Reducing the Risk of Benign Prostatic Hyperplasia Progression

FUTURE OPTIONS IN CAP TREATMENT Reducing the Risk of Benign Prostatic Hyperplasia Progression Claus G. Roehrborn, MD Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX The incidence of benign prostatic hyperplasia increases with age; the probability of progression rises with age at diagnosis and with baseline symptom severity. Although it is not life-threatening, the condition and its complications have a serious impact on quality of life. Acute urinary retention (AUR), though no longer thought an indication for immediate surgery, still requires treatment, often including surgery. Drug therapy with -adrenergic receptor blockers or 5--reductase inhibitors, such as finasteride, reduces the risk for AUR and the need for surgery, as well as symptoms and bother. Finasteride therapy also results in long-term reduction in prostate volume. [Rev Urol. 2002;4(suppl 5):S29–S38] © 2002 MedReviews, LLC Key words: Acute urinary retention • Benign prostatic hyperplasia • Finasteride • Lower urinary tract symptoms • 5--reductase inhibitors enign prostatic hyperplasia (BPH) represents a considerable health problem to aging men through its associated signs, symptoms, and complications. Although not a life-threatening condition, BPH can have an impact on a patient’s quality of life (QOL), as evidenced in community- and clinic-based studies.1 The estimated prevalence of the disease from community-based studies is 40% for men in their 70s2,3; histologic evidence of BPH in autopsy studies is found in 60%–80% of men aged 60–69 years.4 The term benign prostatic hyperplasia is correctly used to describe histopathologic hyperplastic changes in the prostate, but clinicians have commonly used it to describe a clinical syndrome consisting of three components: lower urinary tract symptoms (LUTS), benign prostatic B VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S29 Reducing the Risk of BPH Progression continued enlargement (BPE), and bladder outlet obstruction (BOO). Another term, benign prostatic obstruction, is used when BOO and BPE occur concurrently. Different combinations of these properties can result in a wide spectrum of clinical appearances; for example, LUTS can exist in the absence of BPE or BOO. LUTS and BPH predominantly affect QOL by interfering with activities of daily living and social activities. It may, however, also become a progressive disorder, progression being defined as a worsening of clinical parameters in the course of the natural history of the disease, including: 1. Deterioration of symptoms and disease-specific QOL 2. Decrease in urinary flow rate 3. Increase in prostate volume 4. Outcomes such as acute urinary retention (AUR) and the need for surgery either for AUR or for other symptoms. The natural history of BPH can theoretically be evaluated by studies of a variety of designs: • Longitudinal studies of untreated cohorts of men with LUTS diagnosed with clinical BPH by any definition (watchful waiting cohorts) • Studies of the behavior of men diagnosed with LUTS and BPH and enrolled in controlled studies of LUTS and BPH (control groups) and receiving: ■ No treatment (compared to active intervention), ■ Placebo treatment (compared to medical treatment), or ■ Sham treatment (compared to device or surgical treatment) • Longitudinal studies of unselected (ie, undiagnosed) men living in the community who are less likely to progress and request or require therapy (longitudinal population-based studies). S30 VOL. 4 SUPPL. 5 2002 Evidence for Progression The distinction between changes in parameters and rates of outcomes observed in placebo and sham control groups and those in longitudinal population-based studies becomes blurred when placebo control is carried out over a period of time long enough to allow natural history changes to take place and confound the situation. The Proscar Long-term Efficacy and Safety Study (PLESS) followed a cohort of over 3000 men with moderate symptoms and enlarged prostate glands randomized to treatment with finasteride 5 mg daily or to placebo over 4 years.5 In most studies, the combined placebo effect over both placebo and sham control arms score and maximum flow rate changes emerge.7 Whereas the initial placebo response in the lowest PSA tertile for both symptoms and