Key Points
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Cardiovascular disease is the leading cause of death among women in the United States.
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Women receive fewer preventive recommendations, such as lipid-lowering therapy, aspirin, and lifestyle advice, than do men with similar Framingham risk scores.
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The Framingham risk score and the Reynolds score can be used to estimate CVD risk in women.
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Dyslipidemia treatment recommendations are similar between women and men. Clinical trials demonstrate the efficacy and safety of statin dyslipidemia therapy, including more intensive treatments, for protection against major cardiovascular events in women.
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Blood pressure and diabetes treatment recommendations do not differ between women and men. Impaired glucose tolerance during pregnancy is a risk factor for future CVD in women.
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The use of aspirin for women aged 55 to 79 years is recommended when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage.
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Women should accumulate a minimum of 30 minutes of moderate-intensity physical activity (e.g., brisk walking) daily.
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Women should consume a diet rich in fruits and vegetables, whole-grain high-fiber foods, and fish at least twice a week, with limited intake of saturated fat (<7% to 10%) and cholesterol (<300 mg/day); alcohol intake should be limited to no more than one drink per day; sodium intake should be limited to <2.3 g/day; and consumption of trans –fatty acids should be as low as possible.
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Hormone therapy used for contraception, management of menopause symptoms, or other clinically indicated conditions should not be used for CVD prevention.
This work was supported by contracts from the National Heart, Lung, and Blood Institute, N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, R01 HL090957-01A1, R03 AG032631-01; a GCRC grant MO1-RR00425 from the National Center for Research Resources; and grants from the Gustavus and Louise Pfeiffer Research Foundation (Danville, NJ), the Women’s Guild of Cedars-Sinai Medical Center (Los Angeles, Calif), the Edythe L. Broad Women’s Heart Research Fellowship, Cedars-Sinai Medical Center (Los Angeles, Calif), and the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center (Los Angeles, Calif).
Cardiovascular disease (CVD), the leading cause of death among women regardless of race or ethnicity, accounts for more than 500,000 deaths in the United States each year. This amounts to more deaths from CVD than from lung cancer, chronic obstructive lung disease, and breast cancer combined. In many countries including the United States, more women than men die of CVD every year, a fact largely unknown by physicians and lay public. Typically, women cite cancer, specifically breast cancer, as a major threat to their health. Nevertheless, the annual mortality of women from CVD is twice that for all cancers combined, and almost one in two women will die of CVD compared with one in 30 of breast cancer. Paradoxical sex differences are observed in which women have less anatomically obstructive coronary artery disease (CAD) and relatively preserved left ventricular function yet higher rates of myocardial ischemia and mortality compared with similarly aged men. Accordingly, the term ischemic heart disease (IHD) is more appropriate for a discussion specific to women, rather than CAD or coronary heart disease (CHD). Data from the National Heart, Lung, and Blood Institute (NHLBI)–sponsored Women’s Ischemia Syndrome Evaluation (WISE) and related studies implicate adverse coronary reactivity, microvascular dysfunction, and plaque erosion or distal microembolization as contributory to female-specific IHD pathophysiology. Thus, knowledge beyond an anatomic description of obstructive CAD may provide important clues to IHD risk detection and treatment for women.
Awareness
In a survey conducted by the American Heart Association (AHA) in 2003, only 13% of U.S. women (7% in 1997) perceived heart disease as a major health risk. Black and Hispanic women are less likely than white women to be aware that heart disease is the primary cause of death in women. Only about one third of women recall discussing heart disease risk with their physicians. Women receive fewer preventive recommendations, such as lipid-lowering therapy, aspirin, and lifestyle advice, than do men with similar Framingham risk scores.
