High Cholesterol: To Be Treated More High Cholesterol: To Be Treated More Aggressively in Post Menopausal Women?Aggressively in Post Menopausal Women?

L.Bucciarelli MD, PhDCardiovascular Department

IRCCS Multimedica

High Cholesterol: To Be Treated More High Cholesterol: To Be Treated More Aggressively in Post Menopausal Women?Aggressively in Post Menopausal Women?

L.Bucciarelli MD, PhDCardiovascular Department

IRCCS Multimedica

Tenth International Symposium

HEART FAILURE & Co.CARDIOLOGY SCIENCE UPDATE FEMALE DOCTORS SPEAKING

ON FEMALE DISEASES

Milano9 - 10 aprile 2010

Women aged over 60 years represent 13%

of the population in Italy

National Health Plan Istituto Superiore della Sanità 1998-2000

Menopause ChangesMenopause Changes

• Decreased estrogenDecreased estrogen

• Increased serum lipid levelsIncreased serum lipid levels• Increased plasma fibrinogen levelsIncreased plasma fibrinogen levels• Increased lipid peroxidation and oxidative Increased lipid peroxidation and oxidative

stress generationstress generation

Castelao JE et al. Medical hypotheses 2007

*P<0.001; †P<0.05; ‡P<0.01; §P<0.1.

0 1 2 3 4 5 6

Coronary mortality

Sudden death

Angina pectoris

MI

CHD

Cardiac failure

Intermittent claudication

Stroke

Any CVD event

Age-Adjusted Risk Ratio

*

§

*

†

*

†*

†‡

*

††

Male

Female

‡

Relative Risk of CVD in Subjects With and Without Relative Risk of CVD in Subjects With and Without Diabetes: Framingham Heart StudyDiabetes: Framingham Heart Study

Kannel WB et al. Am Heart J. 1990

• The risk increases markedly in the post-menopausal period

• More postmenopausal women have high levels of plasma cholesterol than men of the same age, after 10 years post-menopause the risk is similar in women as in men

• Historically women less attention and treatment for :

cholesterol screening

lipid-lowering therapies

heparin

beta-blockers

aspirin

Post Menopausal Women and CHDPost Menopausal Women and CHD

Second report of the National Cholesterol Education Program Adult Treatment Panel JAMA 1993

MI therapy

Multifactorial Approach for an Effective Multifactorial Approach for an Effective Macrovascular Disease PreventionMacrovascular Disease Prevention

CVD Menopause

GlucoseGlucoseControlControl

LipidLipidControlControl

Blood PressureBlood PressureControlControl

Anti-ThromboticAgents

Diet &Physical Activity

Anti-cholesterolemic TherapyAnti-cholesterolemic Therapyin Postmenopausal Womenin Postmenopausal Women

EP StatinsCombined therapy (EP+Statins)

Estrogen Replacement in Estrogen Replacement in Postmenopausal WomenPostmenopausal Women

• Greater increasing of HDL level and lowering lipoprotein(a) compared to Statin

• Estrogen may directly stimulate the release of NO

• Increasing of triglicerides

Primary Target in Cardiovascular PreventionPrimary Target in Cardiovascular Prevention

LDL-C

Statin Treatment

LDL-CIncreased acitvity of LDLr

Triglicerides

Statin Treatment in PostmenopauseStatin Treatment in Postmenopause

Stabilitization/Regression of atherosclerotic plaque

National Cholesterol Education Program

Effects on Lipid CoreEndothelial Function

NO Bioactivity

Estrogen Replacement and Statin Estrogen Replacement and Statin in Primary interventionin Primary intervention

Koh K et al. Circulation 1999

• Conjugated equine estrogen (CE) 0.625mg 6 wks• Simvastatin 10 mg 6 wks• CE+Statin 6 wks

baselineAfter therapy

Estrogen Replacement and Statin Estrogen Replacement and Statin in Primary interventionin Primary intervention

• Estrogen may reduce PAI-1 level, enhancing fibrinolysis• Estrogen may reduce E-selectin, ICAM-1 and VCAM-1

Koh K Circulation 1999

EP Replacement and Statin EP Replacement and Statin in Secondary Intervention Studyin Secondary Intervention Study

• Greatest improvements in LDL/HDL ratio realized by combined E-P replacement (HRT) + Lovastatin therapy (HMG)

• Statin reduces the estrogen related triglycerides increasing

Harrington DM J et al. of the American College of Cardiology 1999

-15%

-26%

15%

9%

-43%

-33%

17%

-30%

-35%

10%

-8% -10%

Aggressive VS Moderate Lipid-Lowering Therapy Aggressive VS Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women:in Hypercholesterolemic Postmenopausal Women:

BELLES TrialBELLES Trial

HYPOTHESISHYPOTHESIS Raggi P Circulation 2005

Hypercholesterolemic postmenopausal women with indication for lipid-lowering therapyHypercholesterolemic postmenopausal women with indication for lipid-lowering therapy

Where treatd with intensive and moderate lowering lipid tratment.Where treatd with intensive and moderate lowering lipid tratment.

