The Efficacy of Drugs for the Treatment of LUTS/BPH, A Study in 6 European Countries

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1 european urology 51 (2007) available at journal homepage: Benign Prostatic Hyperplasia The Efficacy of Drugs for the Treatment of LUTS/BPH, A Study in 6 European Countries Annie Hutchison a, *, Richard Farmer a, Katia Verhamme b, Richard Berges c, Remigio Vela Navarrete d a Postgraduate Medical School, University of Surrey, Guildford, United Kingdom b Erasmus MC, Department Medical Informatics, Rotterdam, The Netherlands c Department of Urology, PAN-Klinik, Köln, Germany d Fundacion Jimenez Diaz, Madrid, Spain Article info Article history: Accepted June 8, 2006 Published online ahead of print on June 27, 2006 Keywords: Lower urinary tract symptoms TRIUMPH Benign prostatic hyperplasia International prostate symptom score Alpha-blockers Phytotherapy Finasteride Abstract Objectives: This paper profiles the usage and effectiveness of various LUTS/ BPH drugs in real-life practice. Method: The TRIUMPH study recorded the treatment and outcomes of 2351 newly-presenting LUTS/BPH patients in 6 European countries over a 1-year follow-up period. At each visit the clinician recorded the treatment, comorbidities, complications and drugs prescribed, and the patient completed an IPSS questionnaire. The results were analysed using change in IPSS as the primary outcome measure. RESULTS: Over the study period 74.9% of patients were prescribed medication, the majority (83% of those medicated) were prescribed only a single drug. Tamsulosin was the most commonly prescribed drug in all countries (38% of medicated cases), although with national variation from 24% in Poland to 70% in Italy. The alpha-blockers were the most effective, with a mean reduction of 6.3 IPSS points. Finasteride was slightly less effective (4.1 points). Significant improvements were seen in 43% of patients on phytotherapy with Serenoa repens or Pygeum africanum compared to 57% of those on finasteride and 68% on alpha-blockers. The only combination therapy found to produce a statistically significant improvement over the use of individual drugs was finasteride + tamsulosin (8.1 points compared to 6.7 for tamsulosin alone and 4.2 for finasteride alone). Conclusions: All drug treatments showed some improvement over watchfulwaiting for most patients over the study period: the alpha-blockers were found to be the most effective. There were marked national differences in prescribing patterns, both in individual drug choice and in the use of combination therapies. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. The TRIUMPH study was supported by Yamanouchi Europe BV. * Corresponding author. Postgraduate Medical School, University of Surrey, Daphne Jackson Road, Manor Park, Guildford, GU2 7WG, United Kingdom. Tel ; Fax: address: a.hutchison@surrey.ac.uk (A. Hutchison) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 208 european urology 51 (2007) Background The management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) requires careful thought. It is generally agreed that treatment choice should be made together with the patient and should be individualized to patients circumstances and personal preference. Initial choices in the management of LUTS/BPH include watchful waiting, pharmacotherapy and surgical intervention [1]. Ultimately the choice of treatment should depend upon its efficacy, speed of onset, durability, tolerability as well as the patient s preference. In addition, because the average patient with LUTS/BPH has a remaining life expectancy of years, both short-term and lifetime management outcomes should be considered [2,3]. Over recent years, pharmacological treatment has become the primary choice for symptomatic BPH, and has been shown to be effective in improving short-term outcomes (maximum flow rate and symptom scores). The two principal drug classes employed are alpha-blockers (e.g. alfuzosin, doxazosin, tamsulosin, and terazosin) and 5-alphareductase inhibitors (e.g. finasteride). Phytotherapy is also available in some countries [4]. Increasingly, evidence indicates that in the long term the selective alpha-blockers such as alfuzosin [5] and tamsulosin [6] and 5-alpha-reductase inhibitors such as