Combination Medical Therapy for Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia
BPH AND BEYOND Combination Medical Therapy for Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia Claus G. Roehrborn, MD Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX Medical therapy with -adrenergic receptor blockers and 5--reductase inhibitors is currently considered first-line treatment for men with moderate to severe symptoms of benign prostatic hyperplasia (BPH). Given the success that has been realized with monotherapy with each of these agents, interest in combination therapy has grown. Large-scale trials to test the efficacy of such combinations are lacking; however, a few studies, such as the Medical Therapy of Prostatic Symptoms trial, have yielded results indicating that the 2 types of agents combined can reduce the risk of symptomatic progression and acute urinary retention, as well as the need for invasive therapy. More research is needed to clarify the roles of these agents in the treatment of BPH and in the optimization of patient quality of life. [Rev Urol. 2005;7(suppl 8):S43–S51] © 2005 MedReviews, LLC Key words: Benign prostatic hyperplasia • Lower urinary tract symptoms • -Adrenergic receptor blockers • 5--Reductase inhibitors n the past 10 years, medical therapy for men with lower urinary tract symptoms (LUTS) suggestive of clinical benign prostatic hyperplasia (BPH), with or without associated bladder outlet obstruction (BOO), has become established worldwide. Medical therapy was recommended as a first-line treatment for men with moderate to severe symptoms by the Agency for Health Care Policy and Research Guidelines for the Diagnosis and Treatment of BPH1-3 and by the recent American Urological Association (AUA) Guidelines for BPH 2003 update.4 This recommendation has been supported by summary recommendations of the International Consultation on BPH, which has been held biannually since 1991.5 I VOL. 7 SUPPL. 8 2005 REVIEWS IN UROLOGY S43 Combination Therapy for LUTS and BPH continued The 2 classes of medications used to treat BPH are -adrenergic receptor blockers and 5--reductase inhibitors. The LUTS associated with BPH have been classified into static and dynamic components, and -adrenergic receptor blockers and 5--reductase inhibitors each target one of these components. Therefore, these medications have been the focus of BPH research. Although the static and dynamic classifications oversimplify urinary tract. It has become clear, however, that other, most likely central, effects also greatly contribute to the symptomatic improvement of BPH. In the 19th century, Cabot6 and White7 demonstrated the effect of ablation on male androgenic hormones. These investigators showed improved symptoms among patients with urinary retention in whom surgical castration had been performed, thus removing the main source of The classification of LUTS is partly based on the assumption that the enlarging transition zone of the prostate produces pressure on the urethra. both the effects of -adrenergic receptor blockers and the complexity of the hydrodynamics of urine flow, they have been a convenient model with which to emphasize the underlying pathophysiologic rationale for using these medications. The classification of LUTS is partly based on the assumption that the enlarging transition zone of the prostate produces pressure on the urethra. This pressure represents the static component of obstruction and leads to a variety of associated symptoms. Conversely, that the prostate, prostatic capsule, and bladder neck all exhibit a rich sympathetic innervation with a high density of 1adrenergic receptors has led to the concept of dynamic obstruction. Dynamic obstruction is caused by tension of the smooth muscle. The tone of this tension is controlled by the sympathetic nervous system via 1-adrenergic receptors. By blocking sympathetic input to the 1-adrenergic receptors, adrenergic receptor blockers aim to relax the smooth muscle of the prostate, its capsule, and the area around the bladder neck and thereby improve urinary flow. This, in turn, relieves both irritative and obstructive symptoms of the lower S44 VOL. 7 SUPPL. 