BPH management. Overview of treatment options Antonio Alcaraz

EAU: International guidelines recommend treatment algorithms to guide medical treatment choices according to patient profile EAU guidelines Aimed at GPs or Urologists? Oelke M et al. Eur Urol 2013. http://dx.doi.org/10.1016/j.eururo.2013.03.004 Accessed on 8th April 2013. 2 Prescribing information can be found at the end of the presentation

Health, United States 2006 (CDC)

Men > 40 yo Medical therapy in BPH evolution. [Dr. Roehrborn, transcript page 6] Clearly, patients with histologic BPH, BPE, or LUTS with bother may also have BOO. However, BOO may be present for a number of other causes that are totally unrelated to the prostate. Medical therapy in BPH evolution.

Men > 40 yo BPH Histological Medical therapy in BPH evolution. [Dr. Roehrborn, transcript page 6] Clearly, patients with histologic BPH, BPE, or LUTS with bother may also have BOO. However, BOO may be present for a number of other causes that are totally unrelated to the prostate. Medical therapy in BPH evolution.

Men > 40 yo LUTS BPH Prostatic growth Histological [Dr. Roehrborn, transcript page 6] Clearly, patients with histologic BPH, BPE, or LUTS with bother may also have BOO. However, BOO may be present for a number of other causes that are totally unrelated to the prostate. Medical therapy in BPH evolution.

Men >40 yo ` LUTS BPH Prostatic growth UT obstruction Histological [Dr. Roehrborn, transcript page 6] Clearly, patients with histologic BPH, BPE, or LUTS with bother may also have BOO. However, BOO may be present for a number of other causes that are totally unrelated to the prostate. Medical therapy in BPH evolution.

BPH prevalence according definition and age 100 80 60 40 20 Esta diapositiva resume lo que todos conocemos en cuanto prevalencia de los sintomas del tu inferior. Dependiendo de la definicion que se utilice la prevalencia cambia. Lo que si es una constante es que independiente de la deficion de HPB utilizada, a medida que aumenta la edad aumenta tambienla presencia de hpb 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 9

The prevalence of LUTS increases with the age Sagnier P-P, et al. J Urol 1994;151:1266-70; Hunter DJW, et al. J Urol 1996;155:1965-70; Garraway WM, et al. Lancet 1991;338:469-71; Bosch JLHR, et al. Br J Urol 1995;75:622-30; Chute CG, et al. J Urol 1993;150:85-9; TsukamotoT, et al. J Urol 1995;154:391-5.

URINARY SYMPTOMS PREVALENCE IN MEN VOIDING 25.7% FILLING 49.7% NO LUTS LUTS POST-VOIDING 16.5% This slide depicts results from the EPIC study, which was a cross-sectional populationbased survey of people ≥18 years of age in Germany, Italy, Sweden, and the United Kingdom. Men (N = 5460) with LUTS were classified according to the 2002 ICS definitions. The overall prevalence of LUTS in men ≥18 years of age was 61.3%. Storage symptoms included urgency, frequency, and nocturia and urgency, stress, mixed, and other incontinence. Voiding symptoms included intermittency, slow stream, straining, and terminal dribble. Post-micturition symptoms included incomplete emptying and postmicturition incontinence. Storage symptoms (49.7%) were reported nearly twice as often as voiding symptoms (25.7%). These numbers represent the percentage of men in the general population who reported at least 1 symptom representative of a particular type of LUTS. 6 OUT OF10 MEN

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 Two pharmacological options target the prostate: alpha-blockers have been used historically to treat the symptoms associated with BOO, as a result of BPH, and 5-ARIs have been used in patients with enlarged prostates to reduce disease progression. More recently, antimuscarinics have been used in men to treat the OAB component of LUTS.

