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What are the Data on 5α-Reductase Inhibitor Treatment of Benign Prostatic Hyperplasia from Everyday Practice?
european urology supplements 6 (2007) 460–466
available at www.sciencedirect.com journal homepage: www.europeanurology.com
What are the Data on 5a-Reductase Inhibitor Treatment of Benign Prostatic Hyperplasia from Everyday Practice? Franc¸ois Desgrandchamps * Department of Urology, Hoˆpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France
Article info
Abstract
Keywords: Benign prostatic hyperplasia 5a-reductase inhibitor Lower urinary tract symptoms
The 5a-reductase (5-AR) inhibitors finasteride and dutasteride have been shown to be efficacious and well tolerated in large-scale, randomised, controlled trials (RCTs) of men with symptomatic benign prostatic hyperplasia (BPH). RCTs are the gold standard in therapeutic investigations, providing the most robust scientific evidence for efficacy and safety. However, there has been a resurgence of interest in the value of everyday practice and open-label studies as an adjunct to RCTs. Although such studies provide less robust evidence, the less stringent enrolment criteria allow examination of efficacy in more representative patient populations. Dutasteride has been studied in a French open-label study that enrolled 400 patients. After 24 wk of daily dutasteride treatment, 73% of patients had met the primary end point for a decrease of at least 3 points on the International Prostate Symptom Score. Dutasteride was well tolerated with a low incidence of sexual adverse events. This study therefore demonstrates that dutasteride produces beneficial effects in clinical practice with an acceptable tolerability profile. Insight into the long-term effects of the 5-AR inhibitors in BPH can also be drawn from the open-label extensions of the phase 3 trials of finasteride and dutasteride. These data sets offer an interesting insight into how symptom-based outcome measures are affected by study unblinding, while also providing valuable information to support the long-term safety and sustained efficacy of these drugs. # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. * Tel. +33 1 42 49 96 21; Fax: +39 1 42 49 96 16. E-mail address: [email protected].
1.
Introduction
The 5a-reductase (5-AR) inhibitors, finasteride and dutasteride, have both been studied in large-scale, randomised, controlled trials (RCTs), providing the highest level of scientific evidence, level 1, for their efficacy and tolerability in the treatment of men with symptomatic benign prostatic hyperplasia
(BPH). Whilst data from large-scale, randomised, blinded studies are rightly considered to provide the most robust evidence for therapeutic interventions, there has been a resurgence of interest in the value of open-label and real-life practice data to supplement blinded findings [1]. In RCTs, restrictive and selective inclusion and exclusion criteria lead to recruitment of relatively
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eursup.2007.01.011
european urology supplements 6 (2007) 460–466
homogeneous patient populations. As a result, RCTs have high internal validity and reproducibility. However, RCTs are associated with some limitations that reduce their external validity and applicability to everyday clinical practice. The criteria for patient selection can lead to patient populations that are not representative of the breadth of patients seen in clinical practice. Available evidence also suggests that participation in a formal study places both physician and patient in a situation in which they act differently from an everyday consultation [2]. Although long-term RCTs provide the gold standard in terms of efficacy and tolerability data, short-term RCTs followed by open-label extension phases may sometimes be more appropriate in certain situations. For example, when class efficacy has already been demonstrated, they may be used to overcome ethical issues associated with long-term placebo use while still providing important long-term tolerability and effectiveness information. This is an important consideration in progressive diseases such as BPH, where long-term outcomes are a key measure of treatment success. Open-label studies, on the other hand, provide a less robust level of evidence compared with RCTs. However, the less stringent enrolment criteria allow recruitment of patient populations that are more representative of daily practice. For example, in one clinical study of hormone therapy for BPH, only 16% of 409 consecutive patients referred by general practitioners fulfilled the inclusion criteria [3]. This highlights the high degree of patient selection for RCTs and shows how few patients from the general population meet the eligibility criteria. Open-label studies also provide insight into compliance in the absence of frequent follow-up and can determine overall treatment effects (including any placebo effect) on subjective parameters such as symptoms in the clinical setting where patients are aware of their treatment allocation [4,5]. As such, they have lower internal but greater external validity. Real-life practice studies provide data that are the most representative of a true clinical setting because these studies have no enrolment criteria. It is, therefore, logical to consider RCTs, openlabel extensions to RCTs, open-label studies, and real-life practice studies as complementary scientific tools, with open-label and real-life practice data having value as an adjunct to those from RCTs [1,2]. Whereas the level of scientific evidence runs in a decreasing manner from RCTs through RCT openlabel extensions and open-label studies, to real-life practice studies, the applicability of the findings to everyday clinical practice can be considered in the opposite direction. In this article, real-life practice
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and open-label data for 5-AR inhibitors are reviewed and are compared and contrasted with those from RCTs, to add further insight into the role of 5-AR inhibitors in the management of BPH in clinical practice.
2.