8 2005 endogenous testosterone. Other therapeutic options aimed at the hormonal control of prostate growth have shown similar efficacy. However, the adverse events associated with these options are generally unacceptable. Medical castration via luteinizing hormone– releasing hormone analogues8 and therapy with steroidal or nonsteroidal anti-androgens have been all but abandoned because they produce nearly unavoidable and universal adverse effects, such as erectile dysfunction, lack of libido, hot flashes, and gynecomastia. The only acceptable method of hormonal therapy for BPH targets the 5--reduced form of testosterone—the biologically more active metabolite dihydrotestosterone (DHT). DHT is a product of the 5--reduction of serum testosterone that is induced by the enzyme 5--reductase. Although there are two 5--reductase isoenzymes in the body, the prostate is particularly rich in the 5-reductase isoenzyme type 2, which can be selectively inhibited by the azasteroid finasteride. By suppressing the conversion of testosterone into DHT, which is biologically 10 times more potent than testosterone, both serum and intraprostatic levels REVIEWS IN UROLOGY of DHT are markedly reduced. This reduction causes the glandular epithelial tissue (mostly in the transition zone of the prostate) to atrophy, resulting in a 20% to 30% overall shrinkage of the prostate, which is sustained over at least 6 years. In addition, serum prostate-specific antigen (PSA) levels are reduced by an average of 50% (albeit with an acknowledged significant variability). Two 5--reductase inhibitors are currently available, finasteride and dutasteride, the latter being an inhibitor of both isoenzymes of 5-reductase.9 At present, it does not appear that there are any significant differences in terms of clinical efficacy between these 2 compounds.4 Although available -adrenergic receptor blockers, such as alfuzosin, doxazosin, tamsulosin, and terazosin, differ in their specificity toward the 1A-, 1B-, and 1D-adrenergic receptors, they appear to have similar efficacy in terms of reducing symptoms and improving flow rate.4,10 Given the different pathophysiologic approaches of -adrenergic receptor blockers and 5--reductase inhibitors, it is not surprising that the use of these drugs in combination has been considered as a treatment approach in the hopes of achieving better efficacy than with either drug alone. Several obstacles, however, have prevented large-scale trials to test this hypothesis from being conducted: lack of potential economic benefit for sponsors; large sample sizes required by power calculation; logistic issues, such as subjects having to take 4 tablets per day, including 2 placebo tablets; and design issues (superiority vs equivalency trials, the latter requiring even larger sample sizes). As a result, the evidence regarding combination therapy mostly consists of data from smaller, shorter, and often non–placebo-controlled trials, as well as two 4-arm, Combintion Therapy for LUTS and BPH randomized, placebo-controlled trials of 1-year duration, which will be discussed in some detail. Non–Placebo-Controlled Studies Pushkar and colleagues published and/or presented data from a series of studies in which patients received combination therapy with finasteride and terazosin.11 The investigators reported superior outcomes with combination therapy. The studies, however, lacked placebo control, and outcome assessment was inconsistent. In 1998, Debruyne and colleagues12 reported results on behalf of the ALFIN Study Group. This randomized, double-blind, multicenter trial compared the effects of 6 months of therapy with a sustainedrelease formulation of the 1-adrenergic receptor blocker alfuzosin, 5 mg twice daily (n = 358); finasteride, 5 mg once daily (n = 344); or both drugs in combination (n = 349). Patients in the alfuzosin, finasteride, and combination therapy groups had decreases from baseline symptom score of 6.3, 5.2, and 6.1 points, respectively. The difference in score reduction was significant between the alfuzosin and finasteride groups (P = .01), as well as between the combination therapy and finasteride groups (P = .03). Improvements