Icgp_cdinwomen

Cardiovascular Disease In Women QUALITY IN PRACTICE COMMITTEE

AUTHORS Dr Naoimh Kenny Dr Ailís ní Ríain

Key to Levels of Evidence and Grades of Recommendations (1)

Levels of Evidence Ia Ib IIa IIb III IV

Evidence obtained from meta-analysis of randomised controlled trials Evidence obtained from at least one randomised controlled trial Evidence obtained from at least one well designed controlled study without randomisation Evidence obtained from at least one other type of well designed quasi-experimental study Evidence obtained from well designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies. Evidence obtained from expert committee reports or opinions and-or clinical experiences of respected authorities

Grades of Recommendations A

Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)

B

Requires the availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation. (Evidence levels IIa, IIb, III)

C

Requires evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)

Scottish Intercollegiate Guidelines Network 97 (www.sign.ac.uk).

Note on the use of the term ‘Cardiovascular Disease’: Throughout this document the term Cardiovascular Disease (CVD) implies ischaemic coronary heart disease and its sequelae. While diseases such as e.g. dysrhythmia and heart failure may be caused by ischaemic heart disease, and related morbidities such as stroke and peripheral arterial disease are closely related, these conditions are not the primary focus of this document. In dealing with non-ischaemic CVD practitioners should refer to other texts.

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Table of Contents I.

II.

Introduction 1.1

Background

1.2

Aims of the Document

1.3

Evidence-Based Medicine

Cardiovascular Risk Assessment 2.1

Identifying Target Population

2.2

Risk Factors

2.3 III.

IV.

2

•

Non-Modifiable

•

Modifiable

•

Other Factors

4

Establishing Total Cardiovascular Risk

Clinical Presentation of CVD in Women 3.1

Chest Pain in Women

3.2

Myocardial Infarction

3.3

Sudden Coronary Death

Investigations

9

10

4.1

Laboratory Investigations

4.2

Other Investigations

4.3

Resting 12-Lead ECG

4.4

Exercise Stress Testing (EST)

V.

Risk Modification

11

VI.

Appendices

14

Appendix 1 – SC RE chart – Risk Evaluation System in Primary Prevention Appendix 2 – European (2003) Guidelines on Blood Pressure Management Appendix 3 – European (2003) Guidelines on Lipid Management Appendix 4 – Patient Information Leaflets References

20

Acknowledgements

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I. Introduction 1.1

Background

Cardiovascular disease (CVD) is the leading cause of mortality in men and women on a global basis. CVD affects men and women equally but evidence suggests that it is neither diagnosed as readily, nor treated as effectively, in women. In Ireland between 2001 and 2005, an average of 2,484 women died each year from ischaemic heart disease (including myocardial infarction (MI)). (2) Yet, women seem largely unaware of their risk of developing cardiovascular disease, retaining the perception that CVD is predominantly a man’s disease. The pattern in which women suffer from CVD differs to that of men. Women delay in presenting for care of symptoms which they don’t attribute to CVD, and indeed are less likely to present for primary preventative care from their physician. This perception that women are not at risk of CVD may be fuelled by the healthcare profession: physicians are slower to commence preventative therapies, and less likely to investigate women for risk factors, diagnose acute cardiac conditions, refer for specialist opinion and provide acute care for conditions such as myocardial infarction, in women. (3,4) At age 40 years a woman has a 31.7% lifetime risk of developing coronary heart disease (compared with 48.6% station of CVD by about 10 years, but they are in a man). (5) Women ‘lag behind’ men with their first manife more likely than men to die after MI (6), coronary artery bypass graft and coronary angioplasty. Fewer women enrol in cardiac rehabilitation courses compared with men, and are more likely to drop out before completion. Heartwatch, a secondary prevention strategy/programme for CVD based in primary care settings in Ireland, clearly illustrates this – data has shown that for the first years of the programme only 24% of participants have been female. Much of the available data on patterns of CVD is taken from studies on men; in the past female subjects were actively excluded from randomised controlled trials and so assumptions about symptoms, for example, of heart disease in women, were basically made by extrapolating information on presentation of heart disease in men. There is evidence, however, that modes of presentation differ significantly in women compared with men. ‘Classic’ chest pain, for example, is not present in all women with angina pectoris. (7) Society and media campaigns may cause women to focus predominantly on wider-known, but less prevalent conditions, such as breast cancer. In 2005, 678 women died from breast cancer in Ireland, compared with men die each year from CVD than 2,225 from ischaemic heart disease. (2) Approximately twice as many wo from all cancers combined. The past three decades has seen a decline in age-adjusted mortality for ischaemic heart disease for both sexes in Ireland, but this decline has been relatively less for women than for men. Irish women have a high rate of ischaemic heart disease compared with their European counterparts – 90 per 100,000 women, compared to European (EU 15) average of 62.2 per 100,000. (8) It is likely that trends in the prevalence of, and death rates from, cardiovascular disease in Ireland will change as a result of the recent changes in the population’s ethnicity. Various ethnic groups now resident in Ireland are represented in significant numbers; these groups may have a native risk for CVD statistically different to that of the indigenous Irish population, and therefore GPs need to have heightened awareness of risk of CVD amongst these groups. Heart disease presents a public-health burden of equal magnitude in both sexes. There has been a decline in coronary deaths, which has left in its wake survivors, largely women and the elderly, with prevalent heart disease that are at risk of disability and recurrent events. The economical implications of these shifts are immense. Overall, the burden of disease remains high and could be further reduced by recognition and aggressive management of those at risk.