Natural history of BPH diagnosed by urologists The Natural History of Patients With Benign Prostatic Hyperplasia as Diagnosed by North American Urologists Barry, Michael J.; Fowler, Floyd J. Jr.; Bin, Lin; Pitts, James C. III; Harris, Christopher J.; Mulley, Albert G. Jr. From the Medical Practices Evaluation Center and General Internal Medicine Division, Massachusetts General Hospital and Center for Survey Research, University of Massachusetts-Boston, Boston, Massachusetts, Department of Urology, Colorado Permanente Medical Group, Denver, Colorado, and South Region Urology of Group Health Cooperative of Puget Sound, Tacoma, Washington. Accepted for publication July 26, 1996. Supported by Grants HS 06336, 06540 and 08397 from the Agency for Health Care Policy and Research. ABSTRACT TOP Purpose: We defined outcomes for men with a clinical diagnosis of benign prostatic hyperplasia. Materials and Methods: We followed for 4 years 500 candidates for elective prostatectomy treated nonoperatively in 5 North American urology practices. Results: There were 371 survivors with complete data at 4 years. Of 60 men with mild, 245 with moderate and 66 with severe baseline symptoms 10, 24 and 39%, respectively, had undergone surgery; 27, 31 and 27%, respectively, were on pharmacological therapy, and 63, 45 and 33%, respectively, were off active treatment at 4 years. Mild or moderate symptoms were noted at 4 years in 83, 59 and 23% of the patients, respectively, while 17, 41 and 77%, respectively, had severe symptoms or had undergone surgery. Conclusions: Outcomes for men with a clinical diagnosis of benign prostatic hyperplasia depend on initial symptom severity. However, the course of symptoms also varies among patients even with the same initial symptom severity. Barry et al, J Urol 157:10, 1997

Evolution of BPH therapy

Evolution of BPH therapy. 70s Surgical treatment for LUTS 1976 Marco Caine: Receptor Alfa 1 Prazosin 1970

Evolution of BPH therapy. 80s Investigation in farmacological therapy 1987 Terasozin approved for the use in high blood pressure Increase of surgical therapy Caine M. J Urol. 1986;136:1. Lepor H. J Urol. 1989;141:1283. Hedlund H, Andersson KE. J Urol. 1989;141:1283.

Evolution of BPH therapy. 90s 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 PSA Sexual dysfunction Sexually active Metabolic syndrome Impact on BPH progression Risk of side effects

EAU guidelines EAU guidelines: α-blockers/PDE5-Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? Prostate size does not affect α1-blocker efficacy in studies with follow-up periods of <1 year but patients with a prostate volume of <40 mL seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups α1-blockers do not reduce prostate size and do not prevent AUR in long-term studies No Prostate volume >40 ml? No Yes Long-term treatment? No Education + Lifestyle Advice with or without α2-blocker/PDE5-I Oelke M et al. Eur Urol 2013. http://dx.doi.org/10.1016/j.eururo.2013.03.004 Accessed on 8th April 2013. Prescribing information can be found at the end of the presentation

EAU Guidelines on the Treatment and Follow-up of Non-neurogenic Male Lower Urinary Tract Symptoms Including Benign Prostatic Obstruction (BPO) * EAU guidelines recommend alpha-1 blockers to be offered to men with moderate-to-severe LUTS based on level 1A evidence. α1-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

a1-adrenoceptor antagonists (a1-blockers) Efficacy Controlled studies have shown that α1-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%. significant efficacy of α1-blockers over placebo was demonstrated within hours to days and maintained over at least 4 years. Alf 053 DA NE (NE) 09-13 M. Oelke et al, EUROPEAN UROLOGY 6 4 ( 2 0 1 3 ) 1 1 8 – 1 4 0

Treatment-Related Efficacy: Alpha- Blockers Have Comparable efficacy for BPH Lepor et al. Curr Opin Urol 2012, 22:7–15

Treatment-Related Adverse Events: Alpha- Blockers for BPH Afuzosin the least reported adverse events 56, 45,48,37 is from insert package data for related alpha-blockers products Lepor et al. Curr Opin Urol 2012, 22:7–15

‘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 0.4mg to 0.8mg 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 0.4mg to 0.8mg 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 0.4mg to 0.8mg AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530-547

AUA meta-analysis: ejaculatory dysfunction with medical therapies 0% 10% 20% 30% PLACEBO Terazosin/Finasteride Doxazosin/Finasteride Alfuzosin/Finasteride FINASTERIDE Terazosin TAMSULOSIN Doxazosin ALFUZOSIN Estimated Occurrence Rate with 95% CI AUA Guidelines on Management of BPH J. Urol. 2003, 170, 530-547

‘Tailor’-made treatment of BPH Sexually active Sexual dysfunction Co-prescription with PDE5 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: EjD, LUTS & Age Prevalence % LUTS Severity 50 to 59 years Reduced amount of semen No ejaculate 88 84 81 78 70 63 50 45 45 38 27 18 LUTS Severity 50 to 59 years 60 to 69 years 70 to 79 years DAN-PSSsex questionnaire Rosen R et al. Eur Urol. 2003;44:637-649

BPH/LUTS, ED and EjD are common problems in aging men MSAM-7: Conclusions BPH/LUTS, ED and EjD 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 (EjD) observed with tamsulosin due to retrograde ejaculation?