in peak flow rate (alfuzosin, 1.8 mL/s; finasteride, 1.8 mL/s; combination therapy, 2.3 mL/s) were not significantly different among treatment groups. Reductions in prostate volume of slightly more than 10% were realized in the finasteride and combination therapy arms. PSA levels also decreased significantly in these 2 treatment arms, whereas no change was observed in the alfuzosin arm. This trial, as well as the previously mentioned studies, lacked a placebo group and, therefore, did not allow systematic analysis of the effect of prostate volume on response to treatment. Another study compared the efficacy of terazosin, finasteride, or a combination of both in 195 men with enlarged prostate glands.13 All patients—those receiving terazosin (n = 64), finasteride (n = 65), or combination therapy (n = 66)—were well matched at baseline. Decreases in symptom score of 4.9, 4.1, and 6.4 points from baseline were realized at Placebo-Controlled Trials To date, 3 placebo-controlled trials studying the issue of combination medical therapy for LUTS and BPH have been published in the peer-reviewed literature: The Veterans Affairs (VA) Cooperative Studies Benign Prostatic Hyperplasia Study; the Prospective European Doxazosin and Combination Therapy (PREDICT) To date, 3 placebo-controlled trials studying the issue of combination medical therapy for LUTS and BPH have been published in the peerreviewed literature. 12 months for the terazosin, finasteride, and combination therapy arms, respectively; the differences between the combination therapy group and both the finasteride and terazosin groups were significant, whereas the difference between the terazosin and finasteride groups was not. Improvements in flow rate of 1.2 mL/s, 4.0 mL/s, and 4.9 mL/s were realized for the terazosin, finasteride, and combination therapy groups, respectively. The authors provided information on study patients with prostates of 40 mL or larger (n = 33). In the finasteride group, these patients had greater improvement in symptom score compared with those with prostates less than 40 mL (n = 32) (6.3 points vs 1.6 points; P < .01). However, prostate size did not influence the change in symptom score in the terazosin or combination therapy groups. Similarly, improvement in peak urinary flow rate was greater for the patients in the finasteride group who had prostate volumes of 40 mL or more (5.4 mL/s vs 3.2 mL/s; P < .05). Although this study also lacked a placebo group, it differed from the previous studies in that it enrolled patients with particularly large prostates (average, 46.8 mL by transrectal ultrasonography [TRUS]). trial; and the Medical Therapy of Prostatic Symptoms (MTOPS) trial, which is the largest, longest, and perhaps most important of the 3 studies.14-20 The VA Cooperative Studies Benign Prostatic Hyperplasia Study The VA Cooperative Studies Benign Prostatic Hyperplasia Study Group conducted a 1-year, double-blind, placebo-controlled trial in men with BPH.19 A total of 1229 men were randomized to receive placebo (n = 305); finasteride, 5 mg/d (n = 310); terazosin at a forced titration to 10 mg/d, with permission to reduce the dosage to 5 mg/d in the event of an adverse effect (n = 305); or a combination of finasteride and terazosin (n = 309). At 52 weeks, symptom scores in the terazosin and combination groups were significantly lower than at baseline and lower than those in the placebo and finasteride groups (Figure 1A). Changes in symptom score from baseline for the finasteride and placebo groups were also significant, but the difference between those groups was not. The same was true for improvement in peak urinary flow rate (Figure 1B). As expected, prostate volume reduction and a decrease in PSA level (by nearly 50%) were noted VOL. 7 SUPPL. 8 2005 REVIEWS IN UROLOGY S45 Combination Therapy for LUTS and BPH continued A B PREDICT 0 ⫺1 ⫺2 ⫺3 ⫺4 ⫺5 ⫺6 ⫺7 ⫺8 ⫺9 ⫺10 4.0 Mean Qmax Change (mL/s) Mean IPSS Change (Points) VA Cooperative VA Cooperative PREDICT 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Placebo Finasteride α-Blocker (terazosin or doxazosin) Combination therapy Figure 1. Improvements in (A) International Prostate Symptom Score (IPSS) and (B) maximum flow rate (Qmax ) in the 4 treatment groups of the Veterans Affairs (VA) Cooperative Trial and the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Data from Lepor H et al. N Engl J Med. 1996;335:533-53917; Kirby RS et al. Urology. 