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I.2

Aims of the Document

This paper has been commissioned by the Women’s Health Council, and has been jointly funded by the Women’s Health Council and the Irish College of General Practitioners. The Women’s Health Council is a statutory body which was established in 1997 to advise the Minister for Health and Children on all aspects of women’s health. In addition to this document there is an accompanying one-page summary sheet for use in the surgery. This document aims to highlight the impact of CVD on women’s health on an individual and societal basis, and to illustrate the differences between CVD in women and men. After reading the document you will: • • •

assess the risk factors for CVD in women understand the gender differences in presentation, diagnosis and outcome accept the importance of treating women with CVD in primary care.

The document is comprised of four main sections focussing on clinical management. The first of these focuses on risk assessment – in particular identifying risk factors and outlining how total cardiovascular risk should be established. The subsequent sections relate to presentation of CVD in women and further management options including investigations and risk modification. Please note the qualifier on the use of the term ‘CVD’; see inside cover for detail. 1.3

Evidence-Based Medicine

Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. Throughout this document you will see levels of evidence (indicated by roman numerals, e.g. Ia), and grades of recommendation (indicated by alphabetical letter, e.g. A). (1) See Inside Cover for Table of Evidence and Recommendations.

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II. 2.1

Cardiovascular Risk Assessment Identifying Target Population

In practice it is important to identify women at risk of CVD. Patients generally fall into two categories: •

patients with established cardiovascular disease, who have a history of symptoms, signs or a cardiovascular event (secondary prevention)

•

asymptomatic patients at moderate or high risk for cardiovascular disease (primary prevention), because of: (a) multiple risk factors resulting in a 10-year risk of >5% now (or if extrapolated to age 60) for developing a fatal CVD event (b) markedly raised levels of single risk factors: -

cholesterol >8 mmol/l, LDL cholesterol >6 mmol/l, blood pressure >180/110 mmHg (9)

(c) diabetes type 2, or diabetes type 1 with microalbuminuria. (9) *

* if using SC

2.2

RE chart (9) (Level III)

Risk Factors

In practice it is thus essential to establish risk factors for each individual. This is achieved by careful historytaking, examination and some minimal investigations. Risk factors for CVD can be classified as non-modifiable, and modifiable.

Non-modifiable • • • • •

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Age Menopausal status Family history Socio-economic status Race

Modifiable • • • • • •

Cigarette smoking Hypertension Lipid abnormalities Diabetes mellitus Obesity Sedentary lifestyle

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Non-modifiable Risk Factors

•

Age Risk increases with age in both men and women. The natural distribution of risk factors, particularly in women, changes dramatically after age 50. (10)

•

Menopausal The single most specific risk factor for women is hormonal status, with the incidence rising sharply after the menopause. (11)

•

Family History There is a suggestion that a positive family history of CVD is a stronger risk factor for women than it is for men (12) (Level IV). Parental history of MI < 60 years is a particularly strong risk factor for women (13) (Level IIa).

•

Socio-economic Factors Low socio-economic status significantly increases risk of CVD and is often associated with the presence of more risk factors, e.g. higher BMI, cigarette smoking, and elevated LDL cholesterol (14) (Level III).

•

Race Certain ethnic groups are at increased risk of CVD e.g. women of central Asian extraction, African-American women.

Modifiable Risk Factors

•

Cigarette smoking Smoking is the major cause of CVD in young and middle-aged women, accounting for up to half of all coronary deaths. There is a dose-response effect associated with smoking in women. A woman who smokes less than five cigarettes per day is twice the risk of an acute MI as a non-smoker, while that risk is 11 times higher for a woman who smokes more than 45 cigarettes a day (15) (Level Ib). Women who smoke have their first MI 19 years earlier than women who do not smoke (16) (Level IV). More than 60% of myocardial infarctions in women younger than 50 years are attributable to smoking. Smoking also has detrimental effects in women as it lowers HDL cholesterol and oestrogen levels, increases serum fibrinogen levels, and causes earlier onset of menopause (17) (Level IV). The overall prevalence of cigarette smoking in Ireland is 24.7%. (2006 Office of Tobacco Control www.otc.ie) There is an almost even split between male and female smokers. Female smoking prevalence rates have increased in past 12 months, whereas male smoking prevalence rates have remained constant.