flow rate was maintained over the entire 4 years of follow-up, the middle tertile experienced a slow deterioration of symptoms back to baseline; in essence, the natural history and progression of disease negated any flow rate gains. In the highest PSA tertile, the symptom score increased steadily over time following an initial placebo response of 1.5 points. Over the subsequent years, the score increased by 0.5 points/y, bringing it at the end of the study back to the original baseline level. The initial response in terms of flow rate improvement was completely negated by the progres- Histologic evidence of BPH in autopsy studies is found in 60%–80% of men aged 60–69 years. interferes with the natural history of the disease, and this effect is maintained for the entire duration of the study. In this trial, however, both the mean International Prostate Symptom Score (IPSS) and the mean maximum flow rate slowly drifted back to baseline after a typical initial placebo response.6 The changes occurring in measurable parameters after the initial placebo effect has taken place thus can be considered to represent the natural history of the disease. The rates of outcomes such as AUR or surgery, as well as changes in prostate volume, which are less or not at all susceptible to the placebo effect, are also valid measures of the natural history of the disease. When the population is stratified by serum prostate-specific antigen (PSA) into tertiles of patients with levels of 0–1.3 ng/mL, 1.4–3.2 ng/mL, and 3.3–10 ng/mL, three distinctly different patterns regarding symptom REVIEWS IN UROLOGY sion/natural history after 2 years, and at the end of the study, this group of patients registered a net worsening of the flow rate by a mean of 1.0 mL/s. Similar results regarding the changes in symptoms and maximum flow rate over time were obtained when the 150 patients for whom prostate volume measurements were available were divided into tertiles (14–41 mL, 42–57 mL, and 58–150 mL). The PLESS study also periodically assessed bother due to urinary symptoms, disease-specific QOL, aspects of sexual function, and overall sense of well-being. Surprisingly, serum PSA at baseline also predicts the rate of deterioration, after an initial placebo response, of scores for bother, QOL, and certain aspects of sexual function.8 The most informative natural history study to date is the Olmsted County Study of Urinary Symptoms and Health Status Among Men, Reducing the Risk of BPH Progression which has given us much information about prevalence and severity of urinary symptoms, bother, worry and embarrassment, QOL changes due to symptoms, and the relationship between symptoms and other parameters such as flow rates, prostate volume, and PSA.9–15 With continued follow-up of this cohort, data have emerged regarding the longitudinal changes in symptoms and flow rate over time in this population-based study. Of 904 men reporting no to mild symptoms (American Urological Association Symptom Index [AUASI] 0–7 points) at baseline, 118 reported moderate to severe symptoms (AUASI > 7 points) at 18 months’ and 196 at 42 months’ follow-up.16 However, 47 men who had developed moderate to severe symptoms at 18 months had no to mild symptoms at 42 months, at which point an average increase in the IPSS of 0.18 (95% confidence interval [CI], 0.13-0.24) points per year of follow-up was recorded. The average annual symptom score slope and variability in slope increased with patient age at baseline from a mean of 0.05 ± 1.06 (standard deviation) points/y among men in their 40s to 0.44 ± 1.35 points/y for men in their 60s and decreased to 0.14 ± 1.42 points/y for men in their 70s.17 More recently, 92-month data showed an annual change of 0.34 points/y, with 31% of all men reporting at least a 3-point increase. The greatest annualized increase was observed in men in their 60s, with 0.6 points/y.18 In addition, 6-year follow-up data on peak flow rate measurements in a subset of about 500 men showed a median peak urinary flow rate slope decrease of 2.1% per year (25th percentile, 4.0; 75th percentile, 0.6). Peak urinary flow rate declined more rapidly with decreasing baseline rate and with increasing baseline age, prostate volume, and symptom sever- ity (all P = .001). When the variables were simultaneously adjusted for each other, a