2003;61:119-126.18 in the finasteride and combination arms only.17 In a subsequent publication, the authors evaluated secondary outcome parameters, including symptom problem score (range, 0-28 points) and BPH Impact Index score (range, 0-13 points), and attempted to stratify patients by baseline prostate volume.16 The PREDICT Trial The PREDICT study group recently published data from a similar European multicenter, randomized, placebo-controlled trial, also lasting 52 weeks.18 The study included 1095 patients with LUTS and BPH aged 50 to 80 years, each with an International Prostate Symptom Score (IPSS) of 12 or higher, a maximum flow rate between 5 mL/s and 15 mL/s with a total voided volume of greater than 150 mL, and an enlarged prostate as determined by digital rectal examination (DRE). Patients were randomized to receive placebo; finasteride, 5 mg; doxazosin titrated to response based on an IPSS improvement of 30% or more and an improvement of 3 mL or greater in maximum flow rate; or a combination of finasteride and doxazosin. S46 VOL. 7 SUPPL. 8 2005 Similar to the results of the VA Cooperative Trial, both doxazosin and the combination of doxazosin and finasteride produced statistically significant improvements in all outcome parameters (IPSS, maximum flow rate, quality-of-life score, and BPH Impact Index score) compared with placebo and finasteride alone (P < .05). Finasteride alone did not differ from placebo with respect to maximum flow rate and quality-of-life score and only marginally differed with respect to BPH Impact Index score and total IPSS (.05 ≤ P < .10) (see Figure 1). The MTOPS Trial The MTOPS trial is not only the largest but also the longest study ever undertaken in the field of LUTS and clinical BPH. The study design has been previously published.19,20 Participants were men aged 50 years or older with an AUA symptom score of 8 to 30 and a maximum urinary flow rate between 4 mL/s and 15 mL/s with a voided volume of at least 125 mL. A total of 3047 patients were enrolled from 1993 through 1998 at 17 academic centers and were followed for 4 to 5 years (average, 4.5 years). REVIEWS IN UROLOGY Patients with a previous medical or surgical intervention for LUTS or BPH, supine blood pressure lower than 90/70 mm Hg, or a serum PSA level of greater than 10 ng/mL were excluded from the study. Subjects were randomly assigned in a double-blind fashion to 1 of 4 treatment groups: placebo, doxazosin, finasteride, or combination therapy. Finasteride was administered as a 5-mg daily dose. The dosage of doxazosin was increased weekly from 1 mg daily to 2-, 4-, and 8-mg daily doses. Participants unable to tolerate the 8-mg dose of doxazosin were given a 4-mg dose; those unable to tolerate both the 8-mg and 4-mg doses were counted as having discontinued doxazosin therapy. Quarterly assessments were conducted in the research centers; DREs, serum PSA measurements, and urinalyses were performed annually. Prostate volume was assessed at baseline and at the end of year 5 or end of study, whichever came first. In contrast with previous trials, the primary outcome in the MTOPS trial was overall clinical progression, defined as the occurrence of 1 of the following 5 events: an increase in the Combintion Therapy for LUTS and BPH Table 1 Baseline Data (Mean ± SD) From the MTOPS Trial* Characteristic Age, y Placebo (n = 737) 62.5 ± 7.5 Doxazosin (n = 756) 62.7 ± 7.2 Finasteride (n = 768) 62.6 ± 7.3 Combination Therapy (n = 786) 62.7 ± 7.1 Race, % white 82 83 84 81 AUA symptom score 16.8 ± 5.9 17.0 ± 5.8 17.6 ± 5.9 16.8 ± 5.8 TRUS, mL 35.2 ± 18.8 36.9 ± 21.6 36.9 ± 20.6 36.4 ± 19.2 Qmax, mL/s 10.5 ± 2.6 10.3 ± 2.5 10.5 ± 2.5 10.6 ± 2.5 PVR, mL 69.6 ± 82.1 69.2 ± 88.2 66.2 ± 80.0 67.5 ± 81.1 PSA, ng/mL 2.3 ± 2.0 2.4 ± 2.1 2.4 ± 2.1 2.3 ± 1.9 Creatinine, mg/dL 1.1 ± 0.1 1.1 ± 0.1 1.1 ± 0.1 1.1 ± 0.1 MTOPS, Medical Therapy of Prostatic Symptoms; AUA, American