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•

Hypertension Hypertension is an independent risk factor for CVD in both women and men, and risk increases continuously as blood pressure rises from levels which are within normal range. For every 20 mmHg systolic or 10 mmHg diastolic increase in BP there is a doubling of CVD mortality. Isolated systolic hypertension (with its higher incidence in older women) is at least as powerful a risk factor as hypertension (12) (Level IV). Additionally, hypertension is an important marker for patients with a highrisk profile (12). Reducing blood pressure with medication decreases cardiovascular morbidity and mortality in women to the same extent as it does in men (18) (Level Ia).

•

Hyperlipidaemia Lipid abnormalities are important predictors of CVD risk in women. In women, low-density lipoprotein (LDL) cholesterol and total cholesterol levels peak between 55 and 65 years – about a decade later than men. Women below the age of 65 years with lipid abnormalities have increased risk of CVD, as compared with men and women older than 65 years (19) (Level III). Elevated triglyceride levels are more common in women and are also a potent independent risk factor for CVD in women (20) (Level Ia). Lowering cholesterol levels in women appears to have similar beneficial effects as in men, but data is limited in women particularly in primary prevention (21) (Level Ia). This is especially relevant from the sixth decade onward for women.

•

Diabetes Mellitus Diabetes mellitus and hyperglycaemia are more potent risk factors for CVD in women than in men and negate the gender differential in age of onset (22) (Level III). Patients with type 1 diabetes have increased risk of developing CVD over non-diabetics, but in women the risk is 3-7 times higher compared with a 2-3 fold risk in men (23) (Level III). The prevalence of type 2 diabetes is increasing in both men and women. All patients with type 2 diabetes, regardless of renal status, are at increased risk of CVD. Mortality from MI is significantly higher in diabetic women than in non-diabetic women or men with or without diabetes (23) (Level III).

• Obesity There is a direct positive association between obesity and the risk of CVD in women (17). Those with BMI > 29 are three times more likely to develop CVD than lean individuals (17) (Level IV). Truncal obesity confers a higher risk than peripheral body fat distribution (24) (Level IIa). Increased waist-hip ratio and waist circumference are highly correlated to the risk of CVD, with waist measurements > 88cm in women bearing significance. Metabolic risk factors tend to cluster in obese patients: -

insulin resistance glucose intolerance low high-density lipoprotein (HDL) small LDL particles high triglycerides hypertension.

This represents the metabolic syndrome and it is more prevalent in women with CVD than in men (25) (Level IIa).

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•

Sedentary Lifestyle Physically active women have a significant reduction in CVD risk as compared with sedentary women (26) (Level Ib). Physical activity helps to combat obesity, reduces blood pressure and risk of type 2 diabetes, and confers extra protection against CVD, which is not explained by reduction in BMI alone. The risk of MI has been shown to reduce by half for women if they were to walk for 30-45 minutes, three times weekly (27) (Level Ib).

Other Factors The following are topical and relevant factors pertaining to estimation of cardiovascular risk in both women and men. Although GPs may chart a patient’s readings as part of risk calculation, at the present time there is insufficient evidence to categorically recommend implementing treatment based on these factors, whilst aiming for reduction in cardiovascular disease. Further research in these areas may provide practitioners with better evidence-based information regarding each of these topics.

• Homocysteine Elevated serum homocysteine levels appear to increase coronary risk both for women and men. It is a modest independent predictor of CVD in healthy populations, but there is insufficient evidence in women regarding effects of treatment to advocate actively lowering homocysteine levels (28) (Level IV).

• C-Reactive Protein C-reactive protein (hs-CRP) is measured using a sensitive laboratory assay on serum CRP, and increased levels in women are associated with greater risk of cardiovascular events (29) (Level III). Although it is a sensitive indicator, it is a non-specific one, and results of interventions to reduce CRP levels in women are not known. Furthermore, screening of hs-CRP levels is not currently available at many hospital-based laboratories in Ireland.

• Estimated GFR There is good evidence that kidney disease (not yet kidney failure) is strongly associated with CVD and is increasingly thought to be a risk factor for it. Decreased renal function (even before microalbuminuria) can be detected using estimated glomerular filtration rate (eGFR) based on serum creatinine, age, sex and race. Calculation of eGFR is complex; however, online calculators facilitate estimation once the patient’s serum creatinine is known. http://www.renal.org/eGFR/eguide.html. (30) Normal GFR is approximately 100 ml / min / 1.73m2, and lower readings may indicate early stages of chronic kidney disease, conferring a greater risk of CVD. As well as usual measures in prevention, these individuals require tighter blood pressure control. (30)

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2.3

Establishing Total Cardiovascular Risk

In asymptomatic, apparently healthy subjects, whose risk factor profile has been established – preventive actions (primary prevention) should be guided in accordance with the total CVD risk. This risk is best established using risk charts. Currently in Ireland there are two such charts in common use in primary care.

