LA DROSPIRENONA EM LA MENOPAUSIA Terapia hormonal basada en evidencias

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, Madrid Teléfono

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 Vast amount of information exist. People tend to be selective and pick pieces of it according to their beliefs and personal experience, thus an overall perspective may be missing.

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

Intervention median, 5.6 yrs range, 4.6-8.6 years
Women's Health Initiative (WHI) Estrogen Plus Progestin E+P Trial: Design and Findings during Active Intervention HR 95% CI CHD 1.29 ( ) Breast Ca 1.26 ( ) Stroke 1.41 ( ) PE 2.13 ( ) Endometrial Ca 0.83 ( ) Colorectal Ca 0.63 ( ) Hip Fracture 0.66 ( ) Global Index 1.15 ( ) Dementia 2.05 ( ) Eligible postmenopausal Age No prior breast cancer No prior hysterectomy N= 16,608 Placebo Conjugated equine estrogen (CEE) mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d Intervention median, 5.6 yrs range, years WHI Writing Group JAMA 2002; 288: Chlebowski, Hendrix, Langer, et al JAMA 2003; 289: Rapp, Espeland, Shumaker et al JAMA 2003;289:

Women's Health Initiative (WHI) Estrogen Alone Clinical Trial: Design and Primary Outcome
HR 95% CI CHD 0.91 ( ) Breast Ca 0.7 ( ) Stroke 1.39 ( ) PE 1.34 ( ) Colorectal Ca 1.08 ( ) Hip Fracture 0.61 ( ) Global Index 1.01 ( ) Dementia 1.49 ( ) Eligible postmenopausal Age No prior breast cancer Prior hysterectomy N= 16,608 Placebo Conjugated equine estrogen (CEE) mg/d Intervention 7.1 yrs 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

HT and CHD: Meta-Analysis of Observational Studies
Hospital-based Population-based cohorts Cross-sectional Prospective/ internal control Summary Population-based case-control Ever Users Current Users 1.0 2.0 0.5 1.5 HT and CHD: Meta-Analysis of Observational Studies 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). From: Grodstein F, Stampfer MJ. Prog Cardiovasc Dis 1995; 38:

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

Relación de los años desde la menopausia con la progresión de arterioesclerosis en el WHI
Adventitia MMP-9 Fibrous Cap Fibrous Cap Fibrous Cap Media Internal Elastic Lamina Plaque Plaque Fatty Streak/Plaque Plaque Necrotic Core Necrotic Core 5 to <10 19% 10 to <15 21% ≥15 43% <5 17% Years Postmenopause % of WHI Enrollees Given that the time of initiation of HT may influence its beneficial or adverse effects on the progression of atherosclerotic lesions, the number of years after menopause that women initiate HT may be very important in determining the outcome of therapy. In this slide, the box shows the percentage of enrollees in WHI within a particular range of years postmenopause; for example, the majority (64%) of the women randomized in WHI were more than 10 years postmenopause. In addition, more than 35% of the women randomized to E+P had hypertension, 50% had a history of smoking, and the majority were obese, all of which are risk factors for CHD. Thus, the majority of women in WHI likely had subclinical or undiagnosed atherosclerosis, which might have limited the efficacy of E+P. 11

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 ( ) >60 years (Mean age 66 years) 1.03 ( ) <60 years (Mean age 54 years) 0.61 ( ) Salpeter S et al. J Gen Intern Med 2004;19:

Absolute Excess Risks (cases per 10,000 pys) by Age in the Combined Trials (E+P and E-Alone) of the WHI CHD * Total mortality * Global index† Outcome Age (years) * P=0.03 compared with age 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) 50–59 60–69 70–79 Years Since Menopause <10 10–19 20 1.27 1.05 1.44 0.89 1.22 1.71 Hazard Ratio for CHD To determine whether certain subgroups of women were at a higher or a lower risk for CHD with CEE/MPA compared with placebo, the investigators evaluated the risk of CHD in certain subgroups, designated by factors such as age and years since menopause. In this analysis, no significant interaction between age or years since menopause and treatment was observed (P = 0.36 for the age analysis and P = 0.33 for years-since-menopause analysis), although there was a numerical trend towards a higher risk with CEE/MPA use among those women with the longest times since menopause. While the investigators noted that the findings of the subgroup analyses should be interpreted with caution because of the small size of many of the subgroups as well as the large number of comparisons performed (approximately 36 tests were performed), these findings are consistent with accumulating data that the timing of initiation of HT in relation to the development of atherosclerosis is an important variable that may influence the potential risks and benefits of HT. 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: Manson JE, et al. N Engl J Med. 2003;349:

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

Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med Mar;124(3): 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, ) in years 1 to 6 and as 0.46 (confidence interval, ) 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 60-69 years 70-79 years CHD/Total MI Stroke DVT/PE Breast cancer Colorectal cancer Hip fracture All-cause mortality Global index Beginning E alone at younger age likely CHD and breast cancer benefit LaCroix, Chlebowski, Manson, et al. JAMA 2011;305(13):

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 Riesgo de ECV< 60 años no existe o es beneficioso y con E solos es beneficioso Riesgo de cancer de mama < 60 años puede? Ser mayor …NURSES´HEALTH STUDY=WHI < 60 AÑOS

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

Dose Response to Estrogen Therapy
Number of moderate-severe hot flushes 80 70 60 50 40 30 20 10 Placebo 0.25 mg E2 0.5 mg E2 1 mg E2 2 mg E2 Significantly (P<0.05) from placebo * Number * * * * * * Notelovitz et al. Obstet Gynecol. 2000;95;726.

annual percentage and each subject’s spinal trabecular
12 10 8 6 4 2 -2 -4 -6 -8 -10 -12 -14 -16 -18 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 Annual percent change spinal TBD +2 SEM -2 SEM Placebo mg mg mg Ettinger et al. Am J Obstet Gynecol 1992 Micronized estradiol

ANGELIQ® 1/2 H2O ESTRADIOL DROSPIRENONA

Numero de bochornos co E 1 mg y drosperinona
Mean number of hot flushes/week ANGELIQ®: Number of Hot Flushes A randomized controlled trial in 225 healthy postmenopausal women demonstrated the efficacy of ANGELIQ in reducing vasomotor symptoms. Eligible patients were 45 to 65 years of age, complained of at least 5 moderate-to-severe hot flushes per day on at least 7 of the 14 days preceding the study, had an intact uterus with normal endometrium as determined by transvaginal ultrasound or biopsy, and had estradiol levels ≤20 pg/mL and serum follicle-stimulating hormone (FSH) levels ≥50 U/L. Subjects were randomly assigned to receive ANGELIQ (at 1 of 3 dose levels: drospirenone 1 mg, 2 mg, or 3 mg plus estradiol 1 mg) or placebo once daily for 16 weeks. The primary endpoint was the change from baseline in the frequency of hot flushes. As this slide shows, ANGELIQ, at each dose level, significantly reduced the mean number of hot flushes relative to placebo by the third week of treatment (P≤0.001, Wilcoxon rank sum test). Hot flushes decreased by 87% with ANGELIQ 2 mg/1 mg and by 44.5% with placebo. References Schering AG, data on file Schürmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric. 2004;7: * Treatment week *P<0.001 Schürmann R et al. Climacteric 2004;7: BL, baseline

EFECTO DE ESTRADIOL/DROSPERINONA SOBRE LA DMO
6 12 18 24 –2.0 0.0 2.0 4.0 6.0 8.0 Change from baseline (%) E/DRSP (n=60) Placebo (n=60) Spine BMD Change from baseline (%) –2.0 0.0 2.0 4.0 6.0 8.0 6 12 18 24 E/DRSP (n=60) Placebo (n=60) P < 0.001 Total hip BMD Warming L et al. Climacteric 2004;7:

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

DMO EN CADERA E/DRSP (n=18) Placebo (n=18) Osteopenic women Months
BL 3 6 12 18 24 Months of treatment -1 1 2 4 Change from baseline in left hip BMD (%) Placebo (n=18) E/DRSP (n=18) P<0.05 Schering AG, data on file BL: baseline; BMD: bone mineral density

DRSP:PROPIEDADES PARA USAR COMO TRH
Porqué un nuevo gestageno Perfil farmacologíco Las diferencias el efecto PARA La eficacia El desafio

WHI HT Trials: Increased Risk of Venous Thromboembolism
HR (95% CI) E+P1 2.06 (1.57, 2.70) E alone2 1.33 (0.99, 1.79) 0.5 1.0 5.0 2.0 Hazard Ratio In the WHI E+P trial, VTE occurred in 167 women assigned to E+P and 76 women assigned to placebo, resulting in a 2-fold greater risk of VTE in the E+P group (hazard ratio [HR], 2.06).1 A similar 2-fold increase in risk was observed individually for DVT and PE.1 For all three outcomes, risk was increased in the first year of follow-up and an increased risk was observed over the duration of the trial. Trend analysis of the HR over time was statistically significant (P=.01), indicating that the increased risk of VTE, while still present, diminished over the course of the study. In the WHI E+P trial, the increased VTE risk associated with HT was greatest in the first year of use.1 The HR for VTE was 4.01 after the first year of follow-up (CI not reported). Thereafter, the annual HRs were 1.97 (Year 2), 1.74 (Year 3), 1.70 (Year 4), 2.90 (Year 5), and 1.04 (Year 6 or later).13 The trend for diminishing risk over time was statistically significant (P=.01). The results from the WHI E-alone trial are less conclusive with respect to the risk of VTE. The incidence of VTE was greater in women assigned to E alone compared with women assigned to placebo (2.8 vs 2.1 per 1000 person-years).2 However, the HR of 1.33 was not statistically significant. Analyzed separately, the increased risk of DVT (HR, 1.47) in the E-alone group was statistically significant, but the risk of PE was not (HR, 1.34).2 Considered at face value, these results might suggest that the VTE risk associated with E alone is less than the risk associated with E+P. However, caution is warranted in making direct, head-to-head comparisons of the results from the WHI HT trials because the studies enrolled distinctly different populations who, presumably, had different risk factors for chronic disease at baseline. 1Cushman M, et al. JAMA. 2004;292: 2Women's Health Initiative Steering Committee. JAMA. 2004;291: 1Cushman M, et al. JAMA. 2004;292: 2Women's Health Initiative Steering Committee. JAMA. 2004;291:

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

No effect on in-situ disease.
WHI: Informe sobre el Cáncer de Mama E-Solo actualizado Overall: HR=0.80; CI= Adherent Pts: HR= CI= 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 E3N y numero de canceres de mama
Int J Cancer 2005;114:448 54,548 women; years follow-up 55% gels; 45% patches E alone cases ( ) E/Progesterone 55 cases ( ) E/Progestins cases ( ) SPEROFF

