1. Women and Coronary Artery Disease (CAD) Prof. Roland KASSAB Prof. Roland KASSAB Head of Division of Cardiology, HDF Head of Division of Cardiology, HDF Metropolitan Palace Hotel, Beirut Metropolitan Palace Hotel, Beirut 1st May 2010 1st May 2010

7. Women and CAD Epidemiology Epidemiology Cardiovascular risk factors Cardiovascular risk factors Risk stratification Risk stratification Diagnosis Diagnosis Prognosis and treatment outcome Prognosis and treatment outcome JUPITER: meta-analysis of Women JUPITER: meta-analysis of Women PCI and CABG PCI and CABG Hormone replacement therapy Hormone replacement therapy Concluions Concluions

8. PROGNOSTIC VALUE : BNP

9. Epidemiology Statistics on Women and Cardiovascular Disease Statistics on Women and Cardiovascular Disease Comparisons to Men Comparisons to Men Age Differences Among Women Age Differences Among Women Racial and Ethnic Group Differences Racial and Ethnic Group Differences

10. CVD and Other Major Causes of Death for Women in the United States: 2004 Source: Adapted from American Heart Association 2008

11. Congestive Heart Failure: Gender Differences Compared to men, women with heart failure are: Compared to men, women with heart failure are: Older Older More likely to have hypertension More likely to have hypertension More likely to have diabetes More likely to have diabetes More likely to have diastolic dysfunction More likely to have diastolic dysfunction Knowledge of diastolic dysfunction prognosis and treatment is limited Knowledge of diastolic dysfunction prognosis and treatment is limited Trials of congestive heart failure treatments have included mainly men Trials of congestive heart failure treatments have included mainly men Source: Stromberg 2003

12. Cardiovascular Disease Mortality: U.S. Males and Females 1980-2004 Source: Adapted from American Heart Association 2008

13. Annual Numbers of U.S. Adults Diagnosed with Myocardial Infarction and Fatal CHD by Age and Sex Categories: 1987-2004 Source: Adapted from American Heart Association 2008 Age in Years

14. Acute MI Mortality by Age and Sex Source: Adapted from Vaccarino 1999

15. Racial and Ethnic Groups Cardiovascular disease is the leading cause of death for African Americans, Latinos, Asian Americans, Pacific Islanders, and American Indians Cardiovascular disease is the leading cause of death for African Americans, Latinos, Asian Americans, Pacific Islanders, and American Indians African American women are at the highest risk for death from heart disease among all racial, ethnic, and gender groups African American women are at the highest risk for death from heart disease among all racial, ethnic, and gender groups Source: American Heart Association 2004

16. Age-adjusted Death Rates for Leading Causes of Death in White and Black/African American Women: U.S. 2004 Source: Adapted from American Heart Association 2008 Per 100,000 Population

17. Summary 1 Among U.S. women, cardiovascular disease is the leading cause of death Among U.S. women, cardiovascular disease is the leading cause of death Among U.S. women, cardiovascular disease is the leading cause of death for whites, African Americans, Latinas, Asian Americans, Pacific Islanders, and American Indians Among U.S. women, cardiovascular disease is the leading cause of death for whites, African Americans, Latinas, Asian Americans, Pacific Islanders, and American Indians Source: American Heart Association 2008

18. Summary 2 Mortality from CVD has decreased more for men in the past 20 years than for women Mortality from CVD has decreased more for men in the past 20 years than for women Over 10,000 women under age 45 suffer an acute myocardial infarction every year Over 10,000 women under age 45 suffer an acute myocardial infarction every year Source: American Heart Association 2008

19. Are All Statins Born Alike ?

20. Cardiovascular Risk Factors in Women Unmodifiable Unmodifiable Age Age Family History Family History Modifiable Modifiable Diabetes Diabetes Dysplipidemia Dysplipidemia Hypertension Hypertension Obesity Obesity Poor Diet Poor Diet Sedentary Lifestyle Sedentary Lifestyle Cigarette Smoking Cigarette Smoking Source: ATP III 2002, Mosca 2007