finasteride or dutasteride may be equally effective in reducing the risk of treatment failure. Although the different alpha-blockers are equivalent in efficacy [3,7,8], they differ in tolerability, with tamsulosin having the lowest risk for interference with blood pressure control [9]. Alpha-blockers as a class have produced consistent improvements in both BPH symptom scores and urinary flow rates in about 60 70% of patients treated [10]. Witharapid onset of action alpha-blockers are often seen as first-line therapy for patients with moderate to severe LUTS, not only in the short term but also in the long-term management of LUTS/BPH. 5-alphareductase inhibitors inhibit the conversion of testosterone to dihyrotesterone (DHT) and, by reducing the production of DHT, reduce the prostate volume in men in with BPH. RCT s have demonstrated that 5-alpha-reductase inhibitors improve symptom scores, improve urinary flow rate and reduce the risk of AUR and surgery [1,3,4,11]. They are an acceptable treatment option for patients with moderate to severe LUTS and an enlarged prostate [3,4], with, overall, approximately 30 50% of patients appearing to respond to treatment [12]. Finasteride appeared to be effective in long-term therapy for up to 4 or 5 years, albeit in alleviating symptoms associated with a significantly enlarged prostate [12 14]. Studies have suggested that phytotherapy with agents such as lipidosterolic extract of Serenoa repens can provide equivalent efficacy to tamsulosin [8,9]. However, when compared with finasteride, Serenoa repens extract had little effect on so-called androgendependent parameters, even though both treatments relieve the symptoms of BPH in about twothirds of patients [15]. Drug combinations evaluated for the treatment of BPH have included terazosin and finasteride [16], doxazosin with finasteride [14,17,18], and dutasteride with tamsulosin [19]. Savage et al. [16] have reported that combination therapy with terazosin and finasteride provides significantly greater reductions in International Prostate Symptom Score (IPSS) than terazosin or finasteride alone, though efficacy results with a combination doxazosin of finasteride appear inconclusive. O Leary et al. [2] suggest the combination with finasteride may be more beneficial in patients at high risk (patients with large prostate volume, high level of prostate-specific antigen, high IPSS, high postvoid residual amount, and low maximum flow rate). The TRIUMPH (TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare) Study compared the management of LUTS suggestive of BPH in real-life practice in six European countries (France, Germany, Italy, Poland, Spain and the UK). Studies in this area based on national medical databases have previously been published [20,21]. This paper presents data from the TRIUMPH study on drug efficacy and patterns of drug prescription in the treatment of LUTS/BPH within Europe. Other papers in this series review the efficacy of management regimes and the characteristics of patients presenting with LUTS/BPH. 2. Methods Between January 2000 and July LUTS/BPH patients presenting for the first time in primary care were recruited to the TRIUMPH study across France, Germany, Italy, Poland, Spain and the UK. Patients in France, Italy and the UK initially attend general practitioners; those in Poland and Spain initially attend office-based urologists, while those in Germany may attend either. 38 patients withdrew, were lost to follow-up or were diagnosed with prostate cancer; of the remainder 2559 patients completed a one-year follow-up period (8 weeks), and 2370 had valid initial and final IPSS questionnaires. In 19 cases the management regime could not be identified and these were excluded from the analysis, leaving 2351 patients. At recruitment and at subsequent follow-up visits the clinician recorded the treatment, co-morbidities, LUTS/BPH

