The management of male LUTS an update for primary care

1. Slide 1 The management of male LUTS � an update for primary care Mr Michael Swinn MD FRCS Consultant Urological Surgeon, and Lead Clinician, SASH 19th January 2010

2. Slide 2 Agenda MTOPS trial, when to refer, evaluation of patients BPH (anatomy, epidemiology, progression Assessment in primary care Advanced BPH Medical Management including combination therapy (MTOPS) BAUS guidelines on primary care management of BPH

3. Slide 3 Prostate Anatomy

4. Slide 4 BPH Anatomy

5. Slide 5 BPH - epidemiology 1 in 3 men over 50 years have moderate to severe LUTS due to BPH 1 in 2 over 70 years �The Greying Population� Incidence increasing worldwide Symptoms may be very bothersome Obstructive - Poor stream, hesitancy, dribbling, incomplete emptying Irritative � frequency, nocturia, urgency, urge incontinence

6. Slide 6 BPH Incidence

7. Slide 7 BPH - Pathogenesis Stromal and epithelial hyperplasia Nodule formation 60% smooth muscle. a1-receptors a1A-receptors predominant in prostate Testosterone DHT AR

8. Slide 8 Risk Factors Age Presence of testosterone More common in blacks Less common in Asians Diet

9. Slide 9 Natural History Slowly progressive Qmax decreases by 0.2ml/year Volume increases by 1-2ml/year Prostatic urethra narrows; less distensible Progressive obstruction Bladder compensates Detrusor hypertrophy High voiding pressures Decreased compliance Detrusor overactivity (instability)

10. Slide 10 BPH Progression

11. Slide 11 Advanced BPH High residual volumes / chronic retention UTIs Acute retention Bladder calculi Bladder diverticula Renal impairment � hydronephrosis Bladder dysfunction

12. Slide 12 Advanced BPH

13. Slide 13 Advanced BPH

14. Slide 14 Bladder Diverticula

15. Slide 15 Bladder Calculi

16. Slide 16 IVU � large prostate

17. Slide 17 BPH Assessment

18. Slide 18 BPH � differential diagnosis UTI Urethral stricture Prostate cancer Prostatitis Bladder cancer Neurological disease Drug side-effects

19. Slide 19 BPH � GP initial assessment History & examination Symptom score - IPSS Digital Rectal Examination (DRE) Urinalysis (U&E), PSA

20. Slide 20 Symptom scores - IPSS AUA 0-8: mild 9-19: moderate 20-35: severe

21. Slide 21 Digital Rectal Examination Size Consistency Anatomical considerations

22. Slide 22 Role of PSA Prostate Specific Antigen �Patient Stress & Anxiety� Glycoprotein protease � liquefies semen after ejaculation Generally increased in BPH 0.3ng/ml per gram of BPH (?) Risk of prostate cancer

23. Slide 23 PSA and Cancer Depends on age & other factors 0-4ng/ml: normal in 60s 4-10ng/ml: 30% risk of cancer >10ng/ml: 50% risk of cancer

24. Slide 24 BPH � further assessment Urinary flow rate (Q-max) Ultrasound IVU TRUS & prostate biopsy Cystoscopy Urine cytology Urodynamics

25. Slide 25 Uroflowmetry Qmax <15ml/s (10ml/s) Volume > 150ml Qmax <10ml/s may require surgery

26. Slide 26 Trans-Rectal UltraSound (TRUS)

27. Slide 27 Medical Management

28. Slide 28 Medical treatment of clinical BPH In 2001, the International Consultation on BPH (ICBPH) published recommendations for evaluation and treatment based on a thorough literature review and the opinion of recognised experts.4 These guidelines stipulate that medical treatment of BPH should improve symptoms, prevent long-term complications, and have minimal morbidity, (i.e. produce minimal side effects and preserve quality of life).4 Treatment of BPH should therefore go beyond immediate relief of symptoms to address the possibility of future complications.5 In 2001, the International Consultation on BPH (ICBPH) published recommendations for evaluation and treatment based on a thorough literature review and the opinion of recognised experts.4 These guidelines stipulate that medical treatment of BPH should improve symptoms, prevent long-term complications, and have minimal morbidity, (i.e. produce minimal side effects and preserve quality of life).4 Treatment of BPH should therefore go beyond immediate relief of symptoms to address the possibility of future complications.5