21. Approximate and Cumulative LDL Cholesterol Reduction Achievable By Dietary Modification Dietary Component Dietary Change Approximate LDL Reduction Major Saturated fat<7% of calories 8-10% Dietary cholesterol<200 mg/day 3-5% Weight reductionLose 10 lbs 5-8% Other LDL-lowering options Viscous fiber5-10 g/day 3-5% Plant/sterol2g/day 6-15% stanol esters Cumulative estimate 20-30% Source: Adapted from ATP III 2002

22. Treatable Risk Factors: The Epidemiology of Cholesterol Levels and Subfractions Low HDL more important in women than men 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 For every 1 mg/dL increase in HDL 3% decrease in CHD risk for women and 2% decrease in CHD risk for men Total cholesterol/HDL ratio very predictive of CHD risk in women Total cholesterol/HDL ratio very predictive of CHD risk in women Triglyceride elevation associated with greater atherogenic significance in women than in men Triglyceride elevation associated with greater atherogenic significance in women than in men Source: Maron 2000

23. 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>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 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 Menopausal transition associated with increasing proportion of this subfraction Source: Keil 2000, Carr 2000, Hokanson 1996

24. Source: MMWR 1992 Relative Risk 1.5 1.4 1.1 1.9 2.4 1.3 1.4 1.6 1.8 0 0.5 1 1.5 2 2.5 HTNCHOLDMObesitySmoking Men Women Relative Risk of Various Factors for CHD for Women and Men

25. Relative Risk of Cardiovascular Events According to Baseline Levels of hs-CRP in Healthy Postmenopausal Women P for trend < 0.001 Source: Ridker 2000

26. Fibrinogen Levels and CHD Risk in Women *Adjusted for age, smoking, BMI, systolic blood pressure, total cholesterol, HDL, triglycerides, and educational level  2.8 >2.8,  3.1 >3.1,  3.6 >3.6 Source: Eriksson 1999 P for trend <0.0001

27. Relative Risk of Cardiovascular Events According to Baseline Levels of Homocysteine in Healthy Postmenopausal Women P for trend = 0.02 (not significant) μμμ μ Source: Ridker 2000

28. Psychosocial Stressors in Women with CHD: The Stockholm Female Coronary Risk Study Among women who were married or cohabitating with a male partner, marital stress was associated with nearly 3-fold increased risk of recurrent CHD events Among women who were married or cohabitating with a male partner, marital stress was associated with nearly 3-fold increased risk of recurrent CHD events Living alone and work stress did not significantly increase recurrent CHD events Living alone and work stress did not significantly increase recurrent CHD events Source: Orth-Gomer 2000

29. Depression and CHD: Results from the Women’s Health Initiative Study Depression is an independent predictor of CHD death among women with no history of CHD Depression is an independent predictor of CHD death among women with no history of CHD Source: Wassertheil-Smoller 2004

31. Risk Stratification: High Risk High Risk Diabetes mellitus Diabetes mellitus Documented atherosclerotic disease Documented atherosclerotic disease Established coronary heart disease Established coronary heart disease Peripheral arterial disease Peripheral arterial disease Cerebrovascular disease Cerebrovascular disease Abdominal aortic aneurysm Abdominal aortic aneurysm Includes many patients with chronic kidney disease, especially ESRD Includes many patients with chronic kidney disease, especially ESRD 10-year Framingham global risk > 20%, or high risk based on another population-adapted global risk assessment tool 10-year Framingham global risk > 20%, or high risk based on another population-adapted global risk assessment tool Source: Mosca 2007