(1) 10-year risk CVD Event Chart (31) From the 2nd Joint Task Force of European and Other Societies on coronary prevention. Features: • • • • • • • •

(2) SC

published in 1998 based on the original Framingham (US) model cites 10-year risk of a CVD event cites 20% or more as high risk has separate risk charts for both genders, smokers and non-smokers has a separate risk chart for use in diabetics utilised by ‘Heartwatch’ programme is available to download from the ICGP website

RE (Systematic Coronary Risk Evaluation) system (9)

From the 3rd Joint Task Force of European and Other Societies on coronary prevention. Features: • • • • • • • •

published in 2003 emphasis on European populations two categories available: high-risk and low-risk European nations cites 10-year risk of fatal CVD cites 5% or more as high risk has separate risk charts for both genders, smokers and non-smokers has separate risk charts for total cholesterol, and Tchol:HDL ratio NO separate risk chart for diabetes*

*For individuals with diabetes (types I and II) every risk factor combination the risk will be at least twice as high in men, and up to four times higher in women compared with that given by the charts.

Both risk estimation systems are valid. For the purposes of this document the SC to. http://www.escardio.org/NR/rdonlyres/E5DD427D-50E2-4F1F-B287C9F24242C29A/0/guidelines_SCORE_FT_2003.pdf

See Appendix 1 for copy of chart and instructions for use. (9)

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RE system will be referred

III. Clinical Presentation of CVD in Women 3.1

Chest Pain in Women

Angina pectoris is the most common initial and subsequent presenting symptom of CVD in women (32) (Level Ib). It is more likely in women to be ‘uncomplicated’, as compared with men – when it is more likely to be a symptom of evolving MI. Classic situations that provoke angina are exertion, emotional stress, cold, sexual activity, and after a meal. It is more common in the first hours after wakening. Symptoms arising from myocardial ischaemia in women may be difficult to diagnose because they may present ‘atypically’ (the ‘typical’ symptoms having been classically taken from studies on men), with the following: • • • •

shoulder, neck or abdominal pain nausea fatigue dyspnoea

and as such, women are more likely to delay seeking medical care when their symptoms do not match their expectations. Women also have a higher prevalence of vasospastic angina and microvascular angina, both of which are associated with atypical chest patterns (33) (Level III). 3.2

Myocardial Infarction

Women tend to have their MIs at older ages than men, with a higher case fatality rate. (34) In these, older, women, advancing age and accumulation of risk factors and co-morbidities may have contributed to their increased morbidity and mortality. Studies suggest that large numbers of women with atypical MI patterns (unstable angina or non-ST-elevation MI) do not have significant large vessel CVD, suggesting differing pathology (e.g. microvascular endothelial dysfunction). (35) Younger women (< 50 yrs) have much higher mortality rates in hospital after an MI, than men. As presenting symptoms of MI in women are different to those in men, more women than men are incorrectly diagnosed at presentation. (6) ‘Non-chest’ symptoms are common in women with MI: • • • 3.3

women < 65 years more likely to present with unstable angina, less likely to have ST-elevation MI women and men >65 years tend to have similar presentation patterns women >65 years are more likely to have heart failure at presentation, as compared with men. Sudden Coronary Death

Sixty-three percent of women who die from CVD present with sudden death (36) (Level IV). Certain risk factors have been shown to predict the risk of sudden cardiac death in women (34) (Level IIa). • •

In younger women who die suddenly due to CVD, smoking is the predominant risk factor. In older women, the dominant risk factor for sudden death is elevated cholesterol (35) (Level III).

Patients presenting with any of the following symptoms or signs require referral to specialist care: • • • •

chest pain syndromes – pressure, vasospastic, nocturnal pain, either stable or unstable dyspnoea accelerated (malignant) hypertension (BP more than 180/110 mmHg with signs of papilloedema and/or retinal haemorrhage) (37) suspected phaeochromocytoma (possible signs include labile or postural hypotension, headache, palpitations, pallor and diaphoresis). (37) (Grade A)

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IV. Investigations 4.1

Laboratory Investigations

For both female and male patients, along with usual laboratory investigations (fasting lipids and blood glucose, U/E, LFT, urinalysis) add in as required: • • •

FBC, TFT if clinical indicators (e.g. hyperlipidaemia) Glucose tolerance test, HBA1c if dictated and/or known hyperglycaemic state Urinary microalbumin if known diabetes.

In women owing to higher prevalence of metabolic syndrome: • 4.2 • • • 4.3

Sex hormones, serum cortisol (if clinical suspicion).

Other Investigations (both genders) BP measurement. BMI calculation. Abdominal girth, hip measurements.

