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Tenth International Symposium
HEART FAILURE & Co.
CARDIOLOGY SCIENCE UPDATE
FEMALE DOCTORS SPEAKING
ON FEMALE DISEASES
Milano
9 - 10 aprile 2010
High Cholesterol: To Be Treated More
Aggressively in Post Menopausal Women?
L.Bucciarelli MD, PhD
Cardiovascular Department
IRCCS Multimedica
Women aged over 60 years represent
13%
of the population in Italy
National Health Plan Istituto Superiore della Sanità 1998-2000
Menopause Changes
• Decreased estrogen
• Increased serum lipid levels
• Increased plasma fibrinogen levels
• Increased lipid peroxidation and oxidative
stress generation
Castelao JE et al. Medical hypotheses 2007
Relative Risk of CVD in Subjects With and Without
Diabetes: Framingham Heart Study
*P<0.001; †P<0.05; ‡P<0.01; §P<0.1.
*
Any CVD event
Male
Female
*
Stroke
*
Intermittent claudication
†
†
Cardiac failure
*
†
CHD
‡
‡
MI
*
Angina pectoris
§
Sudden death
†
Coronary mortality
0
1
†
4
2
3
5
Age-Adjusted Risk Ratio
6
Kannel WB et al. Am Heart J. 1990
Post Menopausal Women and CHD
•
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
MI therapy
beta-blockers
aspirin
Second report of the National Cholesterol Education Program Adult Treatment Panel JAMA 1993
Multifactorial Approach for an Effective
Macrovascular Disease Prevention
Blood Pressure
Control
Lipid
Control
CVD
Menopause
Anti-Thrombotic
Agents
Glucose
Control
Diet &
Physical Activity
Anti-cholesterolemic Therapy
in Postmenopausal Women
EP
Statins
Combined therapy
(EP+Statins)
Estrogen Replacement in
Postmenopausal Women
• Greater increasing of HDL level and
lowering lipoprotein(a) compared to Statin
• Estrogen may directly stimulate the release
of NO
• Increasing of triglicerides
Statin Treatment in Postmenopause
Increased acitvity of LDLr
Triglicerides
LDL-C
Effects on Lipid Core
Endothelial Function
NO Bioactivity
Stabilitization/Regression
of atherosclerotic plaque
Statin Treatment
Primary Target in Cardiovascular Prevention
LDL-C 
National Cholesterol Education Program
Estrogen Replacement and Statin
in Primary intervention
baseline
After therapy
• Conjugated equine estrogen (CE) 0.625mg 6 wks
• Simvastatin 10 mg 6 wks
Koh K et al. Circulation 1999
• CE+Statin 6 wks
Estrogen Replacement and Statin
in 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
in 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
15%
-15%
-30%
-33%
17%
10%
9%
-35%
-26%
-43%
-8%
-10%
Harrington DM J et al. of the American College of Cardiology 1999
Aggressive VS Moderate Lipid-Lowering Therapy
in Hypercholesterolemic Postmenopausal Women:
BELLES Trial
Raggi P Circulation 2005
HYPOTHESIS
Hypercholesterolemic postmenopausal women with indication for lipid-lowering therapy
Where treatd with intensive and moderate lowering lipid tratment.
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)
BELLES 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
Cardiovascular Disease Prevention
in 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 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 LDL
Very High Risk
High-Moderate Risk
MI, Known CAD+ 1 or more ≥2 severe risk factors
risk factors
> 20% 10-year CHD risk
10-20% 10-Year CHD Risk
Moderate Risk
≥2 risk factors
Low Risk
< 2risk factors
<10% 10-Year CHD Risk
<10% 10-Year CHD Risk
LDL Cholesterol Level
190
Target
160
mg/dL
160
130
Target
130
mg/dL
Target
100
mg/dL
Target
130
mg/dL
Optional
100
mg/dL**
100
Optional
70
mg/dL*
70
*Optional terapy in very high risk pts and in pts with elevated TG and C-non-HDL<100 mg/dL;
**Optional terapy
Grundy SM et al. Circulation 2005
Mosca L et al. Circulation 2007
Treatable Risk Factors: The Epidemiology of
Cholesterol 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
and may be harmful for the prevention
of 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 CONTROVERSY
arises by
Women’s Health Initiative (WHI)
The Heart and Estrogen/Progestin Replacement Study (HERS)
The Timing hypothesis
Mendelsohn ME Science 2005
Ongoing trials ...
IN SUMMARY
THE BEST TREATMENT IS……
Lipid lowering
therapy
Few younger women to examin •whether
women
starting HRT
• HRT during
menopausal
transition
during the menopausal transition
achieve
cardioprotection??
• Combined therapy
Kronos Early Estrogen Prevention Study (KEEPS)
Early versus Late Intervention Trial with Estradiol (ELITE)
The Timing hypothesis
IN SUMMARY
THE BEST TREATMENT IS……
•Lipid lowering statin
•HRT during menopausal transition
•Combined therapy
Mendelsohn ME Science 2005
THE CONTROVERSY
arises by
Women’s Health Initiative (WHI)
The Heart and Estrogen/Progestin Replacement Study (HERS)
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??