rapid decline (negative slope ≥ 4.5%/y) was more likely in men 70 years old or older and in those with a rate less than 10 mL/s at baseline than in those 40–49 years old and in those with a rate of ≥15 mL/s, respectively. Prostate vol- after an attempt of catheter removal still undergo surgery. For this reason alone, AUR is from an economical viewpoint, as well as from that of the patient, an important and feared event. For the patient, it presents itself as the inability to urinate, with increasing pain, eventually a visit to the emergency room, catheterization, Serum PSA at baseline also predicts the rate of deterioration, after an initial placebo response, of scores for bother, QOL, and certain aspects of sexual function. ume and symptom severity were not statistically significant predictors of a rapid decline in peak urinary flow rate when variables were considered simultaneously.19 Based on transrectal ultrasonography (TRUS), the growth rate of the prostate in these men 40–79 years old was estimated to be about 0.6 mL per year, or 6 mL per decade. However, prostate growth followed an exponential growth pattern, with a slope estimated at 0.4 mL per year for men aged 40–59 years at baseline and at 1.2 mL per year for those 60–79 years at baseline.20 An updated analysis revealed a median growth rate of about 1.9% per year independent of age and symptoms. However, a higher baseline serum PSA and larger prostate volume predicted greater annualized volume increases.21 Acute Urinary Retention AUR is one of the most significant complications or long-term outcomes resulting from BPH, for a variety of reasons. It has in the past been considered an indication for immediate surgery. Between 25% and 30% of men who underwent transurethral resection of the prostate (TURP) had AUR as their main indication in older series,22 and today most patients who cannot void follow-up visits to the physician, an attempt at catheter removal, and eventually recovery or surgery—both a painful and a time-consuming process. In older literature, the risk of recurrent AUR was cited as being 56%–64% within 1 week of the first episode and 76%–83% in a subset of men with diagnosed BPH.23,24,25 The etiology of AUR is poorly understood. Prostate infection, bladder overdistention,26 excessive fluid intake, alcohol consumption, sexual activity, debility, and bed rest have all been mentioned.27 Descriptive Epidemiology Older estimates of occurrence of AUR range from 4–15 to as high as 130 cases per 1000 person-years (calculated by Jacobsen et al28 based on studies by Birkhoff et al,29 Ball et al,30 and Craigen et al31), which leads to 10-year cumulative incidence rates ranging from 4% to 73%. The selfreported rate of AUR in a cross-sectional study in 2002 Spanish men was 5.1%.32 See Table 1 for a summary of studies on the incidence of AUR. More recent data from carefully controlled studies in better-defined populations shed additional light on the incidence rates in communitydwelling men and in clinical BPH populations. AUR occurred in the VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S31 Reducing the Risk of BPH Progression continued Table 1 Descriptive Studies on the Incidence of Acute Urinary Retention Author/source Ball et al 1981 Cases Cohort (n) Years of follow-up Percent overall Percent / year IR/1,000 pyrs 2 107 5 1.9% 0.37% 3.7 10 26 3 39.0% 13.0% 130.0 8 276 3 2.8% 0.9% 9.6 Self-reported prior events in Spanish men 102 2002 ? 5.1% Prostatectomy candidates 40 500 4 8.0% 1.3% Description of cohort Watchful waiting study 30 Craigen et al 1969 31 Watchful waiting study 15.0 Birkhoff et al 197629 Watchful waiting study Wasson et al 199533 Hunter et al 1996 32 Barry et al 1997 34 Meigs et al 1999 35 95% CI TURP vs watchful waiting VA COOP Physicians’ Health Study, self-reported 50.9 2.5% 25.0 82 6100 3 Olmsted County (Oesterling et al 19939) Community cohort 40-49 years old 57 2115 4 4.5 3.1-6.2 6.8 5.2-8.9 McConnell et al 19985 Placebo group of PLESS Study 99 1376 4 7.2% 1.8% 18.0 Andersen et al 199736 Placebo groups of 2-year BPH studies 57 2109 2 2.7% 1.35% 13.5 IR, incidence rate; pyrs, person-years; TURP, transurethral resection of the prostate; VA COOP, Veterans Affairs Cooperative Study; PLESS, Proscar LongTerm Efficacy and Safety Study. Veterans Affairs (VA) Cooperative Study over 3 