29. Slide 29 Indications & options Bothersome symptoms Mild to moderate Quality of life 2 different options a1- blockade � doxazosin, terazosin, alfuzosin, tamsulosin Smooth muscle relaxation 5a reductase inhibitors � finasteride, dutasteride Regression of BPH; shrinkage of gland

30. Slide 30 (Relative) contraindications Recurrent AUR Large PVR - >300ml Renal impairment Recurrent UTI�s Bladder stones or diverticula Evidence of prostate cancer

31. Slide 31 Clinical Trials PREDICT; Veterans Administration a-blockers have better symptom relief PLESS Lower AUR risk in large prostates on finasteride MTOPS ALFAUR

32. Slide 32 Despite the well-established benefits of medical therapy in the treatment of benign prostatic hyperplasia (BPH), defining the optimal medical approach to preventing disease progression continues to challenge clinicians.1 This slide presentation reviews the issues surrounding pharmacotherapy for BPH and presents the design and results of the recently completed Medical Therapy Of Prostatic Symptoms (MTOPS) study. The largest randomised, placebo-controlled clinical trial ever conducted in men with BPH, MTOPS compared long-term medical therapy with the 5-alpha reductase inhibitor finasteride, the alpha blocker doxazosin, alone and in combination, with placebo.1 Despite the well-established benefits of medical therapy in the treatment of benign prostatic hyperplasia (BPH), defining the optimal medical approach to preventing disease progression continues to challenge clinicians.1 This slide presentation reviews the issues surrounding pharmacotherapy for BPH and presents the design and results of the recently completed Medical Therapy Of Prostatic Symptoms (MTOPS) study. The largest randomised, placebo-controlled clinical trial ever conducted in men with BPH, MTOPS compared long-term medical therapy with the 5-alpha reductase inhibitor finasteride, the alpha blocker doxazosin, alone and in combination, with placebo.1

33. Slide 33 Therapeutic agents: mechanisms of action The two most commonly used medical treatments of BPH, 5-alpha reductase inhibitors and alpha blockers, target different aspects of BPH pathology.6 Alpha blockers improve symptoms and increase urinary flow rate by relaxing prostatic and bladder-neck smooth muscle through blockade of sympathetic input into alpha1-adrenergic receptors.6 5-alpha reductase inhibitors improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargement through hormonal mechanisms, i.e. suppression of the conversion of testosterone into dihydrotestosterone (DHT).6 In light of these different pathophysiologic approaches, the combined use of these drug classes has been the focus of BPH research aimed at improving the efficacy of either treatment used alone.6 The two most commonly used medical treatments of BPH, 5-alpha reductase inhibitors and alpha blockers, target different aspects of BPH pathology.6 Alpha blockers improve symptoms and increase urinary flow rate by relaxing prostatic and bladder-neck smooth muscle through blockade of sympathetic input into alpha1-adrenergic receptors.6 5-alpha reductase inhibitors improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargement through hormonal mechanisms, i.e. suppression of the conversion of testosterone into dihydrotestosterone (DHT).6 In light of these different pathophysiologic approaches, the combined use of these drug classes has been the focus of BPH research aimed at improving the efficacy of either treatment used alone.6

34. Slide 34 Objective of MTOPS Independently conducted by the US National Institutes of Health (NIH) As defined in the NIH protocol, the primary objective of the MTOPS study was to determine whether long-term medical therapy with PROSCAR�, the alpha blocker doxazosin, or a combination of the two agents would prevent or delay the clinical progression of BPH.1 As defined in the NIH protocol, the primary objective of the MTOPS study was to determine whether long-term medical therapy with PROSCAR�, the alpha blocker doxazosin, or a combination of the two agents would prevent or delay the clinical progression of BPH.1