The 5-AR inhibitors: evidence from RCTs
A large body of data from RCTs demonstrates the efficacy and safety of 5-AR inhibitors in the treatment of BPH. Finasteride, a type 2 5-AR inhibitor, was initially studied in two phase 3 trials that enrolled 1645 men with mild to severe symptomatic BPH. Patients were randomised to receive finasteride, 1 or 5 mg, or placebo for 12 mo. At month 12, significant decreases in urinary symptoms and prostate volume, and a significant increase in peak urinary flow rate (Qmax), were observed in patients receiving finasteride 5 mg compared with those receiving placebo [6,7]. In a later RCT, the Proscar Long-term Efficacy and Safety Study (PLESS), finasteride 5 mg significantly reduced the risks of acute urinary retention (AUR) and the need for surgery over 4 yr compared with placebo in 3040 men with moderate to severe lower urinary symptoms (LUTS) due to BPH [8]. Finasteride was shown to be generally well tolerated. A formal meta-analysis of a total of six RCTs in men with BPH showed the beneficial effects of finasteride to be consistent among studies [9]. In contrast with finasteride, which is a selective inhibitor of the type 2 isoenzyme of 5-AR at therapeutic doses, dutasteride is a dual inhibitor of both the type 1 and type 2 isoenzymes [10–12]. More comprehensive inhibition of the 5-AR isoenzymes results in a significantly greater degree and consistency of dihydrotestosterone (DHT) inhibition with dutasteride than finasteride (94.7% 3.3% vs. 70.8% 18.3%; p < 0.001) [13]. The efficacy and safety of the dual 5-AR inhibitor dutasteride has been investigated in three large-scale RCTs enrolling a total of 4325 men with moderate to severe symptomatic BPH. Patients were randomised to receive dutasteride 0.5 mg or placebo for 2 yr. At 24 mo, men receiving dutasteride had significant decreases in severity of urinary symptoms, prostate volume, and risk of AUR or surgery, and a significant increase in Qmax [14]. The significant decreases in prostate volume and improvements in Qmax were observed from month 1, whereas significant benefits in terms of symptom improvement were demonstrated from 3 mo in one study and 6 mo in the pooled analysis. Dutasteride was well tolerated and the incidence of adverse effects was comparable with that observed for
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finasteride [8]. The beneficial effects of 5-AR inhibitors in the treatment of symptomatic BPH have therefore been clearly demonstrated in large-scale RCTs. However, given the selected patient populations in these studies and, in consideration of the other limitations of RCTs, confirmation of these findings in real-life practice would further support the applicability of the findings to the general population.
3. 5-AR inhibitors: evidence from real-life practice and open-label studies A recently published study reported findings from an open-label study of dutasteride in BPH [15]. The study, conducted in France, enrolled 400 patients from 72 centres; patients received dutasteride 0.5 mg for 24 wk. Although open-label studies normally include enrolment criteria, these are usually less narrow than in RCTs. For example, in this study, recruited men had to be aged 50 yr with symptomatic BPH of any degree of severity and a minimum prostate volume of 30 ml. A history of prostate cancer, prostate surgery, or AUR within 6 mo before study entry, previous treatment with 5-AR inhibitors, and treatment with a-blockers, phytotherapy, drugs with antiandrogenic properties, or anabolic steroids within 2 wk of study entry were exclusion criteria. However, unlike the dutasteride phase 3a studies, there were no entry criteria limits in terms of symptom severity, Qmax, and prostate-specific antigen (PSA) level [14]. The primary end point in this open-label study was the proportion of patients with a decrease of 3 points in their International Prostate Symptom Score (IPSS) at 24 wk; secondary end points were the changes from baseline in mean IPSS and mean BPH Impact Index (BII) score at 3 and 6 mo, a visual analogue scale (VAS; from 0 to 100) for bother due to urinary symptoms, a VAS for treatment satisfaction, and data on adverse events during the 24-wk treatment period and 16-wk follow-up period. The VAS end points were chosen because they provide a straightforward assessment of the benefit of therapy in a ‘‘real-world’’ format. Of the 400 patients enrolled, 399 were included in the safety analysis and 366 in the efficacy analysis. A total of 18% of patients withdrew during the 6-mo study, 11% because of adverse events. This compares favourably with a withdrawal rate of 38% in a 6-mo pharmacovigilance study of 12,484 patients treated with the a-blocker tamsulosin [16]. At week 24, 72.5% of patients had met the primary end point for a decrease of at least 3 points on the IPSS; the mean change in IPSS and BII at this point were
Fig. 1 – The proportion of patients with mild (International Prostate Symptom Score [IPSS], 0–7), moderate (IPSS, 8–19), and severe (IPSS, I20) symptoms at baseline and week 24 in a French open-label study of dutasteride in symptomatic benign prostatic hyperplasia [15].
6.2 and 2.3, respectively. There were significant decreases compared with baseline in mean IPSS and mean BII score at weeks 12 and 24. The proportions of patients with mild (IPSS, 0–7), moderate (IPSS, 8– 19), and severe (20) symptoms at baseline and month 24 are shown in Fig. 1. There was a shift in profile from baseline to end point with the proportion of men with severe symptoms decreasing from 28% to 6%, those with moderate symptoms decreasing from 59% to 48%, whereas the proportion of those with mild symptoms rose from 13% to 46%. Mean VAS bother score decreased by 20 points (over a 100-point scale) and there was a significant increase in VAS treatment satisfaction score from baseline to weeks 12 and 24. Although 157 (39%) of the patients reported at least one adverse event during the study, only 77 (19%) of these were adjudged to be related to dutasteride administration. The majority (11%) were sexual disorders (7% erectile dysfunction, 4% decreased libido, and < 1% ejaculatory disorders). In this openlabel setting, dutasteride was therefore well tolerated with a low proportion of men experiencing sexual adverse events, that is, data that were consistent with those reported in the RCTs. This study demonstrates that dutasteride improves symptoms, patient quality of life, and patient discomfort and satisfaction in a clinical practice setting with an acceptable tolerability profile. An interesting aspect to open-label studies is that beneficial effects of treatment on symptom-based parameters often appear amplified compared with RCTs. This is evident when the symptom score results from the dutasteride double-blind and openlabel studies are compared. From similar baseline values, patients assigned to dutasteride in the double-blind trials had a mean change from baseline
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Fig. 2 – Comparison of mean International Prostate Symptom Scores from a French open-label study and the phase 3 programme of dutasteride in men with symptomatic benign prostatic hyperplasia [14,15].