Resting 12-lead ECG

Although widely used as a diagnostic tool, ECG testing in generally considered less accurate in women than in men (Level III); diagnostic criteria were established in predominantly male studies. Individuals with abnormal ECG, or non-diagnostic ECG with symptoms, require referral for specialist opinion. (Grade B) 4.4

Exercise Stress Testing (EST)

EST has been traditionally used in both men and women to elucidate myocardial ischaemia. However it may be less accurate in women (38). (Level III) • •

In younger women with a low likelihood of CVD, EST provides higher false-positive results. On the other hand, single-vessel coronary heart disease, which is more common in women than in men, may not be identified by routine EST.

Because of the high false positive rate, women with atypical angina and a positive EST are likely to have other tests such as: • •

echocardiography nuclear imaging

before progressing to more invasive diagnostic procedures (e.g. coronary angiography). Therefore, in the absence of angina, direct referral for EST is not recommended for women with non-specific chest symptoms as results may be misleading (Grade C). In women who have angina or unexplained symptoms consider referral for specialist opinion (Grade C).

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V. Risk Modification 5.1

Smoking Cessation

Smoking cessation can considerably reduce the risk of CVD in both sexes, and is known to provide protection in both primary and secondary prevention. After 2-3 years of abstinence the level or risk in ex-smokers is similar to those who have never smoked, regardless of the amount or duration of cigarettes smoked or the age at cessation (39). Women smoke for different reasons than men, citing stress, anger, boredom or depression as factors. They are also more likely to use smoking as a weight-control tool, and cite weight-gain as the reason for relapse after quitting. Women may benefit from pharmacotherapy more than men do (40), and studies suggest that the combination of pharmacological therapy plus counselling/support group works best for smoking cessation in women. Consideration of factors unique to women may help physicians to be more successful in treating female smokers (40). Studies involving use of brief intervention techniques to encourage smoking cessation show similar success rates for men and women (41) (Level Ia). Thus smoking cessation approaches should be recommended to both (Grade A). All women should be encouraged to quit smoking. Strategies that may help can be summarized into the following 5 A’s:

A – ask: A – assess: A – advise: A – assist: A – arrange:

systematically identify all smokers at every opportunity determine the patient’s degree of addiction and her readiness to cease smoking urge strongly all smokers to quit agree on a smoking cessation strategy including behavioural counselling, nicotine replacement therapy and/or pharmacological intervention a schedule of follow-up visits (Grade A)

NICE guideline PH1001 Smoking cessation: Quick Reference Guide. (42) (http://guidance.nice.org.uk/PHI1/quickrefguide/pdf/English/download.dspx) 5.2

Hypertension

Reduction of blood pressure provides protection against CVD in primary prevention, and is known also to prevent further morbidity and mortality in secondary prevention, even if the BP readings are ‘normal’. The decision to commence treatment (primary prevention) in hypertensive patients without established CVD depends on the level of BP and on assessment of total cardiovascular risk and presence or absence of target organ damage (Level Ia). In secondary prevention the choice of drug used is influenced by underlying disease. Antihypertensive drugs should not only lower blood pressure effectively. They should have a favourable safety profile and be able to reduce cardiovascular morbidity and mortality. (38) Five classes of drugs are widely in use for treatment of women and men: • • • • •

thiazide-type diuretics beta-blockers ACE inhibitors calcium-channel blockers angiotensin II antagonists.

Recommendations for use of drug category in treating hypertension are outlined in NICE guideline (http://guidance.nice.org.uk/CG34/niceguidance/pdf/English/download.dspx). (37) These guidelines do not make a gender distinction. Currently there is no evidence to suggest benefit in use of one class of drug over another, in women as compared with men. (37) However certain classes of antihypertensive medications are not acceptable for use in pregnancy. (Level Ia) See Appendix 2 for flow-chart in initiating therapy. (Grade A).

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5.3

Hyperlipidaemia

Use of cholesterol-lowering medications decreases the incidence of major coronary events in both men and women (Level Ia). However, their usefulness in primary prevention in women is unknown owing to limited data: women were traditionally either excluded from trials, or included in small numbers. Thus the use of statins in women for primary prevention is controversial: the practice of prescribing statins for women in this way is founded on extrapolation of results in men (Level IV). There is sufficient good evidence to support the use of statins in women for secondary prevention. (Level Ia). Lowering cholesterol after MI reduces major coronary events by a third in women and this benefit is maintained at older ages. This is further borne out by another study which showed that lowering cholesterol after MI in patients with average cholesterol levels reduced death or subsequent MI by 46% in women. (Grade A). See Appendix 3 for recommendations on lipid lowering in women.

5.4

Exercise and Weight Management

Exercise is useful for both primary and secondary prevention of CVD in women. Physical activity may reduce body mass, and with maintained weight loss there are improvements in blood pressure, lipid profile, and glucose handling. Physical activity also acts as a separate protective factor against CVD, with all studies demonstrating an inverse relationship between physical activity and cardiovascular event. Specifically exercise should be prescribed for women with: • •

BMI > 30 or BMI > 25 with co-morbidities (e.g. hypertension).