Despite the availability of numerous preventive and therapeutic options, women often do not take steps to modify their cardiac risk factors; low awareness is likely to contribute to this. Although mortality from IHD has declined gradually among men since 1979 (by 30% to 50%), mortality from IHD in women has increased during the same period. A greater proportion of women (52%) than men (42%) with myocardial infarction (MI) die of sudden cardiac death before reaching the hospital; two thirds of women who suffer MI never completely recover. Since the late 1970s, hospital discharges from heart failure among women have increased at a markedly faster rate than among men. Thus, an understanding of even subtle differences between men and women in development and progression of IHD and in the use of proven therapies and response to therapy could have a significant impact on improving outcomes. Even modest preventive measures can have an enormous impact. It is projected that a reduction in death rate due to chronic diseases by just 2% during one decade would prevent 36 million deaths.
It has long been recognized that the first presentation with IHD occurs on average 10 years later among women than among men, commonly after menopause. Although IHD, in general, is manifested earlier in less developed countries, the approximate 8- to 10-year age gap in time at onset between men and women remains universal ( Fig. 24-1 ). The INTERHEART study, a large cohort study of more than 52,000 individuals with MI, has demonstrated that the age gap between the sexes is consistent across various socioeconomic, climatic, and cultural environments. However, lifetime IHD risk for women is essentially equivalent to that of men. Menopause is associated with a threefold increase in risk, although it is unclear if this is simply attributable to age. It has been widely speculated that the observed sex-related age difference reflects premenopausal protection afforded by circulating estrogen; however, younger premenopausal women face a twofold increase in MI-related mortality compared with age-matched men ( Fig. 24-2 ). The role that endogenous and exogenous reproductive hormones play in IHD remains poorly understood.
Women are underrepresented in IHD prevention studies. Equal inclusion of women in large cardiovascular trials is now mandated by the NHLBI. In practice, women are less likely to receive preventive therapy, possibly because of a lack of perceived sex-specific benefit resulting from studies predominantly conducted in men. Notably, evidence-based guidelines for CVD prevention in women were published by the AHA in 2004 and later updated in 2007.
Risk Stratification
The 2007 AHA update recommends a scheme for a general risk stratification approach to the female patient that classifies her as at high risk, at risk, or at optimal risk ( Table 24-1 ). The 2007 AHA update focuses on the high average lifetime risk for CVD, which approaches one in two women. Conversely, the Framingham risk score focuses on a relatively narrow period of 10-year risk of CHD death or MI that does not adequately reflect the long-term or lifetime risk of women. The limitations of risk stratification with the Framingham risk score in diverse populations of women are well recognized. These include the lack of inclusion of family history, obesity, metabolic syndrome, and physical inactivity; inaccurate estimation of risk in nonwhite populations; and the preponderance of low risk scores in women despite a high prevalence of subclinical disease.
| Risk Status | Criteria |
|---|---|
| High risk | Established coronary heart disease |
| Cerebrovascular disease | |
| Peripheral arterial disease | |
| Abdominal aortic aneurysm | |
| End-stage or chronic renal disease | |
| Diabetes mellitus | |
| 10-year Framingham global risk >20% * | |
| At risk | ≥1 major risk factors for CVD, including |
| Cigarette smoking | |
| Poor diet | |
| Physical inactivity | |
| Obesity, especially central adiposity | |
| Family history of premature CVD (CVD at <55 years of age in male relative and <65 years of age in female relative) | |
| Hypertension | |
| Dyslipidemia | |
| Evidence of subclinical vascular disease (e.g., coronary calcification) | |
| Metabolic syndrome | |
| Poor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise | |
| Optimal risk | Framingham global risk <10% and a healthy lifestyle, with no risk factors |
* Or at high risk on the basis of another population-adapted tool used to assess global risk.
A Framingham risk score >20% can identify a woman at high risk, but a lower Framingham risk score is insufficient to ensure that an individual woman is at low lifetime risk. The Reynolds risk score, derived from almost 25,000 participants in the Women’s Health Study, was recently suggested as a superior alternative risk score for women, although validation and translation into clinical practice are needed. The Reynolds score incorporates novel risk markers, including high-sensitivity C-reactive protein (hsCRP) and a family history of CAD, that may aid in unique detection of risk in women. It also has the advantage of including cerebrovascular events as an outcome; this point is important because of the higher frequency of stroke in women compared with men. Application of the Reynolds risk score reclassified 40% to 50% of women with an intermediate Framingham risk score into higher or lower risk categories.