in American Urological Association Symptom Index (AUA-SI) score of 3.2 at month 6, whereas in the French open-label study, the mean change from baseline in the similar IPSS score at month 6 was 6.2 (Fig. 2). Such an observation is typical for an openlabel study where treatment allocation is unblinded. Although this observation cannot be viewed in isolation from blinded data, it does provide an indication of the level of effect that is achieved when the patient is aware of the active nature of their therapy. Differences in study populations may have also been reflected in these different outcomes. The prospective, cross-sectional, observational, pan-European study, the Trans European Research into the use of Management Policies for BPH in Primary Healthcare (TRIUMPH) study, was initiated to examine the usage and effectiveness of pharmacotherapy for LUTS secondary to BPH in real-life practice in six European countries (France, Germany, Italy, Poland, Spain, and the United Kingdom) [17]. Treatment outcomes were recorded over a 1-yr period for 2351 men with newly diagnosed BPH who received a-blockers, 5-AR inhibitors, or phytotherapy. In 77 patients treated with the 5-AR inhibitor finasteride, a mean reduction in IPSS of 4.1 was observed and 75% of patients experienced an improvement in IPSS. Baseline characteristics for the patient population receiving finasteride were not reported in full; however, mean age was 65.8 yr, mean initial IPSS was 12.5, and 70% had an enlarged prostate (volume not defined). The mean reduction in IPSS seen in this observational study was comparable with that from an AUA metaanalysis of randomised clinical trial data for finasteride [18].
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Further real-life insight can be drawn from a population-based cohort study carried out in The Netherlands that aimed to assess and compare the risk of BPH-related surgery [19]. A total of 1430 men aged at least 45 yr were included in the study and followed for a median of 2.4 yr. Compared with patients undergoing watchful waiting, the risk of BPH-related surgery was reduced by 60% for patients using 5-AR inhibitors. Further, patients using 5-AR inhibitors at any stage had a statistically significant reduced risk of surgery compared with patients using a-blockers. When the occurrence of AUR was considered, 4.5% of patients in the watchful waiting group experienced this event and 2.4% of patients in the a-blocker group compared with 0% of patients who received 5-AR inhibitors. This study therefore serves to provide real-life evidence for the beneficial effects of 5-AR inhibitors in reducing the risk of BPHrelated progression events. Because medical therapy for men with BPH is intended for long-term use, it is important to investigate whether efficacy is maintained and adverse events do not accrue with time for these treatments. Insight into the long-term effects of the 5-AR inhibitors in BPH can be drawn from the openlabel extensions from RCTs. These data sets offer an interesting insight into how symptom-based outcome measures are affected by study unblinding. After the 1-yr, randomised, placebo-controlled component of the two finasteride phase 3 trials, patients were invited to participate in an open-extension study in which all patients received finasteride 5 mg. In total, 6-yr finasteride data were available in 487 patients originally randomised to finasteride and 5-yr finasteride data were available in 238 patients originally randomised to placebo [20]. These long-term data demonstrated that the median decrease in serum DHT levels was approximately 75% after 6 yr versus 70% after the first year of finasteride therapy, showing durable suppression of DHT. Treatment with finasteride also led to sustainable improvements in urinary symptoms, flow rate, and prostate volume (Fig. 3). Further to this report by Lowe et al., 10-yr follow-up data from an individual study centre in the North American trial have also been published [21]. Of 43 originally randomised patients, 51% continued to take finasteride at 10 yr. In this small population, finasteride was well tolerated and no new adverse events were recorded with increasing duration of exposure. Additional 2-yr, open-label data for finasteride are also available following completion of the original 4-yr randomised, controlled PLESS study [22]. These data demonstrated that finasteride treatment led to a sustained decrease in the incidence of AUR and/or
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of sexual adverse events fell; in year 4 of treatment, the incidences of impotence, decreased libido, and ejaculation disorders were 0.4%, 0.1%, and 0.1%, respectively. These data indicate that the nearcomplete, long-term suppression of DHT achieved with dutasteride did not lead to an increased incidence in adverse events [24]. In patients who received dutasteride for 4 yr, prostate volume continued to decrease from months 24 to 48, although this decrease was not statistically significant ( p = 0.07). AUA-SI score also decreased significantly from months 24 to 48 ( p < 0.001); the overall reduction from baseline was 6.5 points (Fig. 4). Fig. 3 – Mean change in quasi-American Urological Association Symptom Score over 6 yr of finasteride treatment in men with symptomatic benign prostatic hyperplasia [20]. The first year was double-blind with the subsequent 5 yr open-label.
