1

Hormone replacement therapy: actueel of obsoleet ?

PROF. DR. H. DEPYPERE

Menopauze kliniek en borstkliniek, Universitair Ziekenhuis, Gent.

2

Evolution of life expectancy in Belgium with people born between 1885-2004

women

Men

3

Causes of Death 2006 “Vlaams gewest”

Men Women

Incidence of Cardiovascular Disease Relation to Menopause Status

0,6 0,6

2,0

3,6

2,2

3,64,0

6,5

0

1

2

3

4

5

6

7

<40 40-44 45-49 50-54

PremenopausalPostmenopausal

Inci

denc

e

(per

100

0 w

omen

)

Age (years) n = 2873 Kannel WB, et al. Ann Intern Med 1976;85:447-552.

The Framingham Study

6

Appelvorm – metabool syndroom –

Van de Voorde J, Depypere H. Inflamm res 1999, 48, 100-101.

Van de Voorde J, Depypere H. Inflamm res 1999, 48, 100-101.

Stevenson JC et al. Climacteric 2005;8:352-359.

* p<0.05 vs placebo ** p<0.001 vs placebo

Lipid Profile with Femoston® 1/10 and 2/10 % change from baseline after 2 year (n=579)

Femoston® 1/10

Femoston® 2/10

-15%

-10%

-5%

0%

5%

10%

15%

20%

Total cholesterol LDL HDL

% c

hang

e fro

m b

asel

ine

0.9%

-3% -5.7%

-15.3%**

17%*

21%*

Placebo

6%

- 1% 0.9%

10

Nurses health study

Hers study

WHI global study cc

WHI estrogen only

Importance of Timing of Intervention on the Effect of Estrogens on Atherogenesis

in Nonhuman Primates

1Clarkson et al. J Clin Endocrinol Metab 1998;83:721. 3Clarkson et al. J Clin Endocrinol Metab 2001;86:41. 2Adams et al. Arterioscler Thromb Vase Biol 1997;17:217. 4Williams et al. Arterioscler Thromb Vase Biol 1995;15:827.

Time

Premenopausal Years Postmenopausal Years Ovariectomy

Plaque Area (% of Placebo)

Healthy diet CEE + atherogenic diet 1. 70%1,2

Atherogenic diet CEE + atherogenic diet 2. 50%3

Healthy diet Atherogenic

diet Healthy diet

+ CEE 3. 0%4

~ 6 Year Human Equivalent

WHI: Total Mortality by Age at Baseline

Rossouw, et al. JAMA 2007;297:1465-1477.

CHD

Stroke

Total Mortality

CHD

Stroke

Total Mortality

CHD

Stroke

Total Mortality

Absolute number controles 95/4356 = 21,8/ 6 = 3,6/1000/Year

N Engl J Med 2007;356:2591-602

Subjects •  1064 postmenopausal women aged 50-59 •  Imaging mean 7.4 years •  Estrogen CEE 0.625 mg vs placebo •  Coronary artery scores Agaston score central reading centre

blinded to treatment

N Engl J Med 2007;356:2591-602

Calcium score

Hazard Ratio 0

10 100

0

10 100

0.5 1.0 2.0 10.0

WHI E ALONE Hazard Ratios for Coronary Calcium

N Engl J Med 2007;356:2591-602

>80% Adherence

ITT

P=0.01 P<0.001

P<0.001

Conclusion •  Women aged 50-59 taking estrogen had less calcified plaque

burden than women taking placebo •  This may translate into a potential cardioprotective action •  This study cannot be used to recommend that homone therapy

should be used solely for cardioprotection •  Reassurance that younger women who take hormone therapy for

menopausal symptoms may benefit from a decrease in coronary risk

CHD Events Associated with HRT in Younger and Older Women

Results: 23 trials 39,049 participants 191,340 patient-years mean duration of follow-up = 4.9 + 1.7 years range of follow-up = 0.5-10 years mean dropout rate (HT) = 12.0% mean dropout rate (Placebo) = 10.8%

Salpeter S, et al. J Gen Intern Med 2006;21:363-366.

CHD Events Associated with HRT in Younger and Older Women

HRT vs. Control OR (95% CI)

All ages 0.99 (0.88-1.11)

<10 years menopause, <60 years old

>10 years menopause, >60 years old Younger vs. Older women WHI-E <60 years old

Salpeter S, et al. J Gen Intern Med 2006;21:363-366.

