CARDIOVASCULAR DISEASE & WOMEN: A Review of The Evidence

Presented By: Dr. Laurie-Ann Baker, MD, CCFP EM Resident University of Calgary

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

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

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

Percentage of total deaths due to CVD by age & sex (Canada 1997)

Risk Factors For Coronary Artery Disease in Women

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

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

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

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 >65 years Low HDL levels is a stronger predictor of CAD mortality in women than in men particularly after age 65

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

Further, in another study of 2500 women aged 71 years or older, those with HDL levels <0.9 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

* 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

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

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

Women with hypertension outnumber men with hypertension in the older age groups (due to survival advantage) Estimated prevalence (BP >140/90 or use of anti-hypertensive) in women older than 45 years is 60% (US statistic)

Smoking

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

The risk in heavy smokers ( > 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)

The prevalence of smoking in recent years has dropped in both men and women however women’s 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

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

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

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

Obesity & Physical Activity

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

Obesity in Canada

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)

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)

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

The Diagnosis of CAD in Women

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

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

Estimating the Risk Estimating the likelihood of CAD by assessment of the patient’s 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

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

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

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

Classification of Chest Pain (Typical Angina) FEATURES: - Substernal - Squeezing, burning, heavy - Exertional or precipitated by emotion - Promptly relieved by rest or nitroglycerin CLASSIFICATION: % prevalence of angiographically significant CAD

Classification of Chest Pain (Atypical Angina) FEATURES: - Left chest, abdominal, back, arm, without mid-chest pain - Sharp or fleeting - Unrelated to exercise - Relieved by antacids CLASSIFICATION: % prevalence of angiographically significant CAD

Determinants of the Likelihood of CAD in Women MAJOR - Post menopausal status / age >65 years - Diabetes - Peripheral Vascular Disease

Determinants of the Likelihood of CAD in Women INTERMEDIATE - Hypertension - Smoking - Lipid abnormalities

Determinants of the Likelihood of CAD in Women MINOR - Obesity - Sedentary lifestyle - Family history of CAD - Other risks factors of CAD

Classification According To Their Probability of CAD

HIGH PROBABILITY OF CAD (>80%) * Typical angina and any of: - Post-menopausal status or age >65 - Diabetes - Peripheral Vascular Disease - Two intermediate determinants

HIGH PROBABILITY OF CAD (>80%) * Atypical angina and any of: - Post-menopausal or age >65 and >1 intermediate determinant - Diabetes plus >1 intermediate or minor determinants - Three intermediate or 2 intermediate plus 1 minor determinants

INTERMEDIATE PROBABILITY (20 – 80%) Typical Angina and 1 intermediate or >2 minor determinants Atypical Angina and post-menopausal / age >65 Nonischemic Pain and post-menopausal / age >65 or diabetes and >2 intermediate and/or minor determinants

LOW PROBABILITY (<20%) Typical Angina and premenopausal with no determinants Atypical Angina and no major determinants Nonischemic pain and no major determinants

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

Diagnostic Evaluation LOW PROBABILITY: - no stress test; likelihood of false-positive test results are greater than the likelihood of a true-positive test

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

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

HRT: What Now??

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

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

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

A second large randomized trial of HRT, the ERA study, also observed no benefit of HRT with the use of quantitative coronary angiography The Women’s 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

The Women’s 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

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

“Men Are From Mars & Women Are From Venus” So …………..

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

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

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 MI’s is approximately 43% Recent surveys of cardiac rehabilitation programs continue to under-represent women impacting secondary prevention / risk factor modification management

The Bottom Line: What’s 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

The Bottom Line: What’s 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

The Bottom Line: What’s 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

The Bottom Line: What’s 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

The Bottom Line: What’s 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

Current & Future Research

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

The Women’s 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 Women’s 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

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

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

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 women’s CAD risks and mortality

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

In the words of Professor Henry Higgins in My Fair Lady…. “WHY CAN’T A WOMAN BE MORE LIKE A MAN?” WHY CAN’T A MAN BE MORE LIKE A WOMAN?

THE END