BPH management Overview of treatment options Antonio Alcaraz
BPH management. Overview of treatment options Antonio Alcaraz
U es EA elin id gu EAU: International guidelines recommend treatment algorithms to guide medical treatment choices according to patient profile Oelke M et al. Eur Urol 2013. http: //dx. doi. org/10. 1016/j. eururo. 2013. 004 Accessed on 8 th April 2013. 2 2 Prescribing information can be found at the end of the presentation
Men >40 yo Histological BPH Prostatic growth `UT obstruction LUTS Medical therapy in BPH evolution.
BPH prevalence according definition and age Prevalence (%) 100 80 60 40 20 0 40– 49 50– 59 60– 69 70– 79 Edad (años) Pathological prevalence(n=1057) DRE(n=6975) History and physical exam(n=1057) Symptoms, IPSS (Scotland, n=699) DRE (n=1057) Symptoms and flujometria (Rochester, n=2115) Combined medical therapy in BPH
URINARY SYMPTOMS PREVALENCE IN MEN N=5460 VOIDING 25. 7% LUTS NO LUTS POSTVOIDING 16. 5% 6 OUT OF 10 MEN FILLING 49. 7%
Management options of LUTS • Prostate – Alfa blockers • Symptomatic control – 5 alfa reductase inhibitors • Disease modification • Long term Symptomatic control – Surgical management • Symptomatic and modification of natural history of the disease • Bladder – Antimuscarinics • Symptomatic control
Evolution of BPH therapy. 90 s • • • Finasteride approved in 1992 Terasozina approved in 1993 Doxasozina approved in 1995 Tamsulosina approved in 1997 Dutasteride 1998
Medical therapy and hospital admission Drug Therapy for BPH and Hospital Admission Souverein et al: Eur Urology 43: 528, 2003
‘Tailor’-made treatment of BPH Drug efficacy Prostate volume Sexual dysfunction Metabolic syndrome Risk of side effects PSA Sexually active Impact on BPH progression
U es EA elin id gu EAU guidelines: α-blockers/PDE 5 -Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? No Prostate volume >40 ml? Yes Long-term treatment? No • Prostate size does not affect α 1 blocker efficacy in studies with followup periods of <1 year but patients with a prostate volume of <40 m. L seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups • α 1 -blockers do not reduce prostate size and do not prevent AUR in longterm studies No Education + Lifestyle Advice with or without α 2 -blocker/PDE 5 -I Oelke M et al. Eur Urol 2013. http: //dx. doi. org/10. 1016/j. eururo. 2013. 004 Accessed on 8 th April 2013. 20 Prescribing information can be found at the end of the presentation
EAU Guidelines on the Treatment and Follow-up of Nonneurogenic Male Lower Urinary Tract Symptoms Including Benign Prostatic Obstruction (BPO) * v EAU guidelines recommend alpha-1 blockers to be offered to men with moderate-to-severe LUTS based on level 1 A evidence. v α 1 -blockers are often considered the first-line drug treatment of male LUTS because of their rapid onset of action, good efficacy, as well as the low rate and severity of adverse events. *we mentioned here the section related to Alpha-blocker only M. Oelke et al, EUROPEAN UROLOGY 6 4 ( 2 0 1 3 ) 1 1 8 – 1 4 0
α-blockers pharmacological selectivity
a 1 -adrenoceptor antagonists (a 1 -blockers) • Efficacy v Controlled studies have shown that α 1 -blockers typically reduce the International Prostate Symptom Score (IPSS), after a run-in period, by approximately 30 -40% and increase the maximum urinary flow rate (Qmax) by approximately 20 -25%. M. Oelke et al, EUROPEAN UROLOGY 6 4 ( 2 0 1 3 ) 1 1 8 – 1 4 0 Alf 053 DA NE (NE) 09 -13 v significant efficacy of α 1 -blockers over placebo was demonstrated within hours to days and maintained over at least 4 years.
