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Current Strategic  on BPH Management – Combination Therapy

Dr. Boyke Subali , SpU RSU . A. Wahab Sjahranie - Samarinda. Current Strategic  on BPH Management – Combination Therapy. Sub Tittle. Prevalence. When should BPH be considered as a disease ?. Current Treatment of BPH. Prevalence of Histologic BPH Increases with Age.

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Current Strategic  on BPH Management – Combination Therapy

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  1. Dr. BoykeSubali, SpU RSU. A. WahabSjahranie - Samarinda Current Strategic  on BPH Management – Combination Therapy

  2. Sub Tittle Prevalence • Whenshould BPH beconsidered • as a disease? • CurrentTreatment of BPH

  3. Prevalence of Histologic BPH Increases with Age Roehrborn CG, et al.International Journal of Impotence Research.2008; 20: S11–S18

  4. BPH influenced Daily activities Garraway WM, et al. Br J Gen Pract. 1993;43(373):318-321.

  5. When should BPH be considered as a disease? When should BPH be considered as a disease? Prostatic parc Bothersome symptoms? Yes!

  6. Benign Prostate Hyperplasia (BPH) • Benign prostatic hyperplasia (BPH) is a pathologic process that contributes to, but is not the sole cause of, lower urinary tract symptoms (LUTS) in aging men • Benign prostatic hyperplasia is defined histologically as a disease process characterized by stromal and epithelial cell hyperplasia. • Originates from transition zone AUA Guideline. J Urol.2003;170:530-547 Roehrborn CG. International Journal of Impotence Research.2008;20:S11–S18 Lee KL et al. J Urol 2004;172:1784–1791

  7. BPH is characterised by non-malignantenlargement of the prostate BPH Normal Hypertrophieddetrusormuscle Bladder Enlargementof the prostate Prostate Obstructedurinary flow Urethra Adapted from Kirby RS et al. Benign Prostatic Hyperplasia. Health Press, Oxford, 1999 available at: http://www.glaxosmithkline.rs/vasezdravlje-bph.html

  8. BPH is caused by an imbalance of cell proliferation (growth) and apoptotic (death) signals – leads to increase in number of prostate cells and prostate size Serum DHT Serum testosterone (T) T Prostate cell 5α-reductasetypes 1 and 2 DHT Growth factors DHT-androgen receptor complex Cell death Unbalanced Increased cell growth Adapted from Kirby RS, McConnell. Benign Prostatic Hyperplasia. Health Press Ltd, 1999

  9. All Men >40 y Histological BPH BPE Enlargement ` BOO Obstruction LUTS/ Bother BPH, LUTS, BPE and BOOClinical, anatomical, and pathophysiological changes BPH = Benign Prostatic Hyperplasia Histological: stromoglandular hyperplasia May be associated with Clinical: presence of bothersome LUTS2 Anatomical: enlargement of the gland (BPE = Benign Prostatic Enlargement)2 Pathophysiological: compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2 Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:107-166.

  10. BPH can cause lower urinary tract symptoms (LUTS) BPH symptoms may include: • Storage symptoms, which can result from enlarged prostate or overactive bladder (OAB) • Frequency • Nocturia • Urgency • Incontinence • Associated symptoms of BPH include: • Dysuria • Haematuria • Haematospermia Voiding symptoms, caused by an enlarged prostate Weak urinary stream Prolonged voiding Abdominal straining Hesitancy Intermittency Incomplete bladder emptying Terminal and post-void dribbling • LUTS are not specific to BPH – not all men with LUTS have BPH and not all men with BPH have LUTS

  11. Diagnostic tests recommended by the EAU BPH guidelines • Medical history • Symptom score • Physical examination (incl. DRE) • PSA • Creatinine measurement* • Urinalysis • Flow rate** • Post-void residual volume** *Not recommended by the AUA guidelines ** Considered optional in the AUA guidelines EAU BPH guidelines. Madersbacher S et al.Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  12. Symptoms score • Evaluating symptom severity is an important part of the initial assessment • Symptom severity is probably best assessed through the use of a validated symptom score • The internationale standard instrument is the International Prostate Symptom Score (IPSS) • The IPSS comprises of 8 questions: • 7 questions about the severity of symptoms • These are identical to the 7 questions of the AUA Symptom Index* • 1 question on global quality of life *The AUA guidelines recommend use of the AUA-SI (7 questions) EAU BPH guidelines. Madersbacher S et al.Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  13. IPSS questionnaire