Population and design: ABEJAC Study Objective: To explore the mechanism of EjD observed with tamsulosin Population and design: Healthy male subjects aged between 18 and 36 years Double-blind, placebo-controlled, Latin Square, 3-way crossover study 3 periods of 5 days treatment (placebo or alfuzosin 10mg OD or tamsulosin 0.8mg OD) with 10 days wash-out between periods Hellstrom W. J. Urol. 2006, 176, 1529-1533

Intent to treat population ABEJAC study Change in ejaculate volume Change in urine sperm concentration *Tam vs Pbo, p<0.001 Tam vs Alf, p<0.001 p=ns +1.7 +0.4 +0.3 +1.4 +1.2 -2.4 * Mean ±sd value at baseline 3.4 ± 1.4 ml Mean ±sd value at baseline 48 ± 0.5 million/ml Placebo Alfuzosin 10mg OD Tamsulosin 0.8mg OD Intent to treat population Hellstrom W. J. Urol. 2006, 176, 1529-1533

Complete unejaculation ABEJAC Study Complete unejaculation 35.4% Percentage of patients 0% 0% Placebo Alfuzosin 10mg OD Tamsulosin 0.8mg OD Among completers (n=48) Hellstrom,WJG. J Urol. 2006, 176, 1529-33

Mechanisms of ejaculatory dysfunction with tamsulosin ? ABEJAC: Conclusions Nearly all volunteers (90%) receiving tamsulosin 0.8mg had reduced ejaculation and 1 out of 3 had no ejaculation which was not retrograde ejaculation The percentage of subjects with reduced ejaculation with alfuzosin 10mg is similar to placebo Mechanisms of ejaculatory dysfunction with tamsulosin ? Hellstrom W. J. Urol. 2006, 176, 1529-1533

EAU guidelines EAU guidelines: α-blockers/PDE5-Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? Prostate size does not affect α1-blocker efficacy in studies with follow-up periods of <1 year but patients with a prostate volume of <40 mL seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups α1-blockers do not reduce prostate size and do not prevent AUR in long-term studies No Prostate volume >40 ml? No Yes Long-term treatment? No Education + Lifestyle Advice with or without α2-blocker/PDE5-I Oelke M et al. Eur Urol 2013. http://dx.doi.org/10.1016/j.eururo.2013.03.004 Accessed on 8th April 2013. Prescribing information can be found at the end of the presentation

LUTS and sexual dysfunction are strongly associated1-2 Background LUTS and sexual dysfunction are strongly associated1-2 The co-prescription of drugs treating LUTS and ED is increasing Both PDE5 inhibitors and α1-blockers may have an impact on blood pressure which differs from one drug to another in a same class 1Rosen et al. Eur.Urol. 2003; 44: 637-649 2Vallancien et al. J.Urol. 2003; 169: 2257-2261

PDE5i and BPH Roehrborn et al. J Urol 2008;180(4):1228-34. Porst et al. Eur Urol 2011;60(5):1105-13. Roehrborn et al. J Urol 2008;180(4):1228-34. Egerdie RB et al. J Sex MDE 2012;9:271–281 Oelke M et al. Eur Urol 2012;61: 917- 925 LVHG: Estudio de BúsquDEa de Dosis Bibliografía: Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administerDE once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008;180(4):1228-34.

