior to finasteride regarding the risk of AUR (0.8% vs. 2.9%) [34,37,38]. The fact that plant extracts (such as a 1 -blockers) have no impact on prostate volume and PSA renders a positive impact on the natural history (AUR/need for surgery) unlikely The a 1 -blockers Two long-term (2 yr and 4.5 yr), placebo-controlled trials allow a reliable assessment of the impact of a 1 -blockers on the natural history [27,28]. The MTOPS study showed that doxazosin given for 4.5 yr has no effect on prostate volume, challenging the in vivo clinical relevance of the in vitro apoptotic potential [27,76]. Doxazosin only delayed the time to AUR by about 2 yr, but did not significantly reduce the cumulative incidence when compared to placebo (2.7% vs. 2.0%) after 4.5 yr [27]. The cumulative incidence of invasive therapy was also not significantly affected by doxazosin [27]. This study has been criticised for the use of a rather old a-blocker and it has been doubted whether these data can be extrapolated to modern a 1 -blockers. Such a trial has been recently published [28]. Roehrborn et al randomised 1522 men 1:1 into a placebo and an alfuzosin arm; patients were followed for 24 mo [28]. Alfuzosin did not reduce the risk of AUR (alfuzosin 2.1% vs. placebo 1.8%, p = 0.82) [28]. There was a trend towards a lower risk for surgery in the alfuzosin arm (5.1% vs. 6.5%) that did not reach statistical significance [28]. In summary, the two long-term placebo-controlled trials as well as indirect evidence from registry data suggest that doxazosin and alfuzosin have no relevant impact on the natural history [27,28]. Souverein et al studied a population-based cohort of 5671 patients using the PHARMO Record Linkage System [77]. Patients taking a 1 -blockers had a significantly increased risk of BPH-related prostatic surgery compared to those receiving 5-ARIs [77]. This difference was sustained after stratification of time period and the inclusion of patients who had surgery within 1 mo of treatment initiation [77]. Despite these data, the concept of a trial without a catheter (TWOC) with a-blockade in patients with AUR became widely accepted [78 80]. Little is known regarding the long-term outcome of these patients. Shah et al reported on an RCT that was extended open label up to 2 years [80]. Of the 33 patients who entered the open-label phase, 13 (40%) had a transurethral prostatectomy (TURP) within the first year and three died due to non-bph causes. Of the remaining 17 patients, 6 (35%) required a TURP for severe LUTS resulting in an overall TURP rate of 68% [80]. These long-term data challenge the role of a TWOC under a-blockade and emphasise the need for more long-term studies on this issue ARIs The 5-ARIs have a well-documented positive impact on the natural history [27,59 61]. Dutasteride reduces the risk for AUR compared to placebo by 48% and the risk for surgery by 55% [61]. Long-term trials with finasteride yielded comparable reductions. In MTOPS (4.5 yr) the risk reduction for AUR was 68% and for the risk of surgery 64%; in the Proscar Long-term Efficacy and Safety Study (PLESS) (4 yr), the respective numbers were 57% and 55% and in the Proscar Worldwide Efficacy and Safety Study (PROWESS) (2 yr) 57% and 40% [27,59,60]. The 2-yr open extension of the 4-yr PLESS trial has documented a sustained decrease in the incidence of AUR and BPH-related surgery [81]. PLESS and MTOPS results underline the link between increased baseline serum PSA levels and prostate volume and the increased risk for AUR/BPH-related surgery. Patients with a prostate volume >30 ml and a serum PSA of >1.6 ng/ml (such as those with a baseline Q max <10.6 ml/s, PVR 39 ml, and older than 62 yr) had an increased risk for AUR/surgery. These data support a risk-stratified patient management (see below); patients at an increased risk for progression are the ideal cohort for long-term 5-ARIs Combination therapy As indicated above, the VA Cooperative Study and PREDICT trials were too short (12 mo) for a reliable assessment in this respect. Hence, only the MTOPS study can provide relevant information [62]. Although combination therapy was most effective in reducing the risk of overall progression, this approach was not superior to 5-ARI monotherapy regarding the impact on AUR or BPH-related surgery [27,48,50]. Within 4.5 yr, the cumulative incidence of AUR was 0.8% for finasteride and 0.5% for combination therapy compared to 2.4% for placebo [27]. Similarly, the incidence of BPH-related surgery was 5.0% for placebo versus 1.8% for finasteride and 1.5%

