LA DROSPIRENONA EM LA MENOPAUSIA Terapia hormonal basada

LA DROSPIRENONA EM LA MENOPAUSIA Terapia hormonal basada en evidencias Dr. Santiago Palacios Instituto Palacios, Salud y Medicina de la Mujer Chairman of CAMS (Council of Affiliated Menopause Societies) Presidente de SIBOMM (Sociedad Iberoamericana de Osteología y Metabolismo Óseo Mineral) Antonio Acuña, 9 - 28009 Madrid Teléfono 91 578 05 17 E-mail: ipalacios@institutopalacios. com www. institutopalacios. com

www. institutopalacios. com Diapositivas / Slides

TRH 2012 § TH -Ventana de oportunidad -Baja y ultra-baja dosis de estrógenos. -Gestágenos con valor añadido § DATOS SOBRE TRH EN EL 2012

TRH: El nuevo paradigma FDA WHI Million Women Study Dec. 2003 4 Reduciendo la dosis Acortando la duración Mujer sintomática

Women's Health Initiative (WHI) Estrogen Plus Progestin E+P Trial: Design and Findings during Active Intervention Eligible postmenopausal Age 50 -79 No prior breast cancer No prior hysterectomy N= 16, 608 Placebo Conjugated equine estrogen (CEE) 0. 625 mg/d + medroxyprogesterone acetate (MPA) 2. 5 mg/d Intervention median, 5. 6 yrs range, 4. 6 -8. 6 years HR 95% CI CHD Breast Ca Stroke PE Endometrial Ca Colorectal Ca Hip Fracture Global Index Dementia 1. 29 (1. 02 -1. 63) 1. 26 (1. 00 -1. 59) 1. 41 (1. 07 -1. 85) 2. 13 (1. 39 -3. 25) 0. 83 (0. 47 -1. 47) 0. 63 (0. 43 -0. 92) 0. 66 (0. 45 -0. 98) 1. 15 (1. 03 -1. 28) 2. 05 (1. 21 -3. 48) WHI Writing Group JAMA 2002; 288: 321 Chlebowski, Hendrix, Langer, et al JAMA 2003; 289: 3253 Rapp, Espeland, Shumaker et al JAMA 2003; 289: 2651 -62

Women's Health Initiative (WHI) Estrogen Alone Clinical Trial: Design and Primary Outcome Eligible postmenopausal Age 50 -79 No prior breast cancer Prior hysterectomy N= 16, 608 Placebo Conjugated equine estrogen (CEE) 0. 625 mg/d Intervention 7. 1 yrs HR 95% CI CHD 0. 91 (0. 75 -1. 12) Breast Ca 0. 7 (0. 59 -1. 01) Stroke 1. 39 (0. 10 -1. 77) PE 1. 34 (0. 87 -2. 06) Colorectal Ca 1. 08 (. 075 -1. 55) Hip Fracture 0. 61 (0. 41 -0. 91) Global Index 1. 01 (0. 91 -1. 12) Dementia 1. 49 (0. 83 -2. 66) Anderson et al JAMA 2004; 291: 1701 Stefanick et al JAMA 2006; 295: 1647

E+P and Total Fractures By Age E+P Effect in All Age Groups Cauley et al. JAMA 2009; 290: 1729

0 HT and CHD: Meta-Analysis of Observational Studies Ever Users Crosssectional Prospective/ internal control Hospitalbased Summary Current Users Based on more than 40 observational studies of HT and CHD, the summary relative risks for CHD were 40 -50% lower among current or ever users of HT compared to never users (p<0. 001). Populationbased cohorts Populationbased casecontrol Crosssectional Prospective/ internal control Summary From: Grodstein F, Stampfer MJ. Prog Cardiovasc Dis 1995; 38: 199 -210. 0. 5 1. 0 1. 5 2. 0

DIFERENCIAS ENTRE ESTUDIOS OBSERVACIONALES Y EL WHI Observational Studies Edad de iniciación de la TH 63 años 52 años Tiempo desde la menopausia 12 años 1 -2 años General – General+ IMC 28 -30 24 -25 Uso de TH Corto Largo CEE+MPA Diversas Síntomas vasomotores Formulaciones de TH

Relación de los años desde la menopausia con la progresión de arterioesclerosis en el WHI Adventitia Media MMP-9 Fibrous Cap Internal Elastic Lamina Fatty Streak/Plaque Years Postmenopause % of WHI Enrollees <5 17% Fibrous Cap Plaque Necrotic Core 5 to <10 19% Necrotic Core 10 to <15 21% ≥ 15 43%