surgery in men with BPH. Interestingly, the incidence of AUR and/or surgery in year 6 was similar in patients who switched from placebo to finasteride in the extension compared with those who had received finasteride continuously throughout the 6-yr period. Adverse events associated with finasteride were sexual in nature, with rates of impotence, decreased libido, and ejaculation disorder of 4.8%, 3.8%, and 3.1% in the first year of therapy, respectively. The incidence of these events in subsequent years of therapy was lower, with a trend of decline over time [20]. Data are also available from the open-label extension of the dutasteride phase 3a trials [23]. Of the 4325 patients who were randomised in the double-blind phase of the studies, 2340 patients were enrolled into the extension – 1188 who had previously received dutasteride and 1152 who had previously received placebo. In the group who had received dutasteride throughout the study, a median decrease from baseline in serum DHT of 93.7% at month 24 was maintained to month 48 (95.3%). Patients who had received placebo for the first 2 yr of the study and then switched to dutasteride had a median decrease in DHT of 95.4% at month 48 that was similar to that in patients receiving 4 yr of dutasteride. As with finasteride, the most common adverse events reported with dutasteride in the first year of therapy were impotence (6.0%), decreased libido (3.7%), and ejaculation disorders (1.8%). Gynaecomastia was also reported in 1.3% of men compared with 0.5% in the placebo group. Over time, with the exception of gynaecomastia, the incidence
Fig. 4 – Mean change in American Urological Association Symptom Index scores (A) and Qmax (B) from baseline over 48 mo from the open-label extension study to the phase 3 programme with dutasteride [23]. Line with striped squares = placebo/dutasteride-treated subjects (P/D); line with dotted squares = dutasteride/dutasteride-treated subjects (D/D). For panel A, *p < 0.001 between treatment groups; yp < 0.001 for differences for both treatment groups from month 24. For panel B, *p < 0.001 between treatment groups; zp = 0.032 between treatment groups; yp = 0.042 between treatment groups; ¤p < 0.001 versus month 24; § p = 0.039 versus month 24; Tp = 0.007 versus month 24.
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Qmax also increased significantly from months 24 to 48 ( p = 0.007). For all these parameters, the magnitude of benefit was significantly greater in patients who received dutasteride compared with those who were originally randomised to placebo and then switched to dutasteride at 2 yr. These findings indicate that for 4 versus 2 yr of treatment, a longer duration of therapy results in greater treatment benefit. Although it is possible that the delayed treatment group may eventually reach equivalence with the group that received dutasteride since baseline, these data do suggest that a delay in treatment results in less favourable outcomes, over the time course studied. Long-term treatment with dutasteride therefore provides durable benefits [23], with no new safety concerns identified during the open-label phase of the study [24]. In long-term trials, it is possible that patients who experience a better treatment response are the most likely to participate in study extensions. To investigate the extent of self-selection in the finasteride open-label extension, baseline data and responses at year 1 for patients with 6-yr data were compared with those for patients who discontinued before completing 6 yr of treatment [20]. The analysis showed that baseline data and responses at year 1 were similar between the two groups, indicating that the long-term data obtained in this study were not subject to significant bias. Similarly, in the dutasteride open-label extension, men who received dutasteride in both the double-blind and open-label phases of the study had similar characteristics (AUA-SI score, prostate volume, Qmax, and change from baseline in AUA-SI score, prostate volume, and Qmax) at month 24 to those patients who chose not to continue in the open-label phase [23]. Overall the completion rate in this study was high; of those who enrolled in the extension, 73% of patients receiving dutasteride from baseline and 70% of those initially randomised to placebo completed the 4-yr study. The role of a-blocker therapy in the management of symptomatic BPH is well established, with this class of therapy offering a rapid onset of symptom amelioration. However, data from the large-scale, comparative Medical Therapy of Prostatic Symptoms (MTOPS) study have demonstrated that, in contrast with 5-AR inhibitors, a-blockers do not significantly reduce the long-term risks of AUR or BPH-related surgery [25]. In real-life practice, this difference in profile has been highlighted in a retrospective analysis of observational data conducted in the United Kingdom [26]. The cohort contained 4500 patients with BPH or LUTS strongly suggestive of BPH. These real-life data from a mean follow-up of 25.2 mo showed that the 3601 patients
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prescribed an a-blocker were significantly more likely to experience AUR or surgery compared with the 879 patients prescribed a 5-AR inhibitor. The impact of 5-AR inhibitor therapy on BPH progression was apparent as early as 3 mo and continued to increase through to month 24.
4.
Conclusions
Although randomised, controlled trials provide the gold standard for efficacy and safety data, everyday practice and open-label studies can offer another perspective, examining efficacy in less highly selected populations, compliance in the absence of frequent follow-up, and overall treatment effects on symptom-based parameters. They should therefore be viewed as a valuable adjunct to, rather than a replacement for, RCTs. The benefits of the 5-AR inhibitors, finasteride and dutasteride, in men with BPH have been clearly demonstrated in large-scale RCTs. They have also been demonstrated in openlabel and observational studies providing results on how these therapies perform in everyday clinical practice. The extensions of the phase 3 trials have also provided valuable information supporting the longterm safety and durability of efficacy of these drugs.
Conflicts of interests The author has nothing to disclose.
Acknowledgements Medical writing support for this manuscript was provided by Alexander Gray.
References [1] 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. [2] Michel MC, Goepel M. Treatment satisfaction of patients with lower urinary tract symptoms: randomised controlled trials vs. real life practice. Eur Urol 2000;38(Suppl 1):40–7. [3] Eri LM, Tveter KJ. Patient recruitment to and cost of a prospective trial of medical treatment for benign prostatic hyperplasia. Eur Urol 1992;22:9–13. [4] van Leeuwen JH, Castro R, Busse M, Bemelmans BL. The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol 2006;50:440– 52, discussion 453.