8 european urology 51 (2007) with combination therapy [27]. Subsequent analyses of the MTOPS study identified prostate volume as a decisive factor; combination therapy had the greatest benefit in reducing symptoms, bother, and the risk of AUR in men with higher baseline prostate volume and PSA [62]. 6. Pharmacoeconomic aspects The Trans European into the Use of Management Policies for BPH in Primary Healthcare (TRIUMPH) study determined medical consumption and costs during a 1-yr follow-up in a cross-sectional European study [82]. Treatment costs for 5057 patients (66 yr) averaged at s858/patient ranging from s292 in the United Kingdom to s1337 in Poland [82]. Medication was the most important (75%) cost driver followed by surgery (15%) and diagnostic steps (8%). Choice of medication, complications, and undergoing surgery were associated with higher costs [82]. Remarkable are the substantial differences in prescribing patterns throughout Europe [83]. The range of prescribing plant extracts in six European countries ranged from 3.5% (Italy) to 37% (Germany), of a-blockers from 60.4% (Germany) to 98.5% (United Kingdom), and of 5-ARIs from 1.5% (United Kingdom) to 7.2% (Poland) [83]. These data suggest that most likely other than medical factors trigger the choice of medical management [83]. Verhamme et al reported on discontinuation rates in a real-life setting (GP-database in the Netherlands) [84]. Discontinuation rates were 33% for a-blockers, 27% for 5-ARIs, and 29% for combination therapy [84]. In real life, the median total duration of use of pharmacologics was short, only 3 mo. Hence, clinical trials artificially improve persistence and adherence [84]. McDonald et al performed a pharmacoeconomic analysis of the MTOPS data and projected the costs over a 15-yr period [85]. As expected, combination therapy was more expensive than monotherapy with doxazosin but also more effective. The calculated costs of combination therapy per quality of life-year gained was $34,085 for all patients; this amount declined to $27,283 for men at a higher risk of progression (PSA > 3.2 ng/ml), a value that was considered cost effective [85]. Disantostefano et al calculated BPH-related costs over 20 yr in detail [8]. Treatment costs within the first year were estimated at $195 (US dollars) for watchful waiting, $628 for a 1 -blockers, $900 for 5-ARIs, $1333 for combination therapy, $4073 for transurethral microwave thermotherapy (TUMT) and $7201 for TURP [8]. The annual costs for subsequent years of the six treatments were $108, $541, $870, $1247, $54, and $54, respectively [8]. After 20 yr the most costly therapy was combination therapy followed by 5-ARIs, TURP, TUMT, a 1 -blockers, and watchful waiting. The a 1 -blockers are the least expensive treatment (apart from watchful waiting) and are effective in relieving symptoms yet have no effect on the natural history [8]. Inthe future real-life pharmacoepidemiologic data by linking dispensing and prescribing data will provide important insights in influencing drug use in the general practice, for example, who is using what and for how long [86]. 7. Prevention Intraprostatic DHT is the principal intracellular androgen in the prostate and plays a key role in the development of BPE. Therefore, early intervention with 5-ARIs is a logical preventive approach. Such data were recently reported for the PCPT [87]. After 7 yr, all LUTS/BPE/BPO parameters were favourable in the finasteride arm: urgency, 12.9% vs. 15.9%; AUR, 4.2% vs. 6.3%; TURP, 1.0% vs. 1.9%; prostatitis, 4.4% vs. 6.1%; and urinary tract infection, 1.0 vs. 1.3% [87]. 8. Targeting the patient 8.1. When to intervene? The optimal time point to initiate medical therapy is a matter of debate. Although all guidelines recommend a conservative approach for men with minimal symptoms, several observations argue in favour of early intervention [2,41,42]. First, the PCPT data suggest even the preventive use with finasteride [87]. Second, long-term data of the watchful waiting versus TURP VA trial showed that patients initially randomised to TURP had a better long-term outcome [88]. And finally, the 4-yr dutasteride trial demonstrated that longer therapy results in a better long-term outcome [89]. The mechanisms leading to these observations remain poorly defined, yet increasing BPO, detrusor hypocontractility, and detrusor overactivity are most likely involved [90]. Medical therapy should not be continued uncritically. Vela-Navarrete et al have shown that within a decade ( ) patients undergoing BPH surgery were older (72 vs. 69 yr) and had larger prostates, and there was a higher rate of open surgery (28.6% vs. 18.8%) [91]. The authors speculated that these observations were due to the progressive nature of the disease, which is not affected by a 1 -blockers [91].