By Electron-beam tomography (EBT) was evaluated the related changes in Coronary Artery Calcium By Electron-beam tomography (EBT) was evaluated the related changes in Coronary Artery Calcium

(CAC) after 1 year terapy and quantified by calcium volume score (CVS)(CAC) after 1 year terapy and quantified by calcium volume score (CVS)

BELLES STUDY SUMMARYBELLES STUDY SUMMARY

• Intensive therapy with atorvastatin did not slow progression of coronary artery calcification more then moderate therapy with pravastatin as measured by EBT

• Changes in total coronary CVS did not correlate with changes in LDL levels in either treatment group or in the overall study population

• Limitations to this study: 1 year follow up

Evidence-based Guidelines Evidence-based Guidelines Cardiovascular Disease Prevention Cardiovascular Disease Prevention

in Women: Current Guidelinesin Women: Current Guidelines

• A five-step approach– Assess and stratify women into high risk, at risk,

and optimal risk categories – Lifestyle approaches recommended for all women– Other cardiovascular disease interventions:

treatment of HTN, DM, lipid abnormalities– Highest priority is for interventions in high risk patients– Avoid initiating therapies that have been shown

to lack benefit, or where risks outweigh benefits

Mosca L et al. Circulation 2004

Mosca L et al. Circulation 2007

OPTIMAL LIPIDS LEVELOPTIMAL LIPIDS LEVEL

• Optimal levels of lipids and lipoproteins in women are as follows (these should be encouraged in all women with lifestyle approaches):– LDL < 100mg/dL– HDL > 50mg/dL– Triglycerides < 150mg/dl– Non-HDL (total chol - HDL) < 130mg/dl

Mosca L et al. Circulation 2007

NCEP ATP III: New Target for LDLNCEP ATP III: New Target for LDL

Grundy SM et al. Circulation 2005Mosca L et al. Circulation 2007

*Optional terapy in very high risk pts and in pts with elevated TG and C-non-HDL<100 mg/dL;**Optional terapy

Very High RiskMI, Known CAD+ 1 or more

risk factors > 20% 10-year CHD risk

LD

L C

ho

lest

ero

l Lev

el

100

160

130

190

Low Risk< 2risk factors

<10% 10-Year CHD Risk

Target 160

mg/dL

High-Moderate Risk≥2 severe risk factors10-20% 10-Year CHD Risk

Target 130

mg/dL

70

Target 100

mg/dL

Optional 70

mg/dL*

Moderate Risk≥2 risk factors

<10% 10-Year CHD Risk

Target 130

mg/dL

Optional 100

mg/dL**

Treatable Risk Factors: The Epidemiology of Treatable Risk Factors: The Epidemiology of Cholesterol Levels and SubfractionsCholesterol Levels and Subfractions

Low HDL more important in women than men

– For every 1 mg/dl increase in HDL 3% decrease in CHD risk for women and 2% decrease in CHD risk for men

Maron et al. Am J of Card 2000

Interventions that are not useful/effective Interventions that are not useful/effective and may be harmful for the prevention and may be harmful for the prevention

of heart diseaseof heart disease

Hormone therapy and selective estrogen-receptor modulators (SERMs) should not be used for the primary or secondary prevention of CVD

Mosca L et al. Circulation 2007

THE CONTROVERSYTHE CONTROVERSYarises by

The Heart and Estrogen/Progestin Replacement Study (HERS)

Women’s Health Initiative (WHI)

The Timing hypothesisThe Timing hypothesis

Mendelsohn ME Science 2005

Ongoing trials ...Ongoing trials ...

Few younger women to examin whether women starting HRT during the menopausal transition achieve cardioprotection??

IN SUMMARYIN SUMMARYTHE BEST TREATMENT IS……THE BEST TREATMENT IS……

• Lipid lowering therapy • HRT during menopausal transition

• Combined therapy

Kronos Early Estrogen Prevention Study (KEEPS) Early versus Late Intervention Trial with Estradiol (ELITE)

The Timing hypothesisThe Timing hypothesis

Mendelsohn ME Science 2005

IN SUMMARYIN SUMMARYTHE BEST TREATMENT IS……THE BEST TREATMENT IS……

•Lipid lowering statin •HRT during menopausal transition

•Combined therapy

THE CONTROVERSYTHE CONTROVERSYarises by

Ongoing trials ... Kronos Early Estrogen Prevention Study (KEEPS) Early versus Late Intervention Trial with Estradiol (ELITE)

younger women to examin whether women starting HRT during the menopausal transition achieve cardioprotection??

The Heart and Estrogen/Progestin Replacement Study (HERS)

Women’s Health Initiative (WHI)