Cambio medio en el IPSS total Looking for dose: IPSS results Cambio medio en el IPSS total *p<0,05, **p<0,01, ***p<0,001, †p = 0,001 † *** * ** *** *** *** *** [Fuente: Roehrborn CG et al. J Urol 2008;180(4):1228-34, Pg 1232 Fig. 3A] Abreviaciones: IPSS: Escala Internacional de Síntomas Prostáticos, ANCOVA: análisis de covarianza Puntos Clave: La progresión en los cambios de los valores totales de la IPSS desde el inicio a las 4, 8 y 12 semanas se analizó mDEiante ANCOVA. El número de sujetos incluidos para los análisis de eficacia fueron como sigue: placebo, N = 210a; tadalafilo 2,5 mg, N = 208a; tadalafilo 5 mg, N = 212; tadalafilo 10 mg, N = 216; tadalafilo 20 mg, N = 208a (aUn paciente aleatorizado en 2 centros fue excluido y otros 2 aleatorizados no recibieron el fármaco de estudio). Criterio de valoración primario: una vez que la dosis diaria de 5 mg de tadalafilo produjo una mejoría estadísticamente significativa en la IPSS en comparación con placebo. En comparación con el placebo, una mejoría significativa en la IPSS se observó con cada dosis diaria de tadalafil (2,5, 5, 10 y 20 mg) en todas las visitas posteriores a la aleatorización. La mejoría fue evidente en el grupo de 2,5 mg y una mejoría mínima adicional se observó en los grupos de 10 y 20 mg. Bibliografía: Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administerDE once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008;180(4):1228-34. *** -4,87 *** *** *** 5mg of tadalafilo/once a day seems to provide the positive profile risk-benefit  selected as a dose for posterior studies Roehrborn et al. J Urol 2008;180(4):1228-34 Tada00045164

Cambio mDEio mínimo en el IPSS total Confirmatory study Tadalafil 5 mg: Cambio mDEio mínimo en el IPSS total ** * Basal Semana 4 Semana 1a Semana 8 Semana 12 Treatment Media Basal (DS) Minimum mean change at 12 weeks (ANCOVA, LOCF) Placebo 16,6 (6,0) -3,6 Tadalafil 5 mg 17,1 (6,1) -5,6** [Fuente: Porst H et al. Eur Urol 2011;60(5):1105-13. Tabla 1 (Pg 1109); Tabla 2 (Pg 1109); Fig. 3A (Pg 1109); LVHJ CSR Tabla LVHJ 11.15 (Pg 106); Tabla LVHJ 11.17 (pg 108); Tabla LVHJ 11.13 (Pg 102); Datos semana 8: home/lillyce/prd/ly450190/integrations/bph_ise_2010/programs_stat/tfl_output/smpssab4.rtf] Abreviaciones: IPSS: Escala Internacional de Síntomas Prostáticos, DS: desviación estándar, MC: mínimos cuadrados, ANCOVA: análisis de covarianza, UOR: última observación realizada, mIPSS: IPSS modificada, IIFE-FE: ámbito de la Función Eréctil del Índice Internacional de la Función Eréctil, N: número de sujetos en el población del análisis de eficacia Puntos Clave: La tabla a la izquierda muestra el cambio mDEio desde el inicio al final del tratamiento. La gráfica a la derecha muestra el cambio mDEio desde el inicio con el tiempo. Los valores “N” son: Placebo, N = 164; Tadalafilo 5 mg, N = 161. Se analizaron los cambios con el tiempo en el valor total de la IPSS desde el inicio hasta la semanas 1 (mIPSS), 4, 8 y 12 usando ANCOVA [Pg 1109, Fig. 3 pie de figura] La rDEucción en el valor total de la IPSS fue evidente tras 1 semana, consiguiendo significación estadística tras 4 semanas, para continuar así hasta el final del periodo de 12 semanas [Pg 1111, Col 1, Par 1] Estos resultados son coherentes con los obtenidos en el estudio de determinación de la dosis con tadalafilo1 [Pg 1111, Col 1, Par 1] Bibliografía: Porst H, Kim DE, Casabé AR, Mirone V, Secrest RJ, Xu L, Sundin DP, Viktrup L; for the LVHJ study team. Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International RandomizDE, Double-Blind, Placebo-ControllDE Trial. Eur Urol 2011;60(5):1105-13. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administerDE once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008;180(4):1228-34. *p<0,05, **p<0,01, Porst et al. Eur Urol 2011;60(5):1105-13. Tada00045164