32. Risk Stratification: At Risk: At Risk: > 1 major risk factors for CVD, including: > 1 major risk factors for CVD, including: Cigarette smoking Cigarette smoking Hypertension Hypertension Dyslipidemia Dyslipidemia Family history of premature CVD (CVD at < 55 years in a male relative, or < 65 years in a female relative) Family history of premature CVD (CVD at < 55 years in a male relative, or < 65 years in a female relative) Obesity, especially central obesity Obesity, especially central obesity Physical inactivity Physical inactivity Poor diet Poor diet Metabolic syndrome Metabolic syndrome Evidence of subclinical coronary artery disease (eg coronary calcification), or poor exercise capacity on treadmill test or abnormal heart rate recovery after stopping exercise Evidence of subclinical coronary artery disease (eg coronary calcification), or poor exercise capacity on treadmill test or abnormal heart rate recovery after stopping exercise Source: Mosca 2007

33. Definition of Metabolic Syndrome in Women Abdominal obesity - waist circumference > 35 in. Abdominal obesity - waist circumference > 35 in. High triglycerides ≥ 150mg/dL High triglycerides ≥ 150mg/dL Low HDL cholesterol < 50mg/dL Low HDL cholesterol < 50mg/dL Elevated BP ≥ 130/85mm Hg Elevated BP ≥ 130/85mm Hg Fasting glucose ≥ 100mg/dL Fasting glucose ≥ 100mg/dL Source: AHA/NHLBI 2005

34. Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

37. Diagnosis of Coronary Artery Disease in Women Chest pain is experienced by most women with CHD, but non-chest pain presentations are more common in women than men Chest pain is experienced by most women with CHD, but non-chest pain presentations are more common in women than men Other Presenting Symptoms Other Presenting Symptoms Upper abdominal pain, fullness, burning sensation Upper abdominal pain, fullness, burning sensation Shortness of breath Shortness of breath Nausea Nausea Neck, back, jaw pain Neck, back, jaw pain Associations Associations Precipitated by exertion Precipitated by exertion Precipitated by emotional distress Precipitated by emotional distress Source: Charney 2002, Goldberg 1998

38. Testing for Ischemic Heart Disease in Women and Factors to Consider TechniqueAssessment Issues in Women Angiography Coronary anatomy Less focal disease Coronary CT Coronary calcification, and anatomy Less well-validated than other techniques Echocardiography Regional wall motion Reader expertise variable Nuclear Cardiology Regional blood flow Attenuation issues Source: Charney 2002, Greenland 2007

39. Drawbacks of Diagnostic Imaging in Women Low exercise capacity –  likelihood of reaching adequate pressure rate product Low exercise capacity –  likelihood of reaching adequate pressure rate product Solution: Pharmacologic stress testing Solution: Pharmacologic stress testing Breast attenuation artifact – higher false positive imaging studies Breast attenuation artifact – higher false positive imaging studies Solution: Gated acquisition; attenuation correction for nuclear imaging Solution: Gated acquisition; attenuation correction for nuclear imaging Solution: Echocardiography Solution: Echocardiography Lower pretest probability of CAD – higher false positive rate Lower pretest probability of CAD – higher false positive rate Solution: Integrate clinical variables, risk factors, into decision-making process Solution: Integrate clinical variables, risk factors, into decision-making process Source: Duvernoy, personal communication

40. Value of the Exercise ECG in Women 68 61 77 70 0 10 20 30 40 50 60 70 80 SensitivitySpecificity Men Women Source: Kwok 1999

41. Value of Stress Echocardiography Compared to Stress ECG in Women Source: Marwick 1995 *P < 0.004 vs. Echo **Old P < 0.005 vs. Echo * **

42. CHD: Differences in Presentation and Findings in Women Compared to Men Lower prevalence of MI Lower prevalence of MI More severe CHF More severe CHF More severe angina More severe angina Less angiographic CAD Less angiographic CAD More ostial lesions More ostial lesions More microvascular dysfunction? More microvascular dysfunction? Abnormal vasomotor tone? Abnormal vasomotor tone? More endothelial dysfunction? More endothelial dysfunction? Source: Jacobs 2003

