1. High Cholesterol: To Be Treated More Aggressively in Post Menopausal Women? L.Bucciarelli MD, PhD Cardiovascular Department IRCCS Multimedica High Cholesterol: To Be Treated More Aggressively in Post Menopausal Women? L.Bucciarelli MD, PhD Cardiovascular Department IRCCS Multimedica Tenth International Symposium HEART FAILURE & Co. CARDIOLOGY SCIENCE UPDATE FEMALE DOCTORS SPEAKING ON FEMALE DISEASES Milano 9 - 10 aprile 2010

2. Women aged over 60 years represent 13% of the population in Italy National Health Plan Istituto Superiore della Sanità 1998-2000

3. Menopause Changes Decreased estrogenDecreased estrogen Increased serum lipid levelsIncreased serum lipid levels Increased plasma fibrinogen levelsIncreased plasma fibrinogen levels Increased lipid peroxidation and oxidative stress generationIncreased lipid peroxidation and oxidative stress generation Castelao JE et al. Medical hypotheses 2007

4. *P<0.001; † P<0.05; ‡ P<0.01; § P<0.1. 0123 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 Diabetes: Framingham Heart Study Kannel WB et al. Am Heart J. 1990

5. 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 CHD Second report of the National Cholesterol Education Program Adult Treatment Panel JAMA 1993 MI therapy

6. Multifactorial Approach for an Effective Macrovascular Disease Prevention CVD Menopause GlucoseControl LipidControl Blood Pressure Control Anti-Thrombotic Agents Diet & Physical Activity

7. Anti-cholesterolemic Therapy in Postmenopausal Women EP Statins Combined therapy (EP+Statins)

8. 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

9. Primary Target in Cardiovascular Prevention LDL-C  Statin Treatment  LDL-C  Increased acitvity of LDLr  Triglicerides Statin Treatment in Postmenopause Stabilitization/Regression of atherosclerotic plaque National Cholesterol Education Program Effects on Lipid Core Endothelial Function NO Bioactivity

10. Statins in Postmenopausal Women Hypercholesterolemia in post-menopausal: reduced activity of LDLr Low statin dose reversing the reduction in LDL receptors activity Lowering triglycerides level Enhanced NO bioactivity improves vasomotor responsiveness Arca M et al. JAMA 1994

11. Estrogen Replacement and Statin in 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 baseline After therapy

12. 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

13. 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 Harrington DM J et al. of the American College of Cardiology 1999 -15% -26% 15% 9% -43% -33% 17% -30% -35% 10% -8% -10%

14. Aggressive VS Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women: BELLES Trial HYPOTHESIS Raggi P Circulation 2005 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)

15. 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

16. 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

17. OPTIMAL LIPIDS LEVEL 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

18. NCEP ATP III: New Target for LDL Grundy SM et al. Circulation 2005 Mosca 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 Risk MI, Known CAD+ 1 or more risk factors > 20% 10-year CHD risk LDL Cholesterol Level 100 160 130 190 Low Risk < 2risk factors <10% 10-Year CHD Risk Target 160 mg/dL High-Moderate Risk ≥2 severe risk factors 10-20% 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 **

19. 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

20. 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

21. THE CONTROVERSY THE CONTROVERSY arises by The Heart and Estrogen/Progestin Replacement Study (HERS) Women’s Health Initiative (WHI) The Timing hypothesis Mendelsohn ME Science 2005

22. Ongoing trials... Few younger women to examin whether women starting HRT during the menopausal transition achieve cardioprotection?? IN SUMMARY 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)

23. The Timing hypothesis Mendelsohn ME Science 2005 IN SUMMARY THE BEST TREATMENT IS…… Lipid lowering statin HRT during menopausal transition Combined therapy

25. THE CONTROVERSY THE CONTROVERSY arises 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)

27. Very High Risk Women Recent heart attack or known CAD, along with one or more of the following: –Multiple major risk factors, particularly in diabetics –Severe or poorly controlled risk factors (i.e., continued smoking) –Multiple risk factors of the metabolic syndrome, especially TG > 200 mg/dL and HDL < 40 mg/dL LDL goal of < 100mg/dL Consider statin, even if LDL < 100mg/dL Optional LDL goal of < 70mg/dL per ATP III 2004 update Grundy 2004

28. Treatable Risk Factors: Cholesterol Level and Subfractions LDL>160 mg/dL associated with 3.3-fold elevation in risk for women less than 65 years old LDL pattern of small, dense particles (more atherogenic) present in 25% of population, but less frequently seen in women Menopausal transition associated with increasing proportion of this subfraction Keil 2000, Carr 2000, Hokanson 1996

29. High Risk Woman > 20% 10-year risk of CHD CHD, large vessel atherosclerotic disease, DM –LDL-lowering pharmacotherapy (preferably a statin) should be initiated simultaneously with lifestyle modification for women with LDL>100mg/dl, consider statin even if LDL<100 mg/dl Grundi 2004, Mosca 2007

30. 2004 Update of ATP III  5 recent clinical trials suggest added benefit of optional lowering of cholesterol more than ATP III recommended  Lifestyle changes remain cornerstone of treatment  Advises that intensity of LDL-lowering drug treatment in high-risk and moderately high-risk patients achieve at least 30% reduction in LDL levels Source: Grundy 2004

31. At-Risk Women: Multiple or Severe Risk Factors, 10-20% 10-Year CHD Risk Initiate drug therapy if LDL > 130 mg/dL after lifestyle therapy Goal LDL < 100 mg/dL, consider drug therapy if LDL ≥ 100 mg/dL Grundy 2004, Mosca 2007

32. At-Risk Women: Multiple Risk Factors, 10-Year CHD Risk < 10% Initiate drug therapy if LDL > 160 mg/dL after lifestyle therapy Grundy 2004, Mosca 2007

33. At-Risk Women: No Other Risk Factors, 10-Year CHD Risk < 10% Initiate drug therapy if LDL > 190 mg/dL after lifestyle therapy Drug therapy optional for LDL 160-189 mg/dL after lifestyle therapy Grundy 2004, Mosca 2007

34. Lipids In high-risk women or when LDL is elevated: –Saturated fat < 7% of calories –Cholesterol < 200mg/day –Reduce trans-fatty acids Major dietary sources are foods baked and fried with partially hydrogenated vegetable oil Mosca 2007

35. Menopausal Hormone Therapy, SERMs and CVD: Summary of Major Randomized Trials Use of EP associated with a small but significant risk of CHD and stroke Use of E without P associated with a small but significant risk of stroke Use of all hormone preparations should be limited to short term menopausal symptom relief Use of a selective estrogen receptor modulator (raloxifene) does not affect risk of CHD or stroke, but is associated with an increased risk of fatal stroke Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

36. Stratify women into high, at risk, and optimal risk categories Encourage lifestyle approaches Treat hypertension, lipid abnormalities, and diabetes Implement pharmacologic interventions for women at high and intermediate risk, pharmacologic interventions may be appropriate for some lower risk women Avoid initiating therapies without benefit, or where risks outweigh benefits Prevention of Cardiovascular Disease in Women Source: Mosca 2007

37. The Mechanisms of Atherosclerosis Adapted from Libby P. Circulation; 2001; 104:365 Acute coronary event Resolution Initiation Intimal thickening Plaque formation StabilisationRegression LDL, VLDL, remnantsHDL LDL, VLDL, remnants HDL