years in one man after TURP and in eight of 276 men in the watchful waiting arm, for an incidence rate of 9.6/1000 person-years.33 Barry and colleagues reported outcomes in 500 men diagnosed with BPH by urologists, who were candidates for prostatectomy by established criteria but elected to be followed conservatively.34 In 1574 person-years, 40 episodes of AUR occurred at a constant rate throughout the 4 years of follow-up, for an incidence rate of 25/1000 person-years. During 15,851 person-years of follow-up in the Physicians’ Health Study, 82 men reported an episode of AUR, for an incidence rate of 4.5/1000 person-years (95% CI, 3.1-6.2).35 Of the 2115 men aged 40–79 years in the Olmsted County Study, 57 had a first episode of AUR during 8344 S32 VOL. 4 SUPPL. 5 2002 person-years of follow-up (incidence 6.8/1000 person-years, 95% CI, 5.2–8.9)28 The best data from men diagnosed with BPH stem from PLESS.5 In this study, 1376 placebo-treated men with enlarged prostates and moderate symptoms had complete follow-up over 4 years; 99 of them experienced an episode of AUR, for a calculated incidence rate of 18/1000 personyears. The placebo treatment groups from three 2-year studies with a similar patient population were meta-analyzed by Andersen and colleagues.36 Of 2109 patients, 57 experienced AUR over the 2 years with a constant hazard, for an incidence rate of 14/1000 person-years. Analytical Epidemiology Several well-controlled studies have provided considerable insights into REVIEWS IN UROLOGY the risk factors for AUR. In the Physicians’ Health Study, rates increased with age and baseline symptom severity.35 In men with mild symptoms, the incidence of AUR was 0.4/1000 person-years in those 45–49 years old and 7.9/1000 person-years in those 70–83 years old. In men with symptom scores of 8–35, rates were 3.3/1000 personyears in those 45–49 years old and 11.3/1000 person-years in those 70–83 years old. Men with a clinical diagnosis of BPH and a symptom score of 8 or more had the highest rates (age-adjusted incidence 13.7/1000 person-years). Each of the seven lower urinary tract symptoms compiled by the AUASI individually predicted AUR. The sensation of incomplete bladder emptying, the need to void again after less than 2 hours, and a weak urinary stream Reducing the Risk of BPH Progression years old with mild symptoms and a flow rate over 12 mL/s, for whom the base risk is 1.0). Although age in communitydwelling men is an important risk factor, in trial populations of men who are already diagnosed with BPH, other factors can be analyzed. In the placebo groups of three 2-year studies38 and a 4-year study (PLESS),39,40,41 prostate volume, serum PSA, and symptom severity all were predictors of AUR episodes. Increases in the incidence of AUR ranged from 5.6% to 7.7% in men with a serum PSA ≤ 1.4 ng/mL, corresponding to symptoms ranging from mild to severe, and from 7.8% to 10.2% for those with a serum PSA ≥ 1.4 ng/mL over 4 years in PLESS.39 In the 2-year studies, the rate of AUR was eight times as high in those with a serum PSA ≥ 1.4 ng/mL as in those with lower levels (3.9% versus 0.4%) and almost three times as high in those with a prostate volume ≥ 40 mL as in those with lower volumes (4.2% Incidence/1,000 person-years 35 30 25 20 15 10 5 0 Mild Moderate or Severe 40-49 2.6 3 50-59 1.7 7.4 60-69 5.4 12.9 70-79 9.3 34.7 Age (y) Mild Moderate or Severe Figure 1. Incidence of acute urinary retention in Olmsted County Study stratified by age and symptom severity. Symptom scale: mild, 0–7; moderate or severe, >7. and a flow rate over 12 mL/s. All other strata of men over 70 years had relative risks ranging from 12.9 to 14.8 (all compared to men 40–49 Figure 2. Relative risk of acute urinary retention in Olmsted County Study. Age 40–49 years, symptom score <7 points, peak urinary flow rate >12, and prostate volume <30 mL serve as baseline, with a relative risk of 1.0. 