Urological Association; TRUS, prostate volume measured by transrectal ultrasonography; PVR, postvoid residual urine volume; PSA, prostate-specific antigen. *All differences not significant. Adapted from McConnell JD et al. N Engl J Med. 2003;349:2387-2398.20 BPH Progression (Percent With Event) AUA symptom score of 4 or more points from baseline, acute urinary retention (AUR), renal insufficiency, recurrent urinary tract infection, or urinary incontinence. An increase in the AUA symptom score of 4 or more points was measured relative to score at time of randomization and confirmed by re-administration of the symptom index within 4 weeks. AUR was defined as the inability to urinate following a trial without catheter. Renal insufficiency had to be attributable to BPH and was defined as a serum creatinine level of at least 1.5 mg/dL and an increase relative to baseline of 50% or more. Recurrent urinary tract infection was defined as 2 or more infections within 1 year, separated by a negative urine culture, or urosepsis. Urinary incontinence was defined as self-reported socially or hygienically unacceptable involuntary loss of urine. All outcomes were reviewed by a clinical review committee unaware of treatment assignments. Secondary outcomes were longitudinal change in AUA symptom score and maximum urinary A Figure 2. Cumulative incidences of (A) overall progression, (B) acute urinary retention (AUR), and (C) crossover to invasive therapy for benign prostatic hyperplasia (BPH) of all participants in the Medical Therapy of Prostatic Symptoms trial stratified by treatment group. Adapted from McConnell JD et al. N Engl J Med. 2003;349:2387-2398.20 Placebo 4.0 P < .0001; df = 3 20 15 10 5 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Years From Randomization Doxazosin C 3.5 Finasteride Combination therepy 10 P = .0034; df = 3 3.0 BPH Invasive Therapy (Percent With Event) AUR (Percent With Event) B 25 2.5 2.0 1.5 1.0 0.5 8 P < .0001; df = 3 6 4 2 0 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Years From Randomization 5.0 5.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Years From Randomization VOL. 7 SUPPL. 8 2005 REVIEWS IN UROLOGY S47 Combination Therapy for LUTS and BPH continued 80 60 50 Doxazosin 40 Finasteride 30 Combination therapy 20 10 Overall Progression Symptom Progression AUR flow rate. All analyses were conducted using the intention-to-treat principle, with life table methods used to estimate the cumulative incidence of outcome events. Of 4391 men screened for eligibility, 3747 were enrolled and randomly assigned to 1 of the 4 treatment groups. Among the treatment groups, mean age at baseline ranged from 62.5 to 62.7 years, and mean AUA symptom score ranged from 16.8 to 17.6 points. Maximum urinary flow rate ranged from 10.3 mL/s to 10.6 mL/s, and TRUS-measured prostate volume ranged from 35.2 mL to 36.9 mL (Table 1). Over a mean follow-up period of 4.5 years, 351 primary outcome events occurred, distributed as follow: approximately 78% due to a rise in the AUA symptom score of 4 or more points; 12% due to AUR; 9% due to urinary incontinence; and 1% due to recurrent urinary tract infection. In this well-controlled study that included quarterly visits and yearly laboratory checks, renal insufficiency due to BPH did not develop in any patient. The rate of overall clinical progression in the subjects who received placebo was 4.5 per 100 person-years. Compared with placebo, doxazosin reduced the risk of progression by 39%; finasteride, by 34%; and combination therapy, by 66% (Figure 2A). The risk reduction for both single and combination therapy S48 VOL. 7 SUPPL. 