Exercise regimes can be prescribed in primary care. Management must be tailored to each individual. All adults should accumulate 30 minutes or more of moderate-intensity physical activity (equivalent to walking briskly at 3-4 miles per hour) on most days of the week (43) (Grade C).

5.5

Diabetes

Aggressive achievement and maintenance of good blood glucose control is paramount for reduction of future cardiovascular events. A diagnosis of diabetes is considered by many to place the individual in a higher risk category for cardiovascular disease than their non-diabetic physiological peers, and thus treatment of the glycaemic state is considered to be secondary prevention. All individuals with impaired glycaemic control should be treated to optimise control. (Grade A).

5.6

Aspirin

There is good evidence for the use of aspirin in secondary prevention in women – it reduces subsequent MI, stroke, and death from CVD by 25% in women with established disease. (44) (Grade A). In healthy women (primary prevention) there is no evidence that aspirin significantly protects women against CVD (although it does provide some protection against stroke). (45,46) (Grade A) Aspirin has been shown to have benefit in women and men with evolving MI. (34) (Grade A)

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5.7

Thrombolytic Therapies

Thrombolysis is associated with a statistically significant reduction in mortality in both women and men. (Grade A). (47)

5.8

Nitrates

There is good evidence that nitrates do not reduce the risk of CVD events in women with known CVD. (Level Ia, Grade A). Neither do nitrates lower mortality rates in women or men with acute MI.

5.9

HRT

There is good evidence that HRT regimens do not confer protection against MI or CVD (i.e. for primary prevention). In fact, treatment may actually increase the risk of CVD during the first year of use. (48) (Level Ib) Studies involving HRT for secondary prevention of heart disease have similar conclusions. Post-menopausal women with established coronary disease had more CVD events on HRT within the first year of treatment, but then comparatively fewer events in years 4 and 5 (Level Ib). These results occurred despite a reduction in LDL levels by 11%, and increase in HDL by 10%. Thus at the present time HRT is not recommended for either primary or secondary prevention of CVD in women. (Grade A) It may be appropriate, however, for women already receiving this treatment to continue it if clinically indicated (49) (Level II). If HRT is clinically indicated for other reasons (e.g. relief of vasomotor symptoms, bone mineral density protection), one should discuss perceived risks of use against perceived benefit with the woman, and facilitate her informed choice in the matter. (Grade C).

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VI.

Appendices

Appendix 1: SC

RE Chart – Risk Evaluation System in Primary Prevention (9)

Instructions: • • • •

To estimate a person’s total ten-year risk of CVD death, find the table for their gender, smoking status and age. Within the table find the cell nearest to the person’s systolic blood pressure (mmHg) and total cholesterol (mmol/l) The effect of lifetime exposure to risk factors can be seen by following the table upwards. This can be used when advising younger people. Low risk individuals should be offered advice to maintain their low risk status. Those who are at 5% risk or higher or will reach this level in middle age should be given maximal attention. To define a person’s relative risk, compare their risk category with that of a non-smoking person of the same age and gender, blood pressure <140/90mmHg and total cholesterol < 5mmol/l.

Qualifiers: Note that the use of the chart is for risk estimation purposes in asymptomatic individuals only. Note that total CVD risk may be higher than indicated in the chart: • • • • • •

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as the person approaches the next age category in asymptomatic subjects with pre-clinical evidence of atherosclerosis (e.g. CT scan, ultrasonography) in subjects with a strong family history of premature CVD in subjects with low HDL cholesterol levels, with raised triglyceride levels, with impaired glucose tolerance, and with raised levels of C-reactive protein, fibrinogen, homocysteine, apolipoprotein B or Lp(a) in obese and sedentary subjects. In individuals with established diabetes (the risk estimated to be double for men, and 4x higher for women).

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Appendix 2: European (2003) Guidelines on Blood Pressure Management (9) • • • • • •

Initiate drug therapy promptly in those with sustained systolic blood pressure (SBP) > 180 mmHg and/or a diastolic blood pressure (DBP) > 110 mmHg regardless of total risk. Those with high risk of developing CVD with sustained SBP of >140 mmHg and/or DBP >90 mmHg also require drug therapy. Lower BP to < 140/90 mmHg. Most individuals don’t need drug therapy if SBP < 140 mmHg and/or DBP < 90 mmHg. Those with a high or very high CVD risk profile and those with diabetes can benefit from reducing BP below the goal of 140/90 mmHg. Choose agents which carry a favourable safety profile, lower blood pressure effectively, and reduce cardiovascular morbidity and mortality. Certain classes of agents, most notably ACE inhibitors and angiotensin II antagonists, are contraindicated in pregnancy and lactation; consideration of this factor must be borne in mind when treating a woman of child-bearing potential.