3 european urology 51 (2007) Table 1 Prescribable LUTS/BPH medications by country Fr Gm It Po Sp UK Alfuzosin Beta sitosterin Brennessel Doxazosin Finasteride Indoramin Meparticina Prazosin Pygeum africanum Serenoa repens Tamsulosin Terazosin = prescribable in country Phytotherapy shown in italics. drugs, complications, and examination results (where available, including digital rectal examination (DRE), PSA, and urine flow measurements). The patient completed an IPSS/qualityof-life questionnaire. All patients had an initial (recruitment) visit and a final (1 year) visit: in addition 21% of patients had one or more intermediate follow-up visits triggered by a change in symptoms or treatment. All visits were taken into account when assigning patients to treatment categories, but only the initial and final IPSS scores were used in the analysis. LUTS/BPH drug availability varied among countries; those prescribable in each country are shown in Table 1. The effectiveness of treatment was evaluated using a change in IPSS between the initial and final visits as the primary outcome measure. A reduction of 4 IPSS points has been suggested as a clinically significant reduction, and this was taken as indicating a worthwhile change insymptom severity. Data was also collected on objective measures such as PSA and prostate volume, however too few patients had both initial and final values to permit their use as an outcome measure (for example only 41 patients had both and initial and final PSAs). Each patient was assigned as a watchful-waiting (WW) if they received neither drugs or surgery over the entire study period, medication if they were prescribed LUTS/BPH drugs at any time in the study but were not treated surgically, or surgery if they were treated surgically regardless of whether or not they also received medication. The treatments considered were those from recruitment to the penultimate follow-up visit (as any treatment initiated at the final visit could not affect the measured outcome). All patients who received drugs were included in the analysis of drug prescribing patterns, regardless of whether or not they were also treated surgically (34 of the 64 surgical patients also received medication). For the analysis of drug efficacy surgical patients were excluded, as were patients receiving more than one drug or class of drug (i.e. switchers). Table 2 shows patient counts by country, source clinician and management regime. Statistical analysis was carried out using Stata (StataCorp, USA: release 9). The distribution of the change in IPSS was non-normal and hence statistical comparisons between groups were made using the non-parametric Kruskal-Wallis test for differences in populations. Change in symptom severity under the different treatments was examined by comparing the centile distributions of the change in IPSS; this showed the effect of treatment across the patient population. In this study a higher centile value indicates a greater improvement in symptoms. Although information on complications and surgery was recorded, there were insufficient cases over the 1-year followup period for valid statistical analysis of the effect of treatment on their incidence. The efficacy of the 3 classes of drug (alpha-blockers, 5- alpha-reductase and phytotherapy) was investigated by randomly matching each patient receiving only one class of drug over the study period to a WW case on age at diagnosis (2 years) and initial IPSS (2 IPSS points), and comparing the medians of the change in IPSS using a non-parametric sign test. There were fewer WW patients than medication cases so a full matching was not possible, however, the numbers of available cases means that this does not affect the statistical validity of the results. 3. Results Over the study period 1456 patients (83% of those prescribed medication) were prescribed only one drug and 1516 patients (86%) were prescribed drugs from only 1 class (Tables 3 and 4). No patient was prescribed more than 3 drugs at any single visit or more than 5 drugs over the study period. There were statistically significant national differences with 34.7% of medicated patients in Italy receiving more than one drug compared to 5.2% in France Table 2 Patient numbers by source, country and management regime Source GP Source Urologist WW Med Surgery Total Cases France (43.8%) 243 (53.8%) 11 (2.4%) 452 Germany (21.7%) 104 (72.7%) 8 (5.6%) 143 Italy (11.1%) 267 (87.3%) 5 (1.6%) 306 Spain (8.9%) 770 (88.1%) 26 (3.0%) 874 Poland (31.2%) 274 (66.3%) 10 (2.4%) 413 UK (54.6%) 70 (42.9%) 4 (2.5%) 163 Total (23.8%) 1728 (73.5%) 64 (2.7%) 2351 Percentages of patients within country.

