women and coronary artery disease (cad) prof. roland kassab prof. roland kassab head of division of...

Women andWomen and Coronary Artery Coronary Artery

Disease (CAD)Disease (CAD) Prof. Roland KASSABProf. Roland KASSAB

Head of Division of Cardiology, HDFHead of Division of Cardiology, HDF

Metropolitan Palace Hotel, BeirutMetropolitan Palace Hotel, Beirut

1st May 20101st May 2010

Women and CADWomen and CAD EpidemiologyEpidemiology Cardiovascular risk factorsCardiovascular risk factors Risk stratificationRisk stratification DiagnosisDiagnosis Prognosis and treatment outcomePrognosis and treatment outcome JUPITER: meta-analysis of WomenJUPITER: meta-analysis of Women PCI and CABGPCI and CABG Hormone replacement therapyHormone replacement therapy ConcluionsConcluions

PROGNOSTIC VALUE : BNPPROGNOSTIC VALUE : BNP

EpidemiologyEpidemiology

Statistics on Women and Cardiovascular DiseaseStatistics on Women and Cardiovascular Disease Comparisons to MenComparisons to Men Age Differences Among WomenAge Differences Among Women Racial and Ethnic Group DifferencesRacial and Ethnic Group Differences

CVD and Other Major Causes of CVD and Other Major Causes of Death Death

for Women in the United States: for Women in the United States: 20042004

0

100,000

200,000

300,000

400,000

500,000

Total CVD CHD Cancer Stroke Asthma +COPD

Source: Adapted from American Heart Association 2008

Congestive Heart Failure: Congestive Heart Failure: Gender DifferencesGender Differences

Compared to men, women with heart Compared to men, women with heart failure are:failure are: OlderOlder More likely to have hypertensionMore likely to have hypertension More likely to have diabetesMore likely to have diabetes More likely to have diastolic dysfunctionMore likely to have diastolic dysfunction

Knowledge of diastolic dysfunction Knowledge of diastolic dysfunction prognosis and treatment is limited prognosis and treatment is limited

Trials of congestive heart failure Trials of congestive heart failure treatments have included mainly mentreatments have included mainly men

Source: Stromberg 2003

Cardiovascular Disease Cardiovascular Disease Mortality: Mortality:

U.S. Males and Females 1980-U.S. Males and Females 1980-20042004

400,000

450,000

500,000

550,000

1980 1985 1990 1995 2000 2004

MenWomen


Annual Numbers of U.S. Adults Diagnosed Annual Numbers of U.S. Adults Diagnosed with Myocardial Infarction and Fatal CHD with Myocardial Infarction and Fatal CHD by Age and Sex Categories: 1987-2004by Age and Sex Categories: 1987-2004

0

100,000

200,000

300,000

35-44 45-64 65-74 75+

MenWomen


Age in Years

Acute MI Mortality by Age Acute MI Mortality by Age and Sexand Sex

0

5

10

15

20

25

30

<50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Death During Hospitalization

(%)

Men

Women

Source: Adapted from Vaccarino 1999

Racial and Ethnic GroupsRacial and Ethnic Groups

Cardiovascular disease is the leading Cardiovascular disease is the leading cause of death for African Americans, cause of death for African Americans, Latinos, Asian Americans, Pacific Latinos, Asian Americans, Pacific Islanders, and American IndiansIslanders, and American Indians

African American women are at the African American women are at the highest risk for death from heart disease highest risk for death from heart disease among all racial, ethnic, among all racial, ethnic, and gender groupsand gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading Age-adjusted Death Rates for Leading Causes of Death in White and Causes of Death in White and

Black/African American Women: U.S. Black/African American Women: U.S. 20042004

0

50

100

150

CHD Stroke LungCancer

BreastCancer

Black/AfricanAmerican WomenWhite Women


Per100,000Population

Summary 1Summary 1

Among U.S. women, cardiovascular Among U.S. women, cardiovascular disease is the leading cause of death disease is the leading cause of death

Among U.S. women, cardiovascular Among U.S. women, cardiovascular disease is the leading cause of death disease is the leading cause of death for whites, African Americans, Latinas, for whites, African Americans, Latinas, Asian Americans, Pacific Islanders, and Asian Americans, Pacific Islanders, and American IndiansAmerican Indians


Summary 2Summary 2

Mortality from CVD has decreased more Mortality from CVD has decreased more for men in the past 20 years than for for men in the past 20 years than for womenwomen

Over 10,000 women under age 45 suffer Over 10,000 women under age 45 suffer an acute myocardial infarction every yearan acute myocardial infarction every year


Are All Statins Born Alike ?Are All Statins Born Alike ?