43. Women and CHD: What Test to Order When For women at high or intermediate risk of coronary artery disease, consider treadmill echocardiogarphy or nuclear perfusion imaging For women at high or intermediate risk of coronary artery disease, consider treadmill echocardiogarphy or nuclear perfusion imaging For women unable to exercise, consider dobutamine stress echocardiography or adenosine or dipyridamole nuclear imaging For women unable to exercise, consider dobutamine stress echocardiography or adenosine or dipyridamole nuclear imaging In high risk women with typical symptoms of coronary artery disease, consider coronary angiography In high risk women with typical symptoms of coronary artery disease, consider coronary angiography For high risk women, consider cardiac catheterization if symptoms persist despite negative non-invasive imaging For high risk women, consider cardiac catheterization if symptoms persist despite negative non-invasive imaging Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

44. Women and CHD: What Test to Order When A stepwise approach beginning with conventional exercise testing may be considered for women who: A stepwise approach beginning with conventional exercise testing may be considered for women who: Are at low or intermediate risk for coronary artery disease Are at low or intermediate risk for coronary artery disease Are able to exercise Are able to exercise Have an electrocardiogram that can be interpreted during stress testing Have an electrocardiogram that can be interpreted during stress testing An image-enhanced test may be more predictive in women than conventional electrocardiogram stress testing, and may also be more cost effective in women at intermediate risk for CHD An image-enhanced test may be more predictive in women than conventional electrocardiogram stress testing, and may also be more cost effective in women at intermediate risk for CHD Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

45. PROGNOSTIC VALUE : pro-BNP

46. Cardiovascular Disease in Women : Prognosis and Treatment Outcomes

47. Women Received Less Interventions to Prevent and Treat Heart Disease Less cholesterol screening Less cholesterol screening Less lipid-lowering therapies Less lipid-lowering therapies Less use of heparin, beta-blockers and aspirin during myocardial infarction Less use of heparin, beta-blockers and aspirin during myocardial infarction Less antiplatelet therapy for secondary prevention Less antiplatelet therapy for secondary prevention Fewer referrals to cardiac rehabilitation Fewer referrals to cardiac rehabilitation Fewer implantable cardioverter-defibrillators compared to men with the same recognized indications Fewer implantable cardioverter-defibrillators compared to men with the same recognized indications Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

48. Prognosis After MI  38% of women die within first year  Compared to 25% of men  35% of women will have second MI within 6 years  Compared to 18% of men Source: Wenger 2004

49. Prognosis Women < 65 yrs have 2 X mortality rate after MI compared to men of same age Women < 65 yrs have 2 X mortality rate after MI compared to men of same age After MI, women have significantly higher rates of: After MI, women have significantly higher rates of: Depression Depression Physical disability Physical disability After CABG, women have significantly higher rates of: After CABG, women have significantly higher rates of: Hospital readmission Hospital readmission Reduced mental health and physical functioning Reduced mental health and physical functioning Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

50. Undertreatment of MI in Women Compared with men: Compared with men: Less emergent thrombolysis Less emergent thrombolysis Less acute catheterization and angioplasty Less acute catheterization and angioplasty Less acute surgical revascularization Less acute surgical revascularization Less use of heparin, beta-blockers, and aspirin Less use of heparin, beta-blockers, and aspirin Source: Chandra 1998, Nohria 1998

51. Benefits of ASA in Women with Established CAD * P = 0.002 **P = 0.0001 * ** Source: Adapted from Harpaz 1996

52. Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for MI with ST-Segment Elevation in Women P < 0.05; reduction in odds = 38% Source: Sabatine 2005

53. Adjusted Odds for Use of Implantable Cardioverter-Defibrillator According to Guidelines by Race and Sex *P <0.05 compared with white men Source: Adapted from Hernandez 2007 * **

55. Gender Gap in Dyslipidemia Treatment Significantly more men than women have annual cholesterol measurements Significantly more men than women have annual cholesterol measurements Significantly more men than women receive effective lipid-lowering therapy Significantly more men than women receive effective lipid-lowering therapy African Americans receive less lipid- lowering treatment compared to whites African Americans receive less lipid- lowering treatment compared to whites Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

56. Meta-Analysis of 11 Clinical Trials of Statin Therapy Including 15,917 Women with Known CHD CHD EventsNon-Fatal MICHD Mortality Source: Grady 2003.