Mortalidad total asociada con la TRH en mujeres jóvenes y mayores: Meta-análisis de 30 estudios controlados randomizados HRT versus Control OR (95% CI) All Ages 0. 98 (0. 87 -1. 18) >60 years (Mean age 66 years) 1. 03 (0. 91 -1. 16) <60 years (Mean age 54 years) 0. 61 (0. 39 -0. 95) Salpeter S et al. J Gen Intern Med 2004; 19: 791 -804

Absolute Excess Risks (cases per 10, 000 pys) by Age in the Combined Trials (E+P and E-Alone) of the WHI Outcome Age (years) 50 -59 60 -69 70 -79 CHD -2 -1 +19* Total mortality -10 -4 +16* Global index† -4 +15 +43 * P=0. 03 compared with age 50 -59 years or <10 years since menopause † Global index is a composite outcome of CHD, stroke, pul embolism, breast ca, colorectal ca, endometrial ca, hip fracture and mortality Source: Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007.

WHI E+P Trial: Time Since Menopause May Be Better Than Age at Predicting CHD Risk with HT Age (years) 1. 27 50– 59 1. 05 60– 69 1. 44 70– 79 Years Since Menopause <10 10– 19 0. 89 1. 22 1. 71 20 Hazard Ratio for CHD The dotted vertical line indicates the overall CHD odds ratio (1. 24). P-values for interaction were not significant. Manson JE, et al. N Engl J Med. 2003; 349: 523 -34.

Timing of Hormone Therapy Initiation in Relation to Stage of Atherosclerosis: Observational Studies vs Clinical Trials Premenopausal Years Postmenopausal Years Since Menopause Onset 10 15 5 Observational Studies 20 Clinical Trials (1° and 2° Prevention) Progression of Cardiovascular Disease Fatty streaks Fatty plaques Atherosclerotic plaques Favorable Lipid and Endothelial Effects of Estrogen Predominate Plaques grow and may rupture Prothrombotic and Proinflammatory Effects of Estrogen Predominate (plaque rupture, thrombo-occlusion) From: J Manson, et al. Menopause 2006. Favorable Influence Adverse Influence of Initiating Exogenous Estrogens

Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med. 2011 Mar; 124(3): 199 -205. Harman SM, Vittinghoff E, Brinton EA, Budoff MJ, Cedars MI, Lobo RA, Merriam GR, Miller VM, Naftolin F, Pal L, Santoro N, Taylor HS, Black DM. Abstract Largely on the basis of the first publication of findings of net harm with menopausal hormone treatment in the Women's Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the "…shortest duration consistent with treatment goals…, " with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the "timing hypothesis"). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary heart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1. 08 (95% confidence interval, 0. 86 -1. 36) in years 1 to 6 and as 0. 46 (confidence interval, 0. 28 -0. 78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk: benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients.

Estrogen Alone Age Specific Results 50 -59 years CHD/Total MI 60 -69 years 70 -79 years 0 Stroke 0 DVT/PE 0 0 Breast cancer Colorectal cancer 0 Hip fracture 0 0 All-cause mortality 0 Global index 0 Beginning E alone at younger age likely CHD and breast cancer benefit La. Croix, Chlebowski, Manson, et al. JAMA 2011; 305(13): 1305 -

Re-analisis de la TRH del WHI ■ Porcentaje de retirada del estudio fué 30% en el grupo E+P y 45% en el de E solos = Por lo que el nivel de evidencia es B ■ La edad de inicio de la THS es importante. La hipotesis del tiempo es cierta Ø Riesgo de ECV< 60 años no existe o es beneficioso y con E solos es beneficioso Ø Riesgo de cancer de mama < 60 años puede? Ser mayor …NURSES´HEALTH STUDY=WHI < 60 AÑOS

TRH 2012 § TH -Ventana de oportunidad -Baja y ultra-baja dosis de estrógenos. -Gestágenos con valor añadido § DATOS SOBRE TRH EN EL 2012

Balance entre desaparición de unos síntomas-aparición de otros Reducción de: Aumento de : Síntomas vasomotores Tensión mamaria Sangrado vaginal

Dose Response to Estrogen Therapy Number of moderate-severe hot flushes 80 Placebo 0. 25 mg E 2 70 0. 5 mg E 2 60 1 mg E 2 Number 50 2 mg E 2 Significantly (P<0. 05) from placebo * 40 30 20 * * * 10 * * * 0 0 1 2 3 4 5 6 7 8 9 10 Notelovitz et al. Obstet Gynecol. 2000; 95; 726. 11 12