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[5] Nickel JC. Placebo therapy of benign prostatic hyperplasia: a 25-month study. Canadian PROSPECT Study Group. Br J Urol 1998;81:383–7. [6] Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992;327:1185–91. [7] The Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate 1993;22:291–9. [8] McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–63. [9] Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996;48:398–405. [10] Bramson HN, Hermann D, Batchelor KW, et al. Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther 1997;282:1496–502. [11] Clark RV. Effective suppression of dihydrotestosterone (DHT) by GI198745, a novel, dual 5 alpha reductase inhibitor. J Urol 1999;161(Suppl 4):268 (abstract 1037). [12] McConnell JD, Wilson JD, George FW, et al. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992;74:505–8. [13] Clark RV, Hermann DJ, Cunningham GR, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab 2004;89:2179–84. [14] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434–41. [15] Desgrandchamps F, Droupy S, Irani J, Saussine C, Comenducci A. Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice. BJU Int 2006;98: 83–8. [16] Shakir S, Pearce G, Mann RD. Finasteride and tamsulosin used in benign prostatic hypertrophy: a review of the
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prescription-event monitoring data. BJU Int 2001;87: 789–96. Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries. Eur Urol 2007;51:207–15, discussion 215–6. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 3. Results of the treatment outcomes analyses. Available at www.auanet.org. Accessed 22 January 2007. Souverein PC, van Riemsdijk MM, de la Rosette JJ, Opdam PC, Leufkens HG. Treatment of benign prostatic hyperplasia and occurrence of prostatic surgery and acute urinary retention: a population-based cohort study in the Netherlands. Eur Urol 2005;47:505–10. Lowe FC, McConnell JD, Hudson PB, et al. Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia. Urology 2003;61:791–6. Lam JS, Romas NA, Lowe FC. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10-year follow-up. Urology 2003;61:354–8. Roehrborn CG, Bruskewitz R, Nickel JC, et al. Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia. J Urol 2004;171:1194–8. Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5a-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 2004;46:488–94, discussion 495. Schulman C, Pommerville P, Hofner K, Wachs B. Longterm therapy with the dual 5alpha-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia. BJU Int 2006;97:73–9, discussion 79–80. McConnell JD, Roehrborn CG, Bautista OM, et al. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. Boyle P, Roehrborn C, Harkaway R, et al. 5-alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery. Eur Urol 2004; 45:620–6, discussion 626–7.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
What are the Data on 5a-Reductase Inhibitor Treatment of Benign Prostatic Hyperplasia from Everyday Practice? Franc¸ois Desgrandchamps * Department of Urology, Hoˆpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France
Article info
Abstract
Keywords: Benign prostatic hyperplasia 5a-reductase inhibitor Lower urinary tract symptoms
The 5a-reductase (5-AR) inhibitors finasteride and dutasteride have been shown to be efficacious and well tolerated in large-scale, randomised, controlled trials (RCTs) of men with symptomatic benign prostatic hyperplasia (BPH). RCTs are the gold standard in therapeutic investigations, providing the most robust scientific evidence for efficacy and safety. However, there has been a resurgence of interest in the value of everyday practice and open-label studies as an adjunct to RCTs. Although such studies provide less robust evidence, the less stringent enrolment criteria allow examination of efficacy in more representative patient populations. Dutasteride has been studied in a French open-label study that enrolled 400 patients. After 24 wk of daily dutasteride treatment, 73% of patients had met the primary end point for a decrease of at least 3 points on the International Prostate Symptom Score. Dutasteride was well tolerated with a low incidence of sexual adverse events. This study therefore demonstrates that dutasteride produces beneficial effects in clinical practice with an acceptable tolerability profile. Insight into the long-term effects of the 5-AR inhibitors in BPH can also be drawn from the open-label extensions of the phase 3 trials of finasteride and dutasteride. These data sets offer an interesting insight into how symptom-based outcome measures are affected by study unblinding, while also providing valuable information to support the long-term safety and sustained efficacy of these drugs. # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. * Tel. +33 1 42 49 96 21; Fax: +39 1 42 49 96 16. E-mail address: [email protected].
1.
Introduction
The 5a-reductase (5-AR) inhibitors, finasteride and dutasteride, have both been studied in large-scale, randomised, controlled trials (RCTs), providing the highest level of scientific evidence, level 1, for their efficacy and tolerability in the treatment of men with symptomatic benign prostatic hyperplasia
(BPH). Whilst data from large-scale, randomised, blinded studies are rightly considered to provide the most robust evidence for therapeutic interventions, there has been a resurgence of interest in the value of open-label and real-life practice data to supplement blinded findings [1]. In RCTs, restrictive and selective inclusion and exclusion criteria lead to recruitment of relatively
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eursup.2007.01.011
european urology supplements 6 (2007) 460–466
homogeneous patient populations. As a result, RCTs have high internal validity and reproducibility. However, RCTs are associated with some limitations that reduce their external validity and applicability to everyday clinical practice. The criteria for patient selection can lead to patient populations that are not representative of the breadth of patients seen in clinical practice. Available evidence also suggests that participation in a formal study places both physician and patient in a situation in which they act differently from an everyday consultation [2]. Although long-term RCTs provide the gold standard in terms of efficacy and tolerability data, short-term RCTs followed by open-label extension phases may sometimes be more appropriate in certain situations. For example, when class efficacy has already been demonstrated, they may be used to overcome ethical issues associated with long-term placebo use while still providing important long-term tolerability and effectiveness information. This is an important consideration in progressive diseases such as BPH, where long-term outcomes are a key measure of treatment success. Open-label studies, on the other hand, provide a less robust level of evidence compared with RCTs. However, the less stringent enrolment criteria allow recruitment of patient populations that are more representative of daily practice. For example, in one clinical study of hormone therapy for BPH, only 16% of 409 consecutive patients referred by general practitioners fulfilled the inclusion criteria [3]. This highlights the high degree of patient selection for RCTs and shows how few patients from the general population meet the eligibility criteria. Open-label studies also provide insight into compliance in the absence of frequent follow-up and can determine overall treatment effects (including any placebo effect) on subjective parameters such as symptoms in the clinical setting where patients are aware of their treatment allocation [4,5]. As such, they have lower internal but greater external validity. Real-life practice studies provide data that are the most representative of a true clinical setting because these studies have no enrolment criteria. It is, therefore, logical to consider RCTs, openlabel extensions to RCTs, open-label studies, and real-life practice studies as complementary scientific tools, with open-label and real-life practice data having value as an adjunct to those from RCTs [1,2]. Whereas the level of scientific evidence runs in a decreasing manner from RCTs through RCT openlabel extensions and open-label studies, to real-life practice studies, the applicability of the findings to everyday clinical practice can be considered in the opposite direction. In this article, real-life practice
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and open-label data for 5-AR inhibitors are reviewed and are compared and contrasted with those from RCTs, to add further insight into the role of 5-AR inhibitors in the management of BPH in clinical practice.