57. Simvastatin and Gender Risk for CHD and Mortality *P <0.05 Source: Scandinavian Simvastatin Survival Study Group 1994

58. Heart Protection Study: Major Findings Randomized, placebo-controlled trial of over 20,000 patients at risk for CVD Randomized, placebo-controlled trial of over 20,000 patients at risk for CVD Statin treatment reduced the risk of heart attacks and strokes by at least one third, as well as reducing the need for arterial surgery, angioplasty and amputations. Statin treatment reduced the risk of heart attacks and strokes by at least one third, as well as reducing the need for arterial surgery, angioplasty and amputations. Major CV events were reduced in women (5082 enrolled) as well as men, and in all age groups, across all cholesterol levels. Major CV events were reduced in women (5082 enrolled) as well as men, and in all age groups, across all cholesterol levels. Source: HPS Writing Group, Lancet 2002

59. Primary Prevention of CHD Events with Statin Treatment: AFCAPS/TexCAPS Relative Risk of First Major Coronary Events P < 0.001 compared to placebo Source: Downs 1998

61. Statins for the Primary Prevention of CVD in Women with Elevated hsCRP or Dyslipidemia: Results from JUPITER and Meta-Analysis of Women from Primary Prevention Statin Trials Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen, Jacques Genest, and Paul M Ridker Brigham and Women’s Hospital Harvard Medical School Boston, MA on behalf of the JUPITER Trial Study Group Circulation 2010; 121:1069-1077

62. Background Statins for patients with CVD is established Similar benefit in women, men Relative risk reduction ~20-30% Statins for women with no CVD is controversial Prior meta-analyses: non-significant RR CHD events 0.87 (0.22-1.68), P=0.17 N = 11, 435 women Walsh and Pignone, JAMA 2004;2243

63. Objectives 1.Pre-specified analysis in JUPITER for efficacy and safety of rosuvastatin in women and men with elevated hsCRP and non-elevated LDL cholesterol 2. Updated meta-analysis of statin therapy for primary prevention of CVD in women

64. JUPITER : Trial Objective To investigate whether rosuvastatin 20 mg vs placebo decreases major CVD events in apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are at increased vascular risk due to enhanced inflammatory response, with hsCRP > 2 mg/L Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin Ridker PM et al NEJM 2008;2195

65. Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA > 60 > 50 6,801 women > 60 years 11,001 men > 50 years 1,315 sites, 26 countries 4-week run-in No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER : Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker PM et al NEJM 2008;2195

66. JUPITER Inclusion and Exclusion Criteria, Study Flow 89,863 Screened 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo Reason for Exclusion (%) LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,600 Completed Study 120 Lost to follow-up 8,600 Completed Study 120 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses 89,890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 17,802 Randomized Reason for Exclusion (%) LDL > 130 mg/dL 52 hsCRP < 2.0 mg/L 36 Withdrew Consent 5 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 4 week Placebo Run-In 8,857 Completed Study 44 Lost to follow-up 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,864 Completed Study 37 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses Ridker et al NEJM 2008

67. JUPITER Baseline Clinical Characteristics WomenMen (N = 6801)(N = 11001) Age, years (IQR)68.0(65.0-73.0)63.0 (58.0-70.0) Ethnicity, % Caucasian61.777.1 Black15.910.4 Hispanic18.98.8 BMI, kg/m 2 (IQR)29.2 (25.7-33.2)27.9 (25.1-31.2) Hypertension, %62.754.1 Smoker, %7.621.0 Family History, %12.211.1 Metabolic Syndrome, %46.738.7 All values are median (interquartile range) or % Mora S et al Circulation 2010; 1069

