CARDIOVASCULAR DISEASE

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CARDIOVASCULAR DISEASE WOMEN A Review of The
Evidence
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Presented ByDr. Laurie-Ann Baker, MD, CCFPEM
ResidentUniversity of Calgary
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Objectives

• Demystifying the truths and examining the myths
• Risk Factors
• The Diagnosis of CAD in Women
• HRT What Now
• The Bottom Line
• Current future research

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Fact

• Cardiovascular disease, primarily CAD, outnumbers
  the next 16 causes of death in women combined,
  including all cancers
• Women are 4 to 8 times more likely to die of CVD
  than of any other disease
• CVD will be the leading cause of death for the
  next 20 years in the developing world

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Fact

• Since 1980, death from CVD has declined in men
  but increased in women
• The Canadian Cardiovascular Society state that
  mortality at presentation is twice that of men
• It has only been in the last decade that there
  has been heightened awareness within the health
  care community that differences between men
  women exist

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Percentage of total deaths due to CVD by age
sex (Canada 1997)
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Risk Factors For Coronary Artery Disease in Women
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Diabetes

• Increases CAD-related mortality rate in women 3
  to 7 times more than in non-diabetic women
• Increases CAD-related mortality rate in men 2 to
  4 times

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• DM is a greater predictor of CAD for women than
  for men
• DM reduces womens life-expectancy advantage
• Difference may be due to a particularly
  deleterious effect of diabetes on lipids and
  blood pressure in women

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Dyslipidemia
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Dyslipidemia

• After age 50, cholesterol levels plateau in men
• Levels of LDL increase an average of 0.05 mmol/L
  per year between ages 40 and 60 in women
• Part of this increase results from declining
  levels of estrogen

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• Decreasing estrogen results in the
  down-regulation of the LDL receptor on the liver
• A high LDL level is a strong predictor of CAD
  risk in women younger than 65 years and a
  somewhat weaker predictor in women gt65 years
• Low HDL levels is a stronger predictor of CAD
  mortality in women than in men particularly after
  age 65

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• FRAMINGHAM HEART STUDY
• - 8 year risk of heart disease was 7 for women
  with a total/HDL ratio less than 5
• - 12 for those with ratios of 5 to 7
• - 20 for those with ratios greater than 7

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• Further, in another study of 2500 women aged 71
  years or older, those with HDL levels lt0.9 had a
  RR of CAD mortality twice that of women with HDL
  levels of 1.6 or more
• Elevated triglycerides are also shown to be a
  significant risk factor in women especially when
  HDL levels fall below 1.03

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• The Air Force / Texas Coronary Atherosclerosis
  Prevention Study (AFCAPS/ TexCAPS) used drug
  intervention with a statin in men and women who
  had average total and LDL levels and slightly low
  HDL levels. A reduction of primary CV events was
  demonstrated in both sexes
• However, the US / Canadian PREVENT trial (2000)
  investigators found that women, especially,
  continue to be under-treated compared to men

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Hypertension

• Major trials of hypertension treatment, ie.
  Hypertension Detection Follow-up Program
  (HDFP), Systolic Hypertension in the Elderly
  (SHEP), have included adequate numbers of women
  and demonstrated benefits of treatment

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• Women with hypertension have a 4-fold risk of
  heart disease compared with normotensive women
• Men with hypertension have a 3-fold increase in
  risk
• Isolated systolic hypertension in older women has
  a 30 prevalence in women older than 65 years

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• Women with hypertension outnumber men with
  hypertension in the older age groups (due to
  survival advantage)
• Estimated prevalence (BP gt140/90 or use of
  anti-hypertensive) in women older than 45 years
  is 60 (US statistic)

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Smoking
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Smoking

• The leading preventable cause of CAD in women is
  cigarette smoking
• More than 60 of MIs in women younger than 50
  yrs can be attributed to tobacco use
• 21 of all CAD deaths attributable to smoking

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• The risk in heavy smokers ( gt 20 cigarettes per
  day) is 2 to 4 times higher than in nonsmokers
• Light smokers (1-4 cigarettes per day) have
  double the risk of nonsmokers
• Stopping smoking decreases the risk of CAD within
  months (Nurses Health Study found the risk of
  CAD decrease by 1/3 two years after cessation)

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• The prevalence of smoking in recent years has
  dropped in both men and women however womens
  rate of cessation is lower than that of men
• Almost one fourth of women smoke cigarettes
• Greatest increase in the prevalence of smoking is
  in women aged 65 years or older