12 10 Annual percent change spinal TBD Changes mean ( 2 SEM) annual percentage and each subject’s spinal trabecular bone density (TBD) in 46 postmenopausal women given micronized estradiol (phase 1). All subjects received calcium supplements 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -2 SEM -16 -18 Ettinger et al. Am J Obstet Gynecol 1992 +2 SEM Placebo 0. 5 mg 1. 0 mg 2. 0 mg Micronized estradiol

ANGELIQ® 1/2 H 2 O DROSPIRENONA ESTRADIOL

Mean number of hot flushes/week Numero de bochornos co E 1 mg y drosperinona * Treatment week Schürmann R et al. Climacteric 2004; 7: 189 -196 *P<0. 001 BL, baseline

EFECTO DE ESTRADIOL/DROSPERINONA SOBRE LA DMO Spine BMD Change from 8. 0 baseline (%) E/DRSP (n=60) 6. 0 4. 0 P < 0. 001 2. 0 Placebo (n=60) 0. 0 – 2. 0 0 6 12 18 24 Total hip BMD Change from 8. 0 baseline (%) 6. 0 E/DRSP (n=60) 4. 0 2. 0 P < 0. 001 0. 0 Placebo (n=60) – 2. 0 0 Warming L et al. Climacteric 2004; 7: 103 -111 6 12 18 24

EFECTO DE E/DRSP SOBRE LA DMO EN OSTEOPENICAS E/DRSP (n=18) Placebo (n=18) Change from baseline in lumbar spine BMD (%) 6 5 4 3 2 1 0 -1 -2 Months of treatment BL 3 6 12 18 24 Osteopenic women Schering AG, data on file BL: baseline; BMD: bone mineral density

DMO EN CADERA Change from baseline in left hip BMD (%) E/DRSP (n=18) Placebo (n=18) 4 3 2 P<0. 05 1 0 -1 Months of treatment BL 3 6 12 18 24 Osteopenic women Schering AG, data on file BL: baseline; BMD: bone mineral density

TRH 2012 ■ TH -Ventana de oportunidad -Baja y ultra-baja dosis de estrógenos. -Gestágenos con valor añadido ■ DATOS SOBRE TRH EN EL 2012

DRSP: PROPIEDADES PARA USAR COMO TRH 1. Porqué un nuevo gestageno 2. Perfil farmacologíco 3. Las diferencias el efecto PARA 4. La eficacia 5. El desafio

WHI HT Trials: Increased Risk of Venous Thromboembolism HR (95% CI) E+P 1 E alone 2 2. 06 (1. 57, 2. 70) 1. 33 (0. 99, 1. 79) 0. 5 1. 0 2. 0 Hazard Ratio 1 Cushman 2 Women's M, et al. JAMA. 2004; 292: 1573 -80. Health Initiative Steering Committee. JAMA. 2004; 291: 1701 -12. 5. 0

Impact of HT on DVT by route of administration and type of progestin Cannonico et al. Circulation 2007

WHI: Informe sobre el Cáncer de Mama E-Solo actualizado Overall: HR=0. 80; CI=0. 62 -1. 04 Adherent Pts: HR=0. 67 CI=0. 47 -0. 97 No effect on in-situ disease. Only ductal cancers and in women with no prior hormone therapy. More follow-up mammograms/biopsies/aspirations. JAMA 2006; 295: 1647

Estudio Frances E 3 N y numero de canceres de mama SPEROFF 54, 548 women; 0. 1 -10. 6 years follow-up 55% gels; 45% patches E alone 30 cases E/Progesterone 55 cases E/Progestins 268 cases 1. 1 (0. 8 -1. 6) 0. 9 (0. 7 -1. 2) 1. 4 (1. 2 -1. 7) Int J Cancer 2005; 114: 448

WHI Results: Overall Attributable Risk or Benefit per 10, 000 Women/Year Event E+P Arm 1 -7 E-Alone Arm 8, 9 CHD Risk (6) Benefit (5) Breast cancer Risk (8) Benefit (7) Dementia* Risk (23) Risk (12) Stroke Risk (7) Risk (12) VTE Risk (18) Risk (7) PE Risk (8) Risk (3) Colorectal cancer Benefit (6) Risk (1) Hip fractures Benefit (5) Benefit (6) Total fractures Benefit (47) Benefit (56) *Only in women 65 years of age at baseline. 1 Manson JE, et al. N Engl J Med. 2003; 349: 523 -34; 2 Chlebowski RT, et al. JAMA. 2003; 289: 3243 -53; 3 Shumaker SA, et al. JAMA. 2003; 289: 2651 -62; 4 Wassertheil-Smoller S, et al. JAMA. 2003; 289: 2673 -84; 5 Writing Group for the WHI Investigators. JAMA. 2002; 288: 321 -33; 6 Chlebowski RT, et al. N Engl J Med. 2004; 350: 991 -1004; 7 Cauley JA, et al. JAMA. 2003; 290: 1729 -38; 8 Women's Health Initiative Steering Committee. JAMA. 2004; 291: 1701 -12; 9 Shumaker SA, et al. JAMA. 2004; 291: 2947 -58.