0.68 (0.48-0.96)

1.03 (0.91-1.16)

0.66 (0.46-0.95)

0.66 (0.44-0.97)

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ORIGINAL CONTRIBUTION Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy THE WOMEN’S HEALTH INITIAtive (WHI) Estrogen-Alone Trial was a double-blind, placebo- controlled, randomized clinical trial evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among postmenopausal women with prior hysterectomy. The trial intervention was stopped 1 year early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned termination date. Analyses of outcomes during the intervention period suggested that treatment effects differed by age; compared with older women, younger women receiving CEE had a lower risk of coronary heart disease (CHD), colorectal cancer, total death, and the global index of chronic diseases.1 How- For editorial comment see p 1354. ever, the tests for interaction of age with Context The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. Objective To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. Main Outcome Measures The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00;95%CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27;95%CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77;95%CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P=.05 for interaction), total myocardial infarction (P=.007 for interaction), colorectal cancer (P=.04 for interaction), total mortality (P=.04 for interaction), and global index of chronic diseases (P=.009 for interaction). Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted. Trial Registration clinicaltrials.gov Identifier: NCT00000611 JAMA. 2011;305(13):1305-1314 www.jama.com Author Affiliations are listed at the end of this article. Corresponding Author: Andrea Z. LaCroix, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M3-A410, PO 19024, Seattle, WA 98109 (alacroix@whi.org). ©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, April 6, 2011—Vol 305, No. 13 1305 Downloaded from jama.ama-assn.org at University of Gent / UZGent on April 12, 2011

Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00;95%CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27;95%CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77;95%CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P=.05 for interaction), total myocardial infarction (P=.007 for interaction), colorectal cancer (P=.04 for interaction), total mortality (P=.04 for interaction), and global index of chronic diseases (P=.009 for interaction). Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted. Trial Registration clinical trials.gov Identifier: NCT00000611JAMA. 2011;305(13):1305-1314 www.jama.com Downloaded from jama.ama-assn.org at University of Gent / UZGent on April 12, 2011

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Primary Prevention of CHD with HRT in Clinical Perspective*

*Women <60 years old and/or <10 years since menopause when randomized

*Hodis HN, et al. Clin Obstet Gynecol 2008;51:564-586. 1Salpeter S, et al. J Gen Intern Med 2004;19:791-804. 2Salpeter S, et al. J Gen Intern Med 2006;21:363-366. 3Walsh JME, et al. JAMA 2004;21:363-366. 4Ridker PM, et al. N Engl J Med 2005;352:1293-1304.

Hormone Lipid Outcome Therapy1,2* Lowering3 Aspirin4

CHD 0.68 (0.48-0.96) 0.89 (0.69-1.09) 0.91 (0.80-1.03)

Total Mortality 0.61 (0.39-0.95) 0.95 (0.62-1.46) 0.95 (0.85-1.06)

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Primary Prevention of CHD

CHD 50-54 y 10 y Belgium 0,85 % of 0,85 women per 100/10y

55-59 y 10 y Belgium 1,58 % of 1,58 women per 100/10y

Depypere et al, Climacteric 2007, 10; 238-234.

SCORE België: 10-jaar risico op CV overlijden in primaire preventie bij patienten zonder diabetes noch nierinsufficientie

1. European Journal of Cardiovascular Prevention and Rehabilitation 2007;4(Suppl.2):S1-S113. 2. Journal of Hypertension 2007;25:1105-1187.

8 10 13 16 6 7 9 11 4 5 6 8 3 3 4 5

5 6 8 9 3 4 5 7 2 3 4 5 2 2 3 3

3 4 4 5 2 2 3 4 1 2 2 3 1 1 1 2

2 2 3 3 1 1 2 2 1 1 1 2 1 1 1 1

1 1 2 2 1 1 1 1 0 1 1 1 0 0 1 1

0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0

16 20 24 30 12 14 18 22 8 10 13 15 6 7 9 11

10 12 15 18 7 8 10 13 5 6 7 9 3 4 5 6

6 7 9 11 4 5 6 8 3 3 4 5 2 2 3 4

3 4 5 7 2 3 4 5 2 2 3 3 1 1 2 2

2 2 3 4 1 2 2 3 1 1 2 2 1 1 1 1

1 1 1 1 1 1 1 1 0 0 1 1 0 0 0 0

15 18 22 27 10 13 16 20 7 9 11 14 5 6 8 10

10 12 15 18 7 8 11 13 5 6 7 9 3 4 5 6

6 8 10 12 4 5 7 8 3 4 5 6 2 3 3 4

4 5 6 8 3 3 4 5 2 2 3 4 1 2 2 3

2 3 4 5 2 2 3 3 1 1 2 2 1 1 1 2

1 1 1 2 1 1 1 1 0 1 1 1 0 0 0 1

28 34 41 48 20 25 30 36 15 18 22 27 10 13 16 19

19 23 28 34 13 17 20 25 9 12 15 18 7 8 10 13

12 15 19 23 9 11 13 17 6 8 9 12 4 5 7 8

8 10 12 15 6 7 9 11 4 5 6 8 3 3 4 5

5 6 8 10 3 4 5 7 2 3 4 5 2 2 2 3

2 2 3 4 1 2 2 2 1 1 1 2 1 1 1 1

Vrouwen   Mannen  Niet-­‐rokers   Rokers  Niet-­‐rooksters   Rooksters  

Systolisc

he  bloed

druk  (m

mHg

)  