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Menopause

• Natural menopause confers a 3-fold increase in
  CAD risk
• Nurses Health Study cohort showed that women
  under-going bilateral oophorectomy had up to an
  8-fold increase in risk of CAD
• Of interest, the Nurses Health Study showed that
  early natural menopause was not a risk factor for
  CAD after adjustment for tobacco exposure

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• Degree to which estrogen deficiency increases
  risk of CAD in women remains a subject of debate
• Many studies have found the incidence of CAD in
  postmenopausal women higher than that of
  pre-menopausal women of the same age range

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• Although the largest increase in coronary
  mortality in women coincides with menopause,
  vital statistics data do not support that
  menopause, apart from chronological aging
  increases the risk of CAD
• Effects of aging versus estrogen deficiency
  (menopause state) versus lipid increase

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Obesity Physical Activity
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Obesity

• Obesity in both men women has been increasing
  over the past few decades
• Obesity sedentary lifestyle are interrelated
• Obesity is an independent risk factor for
  all-cause mortality is associated with DM,
  hyperlipidemia and hypertension

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Obesity in Canada
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• 30.5 of Canadians between the ages of 20 and 64
  are obese (BMI of 27 or greater)
• Obesity is the most common metabolic condition in
  industrialized nations
• Total direct cost of obesity in Canada was
  estimated to be over 1.8 billion (2.4 of the
  total health care expenditures for all diseases
  in Canada)

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Physical Activity
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Physical Activity

• Physical inactivity contributes to obesity and is
  an independent risk factor for MI
• Investigators in the Nurses Health Study found
  that 30 to 45 minutes of walking three times
  weekly reduces the risk of MI by 50 (even in
  older women)

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• It is estimated that between 39 and 54 of North
  American women do not get adequate physical
  activity
• Exercise has been found to reduce the risk of
  type II DM even in women with obesity and a FHX
  of DM
• HDL levels have shown a dose-response
  relationship in female runners

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The Diagnosis of CAD in Women
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Approach to Diagnosis

• The perception persists that CAD mainly affects
  men is not a serious concern for women
• Women develop angina about 10 years later and a
  first MI about 20 years later than men
• Women are more likely to have angina than MI as
  their initial presentation of CAD

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• Women tend to have more atypical features when
  presenting with CAD than do men
• Women presenting with acute MI tend to be older
  and have more co-morbidity
• Women are less likely than men to attribute their
  symptoms to cardiac disease, even in the setting
  of acute MI

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Estimating the Risk

• Estimating the likelihood of CAD by assessment of
  the patients clinical characteristics and
  coronary risk factors is more easily and
  accurately accomplished in men than in women
• As the prevalence of CAD (particularly
  multi-vessel disease) is lower in women than men
  (except in older women), the predictive value of
  any symptom or non-invasive test is lower

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• The presence of any type of chest pain, whether
  atypical or typical, is associated with a lower
  risk of CAD in pre-menopausal women
• The likelihood of CAD increases after menopause
• Diabetes eliminates the age advantage in women
  over men and confers a substantially greater CAD
  mortality than in non-diabetic women
• DM is an important predictor of the presence
  prognosis of CAD in women

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Diagnostic Evaluation

• The purpose of performing a clinical evaluation
  is to identify those at very high risk, who would
  benefit from immediate coronary angiography, and,
  in lower-risk patients, to accurately identify
  those with significant CAD prior to development
  of acute coronary event

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Diagnostic Evaluation

• Patients can be classified into high,
  intermediate or low probability of CAD, by taking
  into consideration factors such as chest pain
  types (typical, atypical or nonischemic) and
  determinants (major, intermediate and minor) or
  the likelihood of CAD

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Classification of Chest Pain(Typical Angina)

• FEATURES
• - Substernal
• - Squeezing, burning, heavy
• - Exertional or precipitated by emotion
• - Promptly relieved by rest or nitroglycerin

• CLASSIFICATION
• - 60-75 prevalence of angiographically
  significant CAD

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Classification of Chest Pain(Atypical Angina)

• CLASSIFICATION
• - 30-40 prevalence of angiographically
  significant CAD

• FEATURES
• - Left chest, abdominal, back, arm, without
  mid-chest pain
• - Sharp or fleeting
• - Unrelated to exercise
• - Relieved by antacids

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Determinants of the Likelihood of CAD in Women

• MAJOR
• - Post menopausal status / age gt65 years
• - Diabetes
• - Peripheral Vascular Disease

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Determinants of the Likelihood of CAD in Women

• INTERMEDIATE
• - Hypertension
• - Smoking
• - Lipid abnormalities

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Determinants of the Likelihood of CAD in Women