18 16 14 Relative Risk were the best independent symptom predictors. Use of medications with adrenergic or anticholinergic side effects also predicted AUR. The Olmsted County Study analyses focused on age, symptom severity, maximum flow rate, and prostate volume.37 Incidence rates per 1000 person-years were higher in older men: 2.6 and 9.3 for men in their 40s and those in their 70s, respectively, if they had mild symptoms; 3.0 and 34.7, respectively, if they had more than mild symptoms (Figure 1). Relative risk was higher for older men, men with moderate to severe symptoms (3.2), those with a peak flow rate < 12 mL/s (3.9) and those with a prostate volume > 30 mL by TRUS (3.0), all compared to a baseline risk of 1.0 for the corresponding groups (Figure 2). The highest relative risk in proportional hazard models exists for 60- to 69-year-old men with more than mild symptoms and a flow rate of less than 12 mL/s (10.3) and for 70- to 79-year-old men unless they had mild symptoms 12 10 8 6 4 2 0 40-49 50-59 60-69 Age (y) 70-79 0-7 8+ Symptom score <12 >12 Flow rate (mL/sec) VOL. 4 SUPPL. 5 2002 <30 >30 Prostate volume (mL) REVIEWS IN UROLOGY S33 Reducing the Risk of BPH Progression continued Surgery for Benign Prostatic Hyperplasia Both surgery and AUR represent distinct endpoints in the disease progression of BPH. There are, however, clear differences. AUR is an outcome mandating management, and surgery is one of the commonly employed management methods. AUR is probably one of the clearer indications for surgery, leaving the treating physician little choice in a patient in whom a trial without catheter (TWOC) has failed. Older series of the natural history of BPH, such as the one reported by Craigen and colleagues,31 projected somewhat unrealistic estimates of 35% incidence of prostatectomy at 1 year and 45% at 7 years. Diokno reported annual incidence rates of 2.6% and 3.3% for years 1 and 2, respectively, in his cohort of men followed longitudinally.43 Frequency, hesitancy, straining, and an interrupted stream were all associated with increased risk. The first study of substantial quality reporting on incidence rates and risk factors of prostate surgery was the Baltimore Longitudinal Study of Aging (BLSA).44,45 Over 1000 men S34 VOL. 4 SUPPL. 5 2002 14 Incidence 12 10 8 6 4 2 PSA (ng/mL) 0 Prostate volume (mL) vs 1.6%).38 A detailed analysis showed a near-linear increase in risk for AUR with increasing thresholds of serum PSA in PLESS, an observation that applies to both spontaneous and precipitated AUR.41 The risk for both types of AUR increases with increasing serum PSA, as well as with prostate volume stratified by tertiles (Figure 3). An analysis of over 100 possible outcome predictors, alone or in combination, revealed a combination of serum PSA, urinating more than every 2 hours, symptom problem index, maximum urinary flow rate, and hesitancy to be only slightly superior to PSA alone in predicting AUR episodes.42 Spontaneous Precipitated Combined 0-1.3 1.4 1.5 2.9 1.4-3.2 2.5 3.3 5.8 >3.3 7.6 4.0 11.6 14-41 0.0 1.4 4.4 42-57 1.7 3.3 5.0 >57 6.0 8.0 14.0 Figure 3. Incidence rates of spontaneous and precipitated acute urinary retention in the Proscar Long-Term Efficacy and Safety Study over 4 years in placebo-treated patients stratified in prostate-specific antigen (PSA) and prostate volume tertiles. were followed for 30 years with yearly symptom assessments, questionnaires, and examinations. Age, incomplete emptying, and change in size and force of stream were all independently associated with the risk of prostate surgery, as was an enlarged prostate reported on digital rectal examination (DRE). Of 464 men without risk factors, only 3% required surgery during follow-up. For men with one risk factor the cumulative incidence was 9%; for those with two risk factors, 16%; and for those with three risk factors, as much as 37%. In a similar study, the VA Normative Aging Study, nocturia and hesitancy emerged as independent predictors of surgery in 1868 men aged 49–68 followed for over 20 years.46 Age and any of five lower urinary tract symptoms (dysuria, incontinence, trouble initiating flow, nocturia, and slow stream) were associated with the risk of surgery in 16,219 men over 40 years old enrolled in the Kaiser Permanente Health Plan in California, of whom 1027 underwent prostatectomy over 12 years of follow-up.47,48 In the VA Cooperative Trial com- REVIEWS IN UROLOGY paring surgery with watchful waiting, 65 (24%) of 276 patients assigned to watchful waiting crossed over to surgery within 3 years of follow-up; 20 met predefined endpoints (azotemia, high residual urine volumes, incontinence, or high symptom scores). High baseline bother score was a strong predictor of need for