high cholesterol: to be treated more aggressively in post menopausal women? l.bucciarelli md, phd...
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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)