• MINOR
• - Obesity
• - Sedentary lifestyle
• - Family history of CAD
• - Other risks factors of CAD

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Classification According To Their Probability of
CAD
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• HIGH PROBABILITY OF CAD (gt80)
• Typical angina and any of
• - Post-menopausal status or age gt65
• - Diabetes
• - Peripheral Vascular Disease
• - Two intermediate determinants

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• HIGH PROBABILITY OF CAD (gt80)
• Atypical angina and any of
• - Post-menopausal or age gt65 and gt1
  intermediate determinant
• - Diabetes plus gt1 intermediate or minor
  determinants
• - Three intermediate or 2 intermediate plus 1
  minor determinants

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• INTERMEDIATE PROBABILITY (20 80)
• Typical Angina and 1 intermediate or gt2 minor
  determinants
• Atypical Angina and post-menopausal / age gt65
• Nonischemic Pain and post-menopausal / age gt65 or
  diabetes and gt2 intermediate and/or minor
  determinants

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• LOW PROBABILITY (lt20)
• Typical Angina and premenopausal with no
  determinants
• Atypical Angina and no major determinants
• Nonischemic pain and no major determinants

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Diagnostic Testing

• The prevalence of CAD, particularly multi-vessel
  disease, is lower than in men (with the
  exception of the older age group)
• As a result, the predictive value of any symptom
  or non-invasive test is lower in women than in
  men
• Utility of diagnostic testing is related to the
  pretest probability of disease, therefore it is
  necessary to make a careful assessment of risk in
  order to guide the choice of diagnostic modality
  or to determine if the test is required

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Diagnostic Evaluation

• LOW PROBABILITY
• - no stress test likelihood of false-positive
  test results are greater than the likelihood of a
  true-positive test

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Diagnostic Evaluation

• INTERMEDIATE
• - Those who are able to exercise and who have a
  normal resting ECG, should undergo exercise
  stress
• - If negative, no further workup (high negative
  predictive value)
• - If inconclusive, or if baseline ECG
  abnormalities, or if goal is to localize and
  quantify ischemia these go on to stress imaging
  studies

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Diagnostic Evaluation

• HIGH PROBABILITY
• - Stress testing or coronary angiography
  depending on their severity and stability of
  symptoms
• - If negative stress test, may follow closely
  and observe (controversial)
• If inconclusive stress test, angiography

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HRT What Now??
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HRT Observational Studies

• Numerous observational studies including a
  meta-analysis of more than 30 observational
  studies by Stampfer Colditz (1991) showed
  reductions up to 60 in the risk of a major
  coronary event in healthy current estrogen users
  compared with women who have never used estrogen
  replacement

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HRT RCTs

• In the first large randomized trial of HRT in
  women, the HERS trial found there was no
  significant difference in the combined incidence
  of CHD death and nonfatal MI at 5 years
• There was a mean reduction in LDL levels of 11
  and increases in HDL of 10 however there was
  also an increase in primary coronary events in
  year one

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• Increased risk (RR 1.57) of a second CV event in
  the first year of treatment, followed by a
  non-significant reduction in risk in the last two
  years
• Based on no cardiovascular benefit and a pattern
  of early increase in risk of CAD events, the
  investigators do not recommend HRT for secondary
  prevention of CVD
• Extended follow-up of the HERS cohort is underway

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• A second large randomized trial of HRT, the ERA
  study, also observed no benefit of HRT with the
  use of quantitative coronary angiography
• The Womens Health Initiative (WHI) is a
  nine-year primary prevention study with
  approximately 27, 000 post-menopausal women
  randomized to treatment with placebo, CEE alone
  or CEE and MPA. This trial is scheduled for
  completion in 2005

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• The Womens Health Initiative (WHI) Study stopped
  the CEE MPA arm of their study this past summer
  (2002)
• The overall health risks exceeded the benefits
  from the use of CEE MPA in healthy post
  menopausal women and the investigators therefore
  concluded that this regime should not be
  initiated or continued for primary prevention of
  CAD

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The SOGC Recommends

• HRT indeed should not be initiated or continued
  for the sole purpose of preventing cardiovascular
  event (primary or secondary)
• HRT for the prevention of bone loss to decrease
  the risk of fracture
• HRT for extreme perimenopausal symptoms

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Men Are From Mars Women Are From VenusSo
..
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What Are We Doing About It?