surgery.49 The probability of undergoing surgery over 4 years increased from 10% in those men diagnosed with BPH who had mild symptoms to 24% in those with moderate symptoms and 39% in those with severe symptoms at baseline as reported in a natural history and observation study by Barry and colleagues.50 The Olmsted County Study and the placebo arm of PLESS provide additional insights into the risk factors for undergoing prostate surgery in community-dwelling men and in men enrolled in a BPH treatment trial. In the Olmsted County Study, during more than 10,000 personyears of follow-up, 167 men were treated, yielding an overall incidence of 16.0/1000 person-years. There was a strong age-related correlation with risk for need of any treatment: 3.3/1000 person-years for men 40–49 years old and more than 30/1000 person-years for those 70 years old or older. Men with moderate to severe symptoms, depressed peak urinary flow rates (≤12 mL/s), enlarged prostate (>30 mL), or elevated serum PSA (≥1.4 ng/mL) had about four times the risk of BPH treatment of those who did not. After adjustment for all measures simultaneously, an enlarged prostate (hazard ratio [HR], 2.3; 95% CI, 1.1-4.7), depressed peak flow rate (HR, 2.7; 95% CI, 1.4-5.3), and moderate to severe symptoms (HR, 5.3; 95% CI, 2.5-11.1) at baseline each independently predicted subsequent need for treatment. Overall, nearly one in four men received treatment in the eighth decade of life. These data suggest that men with moderate to severe LUTS, impaired flow rates, or enlarged prostates are more likely to undergo treatment, with increases in risk of similar magnitude to those associated with adverse outcomes, such as AUR.51 Over 1500 patients with moderate LUTS and enlarged prostate glands were followed in PLESS on placebo for 4 years. Of these, 10% and 2.5% per year, respectively, underwent surgery for BPH.5 Although the like- Prostate volume (median % change from baseline ± SE) Reducing the Risk of BPH Progression 0 Controlled Open extension Placebo -5 -10 -15 Fin 1 mg Finasteride 5 mg -20 -25 -30 0 Fin 5 mg 1 2 4 5 6 Years of study Number of patients Placebo/Fin 5 mg 514 173 173 169 173 173 185 Fin 1 mg/Fin 5 mg 503 163 175 177 170 173 190 Fin 5 mg/Fin 5 mg 503 161 169 173 163 178 183 Figure 4. Prostate volume reduction in original phase III, placebo-controlled study and in open-label extension over 6 years. Original treatment assignment is marked. Fin, finasteride. from the lowest to the highest prostate volume tertile. Reducing the Risk of Progression Considering the evidence for progression in terms of symptoms, bother, QOL, urinary flow rate, and outcomes such as AUR and prostate surgery, efforts to reduce such risk seem reasonable. Although surgical interven- Overall, nearly one in four men received treatment in the eighth decade of life. lihood of undergoing surgery was linear, ie, remained constant throughout the duration of the study, it was different when patients were stratified by either prostate volume or serum PSA in tertiles at the beginning of the study. Similar to the incidence of AUR, the rates of surgery increased by 6.2% to 14.6% for patients in the lowest to the highest PSA tertile and by 6.7% to 14.0% 3 tions such as TURP ultimately reduce the risk for progression, for the purposes of this discussion, only risk reduction affected by medical intervention shall be considered, since it is the goal of such risk reduction to avoid exactly such interventions. There is abundant evidence to suggest that -adrenergic receptor blockers are effective in improving the symptoms and bother associated with BPH and LUTS.52,53 Due to the fact that none of the placebo-controlled trials was carried out for longer than 12 months, less certainty exists regarding the long-term prevention of symptomatic progression, as open-label extension studies are subject to a positive responder bias.54 Similarly, finasteride leads to a durable improvement in symptoms and bother over time, which is sustained up to 4 years in placebo-controlled studies, and for up to 6 years in open-label extension studies.7,8 The specific question of symptomatic progression and its prevention by any medical therapy will likely be answered by the Medical Therapy of Prostatic Symptoms (MTOPS) study, a 5-year trial comparing placebo versus doxazosin