35. Slide 35 Study design: overview MTOPS was a prospective, double-blind, placebo-controlled, multicentre, randomised clinical trial.1 MTOPS was the longest, largest trial of medical management of BPH. Unlike some previous trials of combination therapy, which have been of short duration and of more limited scope (evaluation of symptoms only),12 MTOPS evaluated overall BPH progression over an average follow-up of 4.5 years.1 The MTOPS trial enrolled men at least 50 years of age with moderate to severe symptoms of BPH (American Urological Association Symptom Index [AUA-SI] of 8�30), maximum urinary flow (Qmax) of 4 to 15 ml/second, and a voided volume of at least 125 ml. Prior medical, surgical, or experimental interventions for BPH were reasons for exclusion.1 The 3047 eligible men were randomly assigned to doxazosin 4�8 mg/day (n=756), PROSCAR� (finasteride) 5 mg/day (n=768), PROSCAR 5 mg/day + doxazosin 4�8 mg/day (n=786), or placebo (n=737) for an average follow-up of 4.5 years. Treatment with doxazosin began at 1 mg/day and increased to 2, 4, and 8 mg/day, with each dose taken for one week. The goal was 8 mg/day, but patients unable to tolerate this dosage were allowed to receive 4 mg/day. All medications (including placebo) were taken once daily at bedtime.1 MTOPS was a prospective, double-blind, placebo-controlled, multicentre, randomised clinical trial.1 MTOPS was the longest, largest trial of medical management of BPH. Unlike some previous trials of combination therapy, which have been of short duration and of more limited scope (evaluation of symptoms only),12 MTOPS evaluated overall BPH progression over an average follow-up of 4.5 years.1 The MTOPS trial enrolled men at least 50 years of age with moderate to severe symptoms of BPH (American Urological Association Symptom Index [AUA-SI] of 8�30), maximum urinary flow (Qmax) of 4 to 15 ml/second, and a voided volume of at least 125 ml. Prior medical, surgical, or experimental interventions for BPH were reasons for exclusion.1 The 3047 eligible men were randomly assigned to doxazosin 4�8 mg/day (n=756), PROSCAR� (finasteride) 5 mg/day (n=768), PROSCAR 5 mg/day + doxazosin 4�8 mg/day (n=786), or placebo (n=737) for an average follow-up of 4.5 years. Treatment with doxazosin began at 1 mg/day and increased to 2, 4, and 8 mg/day, with each dose taken for one week. The goal was 8 mg/day, but patients unable to tolerate this dosage were allowed to receive 4 mg/day. All medications (including placebo) were taken once daily at bedtime.1

36. Slide 36 Clinical progression of BPH: Confirmed ?4-point increase in AUA-SI AUR Recurrent urinary tract infections/ urosepsis Urinary incontinence Renal insufficiency Natural history of BPH with respect to: BPH symptoms Qmax Prostate volume Sexual function Quality of life Study design: outcomes

37. Slide 37 Characteristic Value* Age (years) 62 AUA-SI score 16 TRUS Prostate volume (cc) 31.4 Patients with prostate volume <40 cc 70% Post-voiding residual urine volume 39ml Qmax (ml/second) 10.7 Baseline characteristics of patients The treatment groups were well matched at baseline and did not differ significantly from one another. The median age of patients was 62 years, and the median AUA symptom score was 16.0 points. Median prostate volume was 31.4 cc; in 70% of patients, the volume was =40 cc. Approximately 16% of patients had a prostate size of <20 cc. Median post-void residual urine volume was 39.0 ml, and the median Qmax was 10.7 ml/second.1,14,16 The treatment groups were well matched at baseline and did not differ significantly from one another. The median age of patients was 62 years, and the median AUA symptom score was 16.0 points. Median prostate volume was 31.4 cc; in 70% of patients, the volume was =40 cc. Approximately 16% of patients had a prostate size of <20 cc. Median post-void residual urine volume was 39.0 ml, and the median Qmax was 10.7 ml/second.1,14,16