WHI Results: Overall Attributable Risk
Event Attributable Risk or Benefit per 10,000 Women/Year E+P Arm1-7 E-Alone Arm8,9 CHD Risk (6) Benefit (5) Breast cancer Risk (8) Benefit (7) Dementia* Risk (23) Risk (12) Stroke Risk (7) VTE Risk (18) PE Risk (3) Colorectal cancer Benefit (6) Risk (1) Hip fractures Total fractures Benefit (47) Benefit (56) *Only in women 65 years of age at baseline. 1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Chlebowski RT, et al. JAMA. 2003;289: ; 3Shumaker SA, et al. JAMA. 2003;289: ; 4Wassertheil-Smoller S, et al. JAMA. 2003;289: ; 5Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6Chlebowski RT, et al. N Engl J Med. 2004;350: ; 7Cauley JA, et al. JAMA. 2003;290: ; 8Women's Health Initiative Steering Committee. JAMA. 2004;291: ; 9Shumaker SA, et al. JAMA. 2004;291: This slide provides the values for the HRs, CIs, and attributable risks from the WHI. Overall HRs for the major outcomes for CEE/MPA compared with placebo are shown in the black box. For each HR, the CIs that reached statistical significance (ie, those that did not include 1.0) are highlighted in yellow. With the exception of total fractures, the absolute excess risk or benefit attributable to CEE/MPA or CEE alone was low. The WHI findings predict that over 1 year, 10,000 women taking CEE/MPA compared with placebo might be expected to experience 6 more CHD events, 8 more invasive breast cancers, 7 more strokes, 18 more VTEs, 8 more PEs, 6 fewer colorectal cancers, 5 fewer hip fractures, and 47 fewer total fractures. In a subgroup of women age 65 years and older at baseline in the CEE/MPA arm, 23 more cases of probable dementia would be predicted by these findings; in the CEE-only arm, 12 more cases of probable dementia would be predicted – neither prediction is significant. These risk estimates apply only to the population of women represented by the subjects who participated in the WHI, that is, older women initiating HT for the first time who have significant risk factors for chronic disease, such as overweight/obesity and history of smoking. Writing Group for the WHI Investigators. JAMA. 2002;288:321-33 Chlebowski RT, et al. N Engl J Med. 2004;350: Cauley JA, et al. JAMA. 2003;290: Women's Health Initiative Steering Committee. JAMA. 2004;291: Shumaker SA, et al. JAMA. 2004;291: Manson JE, et al. N Engl J Med. 2003;349: Chlebowski RT, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289: Wassertheil-Smoller S, et al. JAMA. 2003;289:

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

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.

Comparación de Drospirenona con Otras Progestinas (continuación)
Presentation Paris 28. Januar 2018 Comparación de Drospirenona con Otras Progestinas (continuación) Actividad Progestagénica Actividad Androgénica Antiandrogénica Antialdosterona Actividad Glucocorticoide Progesterona + – (+) Drospirenona Ciproterona Desogestrel Dienogest Gestodeno Levonorgestrel MPA Noretisterona Norgestimato Tibolona + actividad relevante; (+) actividad no relevante; – no actividad MPA: Acetato de medroxiprogesterona Schindler AE et al. Maturitas. 2003;46(suppl 1):S7-S16; Rübig A. Climacteric. 2003;6(suppl 3):49-54.

Renin-angiotensin-aldosterone system (RAAS)
Na+/water retention K+ elimination Angiotensin II Aldosterone - Increased plasma volume - Increased blood pressure in susceptibles - Water retention-related symptoms (edema, bloating, weight gain, breast tension) Progesterone Angiotensin I Renin substrate (angiotensinogen) Renin + Estrogen Kidney: Enzyme renin produced. This catalyzes in the blood stream the conversion of the precurser peptide angitensinogen (renin substrate), which is produced in the liver to the inactive peptide AG I. This comes to the lung where the ACE catalyzes the conversion to AG II. This has a variety of effects in the organism. One is to stimulate the adrenal gland to release Ald. This has again a variety of effects and increases the Na retention and potassium elemination….