ANTIANDROGÉNICOS E A NORETIS ANMIN. IE ANAND. CPA ANT E

Why we need a new Progestin Recommendations on Postmenopausal Hormone Therapy ■ HT include a wide range of hormonal products with potentially different risks and benefits. Thus, the term “class effect” is confusing and inappropriate. ■ In general, progestogen should be added to systemic estrogens for all women with a uterus to prevent endometrial hyperplasia and cancer. However, progesterone and some progestins have specific beneficial effects that could justify their use besides the expected actions on the endometrium.

DRSP: PROPIEDADES PARA USAR COMO TRH 1. Porqué un nuevo gestageno 2. Perfil farmacologíco 3. Las diferencias el efecto PARA 4. La eficacia 5. El desafio

Comparación de Drospirenona con Otras Progestinas (continuación) Actividad Progestagénica Actividad Androgénica Antialdosterona Actividad Glucocorticoide Progesterona + – (+) + – Drospirenona + – + + – Ciproterona + – (+) Desogestrel + (+) – – – Dienogest + – – Gestodeno + (+) – Levonorgestrel + (+) – – – MPA + (+) – – (+) Noretisterona + (+) – – – Norgestimato + (+) – – – Tibolona + + – – – + actividad relevante; 39 (+) actividad no relevante; MPA: Acetato de medroxiprogesterona – no actividad Schindler AE et al. Maturitas. 2003; 46(suppl 1): S 7 -S 16; Rübig A. Climacteric. 2003; 6(suppl 3): 49 -54.

DRSP: PROPIEDADES PARA USAR COMO TRH 1. Porqué un nuevo gestageno 2. Perfil farmacologíco 3. Las diferencias el efecto PARA 4. La eficacia 5. El desafio

Renin-angiotensin-aldosterone system (RAAS) Angiotensin I + Estrogen Renin substrate (angiotensinogen) Renin - Increased plasma volume - Increased blood pressure in susceptibles - Water retention-related symptoms (edema, bloating, weight gain, breast tension) Na+/water retention K+ elimination Progesterone Aldosterone Angiotensin II

Renin-angiotensin-aldosterone system (RAAS) Angiotensin I + Estrogen Renin substrate (angiotensinogen) Renin - Increased plasma volume - Increased blood pressure in susceptibles - Water retention-related symptoms (edema, bloating, weight gain, breast tension) Na+/water retention K+ elimination Progesterone Drospirenone Aldosterone Angiotensin II

DRSP: PROPIEDADES PARA USAR COMO TRH 1. Porqué un nuevo gestageno 2. Perfil farmacologíco 3. Las diferencias el efecto PARA 4. La eficacia 5. El desafio

Effects on endometrium Participants, no* Endometrial hyperplasia, no (%) Simple without atypia Complex with atypia 1 -year probability Archer D et al. Menopause 2005; 12: 716 -27 Estradiol 1 mg 173 E/DRSP® 8 (4. 6) 1 (0. 7) 4 (2. 3) 3 (1. 7) 1 (0. 6) 0. 060 1 (0. 7) 0 (0) 0. 007 149

Amenorrhea Warming L et al. Climacteric 2004; 7: 103 -111

(mg/d. L for lipids) Mean change from baseline CAMBIOS LIPIDICOS CON E/DRSP Archer D et al. Menopause 2005; 12: 716 -27

progestins and breast cancer Number of genes regulated by progestin treatment in T 47 D breast cancer cells The number of up-regulated (white bars) and down-regulated (black bars) genes are indicated. DRSP acts differently from other progestins on gene expression in breast cancer cells. Bray et al, Journal of Steroid Biochemistry & Molecular Biology, 2005

DRSP: PROPIEDADES PARA USAR COMO TRH 1. Porqué un nuevo gestageno 2. Perfil farmacologíco 3. Las diferencias el efecto PARA 4. La eficacia 5. El desafio

Presión arterial en el subgrupo de mujeres hipertensas del estudio de seguridad endometrial (análisis post hoc) * * # 49 Archer et al. Menopause. 2005; 12: 716. * p<. 001 vs basal # p=. 011 vs basal