≥170  ≥150  ≥130  <130  

≥170  ≥150  ≥130  <130  

≥170  ≥150  ≥130  <130  

≥170  ≥150  ≥130  <130  

≥170  ≥150  ≥130  <130  

≥170  ≥150  ≥130  <130  

LeeFijd  

≥68  j  

≥63  j  

≥58  j  

≥53  j  

≥48  j  

<45  j  

Totaal  cholesterol  (mg/dl)  

SCORE  België  

10-­‐jaar  risico  op  CV  overlijden  

≥10%  

5-­‐9%  

2-­‐4%  

<2%  

<175   ≥275  ≥225  ≥175   <175   ≥275  ≥225  ≥175   <175   ≥275  ≥225  ≥175   <175   ≥275  ≥225  ≥175  

Absolute number controles WHI 95/4356 = 21,8/ 6 = 3,6/1000/Year Score = 3,6/100/10 year Belgium 55-59 y Score 1,58/100/10 year

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Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6409 (Published 09 October 2012) Cite this as: BMJ 2012;345:e6409

Louise Lind Schierbeck, registrar1, Lars Rejnmark, associate professor, consultant2, Charlotte Landbo Tofteng, staff specialist 11, Lis Stilgren, consultant3, Pia Eiken, consultant, senior endocrinologist4, Leif Mosekilde, professor, senior consultant2, Lars Køber, professor, consultant5, Jens-Erik Beck Jensen, associate professor, consultant1

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Objective: To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women. Design Open label, randomised controlled trial. Setting Denmark, 1990-93. Participants: 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone. Interventions: In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.

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Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction. Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer. Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.

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Hormone therapy for preventing cardiovascular disease in post-menopausal women Review Intervention Authors Henry MP Boardman, Close author notesCorresponding authorUniversity of Oxford, John Radcliffe Hospital, Department of Cardiovascular Medicine, Oxford, UK Henry MP Boardman, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Harry.Boardman@cochrane.nhs.uk. hboardman@doctors.org.uk. Search for more papers by this author Louise Hartley, Close author notesWarwick Medical School, University of Warwick, Division of Health Sciences, Coventry, Warwickshire, UK Search for more papers by this author Anne Eisinga, Close author notesUK Cochrane Centre, Oxford, Oxfordshire, UK Search for more papers by this author Caroline Main, Close author notesUniversity of Birmingham, Cancer Research UK Clinical Trials Unit (CRCTU), School of Cancer Sciences, Birmingham, UK Search for more papers by this author Marta Roqué i Figuls, Close author notesCIBER Epidemiología y Salud Pública (CIBERESP), Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Catalunya, Spain Search for more papers by this author Xavier Bonfill Cosp, Close author notesCIBER Epidemiología y Salud Pública (CIBERESP) - Universitat Autònoma de Barcelona, Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Catalonia, Spain Search for more papers by this author Rafael Gabriel Sanchez, Close author notesHospital Universitario de la Paz, Universidad Autónoma de Madrid, Instituto de Investigacion IdiPAZ, Red Espanola de Investigacion Cardiovascular RD/12/0042/0008, Madrid, Spain Search for more papers by this author Beatrice Knight Close author notesUniversity of Exeter Medical School, NIHR Exeter Clinical Research Facility, Exeter, UK Search for more papers by this author First published: 10 March 2015

Hormone therapy for preventing cardiovascular disease in post-menopausal women Henry MP Boardman et al. Cochrane review First published: 10 March 2015

We identified six new trials through this update. Therefore the review includes 19 trials with a total of 40,410 post-menopausal women. On the whole, study quality was good and generally at low risk of bias; the findings are dominated by the three largest trials.

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Selection criteria RCTs of women comparing orally administered hormone therapy with placebo or a no treatment control, with a minimum of six months follow-up.

Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95, moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; moderate quality evidence), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73, high quality evidence) compared to placebo or no treatment.

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Cochrane review 2015

Selective treatment

- Number needed to treat

- Initiation of therapy

- Selection of women