  14. Total IPSS indicates symptom severity EAU BPH guidelines. Madersbacher S et al.Eur Urol 2004; 46: 547–554

  15. Physical examination • Physical examination during the initial assessment of a man with LUTS suggestive of BPH should include: • Focused neurological examination • Digital rectal examination (DRE) • To help evaluate prostate size • To help exclude the presence of prostate cancer, as well as prostatitis and other pelvic pathologies EAU BPH guidelines. Madersbacher S et al.Eur Urol 2004; 46: 547–554

  16. The clinical utility of PSA in assessing men with LUTS suggestive of BPH • Strong relationship between serum PSA and prostate volume enables clinicians to estimate prostate size in BPH patients • Serum PSA thresholds can be used to predict the presence of a prostate >30ml or >40ml with sensitivity between 60-70% and specificity 70%. • Along with current prostate size, serum PSA provides prognostic information about: • Prostate growth • Symptoms and bother deterioration • Sexual dysfunction • Flow rate worsening • Risk for AUR and surgery • In general higher levels of serum PSA indicate faster and greater risk for progression Roehrborn CG. Int J Impot Res 2008; 20: s19–26

  17. Urinalysis • Although benign prostatic obstruction is the most frequent cause of LUTS in men, LUTS can also be caused by urinary tract infection or bladder cancer • The absence of haematuria or pyruria on urinalysis helps to rule out these conditions • Guidelines recommend urinalysis to aid differential diagnosis EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  18. Flow rate determined by uroflowmetry • Uroflowmetry is a simple non-invasive test that can reveal abnormal voiding. • Serial flows (two or more) with a voided volume exceeding 150 ml are recommended to obtain a representative flow test. • LUTS in the presence of a normal peak flow rate (Qmax= 15ml/s) are more likely to have a non-BPH-related cause, and men with Qmax <10 ml/sec are more likely to have urodynamic obstruction • Uroflowmetry is recommended by the EAU as part of the initial assessment of a man with LUTS, as well as being required prior to prostatectomy • Uroflowmetry is considered by the AUA to be an option following the initial patient evaluation EAU BPH guidelines. Madersbacher S et al. EurUrol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  19. Measurement of post-void residual (PVR) volume • Measurement of PVR urine is recommended by the EAU guidelines and considered optional by the AUA • PVR volume is calculated by measurement of bladder height, width and length obtained by transabdominalultrasonography • This is a simple, accurate and non-invasive method • Large PVR volumes (>200 mL) may indicate bladder dysfunction and predict a less favourable response to BPH treatment EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554

  20. Current Treatment of BPH

  21. Aims of treatment: EAU and AUA guidelines • The aim of therapy is to improve lower urinary tract symptoms (LUTS) and quality of life, and to prevent BPE/BPO-related complications such as urinary retention or upper urinary tract dilatation (EAU) • The patient's perception of the severity of the condition, as well as the degree to which it interferes with his lifestyle or causes embarrassment, should be the primary consideration in choosing therapy (AUA) BPE = Benign prostatic enlargement BPO = Benign prostatic obstruction EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  22. Treatment – initial management • Initial management of men with LUTS suggestive of BPH can be categorized into: • Watchful waiting • Medical therapy • Surgical management • Non-surgical intervention / Minimally invasive therapy EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  23. Management • The following are important components of WW: • Education • Reassurance • Periodic monitoring • Lifestyle modifications Brown C et al. Curr Opin Urol 2004; 14: 7–12

  24. Medical therapy The following medical treatments are recommended for BPH treatment : • Alpha blockers (as monotherapy) • 5 alpha-reductase inhibitors - 5ARIs (as monotherapy) • Combination therapy EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554 AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