Further information regarding initiating drug treatment from different categories is available at NICE clinical guidelines (http://guidance.nice.org.uk/CG34/niceguidance/pdf/English/download.dspx) Hypertension: management of hypertension in adults in primary care. (37)

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Appendix 3 – European (2003) Guidelines on Lipid Management (9)

• • • •

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diet and exercise should be the cornerstone of serum lipid management (Grade C) if after 3-6 months, there is failure to reduce either/both total cholesterol to <5mmol/l, and LDL < 3mmol/l then drug therapy should be considered. for patients with clinically established CVD and/or diabetes the treatment goals should be lower: total cholesterol < 4.5mmol/l and LDL cholesterol < 2.5 mmol/l. no specific treatment goals are given for HDL and TG but they are markers of increased CVD risk. (ie HDL < 1.2 mmol/l, and fasting TG > 1.7 mmol/l mark increased risk) (Grade B)

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Appendix 4 – Patient Information Leaflets Listed are some examples of patient information leaflets which are accessible at the online addresses provided. They may be utilised according to the needs of your patient.

Heart Disease and Heart Attacks: What Women Need to Know. Family Doctor (USA) 2006 (50) http://familydoctor.org/online/famdocen/home/common/heartdisease/risk/287.html Coronary Heart Disease. Prodigy, NHS. 2007 (51) http://www.cks.library.nhs.uk/patient_information_leaflet/Coronary_heart_disease

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References (1) Scottish Intercollegiate Guideline Network. Risk estimation and the prevention of cardiovascular disease: a national clinical guideline. 2007; Available at: http://www.sign.ac.uk/pdf/sign97.pdf. Accessed May 8, 2007. (2) Central Statistics Office Ireland. Central Statistics Office Website. 2007; Available at: http://www.cso.ie/. Accessed May 8, 2007. (3) O'Donnell S, Condell S, Begley C, Fitzgerald T. Prehospital care pathway delay: gender and myocardial infarction. Journal of Advanced Nursing 2006;53(3):268-276. (4) Hippisley-Cox J, Pringle M, Crown N, Meal A, Wynn A. Sex inequalities in ischaemic heart disease in general practice: cross sectional survey. BMJ 2001 Apr 7;322(7290):832. (5) Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet 1999 Jan 9;353(9147):89-92. (6) Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N.Engl.J.Med. 1999 Jul 22;341(4):217-225. (7) The Women's Health Council. Women and cardiovascular health: a position paper of The Women's Health Council. 2003; Available at: http://www.whc.ie/publications/31658_WHC_Cardiovascular.pdf. Accessed May 8, 2007. (8) Eurostat. Eurostat yearbook 2003: the statistical guide to Europe. 2003. (9) De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur.Heart J. 2003 Sep;24(17):16011610. (10) Ulmer H, Kelleher C, Diem G, Concin H. Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J.Womens Health.(Larchmt) 2004 Jan-Feb;13(1):41-53. (11) Critchley H, Gebie A, Beral V. Metabolic effects of the menopause and hormone replacement therapy. In: Critchley H, Gebie A, Beral V, editors. Menopause and Hormone Replacement London: RCOG Press; 2004. p. 15-22. (12) Roeters van Lennep JE, Westerveld HT, Erkelens DW, van der Wall EE. Risk factors for coronary heart disease: implications of gender. Cardiovasc.Res. 2002 Feb 15;53(3):538-549. (13) Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007 Feb 14;297(6):611619. (14) Winkleby MA, Kraemer HC, Ahn DK, Varady AN. Ethnic and socioeconomic differences in cardiovascular disease risk factors: findings for women from the Third National Health and Nutrition Examination Survey, 19881994. JAMA 1998 Jul 22-29;280(4):356-362. (15) Willett WC, Green A, Stampfer MJ, Speizer FE, Colditz GA, Rosner B, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N.Engl.J.Med. 1987 Nov 19;317(21):1303-1309. (16) Hansen EF, Andersen LT, Von Eyben FE. Cigarette smoking and age at first acute myocardial infarction, and influence of gender and extent of smoking. Am.J.Cardiol. 1993 Jun 15;71(16):1439-1442. (17) Ulstad V. Coronary heart disease. In: Rosenfeld J, editor. Handbook of Women's Health: an evidencebased approach Cambridge: Cambridge University Press; 2001. p. 483-507. (18) Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann.Intern.Med. 1997 May 15;126(10):761-767.