4 210 european urology 51 (2007) Table 3 Numbers of drugs prescribed at a single visit and over the study period Max num drugs * At single visit Over study period All Fr Gm It Po Sp UK (87.2%) 1456 (82.6%) 94.8% 90.0% 65.3% 81.6% 86.6% 90.1% (12.4%) 259 (14.7%) 4.4% 9.1% 25.1% 16.7% 12.6% 5.6% 3 8 (0.5%) 36 (2.0%) 0.8% 0.9% 6.3% 1.4% 0.7% 4.2% 4 9 (0.5%) 2.6% 0.3% 5 2 (0.1%) 0.7% Total patients Includes surgical patients. * Drugs co-prescribed at a visit. ( p = ). Over the follow-up period 47 patients received 3 or more drugs, in 28 different combinations. There was no discernable pattern to the multiple drug prescribing. The pattern of prescribing to patients receiving only a single drug or class of drug over the study period is shown in Table 4. In all countries tamsulosin was the most commonly used single drug, prescribed to 38% of patients overall, although national levels of prescription varied from 24% in Poland to nearly 70% in Italy. Alpha-blockers were the most popular class in all countries, prescribed to 79% of medicated patients. There were marked national differences in the use of phytotherapy (where prescribable), with 37% of medicated patients in Germany treated solely with phytotherapy compared to less than 4% in Italy Drug efficacy Six of the drugs (beta-sitosterin, brennessel, other phytotherapy, prazosin, meparticina and indoramin) did not show a statistically significant change in mean IPSS, and were excluded from further analyses of named drugs. Fig. 1 shows the mean reduction in IPSS for each of the remaining drugs, and, for comparison, the mean change in WW patients. All of the drugs produced a greater improvement in symptoms than was reported by WW patients. The most effective single drug was tamsulosin, closely followed by the other alpha-blockers. The phytotherapy drugs were the least effective. The proportions of single drug or single drug class patients showing improvement in symptoms (together with various patient characteristics) are Table 4 Prescribing patterns by country for patients prescribed a single drug or single class of drug over the study period All Countries Fr Gm It Po Sp UK Named Drug Alfuzosin 149 (10.2%) 12.7% 10.1% 5.1% 13.3% 4.6% 6.3% Doxazosin 217 (14.9%) 11.0% 5.1% 1.7% 21.6% 18.3% 1.6% Finasteride 78 (5.4%) 3.0% 3.0% 6.2% 7.4% 3.8% 1.6% Beta-sitosterin 9 (0.6%) 8.1% 0.2% Serenoa repens 83 (5.7%) 16.5% 16.2% 4.0% 1.1% 5.8% Brennessel 8 (0.5%) 5.1% 0.5% Other phytotherapy 36 (2.5%) 0.4% 3.0% 5.0% Pygeum africanum 91 (6.3%) 8.9% 9.1% 5.0% Prazosin 4 (0.3%) 0.4% 4.7% Tamsulosin 559 (38.4%) 46.0% 46.5% 69.5% 24.3% 42.1% 39.1% Terazosin 161 (11.1%) 0.8% 3.0% 8.5% 11.7% 19.6% 29.7% Other non-phytotherapy 54 (3.7%) 0.4% 3.4% 5.9% 0.8% 10.9% Meparticina 3 (0.2%) 1.7% Indoramin 4 (0.3%) 6.3% Total patients Drug Class Phytotherapy 237 (15.6%) 25.3% 36.8% 3.5% 15.9% 10.5% Alpha-blockers 1201 (79.2%) 71.8% 60.4% 91.0% 77.0% 85.9% 98.5% 5-alpha reductase 78 (5.1%) 2.9% 2.8% 5.5% 7.2% 3.6% 1.5% Total patients Includes surgical patients.