68. JUPITER Baseline Blood Levels (median, interquartile range) WomenMen (N = 6801)(N = 11001) hsCRP, mg/L4.6(3.1 - 7.7)4.1 (2.7 – 6.8) LDL, mg/dL 109 (96 - 120)108(93 - 119) HDL, mg/dL54(46 – 66)45(38 – 55) Triglycerides, mg/L118(88 - 163)118 (84 - 174) Total Cholesterol, mg/dL192 (175 - 205)182(165 - 195) Glucose, mg/dL93(87 – 101)95(88 – 102) HbA1c, %5.8(5.5 – 6.0)5.6 (5.4 – 5.9) All values are median (interquartile range). Mora S et al Circulation 2010; 1069

69. JUPITER Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months Women Men Rosuva Placebo Rosuva Placebo hsCRP, mg/L - 1.8 - 0.6- 1.7 - 0.8 (- 3.6, - 0.6) (- 2.2, +0.8) (- 3.4, - 0.4) (- 2.5, +0.8) LDL, mg/dL - 51 + 4- 49+ 3 (- 65, - 27) (- 7, +17) (- 62, - 29) (- 9, +15) HDL, mg/dL + 3 + 1 + 3 + 1 (- 2, + 8) (- 4, + 6) (- 2, + 8) (- 3, + 5) Triglycerides, mg/L - 17 - 1- 16+ 2 (- 44, + 3) (- 23, +21) (- 50, +7) (- 26, +27) Total Cholesterol, mg/dL - 51 + 4- 50 + 3 (- 68, - 27) (- 9, +19) (- 66, - 28) (- 9, +17) All values are median (interquartile range) change from baseline to 12 months Mora S et al Circulation 2010; 1069

70. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV DeathRosuvaPlacebo No. (Rate)* HR 95% CI P for heterogeneity Women Women 39 (0.56) 70 (1.04) 0.540.37-0.80 P=0.0020.80 Men Men 103 (0.88) 181 (1.54) 181 (1.54)0.580.45-0.73 P<0.0001 * Rates are per 100 person-years Mora S et al Circulation 2010; 1069

71. JUPITER Primary Trial Endpoint : Number Needed to Treat (5-years)RosuvaPlacebo No. (Rate) NNT* Women Women 39 (0.56) 70 (1.04) 36 Men Men 103 (0.88) 181 (1.54) 181 (1.54)22 All All 142 (0.77) 251 (1.36) 25 * Calculated based on the method of Altman and Andersen Mora S et al Circulation 2010; 1069

72. JUPITER Components of the Primary Endpoint Endpoint Women Men P for Heterogeneity Primary Endpoint 0.54 0.58 0.80 0.37 - 0.80 0.45 - 0.73 Nonfatal MI 0.560.29 0.24 0.24 - 1.33 0.16 - 0.54 Nonfatal Stroke 0.840.33 0.04 0.45 – 1.58 0.17 – 0.63 MI, Stroke, CVD Death 0.730.44 0.06 0.48 – 1.13 0.31 – 0.61 Revasc/Unstable Angina 0.240.63 0.01 0.11 – 0.51 0.46 – 0.85 All-cause Death 0.770.82 0.74 0.55 – 1.06 0.66 – 1.03 Mora S et al Circulation 2010; 1069