versus finasteride versus combination therapy in over 3000 patients. The risk of future prostate growth is completely eliminated by therapy with finasteride, as long-term openlabel extension studies have shown a VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S35 Reducing the Risk of BPH Progression continued A Placebo group B Finasteride group 30 30 Either Either 25 Surgery AUR Cumulative incidence (%) Cumulative incidence (%) 25 20 15 10 Surgery AUR 20 15 10 5 5 0 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 >6.0 >6.5 >7.0 >7.5 >8.0 >0.0 >0.5 >1.0 >1.5 >2.0 >2.5 >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 >7.5 >8.0 PSA level (ng/mL) PSA level (ng/mL) Figure 5. Cumulative incidence of AUR, surgery, or either by increasing threshold of serum prostate-specific antigen (PSA) level at baseline over 4 years in the Proscar Long-Term Efficacy and Safety Study in the (A) placebo and (B) finasteride groups. durable reduction in prostate volume by 20% or more over 6 years and longer, with no suggestion that there will be any future volume increases (Figure 4). Regarding the risk reduction for AUR and surgery, data from placebocontrolled trials are available for the 5--reductase inhibitor finasteride, and suggestions of risk reduction are available from various -adrenergicreceptor-blocker trials. The incidence 0.16% in the second year, and 0.11% in the third year were reported.58 These last two studies, although not placebo-controlled, suggest an incidence rate lower than might be expected without active therapy in a cohort of men with moderate to severe symptoms and clinical BPH. PLESS was a 4-year study of finasteride 5 mg daily versus placebo in over 3000 men with enlarged prostate glands and moderate to The risk of future prostate growth is completely eliminated by therapy with finasteride. of either spontaneous or precipitated AUR, despite the fact that the treating physicians at the time of the decision for or against surgery were blinded as to the treatment allocation. The risk reduction induced by finasteride for both spontaneous and precipitated AUR as well as surgery is dependent on serum PSA and prostate volume at baseline (Figure 5). Stratified by PSA tertiles, the reduction ranges from 7% to 77% for spontaneous and from 35% to 66% for both types of AUR as a result of the higher risk in the placebo-treated patients. Conclusions rates of AUR in a 6-month study of alfuzosin 2.5 mg t.i.d. involving 518 patients were 0.4% versus 2.4% (P = .04) in the alfuzosin versus the placebo arm.55 A pooled analysis of 11 studies of alfuzosin versus placebo suggests incidence rates of 0.3% versus 1.4%.56 Of 2829 patients treated over 1 year in an open-label study, 1.2% experienced AUR.57 Lastly, in a phase IV study of 7093 patients treated in general practice with alfuzosin up to 3 years, incidence rates for AUR of 0.77% in the first year, S36 VOL. 4 SUPPL. 5 2002 severe LUTS.5 The risk of AUR was found to be linear and cumulative over the 4 years of the study, and overall, 6.6% of placebo versus 2.8% of finasteride-treated patients experienced AUR, for a risk reduction of 57%. Many of the patients experiencing AUR subsequently underwent surgery, and the overall risk for either AUR or surgery was reduced by 51%, from 13.2% to 6.6%. It is of interest that fewer finasteride-treated than placebo-treated patients underwent surgery subsequent to an episode REVIEWS IN UROLOGY BPH can be a progressive disease, and the likelihood that a patient will experience progression can to some degree be predicted by baseline parameters, most notably age, prostate volume, and serum PSA. Although the risk for progression, AUR, and surgery increases with advancing age and with increasing volume and serum PSA, medical interventions have demonstrated the ability to reduce the risk of progression as measured by any of the parameters chosen. Most notably, the 5--reductase inhibitor finasteride Reducing the Risk of BPH Progression leads to a 50% or greater reduction in the risk for AUR or surgery, with the magnitude of the risk reduction being greater in patients at greater risk. This constellation allows tailored management of patients who are at greatest risk and in whom medical intervention is most likely to be costeffective. 9. 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