5 european urology 51 (2007) Fig. 1 Mean change in IPSS (with 99% CI) for patients prescribed only the named drug during the study period. shown in Table 5, and the effect of drug classes across the patient population are shown in Fig. 2. The patient s characteristics are one of the factors influencing the choice of drug, with, for example, phytotherapy tending to be used on younger patients with less severe symptoms and to those who entered the study with smaller prostates. Finasteride patients tended to have larger prostates. Overall 87% of patients prescribed alpha-blockers showed a reduction in symptoms (mean reduction 6.3 IPPS points), compared to 74% of those on phytotherapy (3.2 point reduction) and 75% of those on for 5-alpha-reductase (4.1 point reduction). However only 43% of phytotherapy patients reported a worthwhile improvement (4 or more IPSS points), compared to 68% of alpha-blocker patients and 58% of those on 5-alpha-reductase. The alpha-blockers tamsulosin, doxazosin, terazosin and alfuzosin were equally effective, giving worthwhile improvements in 60% to 70% of patients. Finasteride was slightly less effective, with 57% of patients reporting a worthwhile improvement. There was a correlation between the initial symptom severity and the change in IPSS (r = in WW patients): patients with a higher initial IPSS were more likely to report a greater reduction in symptom severity. To adjust for the effect of the initial IPSS level and age at diagnosis patients receiving only a single class of drug were randomly matched to WW cases on these factors, Table 5 Patient characteristics and proportions of patients showing improvements for those prescribed a single drug or class of drugs p-value change IPSS cf. WW Improvement in IPSS > 4 Any Improvement in IPSS Proportion large prostate * Mean change QoL Mean age at diagnosis Mean change IPSS Mean QoL Mean initial IPSS * No. Cases WW % 59.2% 18.1% Alfuzosin % 88.7% 69.7% Doxazosin % 85.9% 67.6% Finasteride % 75.3% 57.1% Serenoa repens % 78.0% 42.7% Pygeum africanum % 72.2% 43.3% Tamsulosin % 87.4% 76.6% Terazosin % 89.4% 75.0% Other non-phytotherapy % 88.9% 66.7% Phytotherapy % 73.5% 42.7% Alpha-blockers % 87.0% 67.8% alpha reductase % 75.3% 57.1% Excludes surgical patients. Phytotherapy in italics. No further information is available on drugs recorded as other non-phytotherapy. As proportion of those with recorded prostate size by DRE.

6 212 european urology 51 (2007) Fig. 2 Reduction in IPSS over study period for patients receiving only a single class of drug. Fig. 3 Reduction in IPSS over study period for patients receiving only a named non-phytotherapy drug over the study period. and the median change in IPSS in the matched pairs was tested. The results are shown in Table 6. All 3 classes of drug produced statistically significant improvements in symptom severity (albeit marginal in the case of finasteride). Patients receiving medication also reported an improved quality of life (QoL) compared to those on WW, with a mean improvement of 1.6 points (on a 6 point scale) compared to an improvement of 0.4 points in WW cases. The greatest improvement in QoL was reported with tamsulosin (1.9 points) and the least with the phytotherapies (1 point). The efficacy of named non-phytotherapy drugs is compared to WW in Fig. 3. All produced a statistically significant improvement in symptoms compared to WW. Overall finasteride gave the smallest improvement (mean change of 4.1 IPSS points) and tamsulosin produced the greatest (mean 6.7 points), although (as shown in Fig. 1) all the alpha-blockers were broadly equivalent in efficacy. The alphablockers were not significantly different in efficacy, although the difference between tamsulosin and finasteride was statistically significant ( p = ). Serenoa repens ( p = ) and Pygeum africanum ( p = ) (Fig. 4) both produced a significant improvement in symptoms compared to WW and were about equally effective, giving a mean change of just over 3 IPSS points Combination therapies 226 patients (12.9% of those medicated) received more than one drug at any single visit, of whom 218 (96.5%) received 2 drugs. There were 39 different combinations of two drugs; overall 137 (62.8%) of the 2-drug therapies included finasteride; 31 patients (14.2%) were prescribed phytotherapy in combination with another drug, and 7 (3.2%) were prescribed 2 phytotherapy drugs. Table 7 shows the 5 most common combinations together with their p-values under