73. JUPITER Adverse Events and Measured Safety Parameters Event Women Men Rosuva Placebo Rosuva Placebo Any SAE 7.7 7.4 7.6 7.9 Muscle weakness 8.98.3 8.1 7.9 Myopathy0.07 0.06 0.04 0.04 Rhabdomyolysis 0 0 0.01 0 Incident Cancer 1.4 1.4 0.2 0.2 Cancer Deaths 0.2 0.2 0.2 0.3 Hemorrhagic stroke0.04 0.04 0.02 0.05 GFR (ml/min/1.73m 2 at 12 mth) 64.1 64.2 71.0 70.5 ALT > 3xULN0.040.07 0.16 0.10 Fasting glucose (24 mth) 96 95 99 99 HbA1c (% at 24 mth) 5.9 5.9 5.9 5.8 Incident Diabetes* 1.5 1.0 1.4 1.2 All values are medians or rates per 100 person-years *Physician reported, P for heterogeneity by sex = 0.16 Mora S et al Circulation 2010; 1069

74. Meta-analysis of Exclusively Primary Prevention Statin Trials in Women.1.1.5.51510 AFCAPS/TexCAPS1998 MEGA2006 JUPITER2008 0.63 (0.49-0.82) P<0.001 P for heterogeneity 0.56 ALL Favors StatinFavors Placebo(0.34-1.31)(0.49-1.10) (0.37-0.80)21/49856/2718 70/337514/49940/2638 39/3426 RR 95% CI PlaceboStatin0.670.73 0.54 Year 13 154 Women, 240 CVD events Mora S et al Circulation 2010; 1069

75. Study Limitations JUPITER median follow-up 1.9 years (max 5) Limited long-term safety data for rosuvastatin Low absolute event rates in women <65 years Meta-analysis: degree of LDL cholesterol lowering differed Mora S et al Circulation 2010; 1069

76. Conclusions – JUPITER sex-specific analysis Among apparently healthy women with elevated hsCRP and non-elevated LDL cholesterol, rosuvastatin resulted in similar and significant relative risk reduction in CVD compared with men Women had lower absolute event rates, especially <65 years old Women had more benefit for revascularization / unstable angina, men had more benefit for stroke Subgroup analysis suggested women with family history of premature CHD benefit more than those without family history Higher physician-reported diabetes in women compared with men, but test for heterogeneity by sex non-significant Overall safety in women similar to men Mora S et al Circulation 2010; 1069

77. JUPITER Conclusions – Meta-Analysis For primary prevention of CVD in women, statin allocation yielded significant relative risk reduction by one third This relative risk reduction is similar to prior results in men for primary prevention and men or women for secondary prevention These findings may have guideline implications for statin therapy in apparently healthy women meeting JUPITER entry criteria, even without high risk Framingham scores Mora S et al Circulation 2010; 1069

79. Interventional Procedures and Surgery Higher complication and death rates Higher complication and death rates Smaller artery size Smaller artery size More co-existing illnesses (older at presentation) More co-existing illnesses (older at presentation) Higher rates of diabetes Higher rates of diabetes More urgent and emergent presentations More urgent and emergent presentations Higher incidence of congestive heart failure in women from diastolic dysfunction Higher incidence of congestive heart failure in women from diastolic dysfunction Source: Jacobs 2003

80. Coronary Revascularization in Women Compared to Men Increased use of PTCA compared to stents, because of smaller vessel size Increased use of PTCA compared to stents, because of smaller vessel size Decreased rates of glycoprotein IIb/IIIa inhibitor use, possibly because of increased bleeding complications in women Decreased rates of glycoprotein IIb/IIIa inhibitor use, possibly because of increased bleeding complications in women Higher in-hospital mortality for CABG and PCI Higher in-hospital mortality for CABG and PCI Higher rates of vascular complications Higher rates of vascular complications Higher transfusion rates Higher transfusion rates Source: Jacobs 2003

81. Revascularization Outcomes in Women: Improvements in Recent Years NHLBI registry data shows improved clinical success rates and lower major complication rates for women undergoing PTCA NHLBI registry data shows improved clinical success rates and lower major complication rates for women undergoing PTCA Retrospective data suggest that women have lower mortality rates when undergoing off-pump CABG, compared to standard CABG Retrospective data suggest that women have lower mortality rates when undergoing off-pump CABG, compared to standard CABG Source: Jacobs 1997, Petro 2000