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

Effects on endometrium
Estradiol 1 mg E/DRSP® Participants, no* 173 149 Endometrial hyperplasia, no (%) 8 (4.6) 1 (0.7) Simple without atypia 4 (2.3) Complex without atypia 3 (1.7) 0 (0) Complex with atypia 1 (0.6) 1-year probability 0.060 0.007 Archer D et al. Menopause 2005;12:716-27

Amenorrhea ANGELIQ®: Number bleeding days by cycle
Angeliq®; a continuous combined preparation, is given with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. During the first months of treatment, bleeding and spotting are quite common but decrease with time. Compliance, especially with continuous combined preparations, is strongly related to the bleeding profile which needs to meet the women's expectations of a no-bleed treatment . Results from the Endometrium Study I demonstrated that with Angeliq®, a total of 88% of women had no bleeding after 12 months. The bleeding profile for Angeliq‚ was very good. The mean number of bleeding days per cycle at study endpoint was 0.9. If any kind of bleeding was reported at study endpoint, in most of the cases the maximum intensity was classified as spotting. References Archer D, Thorneycroft I, Foegh M, et al. A multicenter trial of the efficacy and safety of drospirenone-estradiol combinations when used for hormone therapy. Submitted 2005. Schering AG, data on file (Clinical Study Report A02827). Warming L et al. Climacteric 2004;7:

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

progestins and breast cancer
Number of genes regulated by progestin treatment in T47D breast cancer cells Excluding drospirenone, the progestins-regulated a significant number of genes in the T47Dco cells. The synthetic progestins show a high degree of similarity in their transcriptional responses, and each progestin regulates between 77 and 91% of the genes regulated by P4. DRSP acts differently from other progestins on gene expression in 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

Presentation Paris 28. Januar 2018 Presión arterial en el subgrupo de mujeres hipertensas del estudio de seguridad endometrial (análisis post hoc) * * # * p< .001 vs basal # p= .011 vs basal Archer et al. Menopause. 2005;12:716.

Dose ranging study: Results Placebo-adjusted mean change in 24-hour ambulatory systolic and diastolic blood pressure (ABPM) Mean change in blood pressure (mmHg) SBP DBP * † * ‡ ‡ DRSP 3 mg/E2 (n=125) DRSP 2 mg/E2 (n=123) DRSP 1 mg/E2 (n=123) E2 (n=125) *P<0.01; †P<0.001; ‡P<0.0001 White WB et al. Hypertension 2006;48:

Effect of DRSP and estradiol on blood pressure
Mean change in blood pressure [mmHg] –2.9* –6.0† DRSP 2 mg/E2 (n=124) *P<0.05; †P<0.001 White B et al. J Am Soc Hypert 2008; 2(1): 20-27

Additional effect on systolic BP Adverse effect on potassium
DRSP/E2 has an additive effect on BP when given along with antihypertensive drugs E2/DRSP (3mg) + antihypertensive drug Additional effect on systolic BP Adverse effect on potassium Enalapril 10 mg BID -9.2 mm Hg No ACEI/ARB at high dose -8.6 mm Hg HCTZ 25 mg -7.2 mm Hg 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. % change in mortality Ictus Coronary disease Total – – – 3 – – – 4 – – – 7 Reduction of Systolic B.P. mmHg 2 3 5

Study Outline Design: Controlled, prospective, non-interventional, active surveillance study in 7 European countries: Austria, Belgium, Germany, Italy, Netherlands, Spain, Turkey Treatment: 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) Angeliq* Other cc HRT * 2 mg DRSP, 1 mg E2

Exposure – 101,715 WY Exposure [WY]

Serious Adverse Events by Organ System (ICD 10)
Events/10,000 WY *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 HRcrude: 0.6 (95% CI: 0.5 – 0.7); p<0.001 Events/10,000 WY * adjusted for age, BMI, family history of VTE/ATE, region, user status, diabetes, smoking, hypertension

Venous Thromboembolism (VTE)
Events/10,000 WY 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)
HRadj.: 0.5 (95% CI: 0.3 – 0.8) HRcrude: 0.4 (95% CI: 0.2 – 0.7) Events/10,000 WY

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 1950s la TRH elisir de la juventud
Años 1970s la TRH produce ca de endometrio Años 1980s la TRH previene el ca de endometrio Años 1980s y 90s TRH aumenta el ca de mama Años 1990s 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

LA DROSPIRENONA EM LA MENOPAUSIA Terapia hormonal basada en evidencias

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