  25. Need for a new approach • Dependence on alpha-blocker monotherapy is failing a proportion of men with BPH • Need to move away from ‘one-size-fits-all’ medicine to a more personalised approach • Need for tailored solutions consistent with treatment guidelines • Appropriate treatment needed for men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/ml • Emberton M et al. BJU Int 2011 Jan 25. doi: 10.1111/j.1464-410X.2010.10041.x

  26. What is the optimal treatment for men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/ml? CombAT study provides insights into treatment of men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/ml Entry criteria for CombAT: Male aged ≥50 years Diagnosis of BPH by history and DRE IPSS≥12 (moderate-to-severe symptoms) Prostate volume ≥30 cc by TRUS Serum PSA 1.5–10.0 ng/ml Two voids at screening with Qmax >5 and ≤15 ml/sec (moderate-to-severe impairment) and minimum voided volume of ≥125 ml Siami P et al. Contemp Clin Trials 2007;28:770–779

  27. What can we learn from the CombAT data? What benefit does combination therapy with dutasteride and tamsulosin have on: Symptoms? Quality of life? Risk of long-term complications such as AUR and BPH-related surgery?

  28. Roehrborn CG et al. Eur Urol 2010;57:123–131; Barry MJ et al. J Urol 1995;154:1770–74 Superior symptom relief with combination therapy with dutasteride and tamsulosin versus either monotherapy 0.0 -1.0 -2.0 -3.0 -4.0 -5.0 -6.0 -7.0 -8.0 p <0.001 combination versus tamsulosin p <0.001 combination versus dutasteride Symptom improvement with combination therapy starts asrapidly as tamsulosinmonotherapy -2.8 -3.4 Symptom improvement of at least 3 units is generally considered to be perceptible for the patient and accepted as the minimum threshold of clinical relevance -3.8 -3.8 -3.8 -4.0 -4.0 -4.0 -4.1 -4.2 -4.2 Adjusted mean change from baseline in IPSS -4.3 -4.4 -4.4 -4.4 -4.5 -4.5 -4.7 -4.8 -4.5 -4.8 -4.8 -4.8 -4.9 -4.9 -5.0 -5.1 -5.2 -5.2 -5.2 -5.3 -5.3 -5.3 -5.4 -5.4 -5.6 -6.0 -6.0 -6.2 -6.2 -6.2 -6.3 -6.3 -6.3 -6.3 -6.4 -6.4 -6.5 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Baseline Study month Combination (n = 1575) Dutasteride (n = 1592) Tamsulosin (n = 1582)

  29. Patients with LUTS consider storage symptoms to be most bothersome symptoms Storagesymptoms Bother index n=1803 to 2046, depending on the symptom Häkkinen JT et al.EurUrol 2007;51:473–478

  30. Combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years:Storage symptoms Adjusted mean change from baseline in IPSS storage score * * *p<0.001 versus combination Montorsi F et al.BJU Int2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x

  31. Many men with moderate-to-severe symptoms (IPSS ≥8) have both storage and voiding symptoms: findings from a population-based survey Prevalence of LUTS subtypes (%) Age (years) Storage symptoms: sum of scores on IPSS items 2, 4 and 7 was ≥4 and score on item 4 (i.e. urgency) was ≥1 Voiding symptoms: sum of scores on IPSS items 1, 3, 5 and 6 was ≥5 Mixed symptoms: criteria met for both storage and voiding symptoms Glasser DB et al.Int J ClinPract 2007;61:1294–1300

  32. Combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years:Voiding symptoms Adjusted mean change from baseline in IPSS voiding score * * *p<0.001 versus combination Montorsi F et al. BJU Int2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x

  33. Symptoms: What can we conclude? • Over 4 years, combination therapy with dutasteride and tamsulosin provided significantly superior symptom improvement compared with either monotherapy for: • Total symptoms • Storage symptoms • Voiding symptoms • Symptom improvement starts as rapidly as tamsulosin monotherapy

  34. The BII • A disease-specific 4-item instrument that measures the impact of LUTS on • Physical discomfort • Worry about health • Degree of bother • Limitations of daily activities • Total scores range from 0 (no impact) to 13 (highest negative impact) Montorsi F et al.Int J ClinPract 2010;64:1042–1051