82. Sex Differences for In-Hospital Mortality After CABG: Higher Mortality in Younger Women P for interaction between sex and age = 0.002. ≥ Source: Adapted from Vaccarino 2002

83. CABG Outcomes in Women: A Vicious Cycle Perception: Higher post- operative morbidity/mortality in women Prompt referral for CABG discouraged in women Women referred at later stages of disease, w/ more comorbidities Higher operative risk for women Fewer long-term benefits for women Source: Adapted from Vaccarino 2003

85. “Hormone Replacement Therapy” Risk-Benefit Balance: 1960’s-1990’s Risks Benefits CHD Osteoporosis Vasomotor Symptoms GU Symptoms Skin Preservation Source: Limacher 2002

86. Postmenopausal Estrogen Therapy Meta-analysis of observational data: 35% CHD risk reduction in women using hormone therapy Meta-analysis of observational data: 35% CHD risk reduction in women using hormone therapy Lipid Effects:  LDL Cholesterol Lipid Effects:  LDL Cholesterol  Lipoprotein (a)  HDL Cholesterol Metabolic Effects:  Fasting glucose  Fasting insulin levels Metabolic Effects:  Fasting glucose  Fasting insulin levels Fibrinolytic Effects:  tissue plasminogen activator,  plasminogen-activator inhibitor 1 Fibrinolytic Effects:  tissue plasminogen activator,  plasminogen-activator inhibitor 1 Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

87. HERS: Cumulative Incidence of CHD Events Follow-up, yrs (No. at Risk) Incidence, % 02345 1 10 5 15 (2763)(2631)(2506)(2392)(1435) (113) Estrogen-Progestin Placebo Source: Adapted from Hulley 1998

88. Women’s Health Initiative Estrogen and Progestin Arm: Absolute Excess Risk  Excess CHD events: 7/10,000 woman-years  Excess stroke events : 8/10,000 woman-years  Excess pulmonary emboli: 8/10,000 woman-years  Excess invasive breast cancer: 8/10,000 woman- years Source: Writing Group for the WHI Investigators 2002

89. Women’s Health Initiative Estrogen and Progestin Arm: Absolute Benefits  Fewer colorectal cancers: 6/10,000 woman- years  Fewer hip fractures: 5/10,000 woman-years Source: Writing Group for the WHI Investigators 2002

90. Women’s Health Initiative: Estrogen Alone in Postmenopausal Women Compared to Placebo: Major Clinical Outcomes * * P <.05 * Favors Treatment Favors Placebo Source: Adapted from WHI Steering Committee 2004

91. HT Risk-Benefit Balance: 2004 Benefits Vasomotor Symptoms Osteoporosis Vaginal Atrophy Colon Cancer Skin Preservation Depression Risks DVT/PE Gallbladder Disease Breast Cancer Breast/Bleeding Side Effects CHD Stroke Dementia Pancreatitis ?Ovarian Cancer Source: ACOG Task Force for Hormone Therapy 2004

92. Raloxifene Use for the Heart (RUTH) Trial: Primary and Secondary CVD Outcomes Source: Adapted from Barrett Connor 2006 * * p <.05

93. 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 Hormone therapy and selective estrogen-receptor modulators (SERMs) should not be used for the primary or secondary prevention of CVD Source: Mosca 2007

94. Menopausal Hormone Therapy, SERMs and CVD: Summary of Major Randomized Trials Use of estrogen plus progestin associated with a small but significant risk of CHD and stroke Use of estrogen plus progestin associated with a small but significant risk of CHD and stroke Use of estrogen without progestin associated with a small but significant risk of stroke Use of estrogen without progestin 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 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 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

96. Conclusions ♥ Gender differences exist in diagnosis, treatment, and prognosis of CHD ♥ Knowledge of gender differences is essential for appropriate therapy ♥ Evidence-based guidelines provide a new framework for prevention and treatment of cardiovascular disease in women

98. THANK YOU