38. Slide 38 Impact of medical therapy on clinical progression of BPH Data from up to 5.5 years of follow-up in MTOPS showed that combination therapy with PROSCAR� (finasteride) and doxazosin was effective in providing a 66% reduction in risk of BPH progression versus placebo (p<0.001) and significantly greater than that with either drug alone (p<0.001). Both monotherapy groups also significantly reduced the risk of BPH progression versus placebo by 34% with PROSCAR (p=0.002) and by 39% with doxazosin (p<0.001).1,16,17 There was no significant difference in risk reduction between the doxazosin monotherapy arm and the monotherapy arm with PROSCAR. Combination therapy was superior to monotherapy in reducing the risk of BPH progression as defined by these combined endpoints (p<0.001). Combination therapy reduced the risk of BPH progression by 49% versus PROSCAR (p<0.0001) and by 46% versus doxazosin (p=0.0004).17Data from up to 5.5 years of follow-up in MTOPS showed that combination therapy with PROSCAR� (finasteride) and doxazosin was effective in providing a 66% reduction in risk of BPH progression versus placebo (p<0.001) and significantly greater than that with either drug alone (p<0.001). Both monotherapy groups also significantly reduced the risk of BPH progression versus placebo by 34% with PROSCAR (p=0.002) and by 39% with doxazosin (p<0.001).1,16,17 There was no significant difference in risk reduction between the doxazosin monotherapy arm and the monotherapy arm with PROSCAR. Combination therapy was superior to monotherapy in reducing the risk of BPH progression as defined by these combined endpoints (p<0.001). Combination therapy reduced the risk of BPH progression by 49% versus PROSCAR (p<0.0001) and by 46% versus doxazosin (p=0.0004).17

39. Slide 39 Most BPH progression events due to symptom progression Distribution of BPH progression events In MTOPS, 78% of BPH progression events were due to substantially increased symptom scores. The remaining events were attributable to AUR (12%), incontinence (9%), and urinary tract infections or urosepsis (1%). No patient experienced renal insufficiency due to BPH.14,16In MTOPS, 78% of BPH progression events were due to substantially increased symptom scores. The remaining events were attributable to AUR (12%), incontinence (9%), and urinary tract infections or urosepsis (1%). No patient experienced renal insufficiency due to BPH.14,16

40. Slide 40 Impact of medical therapy on symptom control Substantial worsening of symptoms was defined as a confirmed increase of four or more points in the AUA score. Combination therapy with PROSCAR� (finasteride) and doxazosin reduced the risk of substantial symptom worsening by 64% versus placebo (p<0.001).1,16,17 Risk reduction with combination therapy was 48% versus PROSCAR (p=0.0006).1,17 The differences in risk reduction between the doxazosin monotherapy arm and the monotherapy with PROSCAR arm, and the combination arm, were not statistically significant. Substantial worsening of symptoms was defined as a confirmed increase of four or more points in the AUA score. Combination therapy with PROSCAR� (finasteride) and doxazosin reduced the risk of substantial symptom worsening by 64% versus placebo (p<0.001).1,16,17 Risk reduction with combination therapy was 48% versus PROSCAR (p=0.0006).1,17 The differences in risk reduction between the doxazosin monotherapy arm and the monotherapy with PROSCAR arm, and the combination arm, were not statistically significant.

41. Slide 41 Impact of medical therapy on the risk of AUR Combination therapy with PROSCAR� (finasteride) and doxazosin significantly reduced the risk of AUR by 81% versus placebo (p<0.001). The risk of AUR also decreased significantly�by 68%�with PROSCAR alone versus placebo (p=0.009), but not with doxazosin alone versus placebo (p=0.23).1,16,18 MTOPS also showed that administering doxazosin alone over time did not significantly reduce the risk of AUR.1,16 According to study author John McConnell, MD, this indicates that the alpha-adrenergic-mediated smooth muscle tone is not the only factor underlying the development of problems with urethral resistance, which is what accounts for urinary retention.19Combination therapy with PROSCAR� (finasteride) and doxazosin significantly reduced the risk of AUR by 81% versus placebo (p<0.001). The risk of AUR also decreased significantly�by 68%�with PROSCAR alone versus placebo (p=0.009), but not with doxazosin alone versus placebo (p=0.23).1,16,18 MTOPS also showed that administering doxazosin alone over time did not significantly reduce the risk of AUR.1,16 According to study author John McConnell, MD, this indicates that the alpha-adrenergic-mediated smooth muscle tone is not the only factor underlying the development of problems with urethral resistance, which is what accounts for urinary retention.19