Cardiovascular Risk Factors in Cardiovascular Risk Factors in WomenWomen

UnmodifiableUnmodifiable AgeAge Family HistoryFamily History

ModifiableModifiable Diabetes Diabetes DysplipidemiaDysplipidemia HypertensionHypertension ObesityObesity Poor DietPoor Diet Sedentary LifestyleSedentary Lifestyle Cigarette SmokingCigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative Approximate and Cumulative LDL Cholesterol Reduction LDL Cholesterol Reduction

Achievable By Dietary Achievable By Dietary ModificationModification

Dietary Component Dietary Change Approximate LDL Reduction

Major

Saturated fat <7% of calories 8-10%Dietary cholesterol <200 mg/day 3-5%Weight reduction Lose 10 lbs 5-8%

Other LDL-lowering options

Viscous fiber 5-10 g/day 3-5%Plant/sterol 2g/day 6-15% stanol esters

Cumulative estimate 20-30% Source: Adapted from ATP III 2002

Treatable Risk Factors: The Treatable Risk Factors: The Epidemiology of Cholesterol Levels Epidemiology of Cholesterol Levels

and Subfractionsand Subfractions Low HDL more important in women than menLow HDL more important in women than men

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

Total cholesterol/HDL ratio very predictive of CHD Total cholesterol/HDL ratio very predictive of CHD risk in womenrisk in women

Triglyceride elevation associated with greater Triglyceride elevation associated with greater atherogenic significance in women than in menatherogenic significance in women than in men

Source: Maron 2000

Treatable Risk Factors: Treatable Risk Factors: Cholesterol Level and Cholesterol Level and

SubfractionsSubfractions LDL>160 mg/dL associated with 3.3-fold LDL>160 mg/dL associated with 3.3-fold

elevation in risk for women less than 65 elevation in risk for women less than 65 years oldyears old

LDL pattern of small, dense particles LDL pattern of small, dense particles (more atherogenic) present in 25% of (more atherogenic) present in 25% of population, but less frequently seen in population, but less frequently seen in womenwomen

Menopausal transition associated with Menopausal transition associated with increasing proportion of this subfractionincreasing proportion of this subfractionSource: Keil 2000, Carr 2000, Hokanson 1996

Source: MMWR 1992

Rel

ativ

e R

isk

1.5 1.51.4

1.1

1.9

2.4

1.31.4

1.6

1.8

0

0.5

1

1.5

2

2.5

HTN CHOL DM Obesity Smoking

Men

Women

Relative Risk of Various Factors Relative Risk of Various Factors for CHD for Women and Menfor CHD for Women and Men

Relative Risk of Cardiovascular Events Relative Risk of Cardiovascular Events According to Baseline Levels of hs-CRP According to Baseline Levels of hs-CRP

in Healthy Postmenopausal Womenin Healthy Postmenopausal Women

2.1 2.1

4.4

1

0

1

2

3

4

5

Median = 0.06mg/dl

Median = 0.19mg/dl

Median = 2.1mg/dl

Median = 4.4mg/dl

Quartile of Plasma Levels

Relative Risk

P for trend < 0.001

Source: Ridker 2000

Fibrinogen Levels and CHD Risk Fibrinogen Levels and CHD Risk in Womenin 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

2.19

1.7

1

2.98

0

0.5

1

1.5

2

2.5

3

3.5

Fibrinogen, g/ L

Od

ds

Rate

fo

r C

HD

Even

t*

P for trend <0.0001

Relative Risk of Cardiovascular Events Relative Risk of Cardiovascular Events According to Baseline Levels of According to Baseline Levels of

Homocysteine in Healthy Homocysteine in Healthy Postmenopausal WomenPostmenopausal Women

1.1 1.1

2

1

0

0.5

1

1.5

2

1 Median = 8.2

mol/liter

2 Median = 10.3

mol/liter

3 Median = 12.1

mol/liter

4 Median = 15.7

mol/liter

Quartile of Plasma Levels

Relative Risk

P for trend = 0.02 (not significant)