Cambio medioo desde el inicio Tadalafil vs Tamsulosin 4/28/2017 Mean change at 12 weeks (ANCOVA, LOCF) Basal Semana1# Semana 4 Semana 12 IPSS1 Qmax1 IIFE-FE2 Basal 16,8- 17,4 9,4- 10,5 14,0- 16,1 Placebo - 4,2 1,2 2,1 Tadalafilo 5 mg - 6,3* 2,4* 6,0* Tamsulosina 0,4 mg - 5,7* 2,2* 1,7 Cambio medioo desde el inicio IPSS Total * -4,2 * * * -5,7 * -6,3 * Tadalafilo 5 mg Tamsulosina 0.4 mg [Fuente: Oelke M et al. Eur Urol 2012;61(5):917-25. Tabla 1 (Pg 920); Tabla 2 (Pg 921); Fig. 3 (Pg 921); LVID CSR Body Pg 94, Tabla LVID. 11.14; Pg 100, Tabla LVID.11.17] Abreviaciones: IPSS: Escala Internacional de Síntomas Prostáticos, MC: mínimos cuadrados, ANCOVA: análisis de covarianza, UOR: última observación realizada, Qmax: flujo urinario máximo, IIFE-FE: ámbito de la Función Eréctil del Índice Internacional de la Función Eréctil, PF: punto final, DE: disfunción eréctil, mIPSS: IPSS modificada Puntos Clave: La tabla a la izquierda muestra el cambio mDEio desde el inicio al final del tratamiento. La gráfica a la derecha muestra los cambios con el tiempo desde el nivel basal. El cambio con el tiempo en la IPSS total desde el nivel basal hasta las semanas 1 (mIPSS), 4 y 12 se analizó mDEiante ANCOVA. [Pg 921, Fig. 3 pie de página] Las diferencia en los MC promDEio en la IPSS frente a placebo fueron significativas tanto para tadalafilo como para tamsulosina tras 1 semana (mIPSS: p = 0,003 and p = 0,005, respectivamente) y a las 4 semanas (p<0,001 y p<0,001, respectivamente). [Pg 919, Col 2, Par 5] El cambio desde el nivel inicial a la semana 12 (UOR) en la IPSS total fue estadísticamente significativo tanto para tadalafilo como para tamsulosina, en comparación con el placebo (p = 0,001 and p = 0,023, respectivamente). [Pg 919, Col 2, Par 5] La magnitud de la mejoría en la IPSS total al final del tratamiento con tadalafilo 5 mg en este estudio fue coherente con informes anteriores,3-5 y fue comparable con lo observado en estudios previos con -bloqueante6 y con la tamsulosina 0,4 mg en el presente estudio. [Pg 922, Col 1, Par 2] Las diferencias con el placebo en el BII fueron estadísticamente significativas tanto para tadalafilo (p = 0,003) como para la tamsulosina (p = 0,026). [Pg 919, Col 2, Par 6] Las diferencias con el placebo en el BII también fueron significativas a las 4 semanas tanto para tadalafilo como para tamsulosina; p<0,001 para ambos. [Pg 919, Col 2, Par 6] En comparación con el placebo, el cambio promDEio en los CM desde el inicio al final del tratamiento en el ámbito IIFE-FE en varones sexualmente activos con DE (placebo, N = 105; tadalafilo 5 mg, N = 106; tamsulosina 0,4 mg, N = 98) [LVID CSR Body, Pg 100, Tabla LVID.11.17] fue significativo para tadalafilo (p<0,001), pero no para tamsulosina (p = 0,699). [Pg 920, Col 1, Par 2; Col 2, Par 1] Bibliografía: Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improvDE lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomizDE, parallel, placebo-controllDE clinical trial. Eur Urol 2012;61(5):917-25. Giuliano F, Oelke M, Mirone V, Xu L, Cox D, Viktrup L. Effects of tadalafil (TAD) or tamsulosin (TAM) on erectile function in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): results from a multicenter, double-blind, randomizDE, placebo (PLA)- controllDE 12-week study. Eur Urol Suppl 2012;11(2):e705 (Abstract). ManEdadment of benign prostatic hyperplasia (BPH). American Urological Association Web site. Revisado en 2010. URL: http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm?sub=bph [Último acceso: 7 febrero, 2012] Porst H, Kim DE, Casabé AR, Mirone V, Secrest RJ, Xu L, Sundin DP, Viktrup L; for the LVHJ study team. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomizDE, double-blind, placebo-controllDE trial. Eur Urol 2011;60(5):1105-13. Egerdie RB, Auerbach S, Roehrborn CG, Costa P, Garza MS, Esler AL, Wong DG, Secrest RJ. Tadalafil 2.5 or 5 mg administerDE once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomizDE, placebo-controllDE, double-blind study. J Sex MDE 2012;9(1):271-81. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administerDE once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008;180(4):1228-34. *p<0,05 frente a placebo (ANCOVA) # Valores basados en la mIPSS The mean change on total IPSS were statistically significative in comparison with placebo, and was similar for both (tadalafil and tamsulosin) in the first week and along 12 weeks. The mean change in IIFE-FE in men sexually active with ED was significantly for tadalafil, but not for tamsulosin. Oelke et al. Eur Urol 2012;61(5):917-25. Giuliano et al. Eur Urol Suppl 2012;11(2):e705(Abstract). Tada00045164