8 2005 Surgery compared with placebo was highly significant (P < .01), and the risk reduction for combination therapy was significant compared with either drug alone (P < .001).20 The risk of AUR was significantly reduced in the finasteride and combination therapy groups compared with placebo. However, although doxazosin therapy delayed the time to AUR, it did not ultimately reduce the cumulative incidence compared with placebo (Figure 2B). Similarly, finasteride and combination therapy significantly reduced the cumulative incidence of crossover to invasive therapy for BPH (Figure 2C), whereas doxazosin slightly delayed but did not ultimately reduce crossover to invasive therapy.20 Figure 4. Mean improvements in (A) American Urological Association (AUA) symptom score and (B) maximum flow rate (Qmax) by treatment group from baseline with intention-to-treat analysis in the Medical Therapy of Prostatic Symptoms trial. Data from McConnell JD et al. N Engl J Med. 2003;349:2387-2398.20 A Mean Change (Points) 0 Rates of urinary incontinence and urinary tract infection were too low in the treatment groups to perform meaningful analyses between treatments or with placebo. Figure 3 depicts the risk reductions achieved with each treatment for overall clinical progression, symptomatic progression, AUR, and surgery. Combination therapy reduces each of these risks by 60% to 80%. These improvements with combination therapy are attributable to doxazosin’s effect on symptomatic progression and finasteride’s effects in terms of prevention of AUR and surgery. Longitudinal change in AUA symptom score and maximum urinary flow rate were recorded following the intention-to-treat principle and are shown in Figure 4. Combination therapy produced the greatest improvements in symptom score (7.4 points) and peak urinary flow rate (5.1 mL/s).20 When interpreting the improvements in symptom score and flow rate for the placebo group (4.9 points and 2.8 mL/s, respectively), it is important to keep in mind that, in the intentionto-treat analysis, subjects who crossed over to active known therapy and/or had a surgical intervention for BPH were nonetheless counted as REVIEWS IN UROLOGY 8 7 6 5 B 7.4 5.6 4.9 4 3 2 1 0 6 Finasteride 6.6 AUA Symptom Score Mean Change (mL/s) Risk Reduction (%) 70 Figure 3. Reductions in risk of overall progression, symptom progression, acute urinary retention (AUR), and surgery in all active treatment groups versus placebo in the Medical Therapy of Prostatic Symptoms trial. Data from McConnell JD et al. N Engl J Med. 2003; 349:2387-2398.20 5.1 5 Doxazosin Combination therapy 4.0 4 Placebo 3.2 2.8 3 2 1 0 Qmax Combintion Therapy for LUTS and BPH Rate per 100 PY 6 P < .0001 5 P = .0003 4 PSA (ng/mL) <1.4 1.4-3.9 ≥4.0 3 2 P < .0001 1 0 B 7 TRUS Volume (mL) <20 20-40 >40 P < .0001 6 Rate per 100 PY A P < .0001 5 4 3 2 P = .0037 1 0 Overall Progression Symptom Progression AUR Overall Progression Symptom Progression AUR Figure 5. Risks of overall progression, symptomatic progression, and acute urinary retention (AUR) for patients in the placebo treatment group of the Medical Therapy of Prostatic Symptoms trial stratified by baseline (A) serum prostate-specific antigen (PSA) level and (B) prostate volume as measured by transrectal ultrasonography (TRUS). PY, person-year. being in the placebo group. Thus, taking into account the prolonged duration of this clinical trial, the estimation of changes in symptom score and flow rate may be overly optimistic, particularly in the placebo group, in which more patients than in any of the other treatment groups crossed over to active known therapy or had surgical intervention for their disease. A protocol analysis, eliminating patients who did not continue on placebo throughout the entirety of the study, would help elucidate the actual natural history of the disease in this group of patients. Figure 5 displays the associations between PSA level (Figure 5A) and prostate volume (Figure 5B) and the risks of overall progression, symptomatic progression, and progression to AUR in the placebo group. It is evident that, as PSA level and prostate volume increase, the risks of overall progression, symptomatic worsening, and AUR increase significantly as well. Indeed, from the lowest to the highest prostate volume categories, the risks of overall progression and symptomatic progression nearly double (P < .0001), and the risk of AUR more than doubles from the lowest to the highest PSA categories. A number-needed-to-treat (NNT) analysis was performed. The NNT to prevent a case of overall clinical pro- gression was 8.4 with combination therapy, 13.7 with doxazosin, and 15.0 with finasteride. In men with serum PSA