μ μμμ

Source: Ridker 2000

Psychosocial Stressors in Psychosocial Stressors in Women with CHD: The Women with CHD: The

Stockholm Female Coronary Stockholm Female Coronary Risk StudyRisk Study

Among women who were married or Among women who were married or cohabitating with a male partner, marital cohabitating with a male partner, marital stress was associated with nearly 3-fold stress was associated with nearly 3-fold increased risk of recurrent CHD eventsincreased risk of recurrent CHD events

Living alone and work stress did not Living alone and work stress did not significantly increase recurrent CHD significantly increase recurrent CHD eventsevents

Source: Orth-Gomer 2000

Depression and CHD: Results Depression and CHD: Results from the Women’s Health from the Women’s Health

Initiative StudyInitiative Study

Depression is an independent predictor of CHD Depression is an independent predictor of CHD death among women with no history of CHDdeath among women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:Risk Stratification: High Risk High Risk

Diabetes mellitusDiabetes mellitus Documented atherosclerotic diseaseDocumented atherosclerotic disease

Established coronary heart diseaseEstablished coronary heart disease Peripheral arterial diseasePeripheral arterial disease Cerebrovascular diseaseCerebrovascular disease Abdominal aortic aneurysmAbdominal aortic aneurysm

Includes many patients with chronic kidney Includes many patients with chronic kidney disease, especially ESRDdisease, especially ESRD

10-year Framingham global risk > 20%, or high 10-year Framingham global risk > 20%, or high risk based on another population-adapted global risk based on another population-adapted global risk assessment toolrisk assessment tool

Source: Mosca 2007

Risk Stratification:Risk Stratification: At Risk:At Risk:

>> 1 major risk factors for CVD, including: 1 major risk factors for CVD, including: Cigarette smokingCigarette smoking HypertensionHypertension DyslipidemiaDyslipidemia Family history of premature CVD (CVD at < 55 years in a Family history of premature CVD (CVD at < 55 years in a

male relative, or < 65 years in a female relative)male relative, or < 65 years in a female relative) Obesity, especially central obesityObesity, especially central obesity Physical inactivityPhysical inactivity Poor dietPoor diet

Metabolic syndromeMetabolic syndrome Evidence of subclinical coronary artery disease (eg Evidence of subclinical coronary artery disease (eg

coronary calcification), or poor exercise capacity on coronary calcification), or poor exercise capacity on treadmill test or abnormal heart rate recovery after treadmill test or abnormal heart rate recovery after stopping exercisestopping exercise

Source: Mosca 2007

Definition of Metabolic Definition of Metabolic Syndrome in WomenSyndrome in Women

Abdominal obesity - waist Abdominal obesity - waist circumference circumference >> 35 in. 35 in.

High triglycerides ≥ 150mg/dLHigh triglycerides ≥ 150mg/dL Low HDL cholesterol < 50mg/dLLow HDL cholesterol < 50mg/dL Elevated BP ≥ 130/85mm HgElevated BP ≥ 130/85mm Hg Fasting glucose ≥ 100mg/dLFasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

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

Diagnosis of Coronary Artery Diagnosis of Coronary Artery Disease in WomenDisease in Women

Chest pain is experienced by most women with CHD, Chest pain is experienced by most women with CHD, but but non-chest painnon-chest pain presentations are more common presentations are more common in women than menin women than men

Other Presenting SymptomsOther Presenting Symptoms Upper abdominal pain, fullness, burning sensationUpper abdominal pain, fullness, burning sensation Shortness of breathShortness of breath NauseaNausea Neck, back, jaw painNeck, back, jaw pain

AssociationsAssociations Precipitated by exertionPrecipitated by exertion Precipitated by emotional distress Precipitated by emotional distress

Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Testing for Ischemic Heart DiseaseDisease

in Women and Factors to in Women and Factors to ConsiderConsider

TechniqueTechnique AssessmentAssessment Issues in WomenIssues in Women

AngiographyAngiography Coronary Coronary anatomyanatomy

Less focal diseaseLess focal disease

Coronary CTCoronary CT Coronary Coronary calcification, calcification, and anatomyand anatomy

Less well-validated Less well-validated than other than other techniquestechniques

EchocardiographEchocardiographyy

Regional wall Regional wall motionmotion

Reader expertise Reader expertise variablevariable

Nuclear Nuclear CardiologyCardiology

Regional Regional blood flowblood flow

Attenuation issuesAttenuation issues

Source: Charney 2002, Greenland 2007

Drawbacks of Diagnostic Drawbacks of Diagnostic Imaging in WomenImaging in Women

Low exercise capacity – Low exercise capacity – likelihood of likelihood of reaching adequate pressure rate productreaching adequate pressure rate product Solution: Pharmacologic stress testingSolution: Pharmacologic stress testing

Breast attenuation artifact – higher false Breast attenuation artifact – higher false positive imaging studiespositive imaging studies Solution: Gated acquisition; attenuation Solution: Gated acquisition; attenuation

correction for nuclear imagingcorrection for nuclear imaging Solution: EchocardiographySolution: Echocardiography

Lower pretest probability of CAD – higher Lower pretest probability of CAD – higher false positive ratefalse positive rate Solution: Integrate clinical variables, risk Solution: Integrate clinical variables, risk

factors, into decision-making processfactors, into decision-making process

Source: Duvernoy, personal communication

Value of the Exercise ECG in Value of the Exercise ECG in WomenWomen

6861

7770

0

10

20

30

40

50

60

70

80

Sensitivity Specificity

MenWomen

Source: Kwok 1999

Value of Stress Value of Stress Echocardiography Compared Echocardiography Compared

to Stress ECG in Womento Stress ECG in Women

81 80 8177

5664

0102030405060708090

100

Sensitivity Specificity Accuracy

%

Echo

ECG

Source: Marwick 1995

*P < 0.004 vs. Echo

**Old P < 0.005 vs. Echo

***

CHD: Differences in CHD: Differences in Presentation and Findings in Presentation and Findings in Women Compared to MenWomen Compared to Men

Lower prevalence of MILower prevalence of MIMore severe CHFMore severe CHFMore severe anginaMore severe anginaLess angiographic CADLess angiographic CADMore ostial lesionsMore ostial lesionsMore microvascular More microvascular dysfunction?dysfunction?

Abnormal vasomotor tone?Abnormal vasomotor tone?More endothelial More endothelial dysfunction?dysfunction?

Source: Jacobs 2003

Women and CHD: Women and CHD: What Test to Order WhenWhat Test to Order When

For women at high or intermediate risk of coronary For women at high or intermediate risk of coronary artery disease, consider artery disease, consider treadmill echocardiogarphytreadmill echocardiogarphy or or nuclear perfusionnuclear perfusion imaging imaging

For women unable to exercise, consider For women unable to exercise, consider dobutaminedobutamine stress echocardiography or stress echocardiography or adenosine or adenosine or dipyridamoledipyridamole nuclear imaging nuclear imaging

In high risk women with typical symptoms of In high risk women with typical symptoms of coronary artery disease, consider coronary artery disease, consider coronary coronary angiographyangiography

For high risk women, consider For high risk women, consider cardiac cardiac catheterizationcatheterization if symptoms persist despite negative non-invasive if symptoms persist despite negative non-invasive imagingimaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD: Women and CHD: What Test to Order WhenWhat Test to Order When

A stepwise approach beginning with conventional A stepwise approach beginning with conventional exercise testing may be considered for women exercise testing may be considered for women who:who: Are at low or intermediate risk for coronary Are at low or intermediate risk for coronary

artery diseaseartery disease Are able to exerciseAre able to exercise Have an electrocardiogram that can be Have an electrocardiogram that can be

interpreted during stress testinginterpreted during stress testing An An image-enhanced testimage-enhanced test may be more predictive may be more predictive

in women than conventional electrocardiogram in women than conventional electrocardiogram stress testing, and may also be more cost stress testing, and may also be more cost effective in women at intermediate risk for CHDeffective in women at intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-PROGNOSTIC VALUE : pro-BNPBNP

Cardiovascular Disease in Cardiovascular Disease in Women : Prognosis and Women : Prognosis and

Treatment OutcomesTreatment Outcomes

Women Received Less Women Received Less Interventions Interventions

to Prevent and Treat Heart to Prevent and Treat Heart DiseaseDisease

Less cholesterol screeningLess cholesterol screening Less lipid-lowering therapiesLess lipid-lowering therapies Less use of heparin, beta-blockers and aspirin Less use of heparin, beta-blockers and aspirin

during myocardial infarctionduring myocardial infarction Less antiplatelet therapy for secondary Less antiplatelet therapy for secondary

preventionprevention Fewer referrals to cardiac rehabilitationFewer referrals to cardiac rehabilitation Fewer implantable cardioverter-defibrillators Fewer implantable cardioverter-defibrillators

compared to men with the same recognized compared to men with the same recognized indicationsindications

Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MIPrognosis 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

PrognosisPrognosis

Women < 65 yrs have Women < 65 yrs have 2 X mortality2 X mortality rate after MI rate after MI compared to men of same agecompared to men of same age

After MI, women have significantly higher rates of:After MI, women have significantly higher rates of: DepressionDepression Physical disabilityPhysical disability

After CABG, women have significantly higher rates of:After CABG, women have significantly higher rates of: Hospital readmissionHospital readmission Reduced mental health and physical functioningReduced mental health and physical functioning

Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Undertreatment of MI in WomenWomen

Compared with men:Compared with men: Less emergent thrombolysisLess emergent thrombolysis Less acute catheterization and Less acute catheterization and

angioplastyangioplasty Less acute surgical revascularizationLess acute surgical revascularization Less use of heparin, beta-blockers, and Less use of heparin, beta-blockers, and

aspirinaspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with Benefits of ASA in Women with Established CADEstablished CAD

2.7

5.15.1

9.1

0123456789

10

Aspirin No Aspirin

Mortality at 3 Years

Follow-Up (%)

CVDMortality

All CauseMortality

* P = 0.002 **P = 0.0001

*

**

Source: Adapted from Harpaz 1996

Addition of Clopidogrel to Addition of Clopidogrel to Aspirin Aspirin

and Fibrinolytic Therapy for MI and Fibrinolytic Therapy for MI with ST-Segment Elevation in with ST-Segment Elevation in

WomenWomen

16.9

24.7

0

5

10

15

20

25

30

Clopidogrel Placebo

% with Antiographic Reocclusion,

Death, or Recurrent MI

Before Angiography

P < 0.05; reduction in odds = 38%

Source: Sabatine 2005

Adjusted Odds for Use of Implantable Adjusted Odds for Use of Implantable Cardioverter-Defibrillator According Cardioverter-Defibrillator According

to Guidelines by Race and Sexto Guidelines by Race and Sex

00.10.20.30.40.50.60.70.80.9

1

White Men Black Men WhiteWomen

BlackWomen

Rel

ativ

e R

isk

*P <0.05 compared with white men

Source: Adapted from Hernandez 2007

** *

Gender Gap in Dyslipidemia Gender Gap in Dyslipidemia TreatmentTreatment

Significantly more men than women have Significantly more men than women have annual cholesterol measurementsannual cholesterol measurements

Significantly more men than women Significantly more men than women receive effective lipid-lowering therapyreceive effective lipid-lowering therapy

African Americans receive less lipid-African Americans receive less lipid-lowering treatment compared to whiteslowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Meta-Analysis of 11 Clinical Trials of Statin Therapy Trials of Statin Therapy

Including 15,917 Women with Including 15,917 Women with Known CHDKnown CHD

-21

-36

-26

-40

-35

-30

-25

-20

-15

-10

-5

0

% Reduction

CHD Events Non-Fatal MI CHD Mortality

Source: Grady 2003.

Simvastatin and Gender Risk Simvastatin and Gender Risk for CHD and Mortalityfor CHD and Mortality

0.65*

1.12

0.66* 0.66*

0

0.2

0.4

0.6

0.8

1

1.2

Total Death Major CoronaryEvent

Rel

ativ

e R

isk

(Co

x re

gre

ssio

n a

nal

ysis

)

WomenMen

*P <0.05

Source: Scandinavian Simvastatin Survival Study Group 1994

Heart Protection Study: Major Heart Protection Study: Major FindingsFindings

Randomized, placebo-controlled trial of over Randomized, placebo-controlled trial of over 20,000 patients at risk for CVD20,000 patients at risk for CVD

Statin treatment reduced the risk of heart Statin treatment reduced the risk of heart attacks and strokes by at least one third, as attacks and strokes by at least one third, as well as reducing the need for arterial well as reducing the need for arterial surgery, angioplasty and amputations.surgery, angioplasty and amputations.

Major CV events were reduced in women Major CV events were reduced in women (5082 enrolled) as well as men, and in all (5082 enrolled) as well as men, and in all age groups, across all cholesterol levels.age groups, across all cholesterol levels.

Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events Primary Prevention of CHD Events with Statin Treatment: with Statin Treatment:

AFCAPS/TexCAPSAFCAPS/TexCAPS

-46

-37

-50-45-40-35-30-25-20-15-10

-50

% MenWomen

Relative Risk of First Major Coronary Events

P < 0.001 compared to placebo

Source: Downs 1998

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 HospitalHarvard Medical School

Boston, MA

on behalf of the JUPITER Trial Study Group

Circulation 2010; 121:1069-1077

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

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

JUPITER : Trial Objective

To investigate whether rosuvastatin 20 mg vs placebo decreases major CVD eventsin 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

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

6,801 women >> 60 60 years11,001 men >> 50 50 years

1,315 sites, 26 countries

4-week 4-week run-inrun-in

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITER : Trial Design

Placebo (N=8901)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

JUPITERInclusion and Exclusion Criteria, Study Flow

89,863 Screened

17,802 Randomized

8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo

Reason for Exclusion (%)

LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3

8,600 Completed Study120 Lost to follow-up


8,901 Included in Efficacy and Safety Analyses


89,890 Screened

Men > 50 yearsWomen > 60 yearsNo CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L

17,802 Randomized

Reason for Exclusion (%)

LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3

4 weekPlaceboRun-In


8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo




Ridker et al NEJM 2008

JUPITERBaseline Clinical Characteristics

Women Men(N = 6801) (N = 11001)

Age, years (IQR) 68.0 (65.0-73.0) 63.0 (58.0-70.0)

Ethnicity, % Caucasian 61.7 77.1 Black 15.9 10.4 Hispanic 18.9 8.8

BMI, kg/m2 (IQR) 29.2 (25.7-33.2) 27.9 (25.1-31.2)

Hypertension, % 62.7 54.1

Smoker, % 7.6 21.0

Family History, % 12.2 11.1

Metabolic Syndrome, % 46.7 38.7

All values are median (interquartile range) or %Mora S et al Circulation 2010; 1069

JUPITERBaseline Blood Levels (median, interquartile range)

Women Men(N = 6801) (N = 11001)

hsCRP, mg/L 4.6 (3.1 - 7.7) 4.1 (2.7 – 6.8) LDL, mg/dL 109 (96 - 120) 108 (93 - 119)

HDL, mg/dL 54 (46 – 66) 45 (38 – 55)

Triglycerides, mg/L 118 (88 - 163) 118 (84 - 174)

Total Cholesterol, mg/dL 192 (175 - 205) 182 (165 - 195)

Glucose, mg/dL 93 (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

JUPITEREffects 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


JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

RosuvaRosuva PlaceboPlacebo

No. (Rate)*No. (Rate)* No. (Rate)*No. (Rate)* HRHR 95% CI95% CI P for P for heterogeneityheterogeneity

WomenWomen 39 (0.56)39 (0.56) 70 (1.04)70 (1.04) 0.540.54 0.37-0.800.37-0.80

P=0.002P=0.002 0.800.80

MenMen 103 (0.88)103 (0.88) 181 (1.54)181 (1.54) 0.580.58 0.45-0.730.45-0.73

P<0.0001P<0.0001

* Rates are per 100 person-years


JUPITERPrimary Trial Endpoint : Number Needed to Treat (5-years)

RosuvaRosuva PlaceboPlacebo

No. (Rate)No. (Rate) No. (Rate)No. (Rate) NNT*NNT*

WomenWomen 39 (0.56)39 (0.56) 70 (1.04)70 (1.04) 3636

MenMen 103 (0.88)103 (0.88) 181 (1.54)181 (1.54) 2222

AllAll142 (0.77)142 (0.77) 251 (1.36)251 (1.36)

2525

* Calculated based on the method of Altman and Andersen


JUPITERComponents 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 0.56 0.29 0.24 0.24 - 1.33 0.16 - 0.54

Nonfatal Stroke 0.84 0.33 0.040.45 – 1.58 0.17 – 0.63

MI, Stroke, CVD Death 0.73 0.44 0.060.48 – 1.13 0.31 – 0.61

Revasc/Unstable Angina 0.24 0.63 0.010.11 – 0.51 0.46 – 0.85

All-cause Death 0.77 0.82 0.740.55 – 1.06 0.66 – 1.03Mora S et al Circulation 2010; 1069

JUPITERAdverse Events and Measured Safety Parameters

Event Women Men Rosuva Placebo Rosuva Placebo

Any SAE 7.7 7.4 7.6 7.9Muscle weakness 8.9 8.3 8.1 7.9Myopathy 0.07 0.06 0.04 0.04Rhabdomyolysis 0 0 0.01 0Incident Cancer 1.4 1.4 0.2 0.2Cancer Deaths 0.2 0.2 0.2 0.3Hemorrhagic stroke 0.04 0.04 0.02 0.05

GFR (ml/min/1.73m2 at 12 mth) 64.1 64.2 71.0 70.5ALT > 3xULN 0.04 0.07 0.16 0.10

Fasting glucose (24 mth) 96 95 99 99HbA1c (% at 24 mth) 5.9 5.9 5.9 5.8Incident 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

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

.1 .5 1 5 10

AFCAPS/TexCAPSAFCAPS/TexCAPS 19981998

MEGAMEGA 20062006

JUPITERJUPITER 20082008

0.63 (0.49-0.82) P<0.001P for heterogeneity 0.56ALL

Favors Statin Favors Placebo

(0.34-1.31)(0.34-1.31)

(0.49-1.10)(0.49-1.10)

(0.37-0.80)(0.37-0.80)

21/49821/498

56/271856/2718

70/337570/3375

14/49914/499

40/263840/2638

39/342639/3426

RR 95% CI Placebo Statin

0.670.67

0.730.73

0.540.54

Year

13 154 Women, 240 CVD events


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


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

JUPITERConclusions – 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


Interventional Procedures Interventional Procedures and Surgeryand Surgery

Higher complication and death ratesHigher complication and death rates Smaller artery sizeSmaller artery size More co-existing illnesses (older at More co-existing illnesses (older at

presentation)presentation) Higher rates of diabetesHigher rates of diabetes More urgent and emergent presentationsMore urgent and emergent presentations Higher incidence of congestive heart failure in Higher incidence of congestive heart failure in

women from diastolic dysfunctionwomen from diastolic dysfunction

Source: Jacobs 2003

Coronary Coronary Revascularization Revascularization

in Women Compared to in Women Compared to MenMen Increased use of PTCA compared to stents, Increased use of PTCA compared to stents,

because of smaller vessel sizebecause of smaller vessel size Decreased rates of glycoprotein IIb/IIIa Decreased rates of glycoprotein IIb/IIIa

inhibitor use, possibly because of increased inhibitor use, possibly because of increased bleeding complications in womenbleeding complications in women

Higher in-hospital mortality for CABG and PCIHigher in-hospital mortality for CABG and PCI Higher rates of vascular complicationsHigher rates of vascular complications Higher transfusion ratesHigher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes Revascularization Outcomes in Women: Improvements in in Women: Improvements in

Recent YearsRecent Years

NHLBI registry data shows improved clinical NHLBI registry data shows improved clinical success rates and lower major complication success rates and lower major complication rates for women undergoing PTCArates for women undergoing PTCA

Retrospective data suggest that women Retrospective data suggest that women have lower mortality rates when undergoing have lower mortality rates when undergoing off-pump CABG, compared to standard off-pump CABG, compared to standard CABGCABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital Sex Differences for In-Hospital Mortality After CABG: Higher Mortality After CABG: Higher Mortality in Younger WomenMortality in Younger Women

2.23

1.86

1.161.47

1.02

0

0.5

1

1.5

2

2.5

< 50 50-59

60-69

70-79

80

Age Group

AdjustedOddsRatio forIn-HospitalMortality

P for interaction between sex and age = 0.002.

≥


CABG Outcomes in Women: CABG Outcomes in Women: A Vicious CycleA 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


““Hormone Replacement Hormone Replacement Therapy” Therapy”

Risk-Benefit Balance: 1960’s- Risk-Benefit Balance: 1960’s-1990’s1990’s

Risks

BenefitsCHD Osteoporosis Vasomotor SymptomsGU SymptomsSkin Preservation

Source: Limacher 2002

Postmenopausal Estrogen Postmenopausal Estrogen TherapyTherapy

Meta-analysis of observational data: 35% CHD Meta-analysis of observational data: 35% CHD risk risk reduction in women using hormone therapyreduction in women using hormone therapy

Lipid Effects:Lipid Effects: LDL Cholesterol LDL Cholesterol

Lipoprotein (a)Lipoprotein (a)

HDL CholesterolHDL Cholesterol Metabolic Effects: Metabolic Effects: Fasting glucose Fasting glucose

Fasting insulin levels Fasting insulin levels Fibrinolytic Effects: Fibrinolytic Effects: tissue plasminogen tissue plasminogen

activator, activator, plasminogen-activator plasminogen-activator inhibitor 1inhibitor 1 Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of HERS: Cumulative Incidence of CHD EventsCHD Events

Follow-up, yrs (No. at Risk)

Inc i

den

ce

, %

0 2 3 4 51

10

5

15

(2763) (2631) (2506) (2392) (1435) (113)

Estrogen-Progestin

Placebo

Source: Adapted from Hulley 1998

Women’s Health Initiative Women’s Health Initiative Estrogen and Progestin Arm: Estrogen and Progestin Arm:

Absolute Excess RiskAbsolute 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

Women’s Health Initiative Women’s Health Initiative Estrogen and Progestin Arm: Estrogen and Progestin Arm:

Absolute BenefitsAbsolute 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

Women’s Health Initiative: Estrogen Alone Women’s Health Initiative: Estrogen Alone in Postmenopausal Women Compared to in Postmenopausal Women Compared to

Placebo: Major Clinical OutcomesPlacebo: Major Clinical Outcomes

0.61

0.77

0.91

1.04

1.08

1.39

0 0.5 1 1.5 2

Stroke

Colorectal Cancer

Total Mortality

CHD

Breast Cancer

Hip Fracture

Relative Risk Compared to Placebo

*

* P < .05*

Favors Treatment Favors Placebo

Source: Adapted from WHI Steering Committee 2004

HT Risk-Benefit Balance: 2004

BenefitsVasomotor SymptomsOsteoporosisVaginal AtrophyColon CancerSkin PreservationDepression

RisksDVT/PEGallbladder DiseaseBreast CancerBreast/Bleeding Side EffectsCHDStrokeDementiaPancreatitis?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Raloxifene Use for the Heart Raloxifene Use for the Heart (RUTH) Trial: Primary and (RUTH) Trial: Primary and Secondary CVD OutcomesSecondary CVD Outcomes

0

100

200

300

400

500

600

CHD events Fatal CHD Stroke Fatal Stroke

RaloxifenePlacebo

Source: Adapted from Barrett Connor 2006

* * p < .05

Interventions that are not Interventions that are not useful/effective useful/effective

and may be harmful for the and may be harmful for the prevention prevention

of heart diseaseof heart disease Hormone therapy and selective Hormone therapy and selective

estrogen-receptor modulators estrogen-receptor modulators (SERMs) should not be used for the (SERMs) should not be used for the primary or secondary prevention of primary or secondary prevention of CVDCVD

Source: Mosca 2007

Menopausal Hormone Therapy, Menopausal Hormone Therapy, SERMs and CVD: Summary of Major SERMs and CVD: Summary of Major

Randomized TrialsRandomized Trials Use of estrogen plus progestin associated with a Use of estrogen plus progestin associated with a

small but significant risk of CHD and strokesmall but significant risk of CHD and stroke Use of estrogen without progestin associated with Use of estrogen without progestin associated with

a small but significant risk of strokea small but significant risk of stroke Use of all hormone preparations should be limited Use of all hormone preparations should be limited

to short term menopausal symptom reliefto short term menopausal symptom relief Use of a selective estrogen receptor modulator Use of a selective estrogen receptor modulator

(raloxifene) does not affect risk of CHD or stroke, (raloxifene) does not affect risk of CHD or stroke, but is associated with an increased risk of fatal but is associated with an increased risk of fatal strokestroke

Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

ConclusionsConclusions

♥ 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

THANK YOUTHANK YOU

women and coronary artery disease (cad) prof. roland kassab prof. roland kassab head of division of...

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