Tadalafil: 12 months effect IPSS per visit1,2 IPSS total media Change at the end of the treatment (UOR, n = 416) mean (DS) Placebo → 5 mg -2,2 (5,3) 0,2 (5,4) 5 mg → 5 mg Periodo doble ciego controladocon placebo [Fuente: LVHG OLE CSR - Tabla LVHG.11.7 and LVHG.11.8] Abreviaciones: IPSS: Escala Internacional de Síntomas Prostáticos, ESE: extensión sin enmascaramiento, UOR: última observación realizada, DS: desviación estándar, STUI/HBP: síntomas del tracto urinario inferior indicativos de hiperplasia benigna de próstata; N: número de sujetos reclutados en la extensión sin enmascaramiento que recibieron al menos una dosis de tadalafilo, n: número de sujetos sin datos que falten de cada visita (Visitas 3, 6 y 8-12). Puntos Clave:1,2 La mayoría de los pacientes (69,9%) completó el periodo de extensión sin enmascaramiento de 1 año Los valores “N” son: Placebo, N = 92; tadalafilo 5 mg, n = 83 Los valores “n” para la semana 0: Placebo, n = 92; tadalafilo 5 mg, n = 83 Los valores “n” para la semana 12: Placebo, n = 92; tadalafilo 5 mg, n = 83 Los valores “n” para la semana 16: Placebo, n = 85; tadalafilo 5 mg, n = 78 Los valores “n” para la semana 24: Placebo, n = 84; tadalafilo 5 mg, n = 76 Los valores “n” para la semana 38: Placebo, n = 72; tadalafilo 5 mg, n = 71 Los valores “n” para la semana 51: Placebo, n = 72; tadalafilo 5 mg, n = 64 Los valores “n” para la semana 64: Placebo, n = 67; tadalafil 5 mg, n = 60 Bibliografía: Donatucci CF, Brock GB, Goldfischer ER, Pommerville PJ, Elion-Mboussa A, Kissel JD, Viktrup L. Tadalafil administerDE once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int 2011;107(7):1110-6. Data on file, Eli Lilly and Company. 2.7.3. Summary-Clinical-Efficacy; LVHG-OLE CSR Extensión abierta con Tadalafilo 5 mg diario Semana Visita 3 6 8 9 10 11 12 The long treatment with tadalafilo 5mg daily were effective in maintain the reduction of LUTS/BPH. This trial of 12 months was the ampliation of the study looking for doses. Donatucci et al. BJU Int 2011;107(7):1110-6. Tada00045164

Conclusions Sildenafil, tadalafil, vardenafil taken daily improved LUTS associated with BPH Lack of significant change in Qmax suggest that a new pathophysiology paradigm may be needed to explain the etiology of LUTS

Can α1-Blockers and PDE5-Inhibitors be Safely Combined?

Interaction Studies 3 placebo-controlled, randomized, cross-over studies assessed the hemodynamic interaction of Tadalafil 20mg with α1-blockers: Doxazosin 0.8mg (18 healthy volunteers)1 Tamsulosin 0.4mg (18 healthy volunteers)1 Alfuzosin 10mg OD (18 healthy volunteers)2 Endpoints: Maximal post-baseline drop in standing and supine SBP and DBP (primary) Outliers (secondary): SBP<85 mmHg, DBP<45 mmHg, drop in SBP vs baseline >30 mmHg, drop in DBP vs baseline >20 mmHg 1Kloner RA et al. J Urol. 2004;172:1935-1940 2Giuliano F. et al. Urology 2006 67, 1199-1204 .

Difference vs Placebo in Maximum Drop in Supine & Standing Blood Pressure SBP DBP SBP DBP * * * *statistically significant (95% CI did not contain 0) * 1Kloner RA et al. J Urol. 2004;172:1935-1940 2Giuliano F. et al. Urology 2006 67, 1199-1204 .