9 1530 european urology 51 (2007) How to intervene? Current knowledge on the natural history, on risk factors for progression, and on the long-term outcome of medical therapy provides the scientific basis for a risk-adapted management [2,16,19,20,41,42]. Plant extracts are currently not clearly recommended by any BPH guidelines [2,41,42]. Thea 1 -blockers are the therapy of choice for patients with moderate of severe bothersome LUTS and a low risk of progression (ie, a prostate volume <30 40 ml). Combination therapy should be reserved for moderately or severely symptomatic patients with a high risk of progression; the a 1 -blocker can be safely stopped after 6 12 mo [65]. The preventive use of 5-ARIs in men with no or mild LUTS combined with a higher risk of progression, despite scientific soundness, is currently not a generally accepted. 9. Conclusions Although the knowledge on the long-term outcome of medical therapy has increased substantially, it is still limited [92]. There is a sharp contrast between the duration of the longest controlled trial (4.5 yr) and the situation in real life with treatment periods up to one to two decades of life. Within the past decade no new classes of drugs in the management of LUTS due to BPH have been introduced into clinical practice [93,94]. The pathogenesis of BPH is still largely unresolved, but multiple partially overlapping and complementary systems (nerve, endocrine, and immune) and local para/luminocrine pleiotropic factors are likely to be involved [95]. It is hoped that upcoming generations of BPH drugs will interfere with these molecular mechanisms, thus enhancing the efficacy of the conservative approach. Conflicts of interest The authors have nothing to disclose. References [1] Marberger M, Harkaway R, de la Rosette J. Optimizing the medical management of benign prostatic hyperplasia. Eur Urol 2004;45: [2] Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, de la Rosette JJ. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: [3] Schulman CC. Long-term aspects of medical treatment of BPH. Eur Urol 2001;40(Suppl 3):8 12. [4] Denis L, McConnell J, Yoshida O. The evaluation and treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction. In: Denis L, Griffiths K, Khoury S, editors. Fourth International Consultation on Benign Prostatic Hyperplasia (BPH). Paris: SCI; p [5] Teillac P, Scarpa RM. Economic issues in the treatment of BPH. Eur Urol Suppl 2006;5: [6] Madersbacher S, Haidinger G, Struhal G, for the Prostate Study Group of the Austrian Society of Urology. Management of lower urinary tract symptoms of elderly men in Austria. Eur Urol 2001;39: [7] Berges RR, Pientka L. Management of the BPH syndrome in Germany: who is treated and how? Eur Urol 1999;36(Suppl 3):21 7. [8] Disantostefano RL, Biddle AK, Lavelle JP. An evaluation of the economic costs and patient-related consequences of treatments for benign prostatic hyperplasia. BJU Int 2006;97: [9] Jacobson SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology 2001;58(Suppl 6A): [10] Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU Int 2006;97(Suppl 2):3 6. [11] Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I. Incidence rates and risk factors for acute urinary retention: the health professionals follow-up study. J Urol 1999;162: [12] Kok ET, Bohnen AM, Groeneveld FP, Busschbach JJ, Blanker MH, Bosch JL. Changes in disease specific and generic quality of life related to changes in lower urinary tract symptoms: the Krimpen study. J Urol 2005;174: [13] Kok ET, Bohnen AM, Bosch JL, Thomas S, Groeneveld FP. Patient s quality of life and coping style influence general practitioner s management in men with lower urinary tract symptoms: the Krimpen study. Qual Life Res 2006;15: [14] Kok ET, Groeneveld FP, Gouweloos J, et al. Determinants of seeking of primary care for lower urinary tract symptoms: the Krimpen study in community-dwelling men. Eur Urol 2006;50: [15] Mishra V, Emberton M. To what extent do real life practice studies differ from randomized controlled trials in lower urinary tract symptoms/benign prostatic hyperplasia? Curr Opin Urol 2006;16:1 4. [16] Roehborn CG. Definition of at-risk patients: baseline variables. BJU Int 2006;97(Suppl 2):7 11. [17] Roberts RO, Lieber MM, Jacobsen DJ, Girman CJ, Jacobsen SJ. Limitations of using outcomes in the placebo arm of a clinical trial of benign prostatic hyperplasia to quantify those in the community. Mayo Clin Proc 2005;80: [18] Anderson JB, Roehborn CG, Schalken JA, Emberton M. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol 2001;39: [19] Emberton M. The hallmarks of BPH progression and risk factors. Eur Urol Suppl 2003;2(8):2 7.

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