Dose ranging study: Results Placebo-adjusted mean change in 24 -hour ambulatory systolic and diastolic blood pressure (ABPM) Mean change in blood pressure (mm. Hg) SBP DBP * ‡ † * ‡ DRSP 3 mg/E 2 (n=125) DRSP 2 mg/E 2 (n=123) DRSP 1 mg/E 2 (n=123) E 2 (n=125) *P<0. 01; †P<0. 001; ‡P<0. 0001 White WB et al. Hypertension 2006; 48: 246 -253

Mean change in blood pressure [mm. Hg] Effect of DRSP and estradiol on blood pressure – 2. 9* – 6. 0† DRSP 2 mg/E 2 (n=124) *P<0. 05; †P<0. 001 White B et al. J Am Soc Hypert 2008; 2(1): 20 -27

DRSP/E 2 has an additive effect on BP when given along with antihypertensive drugs E 2/DRSP (3 mg) + antihypertensive drug Enalapril 10 mg BID ACEI/ARB at high dose HCTZ 25 mg Additional effect on systolic BP Adverse effect on potassium -9. 2 mm Hg No -8. 6 mm Hg No -7. 2 mm Hg No Preston RA, et al. Am J Hypertens 2002; 15: 816– 22 Preston RA, et al. Am J Hypertens 2005; 18: 797– 804 Preston RA, et al. Menopause 2007; 14: 408– 414

Population strategy: Distributions of systolic blood pressure Before intervention After intervention Reduction of B. P. Reduction of Systolic B. P. mm. Hg 2 3 5 % change in mortality Ictus Coronary disease Total – 6 – 8 – 4 – 5 – 3 – 4 – 14 – 9 – 7

Study Outline Design: Treatment: Controlled, prospective, non-interventional, active surveillance study in 7 European countries: Austria, Belgium, Germany, Italy, Netherlands, Spain, Turkey Angeliq* Other cc HRT Objectives: To compare incidence rates of serious adverse events – in particular cardiovascular outcomes – in users of continuous combined HRT products Supervision: Independent Scientific Advisory Board (S. Shapiro, A. Genazzani, A. Gompel, S. Palacios, M. Neves-e-Castro, J. Boivin) * 2 mg DRSP, 1 mg E 2

Exposure [WY] Exposure – 101, 715 WY

Events/10, 000 WY Serious Adverse Events by Organ System (ICD 10) *Any adverse event that results in death, a life-threatening experience, inpatient hospitalization, persistent or significant disability/incapacity, or requires medical/surgical intervention to prevent one of the said outcomes.

Cardiovascular SAEs (N=1, 543) HRadj. * : 0. 7 (95% CI: 0. 6 – 0. 9); p=0. 002 Events/10, 000 WY HRcrude: 0. 6 (95% CI: 0. 5 – 0. 7); p<0. 001 * adjusted for age, BMI, family history of VTE/ATE, region, user status, diabetes, smoking, hypertension

Venous Thromboembolism (VTE) N=74 N=26 Events/10, 000 WY N=24 HRadj: 0. 76 (95% CI: 0. 51 – 1. 26) HRadj: 1. 01 (95% CI: 0. 58 – 1. 77) * adjusted for age, BMI, family history of VTE/ATE, region, user status, diabetes, smoking, hypertension

Arterial Thromboembolism (N=265) Events/10, 000 WY N=95 N=33 N=15 HRadj. : 0. 5 (95% CI: 0. 3 – 0. 8) HRcrude: 0. 4 (95% CI: 0. 2 – 0. 7) N=23 N=99

CONCLUSIONES ● Existen evidencias de que la TRH aumenta la masa osea y reducen las fracturas ● Dosis Bajas de 1 mgr de estradiol han demostrado ser efectivos como dosis normales , pero con menos riesgo. ● El uso de gestagenos similares a la progesterona , confieren menores riesgos y poosibles beneficios añadidos ● El uso de TRH en mujeres sintomaticas de menos de 60 años es beneficioso

CONCLUSIONES ■ ■ ■ Años 1950 s la TRH elisir de la juventud Años 1970 s la TRH produce ca de endometrio Años 1980 s la TRH previene el ca de endometrio Años 1980 s y 90 s TRH aumenta el ca de mama Años 1990 s TRH previene el riesgo cardiovascular Primera decada del siglo XXI la TRH aumenta el riesgo cardiovascular ■ Y en la segunda decada del siglo XXI….

EL PENDULO DE LA TRH VUELVE PERO NO COMETAMOS LOS MISMOS ERRORES