2.
The 5-AR inhibitors: evidence from RCTs
A large body of data from RCTs demonstrates the efficacy and safety of 5-AR inhibitors in the treatment of BPH. Finasteride, a type 2 5-AR inhibitor, was initially studied in two phase 3 trials that enrolled 1645 men with mild to severe symptomatic BPH. Patients were randomised to receive finasteride, 1 or 5 mg, or placebo for 12 mo. At month 12, significant decreases in urinary symptoms and prostate volume, and a significant increase in peak urinary flow rate (Qmax), were observed in patients receiving finasteride 5 mg compared with those receiving placebo [6,7]. In a later RCT, the Proscar Long-term Efficacy and Safety Study (PLESS), finasteride 5 mg significantly reduced the risks of acute urinary retention (AUR) and the need for surgery over 4 yr compared with placebo in 3040 men with moderate to severe lower urinary symptoms (LUTS) due to BPH [8]. Finasteride was shown to be generally well tolerated. A formal meta-analysis of a total of six RCTs in men with BPH showed the beneficial effects of finasteride to be consistent among studies [9]. In contrast with finasteride, which is a selective inhibitor of the type 2 isoenzyme of 5-AR at therapeutic doses, dutasteride is a dual inhibitor of both the type 1 and type 2 isoenzymes [10–12]. More comprehensive inhibition of the 5-AR isoenzymes results in a significantly greater degree and consistency of dihydrotestosterone (DHT) inhibition with dutasteride than finasteride (94.7% 3.3% vs. 70.8% 18.3%; p < 0.001) [13]. The efficacy and safety of the dual 5-AR inhibitor dutasteride has been investigated in three large-scale RCTs enrolling a total of 4325 men with moderate to severe symptomatic BPH. Patients were randomised to receive dutasteride 0.5 mg or placebo for 2 yr. At 24 mo, men receiving dutasteride had significant decreases in severity of urinary symptoms, prostate volume, and risk of AUR or surgery, and a significant increase in Qmax [14]. The significant decreases in prostate volume and improvements in Qmax were observed from month 1, whereas significant benefits in terms of symptom improvement were demonstrated from 3 mo in one study and 6 mo in the pooled analysis. Dutasteride was well tolerated and the incidence of adverse effects was comparable with that observed for
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finasteride [8]. The beneficial effects of 5-AR inhibitors in the treatment of symptomatic BPH have therefore been clearly demonstrated in large-scale RCTs. However, given the selected patient populations in these studies and, in consideration of the other limitations of RCTs, confirmation of these findings in real-life practice would further support the applicability of the findings to the general population.
3. 5-AR inhibitors: evidence from real-life practice and open-label studies A recently published study reported findings from an open-label study of dutasteride in BPH [15]. The study, conducted in France, enrolled 400 patients from 72 centres; patients received dutasteride 0.5 mg for 24 wk. Although open-label studies normally include enrolment criteria, these are usually less narrow than in RCTs. For example, in this study, recruited men had to be aged 50 yr with symptomatic BPH of any degree of severity and a minimum prostate volume of 30 ml. A history of prostate cancer, prostate surgery, or AUR within 6 mo before study entry, previous treatment with 5-AR inhibitors, and treatment with a-blockers, phytotherapy, drugs with antiandrogenic properties, or anabolic steroids within 2 wk of study entry were exclusion criteria. However, unlike the dutasteride phase 3a studies, there were no entry criteria limits in terms of symptom severity, Qmax, and prostate-specific antigen (PSA) level [14]. The primary end point in this open-label study was the proportion of patients with a decrease of 3 points in their International Prostate Symptom Score (IPSS) at 24 wk; secondary end points were the changes from baseline in mean IPSS and mean BPH Impact Index (BII) score at 3 and 6 mo, a visual analogue scale (VAS; from 0 to 100) for bother due to urinary symptoms, a VAS for treatment satisfaction, and data on adverse events during the 24-wk treatment period and 16-wk follow-up period. The VAS end points were chosen because they provide a straightforward assessment of the benefit of therapy in a ‘‘real-world’’ format. Of the 400 patients enrolled, 399 were included in the safety analysis and 366 in the efficacy analysis. A total of 18% of patients withdrew during the 6-mo study, 11% because of adverse events. This compares favourably with a withdrawal rate of 38% in a 6-mo pharmacovigilance study of 12,484 patients treated with the a-blocker tamsulosin [16]. At week 24, 72.5% of patients had met the primary end point for a decrease of at least 3 points on the IPSS; the mean change in IPSS and BII at this point were
Fig. 1 – The proportion of patients with mild (International Prostate Symptom Score [IPSS], 0–7), moderate (IPSS, 8–19), and severe (IPSS, I20) symptoms at baseline and week 24 in a French open-label study of dutasteride in symptomatic benign prostatic hyperplasia [15].