Tadalafil 20mg & Alfuzosin 10mg OD Outliers + Placebo (N=18) Tadalafil 20mg Standing blood pressure SBP < 85 mm Hg 1 DBP < 45 mm Hg SBP decrease >30 mm Hg DBP decrease >20 mm Hg Supine blood pressure SBP decrease >30 mm Hg Key Point(s): The number of subjects with potentially clinically significant reductions in standing SBP was greater following administration of Cialis 20 mg compared to placebo when administered during treatment with doxazosin. Giuliano F. et al. Urology 2006 67, 1199-1204

Tadalafil 20mg & Tamsulosin 0.4mg OD Outliers + Placebo (N=18) Tadalafil 20mg Standing blood pressure SBP < 85 mm Hg DBP < 45 mm Hg SBP decrease >30 mm Hg 1 2 DBP decrease >20 mm Hg Supine blood pressure SBP decrease >30 mm Hg Key Point(s): The number of subjects with potentially clinically significant reductions in standing SBP was greater following administration of Cialis 20 mg compared to placebo when administered during treatment with doxazosin. Kloner RA et al. J Urol. 2004;172:1935-1940 .

Tadalafil 20mg & Doxazosin 0.8mg OD Outliers + Placebo (N=18) Tadalafil 20mg Standing blood pressure SBP < 85 mm Hg 1 5 DBP < 45 mm Hg SBP decrease >30 mm Hg 2 DBP decrease >20 mm Hg Supine blood pressure SBP decrease >30 mm Hg Key Point(s): The number of subjects with potentially clinically significant reductions in standing SBP was greater following administration of Cialis 20 mg compared to placebo when administered during treatment with doxazosin. Kloner RA et al. J Urol. 2004;172:1935-1940 .

Conclusions Tadalafil augments the hypotensive effect of doxazosin but shows marginal hemodynamic interaction with alfuzosin and tamsulosin

EAU guidelines: α-blockers/PDE5-Is should be offered to men with moderate-to-severe LUTS Storage symptoms predominant? No Prostate volume >40 ml? No Prostate size does not affect α1-blocker efficacy in studies with follow-up periods of <1 year but patients with a prostate volume of <40 mL seem to have better efficacy compared with those with larger glands in the longer term and is similar across age groups α1-blockers do not reduce prostate size and do not prevent AUR in long-term studies Yes Long-term treatment? No Education + Lifestyle Advice with or without α2-blocker/PDE5-I Oelke M et al. Eur Urol 2013. http://dx.doi.org/10.1016/j.eururo.2013.03.004 Accessed on 8th April 2013.

2000s. MTOPS study (Medical Therapy of Prostatic Symptoms) 3047 PATIENTS Finasteride 5mg Doxazosin 4-8mg Combined therapy Placebo 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 McConnell 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.

MTOPS – invasive therapy needed Placebo Doxazosin (p=ns) Finasteride (p<0.001) Combo (p<0.001) Incidence (%) 10 8 6 4 2 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Años McConnell 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. McConnell et al. NEJM 2003

MTOPS – Accumulated index of progression 67% McConnell 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. McConnell JD, et al.  MTOPS. N Engl J Med. 2003

CombAT at 4 years – Incidence of AUR or surgery for BPH Table E3_Y4 Summary of AUR or BPH-Related Surgery. This is the first occurrence of either AUR of BPH-related surgery. Risk Reduction is from Table E1_Y4 Summary of Time to AUR or BPH-Related Surge This slide shows the 4-Year Overall Incidence of first AUR or BPH Related Surgery in the bars and the risk reduction (and 95% CI) of combination therapy versus dutasteride and combination versus tamsulosina are shown in the lower part of the graph. If a patient had an AUR first, then BPH-surgery, he was only counted once (as an AUR). The overall incidence of AUR or BPH related surgery was significantly reduced by the combination of dutasteride and tamsuloin compared with tamsulosina (66% risk reduction, P<0.001) but not compared with dutasteride monotherapy (20% risk reduction, p=0.18). In the dutasteride pivotal studies, after 2 years of treatment compared with placebo, AVODART was associated with a statistically significantly lower incidence of AUR (1.8% for AVODART vs. 4.2% for placebo, p<0.001; 57% reduction in risk, [95% CI: 38% to 71%]) and with a statistically significantly lower incidence of surgery (2.2% for AVODART vs. 4.1% for placebo, p<0.001; 48% reduction in risk, [95% CI: 26% to 63%]). CombAT Year 4 Long Presentation 15-Apr-2009

High prostate volume, PSA. High PVR and low Qmax Marked intravesical protrusion. Deterioration with medical therapy.

There are to identify before its happen.