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(19) Manolio TA, Pearson TA, Wenger NK, Barrett-Connor E, Payne GH, Harlan WR. Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. Ann.Epidemiol. 1992 Jan-Mar;2(1-2):161176. (20) Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J.Cardiovasc.Risk 1996 Apr;3(2):213-219. (21) Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004 May 12;291(18):22432252. (22) Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 1991 Feb 6;265(5):627-631. (23) Goldschmid MG, Barrett-Connor E, Edelstein SL, Wingard DL, Cohn BA, Herman WH. Dyslipidemia and ischemic heart disease mortality among men and women with diabetes. Circulation 1994 Mar;89(3):991-997. (24) Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, et al. Abdominal adiposity and coronary heart disease in women. JAMA 1998 Dec 2;280(21):1843-1848. (25) Grundy SM, Cleeman JI, Merz CN, Brewer HB,Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004 Jul 13;110(2):227-239. (26) Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA. Physical activity and mortality in postmenopausal women. JAMA 1997 Apr 23-30;277(16):1287-1292. (27) Colditz GA, Coakley E. Weight, weight gain, activity, and major illnesses: the Nurses' Health Study. Int.J.Sports Med. 1997 Jul;18 Suppl 3:S162-70. (28) Wenger NK. Coronary heart disease: the female heart is vulnerable. Prog.Cardiovasc.Dis. 2003 NovDec;46(3):199-229. (29) Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N.Engl.J.Med. 2000 Mar 23;342(12):836-843. (30) Turner N, Blades S, Iskander D. The short CKD eGuide, derived from the UK CKD Guidelines (2005). 2007; Available at: http://www.renal.org/eGFR/eguide.html. Accessed May 8, 2007. (31) Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur.Heart J. 2003 Jun;24(11):987-1003. (32) Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am.Heart J. 1986 Feb;111(2):383-390. (33) Sullivan AK, Holdright DR, Wright CA, Sparrow JL, Cunningham D, Fox KM. Chest pain in women: clinical, investigative, and prognostic features. BMJ 1994 Apr 2;308(6933):883-886. (34) Albert CM, Chae CU, Grodstein F, Rose LM, Rexrode KM, Ruskin JN, et al. Prospective study of sudden cardiac death among women in the United States. Circulation 2003 Apr 29;107(16):2096-2101. (35) Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998 Jun 2;97(21):2110-2116. (36) American Heart Association. 2002 Heart and Stroke Statistical Update. 2001; Available at: http://www.womenheart.org/pdf/2002_heart_disease_stats.pdf. Accessed May 8, 2007. (37) National Institute for Clinical Excellence. Hypertension: management of hypertension in adults in primary care. 2006; Available at: http://guidance.nice.org.uk/CG34/niceguidance/pdf/English/download.dspx. Accessed May 8, 2007. (38) Stramba-Badiale M, Fox KM, Priori SG, Collins P, Daly C, Graham I, et al. Cardiovascular diseases in women: a statement from the policy conference of the European Society of Cardiology. Eur.Heart J. 2006 Apr;27(8):994-1005. (39) Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Rosner B, et al. Smoking cessation in relation to total mortality rates in women. A prospective cohort study. Ann.Intern.Med. 1993 Nov 15;119(10):992-1000.

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(40) Bedinghaus J, Leshan L, Diehr S. Coronary artery disease prevention: what's different for women? Am.Fam.Physician 2001 Apr 1;63(7):1393-400, 1405-6. (41) Jarvis M. Patterns and predictors of smoking cessation in the general population. In: Bolliger C, Fagerstrom K, editors. The tobacco epidemic. Basel: Karger; 1997. p. 151-164. (42) National Institute for Clinical Excellence. Quick Reference Guide: Brief interventions and referral for smoking cessation in primary care and other settings. 2006; Available at: http://guidance.nice.org.uk/PHI1/quickrefguide/pdf/English/download.dspx. Accessed May 8, 2007. (43) Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995 Feb 1;273(5):402-407. (44) Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994 Jan 8;308(6921):81-106. (45) Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N.Engl.J.Med. 2005 Mar 31;352(13):1293-1304. (46) Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006 Jan 18;295(3):306-313. (47) Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988 Aug 13;2(8607):349-360. (48) Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of coronary heart disease. N.Engl.J.Med. 2003 Aug 7;349(6):523-534. (49) Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998 Aug 19;280(7):605-613. (50) Family Doctor (USA). Heart disease and heart attacks: what women need to know. 2006; Available at: http://familydoctor.org/online/famdocen/home/common/heartdisease/risk/287.html. Accessed May 10 2007. (51) Prodigy, NHS. Coronary Heart Disease. 2007; Available at: http://www.cks.library.nhs.uk/patient_information_leaflet/Coronary_heart_disease. Accessed May 10 2007.

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Acknowledgments The authors acknowledge Ms. Aoife O’Brien and Dr. Sarah Callanan, of the Women’s Health Council, for their assistance and support with the production of this document. At the ICGP, thanks are due to Dr. Margaret O’Riordan and the Quality in Practice committee for their helpful guidance, and to Ms. Gillian Doran and Ms Patricia Patton for their assistance with references. Particular thanks are due to Ms. Yvette Dalton for her work on the formatting, editing and production of the document.

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