Women and Heart Disease (

Women and Heart Disease

Donna M Polk, MD, MPH

Preventive and Rehabilitative Cardiac Center

Cedars-Sinai Medical Center

Cardiovascular Disease Mortality Trends (1979-1999)

American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2001.

Mortality for Women and Men Post-AMI and After Adjustment by Risk Score

Women have higher CHD mortality

*p<0.001; †p<0.002.

Women

Men

5040302010

0

After adjustment by risk score

12 24 36 48

(%)

5040302010

0

Post-AMI

12 24 36 48

(%)

CHD Mortality Post MIWomen < 65 suffer the highest

sex-specific CHD mortality

Vaccarino NEJM 1999;341:217

Women and Cardiovascular Disease

• Every minute someone dies of a heart attack and every 45 seconds, someone has a stroke

• 38% of women will die within 1 year after having an initial recognized MI (vs 25%)

• 64% of women who died suddenly of CHD had no previous symptoms of this disease (vs 50%)

• 53% of women < 65 yrs die within 8 years of their stroke

Women and Heart Disease: Making an Impact

• AHA National Awareness Survey– 1997 – 30% aware heart disease is #1 killer

– 2000 – 34%– 2003 – 46%

• Knowledge gap remains – especially in women younger than 45, Hispanic, and African American women

• “Disconnect” remains – only 13% say heart disease is their own greatest health risk

Mosca, Circulation 2004

Greatest Health Problem

0

5

10

15

20

25

30

35

40

%

BreastCancer

CancerGeneral

HeartDisease

199720002003

Mosca, Circulation 2004

National American Heart Association SurveyWomen’s Awareness 2003:

Perceived Leading Cause of Death by Ethnic Group

Mosca L et al. Circulation 2004; 109:573-9.

%

0

10

20

30

40

50

60

BreastCancer

Cancer(general)

HeartDisease

Unsure

White

Black

Hispanic

Perception of Heart Disease Risk FactorsMosca, Circulation 2004

0

5

10

15

20

25

30

35

40

45

%

SmokingHigh CholesterolFamily HistoryHTNDiabetesHigh TgOverweightLack of exercise

Two Diseases and Their Toll

0 1.25 2.5 3.75 5

0 5 10 15

0 40 80 120

0 600 1200 1800

15-24

25-44

45-64

> 65

AGE(years)

RATE PER 100,000

HEARTDISEASEBREAST CANCER

Mortality rates per 100,000 women in the United States

Murphy SL. Death: final data for 1998. Natl Vital Stat Rep 2000;48:1-105

Women and CAD

• Detection

• Assessment

• Prevention

Diamond and Forrester, NEJM 1987;641

Typical angina chestpain is both less accurateand less precise for prediction of CAD in womencompared to men

Methods - Chest Pain Assessment

• Chest pain assessment (Diamond/CASS): a. is the pain substernal? b. is the pain exertional? c. is the pain relieved with rest/TNG?

Typical Angina = 3/3 present • Chest pain assessment (WISE):

a. is the pain substernal? b. absence of arm/shoulder pain? c. absence of palpitations?

Women’s early warning symptoms of Acute MI

• 515 women with MI surveyed 4-6 months post event

• 95% reported prodromal symptoms

McSweeney, Circ 2003;108:2619-2623

Prodromal Symptoms

0

10

20

30

40

50

60

70

80

unusualfatigue

Sleep SOB CP

% symptoms

McSweeney, Circ 2003;108:2619-2623

Acute Symptoms

0

10

20

30

40

50

60

SOB Weakness Fatigue NO CP

% Syptoms

McSweeney, Circ 2003;108:2619-2623

Sex, Presentation, and Outcomes in Acute Coronary Syndromes (Gusto IIb)

• Despite being older, more diabetes, HTN and CHF, women had:– Less MI with ST elevation (27% vs 37%)– Less MI/more ACS (37% vs 48%)– More hospital complications (bleeding, CVA,

MR, hypotension, AV block, CHF)– Higher 30 day mortality (6% vs 4%)

Hochman et al, NEJM 1999;341;226

Women suffer more plaqueerosions (above) comparedto plaque explosions in men (below), leading to more acute coronary syndromes(unstable angina) and non-Q MI in women,making diagnosis more difficult and leading to delays in treatment.

Gender Differences in Atherosclerosis

Prevalence of Normal or Minimal Disease at Angiography in Women

0

10

20

30

40

50

60

70

CASS 1982 Sullivan1994

Bell 1995 WISE 1998

Normal/MinimalDisease (%)

Cath for symptoms without noninvasive assessment in women results in high rates of normal/minimal disease

V3005V3005

Women and CAD

• Detection

• Assessment

• Prevention

Gender Differences in Exercise Treadmill Testing

Diamond GA, J Chron Dis 1986;39:343

ECG stress testing less accurate in women, but alsonot very accurate in men

ECG Testing in Women

• Overall– Most experience, widely accepted– Convenient access, availability, least expensive

• Sensitivity and specificity– Sensitivity/specificity in women generally lower than

in men1,2

– Sensitivity in women ≥52 years particularly lower • Best reserved for use in younger women at low risk of CHD3

– Specificity in women on ERT4 is lower

1. Morise AP, et al. Am Heart J. 1995;130:741–747. 2. Walling AD, et al. Coron Artery Dis. 1993;4:783–789. 3. Morise AP, et al. Int J Cardiol. 1997;60:55–65. 4. Curzen N, et al. Heart. 1996;76:156–160.

1. Miller DD. J Myocard Ischem. 1995;7(6):263–268. 2. Marwick TH, et al. J Am Coll Cardiol. 1995;26(2):335–341.

ECG Testing in Women

• False-Positive Results– ST-segment abnormality criteria validated

predominantly in men1

– 5- to 20-fold greater false-positive ST-segment response in women1

– Higher false-positive results due to autonomic/hormonal influences2

Hormonal Factors Affecting ECG Ischemia

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30

Menstrual Cycle, d

Att

acks

per

day

, n

Menstrual

Follicular

Luteal

Source: Webb Lancet 1998;351:1556, Lloyd Heart 2000;84:189, Rosano JACC 2000;36:2154, Morise Am J Cardiol 1993;72:1197, J Noninv Cardiol 1997;1:27, Am J Med 1993;94:491, J CV Risk 1997;3:507;

Kawano Ann Int Med 2001;135:977, JACC 2001;37:735, Schulman JACC 2002;39:238., Waters Circulation 2004;109:e53-e55.

1. Gibbons RJ, et al. J Am Coll Cardiol. 1997;30(1):260–315. 2. Morey SS. Am Fam Physician. 1998;57(1):563–565.

Limitations of ECG Testing in Women

• ACC/AHA Exercise Testing Guidelines1,2

– Exercise ECG is less specific in women than in men1

• Reflects lower prevalence of severe CAD1,2

• Reflects inability of many women to exercise to maximum aerobic capacity1,2

• Positive exercise test results in only 27%–58% of women1

– ST-segment response is less accurate in women1

– Pharmacologic stress imaging with modalities other than ECG may be a more accurate alternative to exercise tests1,2

ADA. ADA. Diabetes CareDiabetes Care. 1998;21:1551–1559.. 1998;21:1551–1559.

Noninvasive Testing Options

• Performed at rest and during peak stress

• Stress—exercise or pharmacologic

• Ischemia defined by wall motion abnormalities

Stress EchoStress Echo

Non-Invasive Testing Meta-Analysis in Women

Imaging modality No. studies No pats Sensitivity Specificity

ETT 19 3,721 61 70

Tl-201 5 842 78 64

Ex.ECHO 3 296 86 79

Kwok Y, et al. Kwok Y, et al. Am J CardiolAm J Cardiol. 1999;83:660-666.. 1999;83:660-666.

Non-Invasive Testing Meta-Analysis in Women

Imaging modality No studies No pts Sensitivity Specificity

ETT 19 3,721 61 69

Tl-201 5 842 78 64

ETT Echo 3 296 86 79

Tc-99m MIBIGated

1 115 80 92

Adapted from Kwok Y, et al. Adapted from Kwok Y, et al. Am J CardiolAm J Cardiol. 1999;83:660-666.. 1999;83:660-666.

4856

75 7590

120

0

20

40

60

80

100

120

140

Men Women

Clinical+Exercise+MPI

Incremental Prognostic Value of MPI Testing: Men vs Women

2

Hachamovitch R, et al. J Am Coll Cardiol 1996;28:34-44. Reproduced with permission. Copyright 1996, American College of Cardiology.

2742 Men1394 Women

Incremental Value of Exercise Thallium SPECT Imaging in Women

Pancholy et al., JNC 1995;2:110-116

Historic Challenges in Testing Women

0102030405060708090

100

ECG ECHO MPI

Women

Men

Source: Source: Shaw. Coronary Artery Disease in Women: Shaw. Coronary Artery Disease in Women: What All Physicians Need to Know. ACP Books, 1999:327What All Physicians Need to Know. ACP Books, 1999:327

Women and CAD

• Detection

• Assessment

• Prevention

Risk Factors

• Cigarette smoking• Diabetes• Cholesterol (elevated LDL-cholesterol,

low HDL)• Hypertension • Family history of premature CHD

– CHD in male first degree relative <55 years– CHD in female first degree relative <65

years• Age (men 45 years; women 55 years)

Risk Factors

• Obesity (especially central adiposity)

Body Mass Index (BMI)– Weight (kg)/height (m2)– Weight (lb) x 703/height (in2)

Abdominal obesity – waist circumference >40 in. in men, >35 in. in

women

• Physical inactivity• Stress

Evidence-Based Guidelines for CVD Prevention in Women

Mosca L et al. Circulation. 2004;109:672-693.

Evidenced-Based Guidelines or CVD Prevention in Women: Rationale

• Significant advances in science base needed to be translated into clinical recommendations

• Women were excluded from many early CVD trials and lack of data may be an obstacle to prevention in women

• In the wake of HERS and WHI there was a heightened need to clarify what prevention strategies are based on the highest quality evidence

• Recent survey showed women confused about prevention strategiesMosca L, et al. Circulation. 2004; 109:672-93.


ALOHA to Heart DiseaseLay Guidelines

• A-Assess your risk and rank yourself

• L-Lifestyle interventions are top priority

• O-Other interventions prioritized by expert rating

• H-Highest priority for women at highest risk

• A-Avoid Class III interventions (HRT, antioxidant supplements, and aspirin in low-risk women)

Mosca, L Circulation Patient Page www.circulationaha.org (2004;109;e158-160).

http://www.circulationaha.org/

A - Assessment of CHD Risk

For persons without known CHD, other forms of atherosclerotic disease, or diabetes:

• Count the number of risk factors.• Use Framingham scoring if 2 risk factors* to

determine the absolute 10-year CHD risk.• Determine risk status: high (>20% 10-year risk or

CHD risk equivalents), intermediate (10-20% 10-year risk), or low (<10% risk)

*For persons with 0–1 risk factor, Framingham calculations are not necessary.

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Framingham Risk AssessmentA Cholesterol Management Implementation Tool for the Palm Operating System

Based on ATP III

Spectrum of CVD Risk in Women

Framingham Global Risk Framingham Global Risk

Risk GroupRisk Group (10-y Absolute CHD Risk)(10-y Absolute CHD Risk)

High ≥ 20%

Intermediate 10% to 20%

Lower ≤10%

Optimal ≤10%

Mosca L, et al. Circulation 2004; 109:672-93.

High CVD Risk in Women: Clinical Examples

• Established CHD• Cerebrovascular disease*• Peripheral arterial disease• Abdominal aortic aneurysm• Diabetes mellitus• Chronic kidney disease†

*Cerebrovascular disease may not confer high risk for CHD if the affected vasculature is above the carotids. Carotid artery disease (symptomatic or asymptomatic with >50% stenosis) confers high risk.†As chronic kidney disease deteriorates and progresses to end-stage kidney disease, the risk of CVD

increases substantially


Intermediate CVD Risk in Women: Clinical Examples

• Subclinical CVD‡

• Metabolic syndrome• Multiple risk factors§

• Markedly elevated levels of a single risk factor**• 1st degree relative(s) with onset of atherosclerotic

CVD at ≤ 55 y in men and ≤ 65 y in women

‡Patients with subclinical CVD and >20% 10-year CHD should be elevated to the high-risk category.§Patients with multiple risk factors can fall into any of the 3 categories by Framingham scoring.**Most women with a single, severe risk factor will have a 10-year risk >10%.


Significant Coronary Artery Calcium (Score >400)

Lower/Optimal CVD Risk in Women: Clinical Examples

• Lower• May include women with multiple risk factors,

metabolic syndrome, or ≤ 1 risk factors

• Optimal• Optimal levels of risk factors and heart-healthy

lifestyle


Classification and Levels of EvidenceStrength of Recommendation

ClassificationClass I Intervention is useful and effectiveClass IIa Weight of evidence/opinion is in favor of

usefulness/efficacyClass IIb Usefulness/efficacy is less well established byevidence/opinionClass III Intervention is not useful/effective and may be harmful

Level of EvidenceA Sufficient evidence from multiple randomized trialsB Limited evidence from single randomized trial or other nonrandomized studiesC Based on expert opinion, case studies, standard of care

Generalizability Index1 Very likely that results generalize to women2 Somewhat likely that results generalize to women3 Unlikely that results generalize to women0 Unable to project if results generalize to women


L – Lifestyle Change: First Line of Defense Against Heart Disease

• The AHA expert panel rated the following as Class I recommendations:– Stop cigarette smoking and avoid secondhand tobacco

smoke– Get at least 30 minutes of physical activity each day– Start a cardiac rehabilitation program if recently

hospitalized for heart disease– Eat a heart-healthy diet – Maintain healthy weight by balancing caloric intake with

caloric expenditure

Mosca et al. Circulation 2004

MMWR Vol 53(23) 499-502

MMWR Vol 53(23) 427-431

Prevalence of Current Smoking for Women Ages 18-24 by Education and Race/Ethnicity NHANES III: 1988-94

Source: JAMA. 1999;281:1006-1013.

Tobacco and Cardiovascular Risk

• Women who smoke are 2-6 more likely to have MI

• RR heavy smokers 2x’s that of light smokers for stroke

• Risk for heart disease decreases 50% within 1 year and risk for heart disease and stroke equals a non smoker in 3-5 years

Prognostication by Exercise Capacity

FOLLOW-UP (YEARS)

1.3-5.4

5.5-7.0

7.1-8.08.1-9.29.3-14.6

Source: Mora et al, JAMA 2003;290:1600-7.

Physical Activity

• Recommendations are 30 minutes of moderate-intensity activity most if not all days of the week

Cardiac Rehab mortality Meta-analysis

• 10 randomized trials (4347 patients)• 1968-1987• Followed 2 yrs• All-cause death

25% 0.76 (0.63-0.92)

• CV death 24% 0.75 (0.62-0.92)

• Non-fatal MI– 1.15 (0.93-1.42)

Oldridge, JAMA 1988

BMI and Relative Risk of CHD Over 14 Years: Nurse’s Health Study

• Relative risk of CHD increases for BMI > 23, diabetes risk increases for BMI > 22.

• Risk also significantly increases for weight gain after age 18 years of 5 kg or more.

0

0.5

1

1.5

2

2.5

3

3.5

<21 21-22.9 23-24.9 25-28.9 >29

Obesity and CAD Risk

Kip Circ 2004;109:706-713

Epidemic Patterns for Overweight and Obesity in US Adults

56.352

18.725.6

0

10

20

30

40

50

60

Men WomenOverweight defined as >25 body mass index (BMI); obese defined as >30 BMI.

Nu

mb

er

of p

ers

on

s (in

mill

ion

s)

Overweight Obese

American Heart Association. 2002 Heart and Stroke Statistical Update.Dallas, Tex: American Heart Association; 2001.

Hypertension Obesity Hyper-insulinemia

Diabetes Hypertri-glyceridemia

Small,dense LDL

Low HDL

Hypercoagu-lability

Atherosclerosis

Insulin Resistance

Atherosclerosis and Insulin Resistance

NCEP ATP III: Clinical Identification of the Metabolic Syndrome*

*Diagnosis is established when 3 of these risk factors are present.

Risk Factor

Waist circumference Men Women

Triglycerides

HDL-C Men

Women

Blood Pressure

Fasting glucose

Defining Level

> 102 cm (> 40 inches)> 88 cm (> 35 inches)

≥ 150mg/dL

< 40 mg/dL

< 50 mg/dL

≥ 130 / ≥ 85 mm Hg

≥ 110 mg/dL

National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

NHANES III: Age-Adjusted Prevalence of ≥3 Risk Factors for the Metabolic Syndrome*

*Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%.

Ford ES et al. JAMA. 2002;287:356-359.

24.8

16.4

28.3

22.825.7

35.6

%%

0

5

10

15

20

25

30

35

40

White African-American Mexican-American

MenWomen

Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes

(Ages 35-64)10

9

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD

CHD Cardiac failure

Intermittent claudication

Stroke

Riskratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.

Diabetes as a Risk Factor in Women and Men

Framingham Study: 20-Year Follow-up

0

2

4

6

8

10

12

14

16

18

An

nu

al C

HD

Death

s p

er

10

00

Pers

on

s

Kannel WB, McGee DL. JAMA. 1979;241:2035-2038.

17

8

17

4

MENMEN WOMEN

DMDM

NonNon--DMDM

De Lorgeril, Circ 1999

Psychosocial Factors and Risk of Hypertension

Yan, JAMA 2003

NEJM 2001; 345:1598

B vitamins:Folate 1mgB12 400gB6 10mg

Treatment with B vitamins may reduce heart disease

GISSIPUFARCT

Circ2002105

O – Other Interventions with Class I Recommendations

• Blood pressure – encourage optimal levels of <120/80 mmHg

• Cholesterol levels – optimal cholesterol levels <200 mg/dl, LDL-C< 100 mg/dl, HDL >50 mg/dl, triglycerides <150 mg/dl

• Diabetes – recommend control to HgbA1c < 7%

Vasan et al. Vasan et al. N Engl J Med.N Engl J Med. 2001;345:1291-1297. 2001;345:1291-1297.

High-Normal BP and CVD Risk: Framingham Study

WomenWomen

1010

88

66

44

22

00

Time (years)Time (years)

00 22 44 66 88 1010 1212 1414

P<P<.001.001

MenMen

Cu

mu

lati

ve I

nci

den

ce (

%)

Cu

mu

lati

ve I

nci

den

ce (

%)

1414

1212

1010

88

66

44

22

00

Time (years)Time (years)

00 22 44 66 88 1010 1212 1414

PP<.001<.001

High normal 130-139/85-89 mm HgHigh normal 130-139/85-89 mm HgNormal 120-129/80-84 mm HgNormal 120-129/80-84 mm HgOptimal <120/80 mm HgOptimal <120/80 mm Hg

PrehypertensionPrehypertension

JNC 7: Classification and Management of BP for Adults

BP Classification

SBP* mm Hg

DBP* mm Hg

Lifestyle Modification

Initial Drug Therapy

Without Compelling Indication

With Compelling Indications

Normal <120 and <80 Encourage

Prehyperten-sion

120-139

or 80-89

Yes No antihypertensive drug indicated

Drug(s) for compelling indications ‡

Stage 1 Hypertension

140-159

or 90-99

Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drug(s) for the compelling indications‡

Stage 2 Hypertension

160 or 100

Yes Two-drug combination for most† (usually thiazide type diuretic and ACEI, or ARB, or BB, or CCB)

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Chobanian et al. Chobanian et al. JAMAJAMA. 2003;289:2560-2572.. 2003;289:2560-2572.

PREMIER: Reduction in blood

pressure by treatment group

End point

Advice only

Established recommendations

Established recommendations plus DASH diet

Mean reduction in BP (mm Hg)

--

-3.7* -4.3**

*p<0.001 vs advice only

**p<0.001 vs advice only, p= 0.43 vs established recommendations

Writing Group of the PREMIER Collaborative Research Group. JAMA 2003; 289:2083-2093.

Mean change in number of daily servings of fruit and vegetables by

intervention (unadjusted)

Timepoint Intervention group

Controls

Baseline 3.4 3.4

6-month follow-up

4.9 3.5

John et al. Lancet 2002

Change in systolic BP at 6 months between groups

Group Baseline BP (mm

Hg)

BP at 6 months (mm Hg)

Adjusted difference in change (95% CI)

p value

Intervention 130.2 -2.0 4.0 (2.0-6.0)

<0.0001

Control 129.3 1.4 4.0 (2.0-6.0)

<0.0001


Change in diastolic BP at 6 months between groups

Group Baseline BP (mm Hg)

BP at 6 months

(mm Hg)

Adjusted differenc

e in change (95% CI)

p value

Intervention

79.2 -1.6 1.5 (0.2-2.7)

0.02

Control 79.9 -0.3 1.5 (0.2-2.7)

0.02


Major Risk Factor Interventions: Lipid, Lipoproteins

Optimal levels of lipids and lipoproteins in women:

– LDL-C <100 mg/dL

– HDL-C >50 mg/dL

– Triglycerides <150 mg/dL

– Non–HDL-C (total cholesterol minus HDL-C) <130 mg/dL

Encourage lifestyle approaches (Class I, Level B)GI=1


Framingham Heart Study

CHDlikelihood

ratio

5.0

4.0

3.0

2.0

1.0

0.0Total-C LDL-C VLDL-C

Men Women

Total-C LDL-C VLDL-C

Triglycerides are a significant risk factor women, not men.

163 150 110143 137

6010474 61

0

50

100

150

200

<50 50-59 >59

<80

80-119

>119

Women

Trigly

cerid

es (m

g/dL)

HDL Cholesterol (mg/dL)

CH

D/1

00

0/1

0 y

r

Coronary Heart Disease in Relation to HDL-C and Triglyceride Levels in Women

Framingham Heart Study — National Heart, Lung, and Blood Institute

Castelli WP. Can J Cardiol. 1988;4:5A-10A.

163150

143

60

Age-adjusted Cardiovascular Disease Mortality in Women:

Lipid Research Clinic Follow-Up

At all levels of LDL-C, CVD mortality rates in women with low HDL-C levels were 3 to 4 times greater compared with women with high HDL-C levels.

Bass KM, et al. Arch Intern Med 1993;153:2209-16.

25

20

15

10

5

0

HDL-C <50 mg/dLHDL-C >50 mg/dL

< 131mg/dL 131-160 mg/dL >160 mg/dL LDL-CholesterolC

ardi

ovas

cula

r D

isea

se M

orta

lity

per

1000

Per

son-

Yea

rs

Statin Trials: Therapy Reduces Major Coronary Events in Women

n = number of women enrolled.* 4S = primarily CHD death and nonfatal MI;

CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery;AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death.

Miettinen TA et al. Circulation. 1997;96:4211-4218.Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146.Downs JR et al. JAMA. 1998;279:1615-1622.

4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997)

2 Prevention 1 Prevention

-50-45-40-35-30-25-20-15-10-505

10

Major coronary events*

-34

-46 -46

%

P=0.012

P=0.001

SIMVASTATIN: VASCULAR EVENT by AGE & SEX

Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

ST AT IN wo rs e

Age group (years)

Het2

3 = 4.4

< 65 838 1093

65 - 69 516 677

70-74 550 628

75 138 208

Sex

Het2

1 = 0.4Male 1676 2148

Female 366 458

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Major Risk Factor Interventions: Lipids and Lipoproteins

Heart-healthy diet– Consistently encourage overall healthy eating pattern

• Fruits, vegetables, grains, low-fat or nonfat dairy products, fish, legumes, and sources of protein low in saturated fat.

• Limit saturated fat intake to <10% of calories, limit cholesterol to <300 mg/d, and limit intake of trans fatty acids (Class I, Level B)GI=1

Diet therapy– In high-risk women or when LDL-C is elevated, reduce

saturated fat intake to <7% of calories, cholesterol to <200 mg/d, and trans fatty acid intake (Class I, Level B)GI=1

Mosca L, et al. Circulation 2004;109:672-93.

Lipids and Lipoproteins: Pharmacotherapy

High risk women (10-year absolute CHD risk > 20%)

– Initiate LDL-C–lowering (preferably statin) therapy with lifestyle therapy when LDL-C >100 mg/dL (Class I, Level A)GI=1, and initiate statin therapy when LDL-C <100 mg/dL unless contraindicated (Class 1, Level B)GI=1

– Initiate niacin or fibrate therapy when HDL-C is low, or elevated non–HDL-C (Class I, Level B)GI=1

• Dietary supplement niacin not a substitute for prescription niacin; over-the-counter niacin use only if approved, monitored by a physician


Class I Intervention is useful and effectiveLevel A Sufficient evidence from multiple randomized trials B Limited evidence from single randomized trial or other nonrandomized studies


Intermediate Risk Women (10-yr absolute CHD risk 10%-20%)

• Initiate LDL-C–lowering therapy (preferably statin) if LDL-C level is > 130 mg/dL on lifestyle therapy (Class I, Level A), or niacin or fibrate therapy when HDL-C is low or non–HDL-C is elevated after LDL-C goal is reached (Class I, Level B)GI=1


Class I Intervention is useful and effectiveLevel A Sufficient evidence from multiple randomized trials B Limited evidence from single randomized trial or other nonrandomized studies


Lower Risk Women (10-yr absolute CHD risk <10%)• Consider LDL-C–lowering therapy:

– 0 or 1 risk factor when LDL-C level is > 190 mg/dL

– If multiple risk factors are present when LDL-C is >160 mg/dL (Class IIa, Level B)

– Niacin* or fibrate therapy when HDL-C is low or non–HDL-C

elevated after LDL-C goal is reached (Class IIa, Level B)GI=1


Class I Intervention is useful and effectiveLevel A Sufficient evidence from multiple randomized trials B Limited evidence from single randomized trial or

other nonrandomized studies

H – Highest Priority for Therapy is for Women at Highest Risk

• Those at highest risk– ACE inhibitor therapy (if coughing, subst. ARB)– Aspirin therapy (baby aspirin or maximum dose of 162

mg) unless contraindicated– Beta-blocker therapy in those with prior MI or current

angina– Statin therapy – Niacin or fibrate therapy if low HDL present– Fibrates to lower triglycerides and improve HDL– Warfarin in those with atrial fibrillation unless

contradindicated

A – Avoid “Class III” Interventions

• Combined estrogen and progestin therapy, and *estrogen monotherapy since associated with increased risk of CVD

• Antioxidant supplements such as vitamin E and beta-carotene

• Aspirin for low risk patients not recommended since their benefits may be outweighed by risks, and benefits not proven in low risk women

Stampfer, Prev Med 1991(20):47-63

HERS: Heart and Estrogen/Progestin Replacement Study

• Randomized placebo-controlled trial of HRT in postmenopausal women with CAD

• Randomly assigned to receive 0.625 mg of conjugated estrogen and 2.5 mg medroxyprogesterone acetate (PremPro) or placebo

• Followed for average of 4.1 years• 1o Outcome= Non-fatal MI or CHD death

Hully, JAMA 1998

HERS: Lipid Effects-2

0-1

5-1

0-5

05

10

LDL-C HDL-C Trig% C

ha

ng

e f

rom

Ba

se

lin

e

Placebo

HRT

Hulley et al. JAMA 1998; 280:605

*

* *

*= p<0.001vs

Placebo

Kaplan-Meier Estimates of the Cumulative Incidence of Primary Coronary Heart Disease

(CHD) Events

0(2763)

1(2631)

2(2506)

3(2392)

4(1435)

5(113)

0

5

10

15

Follow-up, y (No. at Risk)

Inci

denc

e, %

Estrogen-Progestin

Placebo

Results

• CHD rates did not differ in women assigned to active vs. placebo treatment

• 50% increase in CHD risk (p=0.05) during the first year in those receiving CEE/MPA

WHI

• WHI randomized 16,608 women aged 50-79 with an intact uterus to continuous combined HRT (Prempro) between 1993-1998.

• 7% had established CVD and mean age at entry 63 years.

• DSMB stopped this arm of the trial after 5.2 years due to adverse increase in breast cancer

JAMA 2002

WHI

-0.01

-0.008

-0.006

-0.004

-0.002

0

0.002

0.004

0.006

0.008

0.01

PremPro

%

4236 or website

Death BreastCA CAD CVD DVT PE HipFX AllFX ColonCAvs Placebo

Odds Ratios:BreastCA 1.2CVD 1.2DVT 2.1HipFX 0.6ColonCA 0.6Mortality 0.0

None of the adjusted CI met statistical significance

VITAMINS: CAUSE-SPECIFIC MORTALITY

(10269) (10267)

VITAMINS PLACEBO Rate ratio & 95% CI

VITAMINS better PLACEBO better

Cause ofdeath

Vascular

664 630Coronary214 210Other vascular

(8.6%) (8.2%)5% SE 5increase

878 840

(NS)

ANY VASCULAR

Non-vascular

359 345Neoplastic103 101Respiratory

90 82Other medical16 21Non-medical

(5.5%) (5.3%)4% SE 6increase

568 549

(NS)

NON-VASCULAR

(14.1%) (13.5%)4% SE 4increase

1446 1389

(NS)

ALL CAUSES

0.4 0.6 0.8 1.0 1.2 1.4

HDL-Atherosclerosis Treatment Study (HATS)Niacin and Statin Regression Trial

Brown BG et al. N Engl J Med 2001;345:1583-1592.

Placebo S + N + AVS + N

Com

posi t

e E

ven

t R

ate

, %

Com

posi t

e E

ven

t R

ate

, %

AV

Coronary Death, MI, Stroke, or Revascularization

89%Reduction

21.4

2.6*

14.3

*P<.05 vs Placebo

23.7

0

5

10

15

20

25

Ridker, P. et al. N Engl J Med 2005;352:1293-1304

Cumulative Incidence Rates of the Primary End Point of Major Cardiovascular Events

Aspirin in the Primary Prevention of Myocardial Infarction and Stroke among Men and Women

Ridker, P. et al. N Engl J Med 2005;352:1293-1304

Conclusions• CVD is leading killer of women yet awareness is

suboptimal

• Diagnosis requires a high index of suspician

• Risk assessment is critical in targeting appropriate preventive therapies

• Lifestyle as well as pharmacologic therapies are effective in women

• If new guidelines are more uniformly implemented, the burden of CVD in women will be reduced

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