6.2 and 2.3, respectively. There were significant decreases compared with baseline in mean IPSS and mean BII score at weeks 12 and 24. The proportions of patients with mild (IPSS, 0–7), moderate (IPSS, 8– 19), and severe (20) symptoms at baseline and month 24 are shown in Fig. 1. There was a shift in profile from baseline to end point with the proportion of men with severe symptoms decreasing from 28% to 6%, those with moderate symptoms decreasing from 59% to 48%, whereas the proportion of those with mild symptoms rose from 13% to 46%. Mean VAS bother score decreased by 20 points (over a 100-point scale) and there was a significant increase in VAS treatment satisfaction score from baseline to weeks 12 and 24. Although 157 (39%) of the patients reported at least one adverse event during the study, only 77 (19%) of these were adjudged to be related to dutasteride administration. The majority (11%) were sexual disorders (7% erectile dysfunction, 4% decreased libido, and < 1% ejaculatory disorders). In this openlabel setting, dutasteride was therefore well tolerated with a low proportion of men experiencing sexual adverse events, that is, data that were consistent with those reported in the RCTs. This study demonstrates that dutasteride improves symptoms, patient quality of life, and patient discomfort and satisfaction in a clinical practice setting with an acceptable tolerability profile. An interesting aspect to open-label studies is that beneficial effects of treatment on symptom-based parameters often appear amplified compared with RCTs. This is evident when the symptom score results from the dutasteride double-blind and openlabel studies are compared. From similar baseline values, patients assigned to dutasteride in the double-blind trials had a mean change from baseline
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Fig. 2 – Comparison of mean International Prostate Symptom Scores from a French open-label study and the phase 3 programme of dutasteride in men with symptomatic benign prostatic hyperplasia [14,15].
in American Urological Association Symptom Index (AUA-SI) score of 3.2 at month 6, whereas in the French open-label study, the mean change from baseline in the similar IPSS score at month 6 was 6.2 (Fig. 2). Such an observation is typical for an openlabel study where treatment allocation is unblinded. Although this observation cannot be viewed in isolation from blinded data, it does provide an indication of the level of effect that is achieved when the patient is aware of the active nature of their therapy. Differences in study populations may have also been reflected in these different outcomes. The prospective, cross-sectional, observational, pan-European study, the Trans European Research into the use of Management Policies for BPH in Primary Healthcare (TRIUMPH) study, was initiated to examine the usage and effectiveness of pharmacotherapy for LUTS secondary to BPH in real-life practice in six European countries (France, Germany, Italy, Poland, Spain, and the United Kingdom) [17]. Treatment outcomes were recorded over a 1-yr period for 2351 men with newly diagnosed BPH who received a-blockers, 5-AR inhibitors, or phytotherapy. In 77 patients treated with the 5-AR inhibitor finasteride, a mean reduction in IPSS of 4.1 was observed and 75% of patients experienced an improvement in IPSS. Baseline characteristics for the patient population receiving finasteride were not reported in full; however, mean age was 65.8 yr, mean initial IPSS was 12.5, and 70% had an enlarged prostate (volume not defined). The mean reduction in IPSS seen in this observational study was comparable with that from an AUA metaanalysis of randomised clinical trial data for finasteride [18].
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Further real-life insight can be drawn from a population-based cohort study carried out in The Netherlands that aimed to assess and compare the risk of BPH-related surgery [19]. A total of 1430 men aged at least 45 yr were included in the study and followed for a median of 2.4 yr. Compared with patients undergoing watchful waiting, the risk of BPH-related surgery was reduced by 60% for patients using 5-AR inhibitors. Further, patients using 5-AR inhibitors at any stage had a statistically significant reduced risk of surgery compared with patients using a-blockers. When the occurrence of AUR was considered, 4.5% of patients in the watchful waiting group experienced this event and 2.4% of patients in the a-blocker group compared with 0% of patients who received 5-AR inhibitors. This study therefore serves to provide real-life evidence for the beneficial effects of 5-AR inhibitors in reducing the risk of BPHrelated progression events. Because medical therapy for men with BPH is intended for long-term use, it is important to investigate whether efficacy is maintained and adverse events do not accrue with time for these treatments. Insight into the long-term effects of the 5-AR inhibitors in BPH can be drawn from the openlabel extensions from RCTs. These data sets offer an interesting insight into how symptom-based outcome measures are affected by study unblinding. After the 1-yr, randomised, placebo-controlled component of the two finasteride phase 3 trials, patients were invited to participate in an open-extension study in which all patients received finasteride 5 mg. In total, 6-yr finasteride data were available in 487 patients originally randomised to finasteride and 5-yr finasteride data were available in 238 patients originally randomised to placebo [20]. These long-term data demonstrated that the median decrease in serum DHT levels was approximately 75% after 6 yr versus 70% after the first year of finasteride therapy, showing durable suppression of DHT. Treatment with finasteride also led to sustainable improvements in urinary symptoms, flow rate, and prostate volume (Fig. 3). Further to this report by Lowe et al., 10-yr follow-up data from an individual study centre in the North American trial have also been published [21]. Of 43 originally randomised patients, 51% continued to take finasteride at 10 yr. In this small population, finasteride was well tolerated and no new adverse events were recorded with increasing duration of exposure. Additional 2-yr, open-label data for finasteride are also available following completion of the original 4-yr randomised, controlled PLESS study [22]. These data demonstrated that finasteride treatment led to a sustained decrease in the incidence of AUR and/or
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of sexual adverse events fell; in year 4 of treatment, the incidences of impotence, decreased libido, and ejaculation disorders were 0.4%, 0.1%, and 0.1%, respectively. These data indicate that the nearcomplete, long-term suppression of DHT achieved with dutasteride did not lead to an increased incidence in adverse events [24]. In patients who received dutasteride for 4 yr, prostate volume continued to decrease from months 24 to 48, although this decrease was not statistically significant ( p = 0.07). AUA-SI score also decreased significantly from months 24 to 48 ( p < 0.001); the overall reduction from baseline was 6.5 points (Fig. 4). Fig. 3 – Mean change in quasi-American Urological Association Symptom Score over 6 yr of finasteride treatment in men with symptomatic benign prostatic hyperplasia [20]. The first year was double-blind with the subsequent 5 yr open-label.