  35. BII: combination therapy with dutasteride and tamsulosin superiorto both monotherapies at 4 years Adjusted mean change from baseline in BII Mean baseline BII = 5.3 p≤0.008 combination versus tamsulosin p≤0.003 combination versus dutasteride -1.2 -1.8 -2.2 Month Dutasteride Combination Tamsulosin Montorsi F et al. Int J Clin Pract 2010;64:1042–1051

  36. The PPSM questionnaire was developedby GSK to assess patient satisfactionwith treatment in the CombATstudy • 12 questions covering six areas • Control of urinary symptoms • Strength of urinary stream • Two aspects of pain of urination • Effect on usual activities • Overall satisfaction • Whether the respondent would ask their doctor for this medication • PPSM total score ranges from 7 (best) to 49 (worst) • Question 12: possible responses are yes, no and not sure Montorsi F et al.Int J ClinPract 2010;64:1042–1051; Black L et al. Health Qual Life Outcomes 2009;7:55

  37. PPSM total score: combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years Adjusted mean change from baseline in PPSM total score Mean baseline PPSM total score = 25 p<0.001 combination versus tamsulosin p<0.001 combination versus dutasteride -4.1 -5.5 -7.0 Month Dutasteride Combination Tamsulosin Montorsi F et al. Int J Clin Pract 2010;64:1042–1051

  38. Satisfaction with treatment (PPSM Q11): combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years Percentage of patients satisfied with treatment 80% 74% 69% p<0.001 combination versus tamsulosin p≤0.002 combination versus dutasteride 0% Month Dutasteride Combination Tamsulosin Montorsi F et al. Int J Clin Pract 2010;64:1042–1051

  39. PPSM Q12: Would you ask your doctor for the medication you received in the study? Percentage of patients responding ‘Yes’ * * *p<0.01 versus combination Montorsi F et al. Int J Clin Pract 2010;64:1042–1051

  40. QoL: What can we conclude? • Combination therapy with dutasteride and tamsulosin provides significantly superior improvements in patient-reported QoL and treatment satisfaction than either monotherapy • Improved overall QoL (IPSS Q8) • Reduced impact of BPH (BII) • Improved treatment satisfaction (PPSM) • Superiority of combination therapy versus both monotherapies was sustained out to 4 years

  41. Roehrborn CG et al. Eur Urol 2010;57:123–131 CombAT 4-year primary endpoint:Time to first AUR or BPH-related surgery 16 14 12 10 8 6 4 2 0 Combination Dutasteride Tamsulosin Percent of patients 8 months 0 12 24 36 48 Time (months) CombinationCumulative no. of eventsNo. at risk DutasterideCumulative no. of eventsNo. at risk TamsulosinCumulative no. of eventsNo. at risk 291610 271623 401611 431457 491484 1021464 581347 651365 1461307 671274 841277 1911176

  42. Conclusions In men with moderate symptoms onwards with prostate volume ≥30 ml and PSA ≥1.5 ng/ml, CombAT shows that over 4 years, combination therapy with dutasteride and tamsulosin Significantly improves symptoms and QoL versus either monotherapy Significantly reduces the risk of AUR or BPH-related surgery versus tamsulosin monotherapy

  43. Implications of CombAT study: What do these results mean for patients? Men with BPH/LUTS may experience a substantial reduction in their quality of life In many men, the progressive course of BPH raises the prospect of worsening symptoms, AUR and the need for surgery4 Major goals of BPH treatment include improvement of symptom scores, lowering risk of disease progression, improving patient-reported quality of life and treatment satisfaction1 In the CombAT study, combination therapy was associated with: Improvement of symptoms2 Reduced risk of BPH clinical progression2 Reduced risk of AUR or BPH-related surgery2 Improved patient-reported health outcomes3 1Madersbacher S et al. Eur Urol 2004;46:547–554; 2Roehrborn CG et al. Eur Urol 2010;57:123–131; 3Montorsi F et al. Int J Clin Pract 2010;4Emberton M et al. Int J Clin Pract 2008; 62: 18–26

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