test for a difference in the effect of the combination and each of the single drugs. Patient numbers in the other combinations were too small to permit analysis. The most effective (and most common) combination of those where the numbers permitted analysis, and the only one producing a statistically significant increase in efficacy, was finasteride + tamsulosin, which produced a worthwhile improvement in 71% of patients. Overall the mean improvement in IPSS under the combination therapy was 8.1 IPSS units, compared to 6.7 for tamsulosin alone and 4.2 for finasteride alone. Table 6 Comparison of patients receiving a single class of drug with WW patients matched on age at diagnosis and initial IPSS Drug treatment Patients matched Median treated Median WW Sign test p-value Phytotherapy 93% Alpha-blockers 41% 4 1 < alpha-reductase 97%

7 european urology 51 (2007) Fig. 4 Reduction in IPSS over study period for patients receiving only a named phytotherapy drug over the study period. 4. Discussion In this prospective study of 2559 patients, newly diagnosed with LUTS/BPH and followed over 1 year, we describe the efficacy of the different medical treatments for LUTS suggestive of BPH in real life practice, using comparison to watchful waiting as the reference. Every European country has its own health care system, its own specific historical and socio-economic background and its own medical traditions. Not surprisingly, differences in prescribing patterns that cannot be accounted for by current clinical guidelines were found. An observational study of this nature has clear limitations for the evaluation of the efficacy. As patients were not randomised to treatments confounding by indication cannot be excluded, and the numbers of patients receiving some medications was too small to permit robust statistical analysis. The relatively short 1-year follow-up period was also a limitation (particularly with regard to the exclusion of patients with prostate cancer), and data was not collected on a number of potentially important factors including body mass index (BMI), ethnic group and socio-economic status. Despite these limitations TRIUMPH remains only trans-european study collating information on the management of LUTS/BPH in primary care. All drug treatments showed some improvement in IPSS compared with WW for most patients over the study period, and this improvement was confirmed (by patient matching) even allowing for the correlation between initial symptom severity and the observed change in IPSS. The study confirmed that the alpha-blockers tamsulosin, doxazosin, terazosin and alfuzosin were about equally effective, producing a worthwhile improvement in symptoms in around 68% of patients (a higher rate than the 30 to 50% reported by Andersen [12]), and these were all marginally more effective than finasteride. The mean reduction in IPSS score for the alpha-blockers was 6.3 points and for 5-alpha-reductase inhibitors 4.1. This is very similar to the results from other studies where overall symptom score reduction of 4 6 points is seen for alpha-blockers and 3 4 points for 5 alphareductase inhibitors [3]. The benefits reported for Serenoa repens and Pygeum africanum were also confirmed. However, the placebo effect is known to be strong with all types of LUTS medications, sometimes producing apparent improvement exceeding those of real drugs. This is especially the case for plant extracts, where the benefit over placebo for most preparations is uncertain [22]. Although earlier studies have reported Senenoa repens to be equally or more effective than tamsulosin [23,24], over a 1-year period these results were not confirmed. These phytotherapies, although giving statistically significant improvements in symptoms, were less effective than the alphablockers or finasteride, and gave worthwhile benefits in less than half of those treated. Table 7 Efficacy of two drug (at a single visit) combinations, and comparison with single drug usage Combination Num cases Mean reduction in IPSS (95% CI) p-values for difference between combination and single drug Combination 1st drug alone 2nd drug alone 1st drug 2nd drug Finasteride + tamsulosin 70 (35.3%) 8.1 ( ) 4.2 ( ) 6.7 ( ) Finasteride + terazosin 27 (32.1%) 6.5 ( ) 4.2 ( ) 6.3 ( ) Finasteride + doxazosin 19 (12.4%) 5.1 ( ) 4.2 ( ) 6.2 ( ) Finasteride + alfuzosin 12 (8.7%) 5.3 ( ) 4.2 ( ) 6.1 ( ) Alfuzosin + tamsulosin 11 (5.5%) 12.3 ( ) 6.1 ( ) 6.7 ( ) Excludes surgical patients.