‘Tailor’-made treatment of BPH Risk of side effects
AUA meta-analysis: dizziness with medical therapies ALFUZOSIN Doxazosin TAMSULOSIN* Terazosin FINASTERIDE Alfuzosin/Finasteride Doxazosin/Finasteride Terazosin/Finasteride PLACEBO 0% 10% 20% 30% Estimated Occurrence Rate with 95% CI *Tamsulosin 0. 4 mg to 0. 8 mg AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530 -547
AUA meta-analysis: symptomatic postural hypotension ALFUZOSIN Doxazosin TAMSULOSIN* Terazosin FINASTERIDE Alfuzosin/Finasteride Doxazosin/Finasteride Terazosin/Finasteride PLACEBO 0% 10% 20% 30% Estimated Occurrence Rate with 95% CI *Tamsulosin 0. 4 mg to 0. 8 mg AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530 -547
AUA meta-analysis: headache with medical therapies ALFUZOSIN Doxazosin TAMSULOSIN* Terazosin FINASTERIDE Alfuzosin/Finasteride Doxazosin/Finasteride Terazosin/Finasteride PLACEBO 0% 10% 20% 30% Estimated Occurrence Rate with 95% CI *Tamsulosin 0. 4 mg to 0. 8 mg AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530 -547
AUA meta-analysis: ejaculatory dysfunction with medical therapies ALFUZOSIN Doxazosin TAMSULOSIN Terazosin FINASTERIDE Alfuzosin/Finasteride Doxazosin/Finasteride Terazosin/Finasteride PLACEBO 0% 10% 20% 30% Estimated Occurrence Rate with 95% CI AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530 -547
‘Tailor’-made treatment of BPH Sexual dysfunction Sexually active Co-prescription with PDE 5 inhibitors? Deleterious effects on ejaculation? Improving erection and ejaculation?
Multinational Survey of Ageing Male (MSAM-7) § Patients: – 12, 815 patients representative of men 50– 80 years in 7 countries (US, UK, F, Ge, I, Sp, NL) • Methods: postal questionnaire – Demographic characteristics – IPSS – DAN-PSSsex, IIEF – Co-morbidity Rosen et al. Eur Urol 2003; 44: 637 - 49
MSAM-7: ED, LUTS & Age Average IIEF* LUTS Age (years) *International Index of Erectile Function (IIEF); 26 to 30 = normal erectile function; 22 to 25 = mild ED; 17 to 21 = mild-to-moderate ED; 11 to 16 = moderate ED; ≤ 10 = severe ED. Rosen R et al. Eur Urol. 2003; 44: 637 -649
MSAM-7: Conclusions § BPH/LUTS, ED and Ej. D are common problems in aging men § Presence and severity of BPH/LUTS is a major, independent risk factor for sexual dysfunction § Sexual function should be considered in the initial evaluation of men with BPH/LUTS Rosen et al. Eur Urol 2003; 44: 637 -49
Is ejaculatory dysfunction (Ej. D) observed with tamsulosin due to retrograde ejaculation?
ABEJAC study Change in ejaculate volume Change in urine sperm concentration p=ns *Tam vs Pbo, p<0. 001 Tam vs Alf, p<0. 001 +0. 4 +1. 7 +0. 3 +1. 4 +1. 2 -2. 4 * Mean ±sd value at baseline 3. 4 ± 1. 4 ml Placebo Intent to treat population Mean ±sd value at baseline 48 ± 0. 5 million/ml Alfuzosin 10 mg OD Tamsulosin 0. 8 mg OD Hellstrom W. J. Urol. 2006, 176, 1529 -1533
ABEJAC Study Percentage of patients Complete unejaculation 35. 4% 0% 0% Placebo Alfuzosin 10 mg OD Tamsulosin 0. 8 mg OD Among completers (n=48) Hellstrom, WJG. J Urol. 2006, 176, 1529 -33
U es EA elin id gu EAU guidelines: α-blockers/PDE 5 -Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? No Prostate volume >40 ml? Yes Long-term treatment? No • Prostate size does not affect α 1 blocker efficacy in studies with followup periods of <1 year but patients with a prostate volume of <40 m. L seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups • α 1 -blockers do not reduce prostate size and do not prevent AUR in longterm studies No Education + Lifestyle Advice with or without α 2 -blocker/PDE 5 -I Oelke M et al. Eur Urol 2013. http: //dx. doi. org/10. 1016/j. eururo. 2013. 004 Accessed on 8 th April 2013. 42 Prescribing information can be found at the end of the presentation
Background § LUTS and sexual dysfunction are strongly associated 1 -2 § The co-prescription of drugs treating LUTS and ED is increasing § Both PDE 5 inhibitors and α 1 -blockers may have an impact on blood pressure which differs from one drug to another in a same class 1 Rosen et al. Eur. Urol. 2003; 44: 637 -649 2 Vallancien et al. J. Urol. 2003; 169: 2257 -2261
PDE 5 i and BPH Roehrborn et al. J Urol 2008; 180(4): 1228 -34. Egerdie RB et al. J Sex MDE 2012; 9: 271– 281 Porst et al. Eur Urol 2011; 60(5): 1105 -13. Oelke M et al. Eur Urol 2012; 61: 917 - 925
Treatment Minimum mean Media Basal change at 12 weeks (DS) (ANCOVA, LOCF) Placebo 16, 6 (6, 0) -3, 6 Tadalafil 5 mg 17, 1 (6, 1) -5, 6** Cambio m. DEio mínimo en el IPSS total Confirmatory study Tadalafil 5 mg: Basal Semana 1 a *p<0, 05, **p<0, 01, Porst et al. Eur Urol 2011; 60(5): 1105 -13. ** Semana 4 * Semana 8 ** Semana 12
Tadalafil: 12 months effect IPSS per visit 1, 2 IPSS total media 20 19 Change at the end of the treatment (UOR, n = 416) mean (DS) 18 17 Placebo → 5 mg -2, 2 (5, 3) 16 5 mg → 5 mg 15 0, 2 (5, 4) 14 13 12 11 Periodo doble ciego controladoc on placebo Extensión abierta con Tadalafilo 5 mg diario 10 Semana 0 Visita 3 12 6 16 8 24 9 38 10 51 11 64 12 The long treatment with tadalafilo 5 mg daily were effective in maintain the reduction of LUTS/BPH. This trial of 12 months was the ampliation of the study looking for doses. 1. Donatucci et al. BJU Int 2011; 107(7): 1110 -6.