levels higher than 4.0 ng/mL (20% of the randomized patients) or baseline TRUS prostate volumes greater than 40 mL (30% of the randomized patients), the NNT was reduced in the combination therapy group (4.7 and 4.9, respectively) and the finasteride group (7.2 for both subgroups). The 10 adverse events most frequently observed among patients in the 4 treatment groups are listed in Table 2. Not unexpectedly, patients who received doxazosin had an increased incidence of dizziness, postural hypertension, and asthenia, whereas those who received finasteride had an increased incidence of erectile dysfunction, decreased libido, and abnormal ejaculation compared with placebo. Patients who received combination therapy experienced both sets of adverse events. However, none of the adverse events occurred in more than 6% of patients, which Table 2 Ten Most Frequent Adverse Events in the MTOPS Trial Rate per 100 PY Adverse Event Erectile dysfunction Dizziness Postural hypotension Asthenia Decreased libido Abnormal ejaculation Peripheral edema Dyspnea Allergic reaction Somnolence Placebo 3.32 2.29 2.29 2.06 1.40 0.83 0.66 0.57 0.46 0.37 Doxazosin 3.56 4.41* 4.03* 4.08* 1.56 1.10 0.88 0.93 0.85* 0.82* Finasteride 4.53* 2.33 2.56 1.56 2.36* 1.78* 0.72 0.56 0.58 0.39 Combination Therapy 5.11* 5.35* 4.33* 4.20* 2.51* 3.05* 1.25* 1.20* 0.73 0.78* *P < .05 for comparison with the placebo group. MTOPS, Medical Therapy of Prostatic Symptoms; PY, person-year. 20 Adapted with permission from McConnell et al. VOL. 7 SUPPL. 8 2005 REVIEWS IN UROLOGY S49 Combination Therapy for LUTS and BPH continued supports the overall safety of combination medical therapy over a prolonged period.20 The initial results of the MTOPS trial have answered several important questions regarding the use of combination therapy for BPH. It has become clear that combination therapy is of significant value in the long-term management of patients with LUTS and clinical BPH, particularly those presenting at the onset with enlarged prostates or slightly elevated serum PSA levels, who are at risk for progression. Monotherapy with an -blocker (in this case, doxazosin) is effective in treating LUTS associated with clinical BPH and preventing symptomatic progression of the disease; however, it is less effective in preventing AUR and not at all effective in preventing crossover to surgical therapy. Further analyses of the MTOPS database is needed to fully understand the implication of these findings. It appears, however, that ongoing disease progression, growth of the prostate, and possibly changes in the Patient IPSS ≤ 7 IPSS >7 Little or no bother Prostate small; PSA low No treatment Prostate large; PSA high Preventive therapy: 5-α-reductase inhibitor Moderate to severe bother Prostate small; PSA low α−Adrenergic blocker Prostate large; PSA high Combination therapy Figure 6. Algorithm for medical therapy of lower urinary tract symptoms and benign prostatic hyperplasia based on symptom severity, bother associated with symptoms, and prostate size/serum prostate-specific antigen (PSA) level. IPSS, International Prostate Symptom Score. detrusor muscle contribute to the fact that doxazosin therapy delays but ultimately does not prevent episodes of urinary retention and crossover to surgery. Although 5--reductase inhibitors (in this case, finasteride) are less effective at treating symptoms, they prevent overall disease progression as well as symptomatic progression. In addition, 5--reductase inhibitors prevent episodes of AUR and crossover to surgical therapy. On the strength of the distinct effects of both single therapies, combination therapy reduces the risks of overall symptomatic progression, AUR, and Main Points • Virtually all options for hormonal control of prostate growth, although effective, have been associated with unacceptable adverse events; currently, the only acceptable method of hormonal therapy for benign prostatic hyperplasia (BPH) is the use of 5--reductase inhibitors, which target the testosterone metabolite dihydrotestosterone. • The symptoms of BPH have been divided into static and dynamic components; thus, current medical therapy for this condition