42. Slide 42 Impact of medical therapy on the need for BPH-related surgery Over the duration of the study, combination therapy with PROSCAR� (finasteride) and doxazosin significantly reduced the incidence of BPH-related surgery by 67% versus placebo (p<0.001). A similarly significant reduction of 64% also occurred with monotherapy with PROSCAR versus placebo (p<0.001). Doxazosin monotherapy, in contrast, did not significantly reduce the incidence of BPH-related surgery versus placebo.1Over the duration of the study, combination therapy with PROSCAR� (finasteride) and doxazosin significantly reduced the incidence of BPH-related surgery by 67% versus placebo (p<0.001). A similarly significant reduction of 64% also occurred with monotherapy with PROSCAR versus placebo (p<0.001). Doxazosin monotherapy, in contrast, did not significantly reduce the incidence of BPH-related surgery versus placebo.1

43. Slide 43 Placebo Doxazosin PROSCAR� PROSCAR�  and doxazosin (n=737) (n=756) (n=768) (n=786) Monotherapy and combination therapy demonstrated long-term tolerability In MTOPS, the adverse events seen with the combination of PROSCAR� (finasteride) and doxazosin were similar to those with each drug used alone in previous trials.17 Dizziness, the most common adverse event with combination therapy, occurred in 5.9% of patients.1,15 Rates of discontinuation of PROSCAR were similar to those of doxazosin (data not shown).1,15 For full details of the tolerability profile, please refer to the summary of product characteristics issued by the manufacturer.In MTOPS, the adverse events seen with the combination of PROSCAR� (finasteride) and doxazosin were similar to those with each drug used alone in previous trials.17 Dizziness, the most common adverse event with combination therapy, occurred in 5.9% of patients.1,15 Rates of discontinuation of PROSCAR were similar to those of doxazosin (data not shown).1,15 For full details of the tolerability profile, please refer to the summary of product characteristics issued by the manufacturer.

44. Slide 44 Conclusions Combination therapy is the most effective form of medical therapy for BPH 66% reduction in risk of BPH progression vs. placebo (p<0.001*) 64% reduction in risk of symptom increase vs. placebo (p<0.001*) 81% reduction in risk of AUR vs. placebo (p<0.001*) 67% reduction in need for BPH-related surgery vs. placebo (p<0.001*) Both PROSCAR� (finasteride) and doxazosin monotherapy reduced symptom worsening vs. placebo Only monotherapy with PROSCAR reduced the incidence of AUR and BPH-related surgery vs. placebo MTOPS, the longest and largest trial of medical management of symptomatic BPH conducted to date,1,15 proved that combination therapy with PROSCAR� (finasteride) and the alpha blocker doxazosin was the most effective option for halting or slowing the progression of BPH. Combination therapy significantly reduced the risk of clinical outcomes: by 67% in BPH progression, 64% in worsening symptoms, 79% in AUR, and 67% in need for BPH-related surgery (all p<0.001 vs. placebo).1,15-17 Monotherapy with either PROSCAR or doxazosin significantly reduced worsening of symptoms. However, only monotherapy with PROSCAR significantly reduced the risk of AUR and the incidence of BPH-related invasive therapy. Over an average follow-up of 4.5 years, both monotherapy and combination therapy were well tolerated and effective.1,15MTOPS, the longest and largest trial of medical management of symptomatic BPH conducted to date,1,15 proved that combination therapy with PROSCAR� (finasteride) and the alpha blocker doxazosin was the most effective option for halting or slowing the progression of BPH. Combination therapy significantly reduced the risk of clinical outcomes: by 67% in BPH progression, 64% in worsening symptoms, 79% in AUR, and 67% in need for BPH-related surgery (all p<0.001 vs. placebo).1,15-17 Monotherapy with either PROSCAR or doxazosin significantly reduced worsening of symptoms. However, only monotherapy with PROSCAR significantly reduced the risk of AUR and the incidence of BPH-related invasive therapy. Over an average follow-up of 4.5 years, both monotherapy and combination therapy were well tolerated and effective.1,15

45. Slide 45 BAUS guidelines See handout. Essentially: BPH can often be managed effectively in primary care DRE + Basic investigations: IPSS, PSA, urinalysis, (U+E) Reasonable to start alpha-blocker esp for bothersome symptoms and small prostates If bothersome and large consider adding 5ARI (MTOPS) Keep under review. If progression � refer. If abnormal investigations - refer