Can α 1 -Blockers and PDE 5 -Inhibitors be Safely Combined?
Interaction Studies § 3 placebo-controlled, randomized, cross-over studies assessed the hemodynamic interaction of Tadalafil 20 mg with α 1 -blockers: ü Doxazosin 0. 8 mg (18 healthy volunteers)1 ü Tamsulosin 0. 4 mg (18 healthy volunteers)1 ü Alfuzosin 10 mg OD (18 healthy volunteers)2 § Endpoints: ü Maximal post-baseline drop in standing and supine SBP and DBP (primary) ü Outliers (secondary): SBP<85 mm. Hg, DBP<45 mm. Hg, drop in SBP vs baseline >30 mm. Hg, drop in DBP vs baseline >20 mm. Hg 1 Kloner RA et al. J Urol. 2004; 172: 1935 -1940 2 Giuliano F. et al. Urology 2006 67, 1199 -1204
Difference vs Placebo in Maximum Drop in Supine & Standing Blood Pressure Supine SBP DBP Standing DBP SBP * *statistically significant (95% CI did not contain 0) * 1 Kloner RA et al. J Urol. 2004; 172: 1935 -1940 2 Giuliano F. et al. Urology 2006 67, 1199 -1204
Conclusions § Tadalafil augments the hypotensive effect of doxazosin but shows marginal hemodynamic interaction with alfuzosin and tamsulosin
U es EA elin id gu EAU guidelines: α-blockers/PDE 5 -Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? No Prostate volume >40 ml? No • Yes • Long-term treatment? Prostate size does not affect α 1 -blocker efficacy in studies with follow-up periods of <1 year but patients with a prostate volume of <40 m. L seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups α 1 -blockers do not reduce prostate size and do not prevent AUR in long-term studies No Education + Lifestyle Advice with or without α 2 -blocker/PDE 5 -I Oelke M et al. Eur Urol 2013. http: //dx. doi. org/10. 1016/j. eururo. 2013. 004 Accessed on 8 th April 2013.
2000 s. MTOPS study (Medical Therapy of Prostatic Symptoms) 3047 PATIENTS Finasteride 5 mg Doxazosin 4 -8 mg Combined therapy Follow-up: 4. 5 years Age >50 IPSS 8 -30 Q max 8 -15 ml/sec No requirements of prostate volume No requirements regarding minimum PSA Mc. Connell JD, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of BPH. N Engl J Med. 2003; 349: 2387. Placebo
MTOPS – invasive therapy needed Incidence (%) 10 Placebo Doxazosin (p=ns) Finasteride (p<0. 001) Combo (p<0. 001) 8 6 4 2 0 0. 5 1. 0 1. 5 2. 0 2. 5 3. 0 3. 5 4. 0 4. 5 5. 0 5. 5 Años Mc. Connell JD, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of BPH. N Engl J Med. 2003; 349: 2387. Mc. Connell et al. NEJM 2003
MTOPS – Accumulated index of progression 67% Mc. Connell JD, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of BPH. N Engl J Med. 2003; 349: 2387. Mc. Connell JD, et al. MTOPS. N Engl J Med. 2003
Comb. AT at 4 years – Incidence of AUR or surgery for BPH
• High prostate volume, PSA. High PVR and low Qmax • Marked intravesical protrusion. • Deterioration with medical therapy.
There are to identify before its happen.
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