• The investigators from the PREVENT (2000)
  published observational data citing that both the
  US Canada treated hyperlipidemia inadequately
  especially in women
• Cox et. Al. (2001) published a cross sectional
  survey showing that women were less likely than
  men to have a recording of BMI, smoking, BP and
  cholesterol profile, and less likely to be on
  lipid lowering therapy and aspirin

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• The Myocardial Infarction Triage Intervention
  Registry as well at the TIMI 9 trial both
  identified that women with identical symptoms and
  profile were less likely to be admitted to the
  CCU or its equivalent and therefore less likely
  to receive thrombolytic therapy

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• Lee et. Al. (2001) reviewed RCTs of ACS from 1966
  2000 and found that age exclusion has declined
  from 58 to 40 comparing trials from 1966 1990
  1991 2000 and enrollment of women has risen
  from 20 to 25 even though the proportion of
  women with MIs is approximately 43
• Recent surveys of cardiac rehabilitation programs
  continue to under-represent women impacting
  secondary prevention / risk factor modification
  management

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The Bottom Line Whats Different for Women?

• PRESENTATION
• - Women present at later age
• - Typical angina is less predictive of CAD
  (pretest probability 50-60 compared to 80-99 in
  men)
• - Women often present with shoulder or jaw pain,
  dyspnea or nausea

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The Bottom Line Whats Different for Women?

• RISK FACTORS
• - Diabetes hypertension have a stronger
  influence in women
• - High HDL levels more common in women
• - Roles of total cholesterol and LDL in women
  remain unclear
• - Risk increases after menopause

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The Bottom Line Whats Different for Women?

• PROGNOSIS
• - Women are more likely to die of a first MI
• - Overall case fatality rates 32 in women and
  27 in men (Framingham Data)
• - 30 day 1 year crude mortality rates are
  approximately double that in men
• - Women have more co-morbidity experience more
  long-term disability

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The Bottom Line Whats Different for Women?

• PRIMARY PREVENTION
• - Initial evidence for the benefit of lipid
  lowering medication in women exists but more
  evidence is required
• - Strong evidence to support adequate B/P
  control
• - Lifestyle, lifestyle, lifestyle

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The Bottom Line Whats Different for Women?

• SECONDARY PREVENTION
• - Women are less likely to undergo angioplasty
  or bypass surgery
• - Fewer women receive cardiac rehabilitation
• - Fewer women receive therapy with aspirin, beta
  blockers or ACE inhibitors

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Current Future Research
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Research Goals

• Since difficulties in diagnosing CAD in women on
  the basis of chest pain and noninvasive testing
  may contribute to the lower referral rates for
  catheterization and revascularization, it is
  important to improve symptom evaluation and
  diagnosis of ischemic heart disease in women

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• The Womens Ischemia Syndrome Evaluation (WISE)
  is ongoing and attempting to add to the limited
  information about the pathophysiology of ischemia
  without substantial epicardial coronary artery
  stenosis
• The Womens Health Initiative Study Group is
  looking at the strategies to prevent and control
  the most common causes of morbidity and mortality
  among postmenopausal women. It will continue to
  evaluate 3 interventions low-fat diet, HRT and
  calcium and vitamin D supplementation

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• The Beyond Endorsed Lipid Levels Evaluation Study
  (BELLES) is currently recruiting postmenopausal
  women and will compare the effects of 12 months
  of atorvastatin or pravastatin on regression of
  coronary atherosclerosis and will give us an
  idea if gender differences exist

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CONCLUSION

• Despite the abundant evidence that CAD is
  virtually epidemic in older women, the belief
  that women have innate protection from coronary
  events still prevails
• Even in the face of considerable morbidity
  mortality rates, prevention treatment
  strategies are still less aggressive for women
  than for men

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• Control of CAD risk factors in women will require
  recognition of the differences as well as the
  similarities between men and women in the
  manifestation of risk factors
• Initial data suggests that women can
  substantially benefit from lipid-lowering drug
  therapies if diet and exercise fail to lower LDL
  levels
• Statins have proved particularly effective in
  lowering womens CAD risks and mortality

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• Estrogen and HRTs to reduce risk have been
  popular in the past however in view of the recent
  HERS and WHI findings, it is not recommended for
  prevention of CVD
• On the basis of the HERS and ERA results, statin
  drugs should be the drug of first choice for
  women with established CAD
• The population of older women can be expected to
  increase in the coming decades and a growing
  health problem will ensue if clinical issues fail
  to be addressed

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• In the words of Professor Henry Higgins in
  My Fair Lady.
• WHY CANT A WOMAN BE MORE LIKE A MAN?
• WHY CANT A MAN BE MORE LIKE A WOMAN?

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THE END