consists of 2 drug classes, the -adrenergic receptor blockers (alfuzosin, doxazosin, tamsulosin, and terazosin) and the 5--reductase inhibitors (finasteride and dutasteride), each targeting one component. • The Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study compared the effects of treatment with placebo, finasteride, terazosin, or a combination of finasteride and terazosin. Symptom scores were reduced significantly in the men who received terazosin or combination therapy, whereas prostate volume and prostate-specific antigen level were significantly reduced in the finasteride and combination groups. • The placebo-controlled Prospective European Doxazosin and Combination Therapy trial compared the effects of finasteride, doxazosin, or a finasteride/doxazosin combination; results demonstrated a significant improvement in symptom score, maximum flow rate, quality-of-life score, and BPH Impact Index score in both the doxazosin and combination groups. • The Medical Therapy of Prostatic Symptoms trial is the largest and longest BPH study of its kind to date. Study results reveal that doxazosin and finasteride both reduced the risk of overall clinical progression of BPH. Furthermore, a combination of the 2 agents significantly reduced this risk more than did either agent alone. In addition, finasteride and combination therapy significantly reduced the risk of acute urinary retention and crossover to invasive therapy. Thus, combination therapy was the most effective treatment overall, especially in patients at high risk for progression. S50 VOL. 7 SUPPL. 8 2005 REVIEWS IN UROLOGY Combintion Therapy for LUTS and BPH crossover to invasive therapy by 60% to 80%. This effect is particularly pronounced in patients prone to progression, such as those with enlarged prostates (in this case, >40 mL) or slightly elevated serum PSA levels (in this case, >1.5 ng/mL). Further detailed analyses of the patient population stratified by baseline parameters and analyses of subsets of patients will no doubt improve our understanding of the natural history of LUTS and BPH and provide insight about the impact of medical therapy on the disease and its manifestations, natural history, and progression. Conclusion We should all strive to practice costeffective medicine. Cost-effectiveness in managing chronic conditions such as LUTS and BPH requires an understanding of the natural history of the disease and the effects of medical and surgical interventions, as well as the ability to identify patients who are most likely to benefit from individualized interventions. The medical therapy algorithm displayed in Figure 6 is a suggestion based on the findings of the MTOPS trial and other large-scale studies. Patients who present with mild or no symptoms (IPSS ≤7) or have moderate symptoms but experience little to no bother from them should be categorized by risk of progression. Those with small prostate glands and low PSA levels (ie, those at lower risk for progression) should be offered a strategy of watchful waiting. Those with large glands or elevated PSA levels can be offered 5--reductase inhibitor therapy to prevent progression to AUR and surgery in the future. Patients with moderate to severe symptoms who are bothered by their symptoms or have symptoms that interfere with daily activities can also be conveniently divided into categories of lower and higher risk of progression. Those with small prostates and low PSA levels are best served with therapy with an -adrenergic receptor blocker. Those with larger prostates and high PSA levels are clearly best served with combination therapy. Further refinement of treatment algorithms is urgently needed, and it is hoped that additional detailed analyses of the MTOPS database will enrich our understanding and ability to better serve and treat our patient population. 8. 9. 10. 11. 12. 13. 14. 15. References 1. 2. 3. 4. 5. 6. 7. Clinical Practice Guideline Number 8: Benign Prostatic Hyperplasia: Diagnosis and Treatment. Rockville, Md: Agency for Health Care Policy and Research, US Dept of Health and Human Services; 1994. AHCPR publication 94-0582. 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