8 214 european urology 51 (2007) Earlier reports of the benefits of combination therapy with finasteride and either terazosin [16] or doxazosin [14,17] were not confirmed. However the MTOPS study [14] found increased benefit in combination therapy only after the first year, and so no direct comparison of results is possible. The only combination therapy found to produce a statistically significant improvement in IPSS over the use of individual drugs in the first year of use was finasteride + tamsulosin, however relatively small numbers of patients were prescribed the other combinations, and it is possible that the study was underpowed to detect any improvement in these groups. Prescribing patterns are complex, and while there is evidence that patient characteristics affect drug selection, for example the use of phytotherapy for younger, less severe patients and finasteride for those with larger prostates, the study found marked national differences in prescribing patterns, both in the individual drug choices and in the use of multiple drugs, that are not explained by patient characteristics alone. This study reports the use of medication in real life practice, and its findings suggest that clinicians are implementing the lessons from placebo controlled, randomised clinical trials, and that the benefits observed in those trials are obtained in practice. However, it appears that adherence to clinical guidelines in daily practice are affected by strong adherence to tradition, differences in national healthcare systems, and (possibly) by differences in drug pricing and marketing. References [1] Marberger M, Harkaway R, de la Rosette J. 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Int J Urol 2000;7: [10] Kirby RS. Clinical pharmacology of alpha1-blockers. Eur Urol 1999;36:48 53, discussion 65. [11] Debruyne F, Barkin J, van Erps P, Reis M, Tammela TLJ, Roehrborn C. On behalf of the ARIA3001, ARIA3002 and ARIB3003 Study Investigators. Efficacy and safety of long-term treatment with the dual 5a-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 2004;46: (Discussion). [12] Andersen JT. Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review. Drugs Aging 1995;6: [13] Clifford GM, Farmer RD. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol 2000;38:2 19. [14] McConnell JD, Roehrborn CG, Bautista OM, Andriole GL, Dixon CM, Kusek JW, et al., for the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: [15] Carraro JC, Raynaud JP, Koch G, Chisholm GD, Di Silverio F, Teillac P, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 1996;29:231 40, discussion [16] Savage SJ, Spungen AM, Galea G, Britanico J, Vapnek JM. Combination medical therapy for symptomatic benign prostatic hyperplasia. Can J Urol 1998;5: [17] Kirby RS. A randomized, double-blind crossover study of tamsulosin and controlled-release doxazosin in patients with benign prostatic hyperplasia. BJU Int 2003;91:41 4. [18] Doggrell SA. Combination of finasteride and doxazosin for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother 2004;5:

9 european urology 51 (2007) [19] Barkin J, Guimarães M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB. On behalf of the SMART-1 Investigator Group. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5a-reductase inhibitor dutasteride. Eur Urol 2003;44: [20] Logie JW, Clifford GM, Farmer RD, Meesen BP. Lower urinary tract symptoms suggestive of benign prostatic obstruction TRIUMPH: the role of general practice databases. Eur Urol 2001;39:42 7. [21] Verhamme KMC, Dieleman JP, Bleumink GS, Bosch JLHR, Stricker BHCh, Sturkenboom MCJM. Treatment strategies, patterns of drug use and treatment discontinuation in men with LUTS suggestive of benign prostatic hyperplasia: the TRIUMPH project. Eur Urol 2003;44: [22] Dreikorn K, Berges R, Pientka L, Jonas U. Phytotherapy of benign prostatic hyperplasia. Current evidencebased evaluation. Urologe (Ausg A) 2002;41:447 51, [German]. [23] Debruyne F, Boyle P, Calais Da Silva F, Gillenwater JG, Hamdy FC, Perrin P, et al. Evaluation of the clinical benefit of Permixon and tamsulosin in severe BPH patients PERMAL study subset analysis. Eur Urol 2004;45: [24] Debruyne F, Koch G, Boyle P, Da Silva FC, Gillenwater JG, Hamdy FC, et al. For the members of the PERMAL Study Group. Comparison of a phytotherapeutic agent (Permixon) with an a-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002;41: Editorial Comment Oliver Reich, Department of Urology, University-Hospital Munich Grosshadern, Ludwig-Maximilians-University, D Munich, Germany oreich@med.uni-muenchen.de The above observational study by Hutchison et al., part of the TRIUMPH project, reveals some attractive information on