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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
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.
Mosca L et al. Circulation 2004; 109:573-9.
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).
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
Mosca L, et al. Circulation 2004; 109:672-93.
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%.
Mosca L, et al. Circulation 2004; 109:672-93.
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
Mosca L, et al. Circulation 2004; 109:672-93.
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
Mosca L et al. Circulation 2004; 109:672-93.
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
John et al. Lancet 2002
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
John et al. Lancet 2002
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
Mosca L, et al. Circulation 2004; 109:672-93.
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
Mosca L, et al. Circulation 2004;109:672-93.
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
Lipids and Lipoproteins: Pharmacotherapy
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
Mosca L, et al. Circulation 2004;109:672-93.
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
Lipids and Lipoproteins: Pharmacotherapy
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
Mosca L, et al. Circulation 2004;109:672-93.
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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