surgery in men with BPH. Interestingly, the incidence of AUR and/or surgery in year 6 was similar in patients who switched from placebo to finasteride in the extension compared with those who had received finasteride continuously throughout the 6-yr period. Adverse events associated with finasteride were sexual in nature, with rates of impotence, decreased libido, and ejaculation disorder of 4.8%, 3.8%, and 3.1% in the first year of therapy, respectively. The incidence of these events in subsequent years of therapy was lower, with a trend of decline over time [20]. Data are also available from the open-label extension of the dutasteride phase 3a trials [23]. Of the 4325 patients who were randomised in the double-blind phase of the studies, 2340 patients were enrolled into the extension – 1188 who had previously received dutasteride and 1152 who had previously received placebo. In the group who had received dutasteride throughout the study, a median decrease from baseline in serum DHT of 93.7% at month 24 was maintained to month 48 (95.3%). Patients who had received placebo for the first 2 yr of the study and then switched to dutasteride had a median decrease in DHT of 95.4% at month 48 that was similar to that in patients receiving 4 yr of dutasteride. As with finasteride, the most common adverse events reported with dutasteride in the first year of therapy were impotence (6.0%), decreased libido (3.7%), and ejaculation disorders (1.8%). Gynaecomastia was also reported in 1.3% of men compared with 0.5% in the placebo group. Over time, with the exception of gynaecomastia, the incidence
Fig. 4 – Mean change in American Urological Association Symptom Index scores (A) and Qmax (B) from baseline over 48 mo from the open-label extension study to the phase 3 programme with dutasteride [23]. Line with striped squares = placebo/dutasteride-treated subjects (P/D); line with dotted squares = dutasteride/dutasteride-treated subjects (D/D). For panel A, *p < 0.001 between treatment groups; yp < 0.001 for differences for both treatment groups from month 24. For panel B, *p < 0.001 between treatment groups; zp = 0.032 between treatment groups; yp = 0.042 between treatment groups; ¤p < 0.001 versus month 24; § p = 0.039 versus month 24; Tp = 0.007 versus month 24.
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Qmax also increased significantly from months 24 to 48 ( p = 0.007). For all these parameters, the magnitude of benefit was significantly greater in patients who received dutasteride compared with those who were originally randomised to placebo and then switched to dutasteride at 2 yr. These findings indicate that for 4 versus 2 yr of treatment, a longer duration of therapy results in greater treatment benefit. Although it is possible that the delayed treatment group may eventually reach equivalence with the group that received dutasteride since baseline, these data do suggest that a delay in treatment results in less favourable outcomes, over the time course studied. Long-term treatment with dutasteride therefore provides durable benefits [23], with no new safety concerns identified during the open-label phase of the study [24]. In long-term trials, it is possible that patients who experience a better treatment response are the most likely to participate in study extensions. To investigate the extent of self-selection in the finasteride open-label extension, baseline data and responses at year 1 for patients with 6-yr data were compared with those for patients who discontinued before completing 6 yr of treatment [20]. The analysis showed that baseline data and responses at year 1 were similar between the two groups, indicating that the long-term data obtained in this study were not subject to significant bias. Similarly, in the dutasteride open-label extension, men who received dutasteride in both the double-blind and open-label phases of the study had similar characteristics (AUA-SI score, prostate volume, Qmax, and change from baseline in AUA-SI score, prostate volume, and Qmax) at month 24 to those patients who chose not to continue in the open-label phase [23]. Overall the completion rate in this study was high; of those who enrolled in the extension, 73% of patients receiving dutasteride from baseline and 70% of those initially randomised to placebo completed the 4-yr study. The role of a-blocker therapy in the management of symptomatic BPH is well established, with this class of therapy offering a rapid onset of symptom amelioration. However, data from the large-scale, comparative Medical Therapy of Prostatic Symptoms (MTOPS) study have demonstrated that, in contrast with 5-AR inhibitors, a-blockers do not significantly reduce the long-term risks of AUR or BPH-related surgery [25]. In real-life practice, this difference in profile has been highlighted in a retrospective analysis of observational data conducted in the United Kingdom [26]. The cohort contained 4500 patients with BPH or LUTS strongly suggestive of BPH. These real-life data from a mean follow-up of 25.2 mo showed that the 3601 patients
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prescribed an a-blocker were significantly more likely to experience AUR or surgery compared with the 879 patients prescribed a 5-AR inhibitor. The impact of 5-AR inhibitor therapy on BPH progression was apparent as early as 3 mo and continued to increase through to month 24.
4.
Conclusions
Although randomised, controlled trials provide the gold standard for efficacy and safety data, everyday practice and open-label studies can offer another perspective, examining efficacy in less highly selected populations, compliance in the absence of frequent follow-up, and overall treatment effects on symptom-based parameters. They should therefore be viewed as a valuable adjunct to, rather than a replacement for, RCTs. The benefits of the 5-AR inhibitors, finasteride and dutasteride, in men with BPH have been clearly demonstrated in large-scale RCTs. They have also been demonstrated in openlabel and observational studies providing results on how these therapies perform in everyday clinical practice. The extensions of the phase 3 trials have also provided valuable information supporting the longterm safety and durability of efficacy of these drugs.
Conflicts of interests The author has nothing to disclose.
Acknowledgements Medical writing support for this manuscript was provided by Alexander Gray.
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