real life treatment of lower urinary tract symptoms (LUTS) in those European countries involved. Still, the methodological limitations of this non-controlled trial clearly have to be stressed. Moreover the low rate of less than 50% of the subjects (2351 out of 4979 men) completing follow-up at 12 months has to be considered when conclusions are to be drawn. On the other hand, the number of patients is substantial and elucidates to some extent the standing of medical therapy for LUTS. Unfortunately in that respect, issues like comorbidities or complication, which were recorded, are not reported on. Moreover, objective outcome parameters like maximal flow and PSA were also obviously recorded but not presented in the article. The fairly convincing outcome of phytotherapy must clearly be seen in the light of a non-placebocontrolled setting. Here, as in several other noncontrolled studies, phytotherapy seem to specifically achieve a better subjective outcome. Of interest, regarding phytotherapy the reported high volume of prescription in Germany has been completely deteriorated recently due to novel prescription policies by federal health authorities. The fact that combination therapy (a-blocker plus 5-a-reductase inhibitors), though heavily advocated, plays only a negligible role in real life practice, is one of the important finding of this work. For the small percentage of men treated with combination therapy an additional effect on IPSS improvement could be demonstrated. Even though in a non-controlled manner, these results might be utilized to reaffirm the MTOPS data. However, the negligible prescription of combination therapy means that most European clinicians unintentionally or intentionally ignore the data of MTOPS and its successors, which promote the combination approach even for smaller prostates. Thus the conclusion by Hutchison et al. in their last paragraph that clinicians are implementing the lessons from placebo controlled, randomised clinical trials cannot be entirely supported. Editorial Comment J.J.M.C.H. de la Rosette J.J.Delarosette@amc.uva.nl The paper of Hutchison et al. presents a study on the efficacy of drugs for the treatment of LUTS. It comes to no surprise that alpha blockers were the most effective whereas tamsulosin was the most commonly prescribed drug in all countries. How should we value the real-life data from this (sponsored) project? Indeed the short term efficacy of alpha-blockers for the treatment of LUTS has been proven in numerous studies. However, still little is known about the efficacy on the longer term. In a real-life study by de la Rosette et al. [1] it was shown that the outcome of medical treatment is favourable on the short term. However severe symptoms, poor flow

10 216 european urology 51 (2007) and an enlarged prostate increase the risk of a significant treatment failure. It is recommended that preselection of the most suitable candidates for alpha blockers may reduce this risk. Several other studies support this conclusion and actually the study of Clifford et al. [2] even suggests that the use of medical therapy only postpones surgery instead of effectively treating patients. Since the efficacy of pharmacotherapy for the treatment of (advanced) male LUTS indeed has some limitations, an increasing number of studies investigate if one can actually prevent progression and thus surgery? Souverein et al. [3] performed a study to investigate whether there is a difference in the risk of progressing to BPH-related prostatatic surgery between patients using alpha-blockers and patients using the 5-alpha-reductase inhibitors (5-ARI). It was concluded that alpha-blocker treated patients had a higher risk of BPH-related surgery compared to 5-ARI treated patients. Moreover it is suggested to perform additional research on the long-term outcomes and risk factors for the natural progression of BPH in order to identify the optimal medical treatment for BPH patients according to their baseline characteristics. Studies like this add to the increasing body of evidence that eventually prevention of progression may be the most logical and effective treatment strategy. References [1] de la Rosette JJ, Kortmann BB, Rossi C, Sonke GS, Floratos DL, Kiemeney LA. Long-term risk of re-treatment of patients using alpha-blockers for lower urinary tract symptoms. J Urol 2002;167: [2] Clifford GM, Logie J, Farmer RD. How do symptoms indicative of BPH progress in real life practice? The UK experience. Eur Urol 2000;38: [3] Souverein PC, Erkens JA, de la Rosette JJMCH, Leufkens HGM, Herings RMC. Drug treatment of benign prostatic hyperplasia and hospital admission for BPH-related surgery. Eur Urol 2003;43: