Coronary Heart Disease in Women

1
Coronary Heart Disease in Women

• Karol E. Watson, MD, PhD
• Assistant Professor of Medicine/ Division of
  Cardiology
• Co-director, UCLA Program in Preventive
  Cardiology
• David Geffen School of Medicine at UCLA

2
Statistics

• Heart Disease and Stroke
• First and third leading causes of death in US
• Accounts for more than 40 of all deaths
• About 95,000 Americans die of heart disease or
  stroke each year
• Amounts to one death every 33 seconds
• Heart Disease is the leading cause of disability
  among working adults

3
Cardiovascular Disease Mortality Trends for
Males and Females
United States 1979-2003
Source CDC/NCHS.
4
Hospital Discharges for Heart Failure by Sex -
United States 1979-2003
700
600
500
Discharges in Thousands
400
300
200
100
0
79
80
85
90
95
00
03
Years
Male
Female
Source National Hospital Discharge Survey,
CDC/NCHS and NHLBI.
5
Prevalence of cardiovascular diseases in adults
by age and sex (NHANES 1999-2004).
Source NCHS and NHLBI. These data include
coronary heart disease, heart failure, stroke and
hypertension.
6
Incidence of cardiovascular disease by age and
sex
7
Annual rate of first heart attacks by age, sex
and race (ARIC 1987-2000).
Source NHLBIs ARIC surveillance study,
1987-2000.
8
Hospital discharges for heart failure by
sex (United States 1979-2004).
Source NHDS, NCHS and NHLBI.
Note Hospital discharges include people
discharged alive, dead and status unknown..
9
Women and Heart Disease
10
Heart Disease is the 1 Killer of Women

• Coronary heart disease is the single leading
  cause of death and a significant cause of
  morbidity among American women.
• In 1997 CHD claimed the lives of 502,938 women
  (men had less deaths)
• Since 1984, CVD has killed more American women
  than men each year.

11
Breast Cancer is the REAL issue!

• Who cares about heart disease docI am more
  concerned about
• BREAST CANCER and lung cancer!
• In a recent survey, 75 of women identified
  cancer as their leading cause of death

12
In perspective

• 1 in 2 women will die of heart disease.
• 1 in 25 women will die of breast cancer.

13
CHD Mortality in Younger Women
Women under 65 suffer the highest relative
sex-specific CHD mortality
14
Coronary Heart Disease in Women

• Presentation and differences from men
• 2/3 of women who die suddenly have no previously
  recognized symptoms.
• Women are more prone to non-cardiac chest pain..
  
• In fact they may experience little or no
  squeezing chest pain in the center of the chest,
  lightheadedness, fainting, or shortness of breath
  with an MI

Source Milner Am J Cardiol 199984396
15
Nationally The Problem AWARENESS

• Perception
• 67 knowledgeable that chest pain can be heart
  disease
• can be heart disease

• Reality
• chest pain is the presenting symptom in women
• Almost half of MIs in women present with SOB,
  nausea, indigestion, fatigue and shoulder pain

16
Causes of Confusion

• Women may experience more dizziness, nausea,
  indigestion, and fatigue than men.
• Women are more likely to have neck, arms, back
  and shoulder pain.

17
Women and Heart Disease

• Risk Factors

18
Trends in total cholesterol among adolescents
ages 12-17 by race and sex (NHES 1966-70
NHANES 1971-74 and 1988-94).
Source NCHS and NHLBI.
19
Non-modifiable Risk Factors

• Age 55
• CAD rates are 2-3xs higher in postmenopausal
  women
• Family history
• CHD in primary 1st degree relative malefemale

20
The 1 Preventable Risk- Smoking

• A. 50 of heart attacks among women are due to
  smoking. Smokers tend to have their first heart
  attack 10 years earlier than nonsmokers.
• B. If you smoke, you are 4-6xs more likely to
  suffer a heart attack and increase your risk of a
  stroke.
• C. Women who smoke and take OCPs increase their
  risk of heart disease 30xs.

21
SMOKING

• Stop!!!!! (avg. attempt 8 times)
• Women who have other smokers in their household
  have a 2.5 X's greater likelihood of relapse.
  Circulation 2002106
• Smoking cessation was associated with a 36
  reduction in mortality among patients with
  CHD. JAMA 2003290

22
Hypertension

• 65 of all hypertension remains either undetected
  or inadequately treated.
• People who are normotensive at 55 have a 90
  lifetime risk of developing HTN.
• Prevalence increases with age and women live
  longer- hypertension is more common in females.
• HTN is more common with OCP and obesity.

23
Women and HTNJNC VII

• The relationship bet. BP and CV events is
  continuous, consistent and independent of other
  risk factors.
• The higher the BP the greater the chance of MI,
  CHF, stroke, and kidney disease.
• Can try to achieve good BP through lifestyle
  changes.

24
Risk Factors Diabetes

• Diabetes increases the risk of CHD 3-7 X in women
  versus 2-3 X in men.
• Diabetic women who smoke have a 84 higher risk
  of developing stroke than nonsmokers.
• 2 of 3 people with diabetes die from CHD or
  stroke.

25
Cholesterol

• More than 55 million women (45million men) have
  TC200.
• Check cholesterol at least once q 5yrs starting
  at age 20.
• 36 Million people in the US should be taking a
  statin according to guidelines, but only 11
  million are.

26
Lifestyle Modification for HTN
27
Glycemic control In Diabetes

• Treatment of hyperglycemia has been shown to
  reduce or delay complications of diabetes such as
  retinopathy, neuropathy, and nephropathy
• keep HBA1C
• FPG
• 2 hour 75g GTT-Impaired glucose tolerance-
  140-199.

28
Cholesterol

• Women at high risk should be considered for
  statin therapy regardless of cholesterol-LDL
  levels.
• Statins have surpassed all other classes of
  agents in reducing the incidence of the major
  adverse outcomes of death, MI, and
  stroke. NEJM 35015 April 8, 2004

29
How weve changed our thinking about Primary
Prevention in Women

• Hormone Therapy
• Risk Factors
• Preventive Medications
• Lifestyle Interventions

30
HERS Combined HT Does Not Decrease All-Cause
Mortality
15
Estrogen-Progestin Placebo
10
Incidence ()
5
0
0(2763)
1(2720)
2(2666)
3(2595)
4(1590)
5(130)
Follow-up, y (no. at risk)
Hulley S, et al. JAMA. 1998280605613.
31
Estrogen Progestin and Disease in WHI
Coronary Heart Disease HR 1.29 95 nCI.
1.021.63 95 aCI. 0.851.97
Stroke HR 1.41 95 nCI. 1.071.85 95 aCI.
0.862.31
Cumulative Hazard
Invasive Breast Cancer HR 1.26 95 nCI.
1.001.59 95 aCI. 0.831.92
Pulmonary Embolism HR 2.13 95 nCI.
1.393.25 95 aCI. 0.994.56
Cumulative Hazard
Estrogen Progestin
Hip Fracture HR 0.66 95 nCI. 0.450.98 95
aCI. 0.331.33
Colorectal Cancer HR 0.63 95 nCI.
0.430.92 95 aCI. 0.321.24
Placebo
Cumulative Hazard
0 1 2 3 4 5 6 7
0 1 2 3 4 5 6 7
Time (y)
Time (y)
32
WHI EP Trial Findings, July 2002 (avg 5.2 y)
Risks
Benefits
105 Increase Dementia
Fracture Reduction (Hip 23)
24 Increase CHD
39 Reduction Colorectal Cancer

31 Increase Stroke
111 Increase Pulmonary Emboli
24 Increase Breast Cancer
STOPPED Early, Clear Harm
Stopped 3.3 yrs early
Also DVTs
JAMA. 2002288321-333
33
Summary of WHI Estrogen-Alone Results

• Event Relative Hazard 95 CI
• Inv. Breast Cancer 0.77 0.59-1.01
• CHD 0.91 0.75-1.12
• Hip Fracture 0.61 0.41-0.91
• All Fractures 0.70 0.63-0.70
• Colorectal Cancer 1.08 0.75-1.15
• _____________________________________________
• p
• JAMA, 4/14/04

34
WHI E Alone Trial Findings, 2004 (avg 6.8 y)
Neutral for CHD Neutral for breast cancer
Risks
49 Increase Dementia
Benefits
39 Increase Stroke
Fracture Reduction (Hip 39)
34 Increase Pulmonary Emboli
STOPPED Early, suggestion of harm
Stopped 1.7 yrs early
Also DVTs
JAMA 20042912947-58
35
Estrogen in the early menopausal years

• Analysis of 24,317 women 50-79 years old in WHI
• whose age at menopause could be defined
• stratified into 3 groups 50-59/ 60-60 /70-79
  y.o.
• CHD, stroke mortality rates analyzed
• Stroke was increased in all women, regardless of
  age at menopause or E vs. E P
• CHD was decreased in women who took E alone vs. E
  P (0.95 vs. 1.23 p0.02)
• In hormone users
• HR for CHD if
• HR for CHD if 10-20 from menopause 1.10
• HR for CHD if 20 years from menopause 1.28

Rossouw, J. E. et al. JAMA 20072971465-1477.
36
Current research centers around the question
Does estrogen mean different things in different
vessels?
37
How weve changed our thinking

• Hormone Therapy
• WHI - Combined hormone therapy increases
  cardiovascular risk overall (but may be
  safe/?beneficial in the early menopausal years)
• WHI - Estrogen only therapy is neutral on CHD
• Risk Factors
• Preventive Medications
• Lifestyle Interventions

38
NHANES III Age-Adjusted Prevalence of 3 Risk
Factors for the Metabolic Syndrome
Men
35.6
Women
28.3
25.7
24.8
22.8
Prevalence( )
16.4
African American
White
Mexican American
Criteria based on ATP III diabetics were
included in diagnosis overall unadjusted
prevalence 21.8. Ford ES et al. JAMA.
2002287356-359.
39
Elevated Triglycerides Increase CHD Risk
Framingham Heart Study
Relative Risk for CHD
Women
Men
For every increase in serum TG level of 89 mg/dL,
risk of CHD increases 30 in men and 69 in
women13.14
Meta-Analysis of 17 Prospective Studies
40
CVD Events in Patients With Diabetes Framingham
Heart Study 30-Year Follow-Up
12
Men

10

Women
8

6
Relative Risk Ratio


4




2
0
Total CVD
CHD
Cardiac Failure
Intermittent Claudication
Stroke
.001relative to nondiabetic patient aged 3564
years. Wilson et al. In Ruderman et al, eds.
Hyperglycemia, Diabetes, and Vascular Disease.
199221-29.
41
Risk of Stroke With Metabolic Syndrome,
Stratified by Gender
Boden-Albala BM et al. American Academy of
Neurology Annual Meeting. Mar 29-Apr 5, 2003
Honolulu, HI.
42
How weve changed our thinking about Primary
Prevention in Women

• Hormone Therapy
• Risk Factors
• Triglycerides, diabetes, and the metabolic
  syndrome are greater risks for women as compared
  to men
• Preventive Medications
• Lifestyle Interventions

43
Meta-analysis from CholesterolClinical Trialists
(CCT) Collaboration
Groups
Events
Treatment
Control
Heterogeneity/trend test
45,002
45,054
RR
Post MI Other CHD None
1681 (11.7) 568 (8.7) 1088 (4.5)
2207 (15.4) 744 (11.4) 1469 (6.1)
0.78 (0.74-0.84) 0.77 (0.68-0.87) 0.72 (0.66-0.80)
P0.2
Sex Male Female
3630 (10.6) 790 (7.3)
2686 (7.8) 651 (6.1)
0.76 (0.72-0.80) 0.82 (0.73-0.93)
P0.1
0.5
1.0
1.5
Control better
Treatment better
Cholesterol Clinical Trialists Collaboration.
Lancet. 20053661267.
44
Physicians Health Study (PHS)
Aspirin Evidence Primary Prevention in Men
22,071 men randomized to aspirin (325mg QOD)
followed for 5 years Aspirin
significantly reduces the risk of MI in men
CIConfidence interval, MIMyocardial infarction
Physicians Health Study Research Group. NEJM
1989321129-35
45
Women's Health Study Low-Dose Aspirin in
Primary Prevention Trial
39,876 initially healthy women, aged ?45
yrs Randomized, blinded, factorial
Placebo n19,942

• Low-Dose Aspirin
• 100 mg on alternate days
• n19,934

• End points (mean, 10.1 yrs)
• Combined end point of nonfatal MI, nonfatal
  stroke, or total cardiovascular death
• Incidence of total malignant neoplasms of
  epithelial cell origin

No history of coronary heart disease,
cerebrovascular disease, cancer (except
nonmelanoma skin cancer), or other major chronic
illness no history of side effects to any of the
study medications not taking aspirin or
nonsteroidal anti-inflammatory medications
(NSAIDs) more than once a week (or were willing
to forgo their use during the trial) not taking
anticoagulants or corticosteroids and not taking
individual supplements of vitamin A, E, or beta
carotene more than once a week.
Ridker PM. Presented at 54th Annual Scientific
Session of the American Collegeof Cardiology
March 7, 2005 Orlando, Fla. Ridker PM, et al.
N Engl J Med. 2005352.
46
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47
Womens Health Study (WHS)
Aspirin Primary Prevention in Women
39,876 women randomized to aspirin (100 mg every
other day) or placebo for an average of 10 years
Aspirin
Placebo
Cumulative Incidence of MI
P0.83
Years
Aspirin does not reduce the risk of MI in low
risk women
MIMyocardial infarction
Ridker P et al. NEJM 20053521293-304
48
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49
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50
Conclusions

• In this large, primary-prevention trial among
  women, aspirin (50 mg/d) lowered the risk of
  stroke without affecting the risk of myocardial
  infarction or death from cardiovascular causes.
  In the subgroup of women 65 years old both
  stroke and MI were significantly decreased

51
Aspirin Evidence Primary Prevention
BDT, 1988
RR of MI in Men
RR of CVA in Men
PHS, 1989
TPT, 1998
HOT, 1998
PPP, 2001
RR 0.68 (0.54-0.86)P0.001
RR 1.13 (0.96-1.33)P0.15
Combined
1.0
2.0
5.0
0.5
0.2
1.0
2.0
5.0
0.5
0.2
RR of MI in Women
RR of CVA in Women
HOT, 1998
PPP, 2001
WHS, 2005
RR 0.99 (0.83-1.19)P0.95
RR 0.81 (0.69-0.96)P0.01
Combined
1.0
2.0
5.0
0.5
0.2
1.0
2.0
5.0
0.5
0.2
Aspirin Better
Placebo Better
Aspirin Better
Placebo Better
CVACerebrovascular accident, MIMyocardial
infarction, RRRelative risk
Ridker P et al. NEJM 20053521293-304
52
How weve changed our thinking about Primary
Prevention in Women

• Hormone Therapy
• Risk Factors
• Preventive Medications
• Statins reduce CHD in both men and women, however
  the NNT in women is greater
• ASA (50 mg/d) reduces the risk of stroke, but not
  MI in low risk women under the age of 65. For
  men, low dose ASA has shown the opposite
• Lifestyle Interventions

53
Womens Health Initiative StudyReducing Total
Fat Intake

• Study the effect of low-fat, high fruit,
  vegetable, and grain diet on breast cancer,
  colorectal cancer and heart disease in
  postmenopausal women
• Diet NOT designed for weight loss
• Women followed 8.1 years
• 48,000 postmenopausal woman
• No intervention 60 of participants
• Intervention (dietary change) 40 of
  participants

54
WHI Heart Disease RESULTS

• No reduction in risk of MI or CHD death
• Small but significant improvements in risk
  factors including
• Body weight
• LDL
• Diastolic blood pressure
• Factor VII C (a blood clotting factor)

55
WHI What went wrong?

• Dietary pattern reduced ALL types of fat
• Diet designed for heart disease would focus on
  reducing saturated and trans fat
• Relied on food frequency questionnaires which
  rely heavily on memory
• Participants started the study late in life

56
Trans Fatty Acids and CHD Risk in WomenSun et.
al. Circulation 2007 115

• Blood samples from 32,836 NHS subjects
• 6 yr F/U 166 CHD events
• Nested case/control
• RBC trans fatty acid content divided into
  quartiles
• Multivariable relative risks
• Q1 vs. Q2 1.6
• Q1 vs. Q3 1.6
• Q1 vs. Q4 3.3

57
How weve changed our thinking about Primary
Prevention in Women

• Hormone Therapy
• Risk Factors
• Preventive Medications
• Lifestyle Interventions
• Diets that lower only total fat intake, and are
  started later in life may not decrease CHD
• Trans fat intake is strongly associated with
  increased CHD in women