D’Agostino and colleagues proposed a sex-specific multivariable risk factor algorithm that can be used to assess general CVD risk and risk of individual cardiovascular events (coronary, cerebrovascular, and peripheral arterial disease and heart failure). The authors used Cox proportional hazards regression to evaluate the risk for development of a first cardiovascular event in 8491 Framingham study participants (mean age, 49 years; 4522 women) who attended a routine examination between 30 and 74 years of age and were free of CVD. Sex-specific multivariable risk functions (“general CVD” algorithms) were derived that incorporated age, total and high-density lipoprotein cholesterol, systolic blood pressure, treatment of hypertension, smoking, and diabetes status. During 12 years of follow-up, 1174 participants (456 women) developed a first cardiovascular event. The general CVD algorithm demonstrated good discrimination (C-statistic, 0.763 [men] and 0.793 [women]) and calibration.
There is considerable evidence that elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase IHD risk in women, although these relationships are less prominent in elderly women compared with younger women. In contrast, low levels of high-density lipoprotein cholesterol (HDL-C) and elevated levels of triglyceride (TG) impart comparable risk in young and elderly women. Despite this evidence, men are more likely to have their lipid levels measured, and abnormal values are generally treated more aggressively than in women. In women enrolled in the HERS study (1993), all of whom had established CHD, 91% failed to meet the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP II, 1993) LDL-C goal of <100 mg/dL. In a trial in patients with stable IHD, 31% of men and only 12% of women reached LDL-C of <100 mg/dL. In the WISE study, which enrolled women with chest pain and myocardial ischemia documented on noninvasive testing between 1996 and 2003, only 24% met their LDL-C goals. These studies document less aggressive treatment of dyslipidemia in high-risk women, including those with documented IHD, compared with men.
Risk Factors and Risk Reduction Interventions
Age
Age is one of the most powerful risk factors for the development of IHD and accompanying clinical events. IHD events including MI lag 10 to 15 years in women compared with men. As men age, they continue to have a linear increase in IHD incidence, particularly during the fifth and sixth decades, whereas women have an almost exponential increase in IHD incidence after the age of 60 years, although population-adjusted curves suggest that this may be due to survivor effects. One in eight women between the ages of 45 and 64 years has evidence of CAD, which increases to one in three after the age of 65 years. With more women living to elderly ages, a majority of IHD victims are not surprisingly now women. It is for these reasons that NCEP ATP III has different age cutoffs for sex; at or above 55 years is the age considered a risk factor for women compared with 45 years for men.
Family History
It is well established that CVD has a hereditary component. However, few prospective studies have evaluated the relationship between family history and future IHD events in women. Retrospective review of much larger data bases of women (e.g., the Nurses’ Health Study) has demonstrated conflicting results. In women with a family history of MI before the age of 60 years, the age-adjusted relative risk was 2.8 for nonfatal MI and 5.0 for fatal cardiovascular events. With adjustment for other cardiovascular risk factors, family history remained an independent risk factor for CVD. NCEP ATP III defines family history of premature CHD before the age of 65 years for women and before the age of 55 years for men. Although family history of premature CHD signifies high risk, risk remains elevated when the definition is broadened to include older first-degree relatives.
Dyslipidemia
More than half of the women in the United States have a TC level >200 mg/dL, and 36% have LDL-C concentration >130 mg/dL. Notably, only 13% of women have HDL-C concentration <40 mg/dL (compared with 23% of Americans overall); the higher threshold of <50 mg/dL is used for women. The relative risk for IHD events associated with elevation of various lipid variables was determined in a nested case-control study from the Nurses’ Health Study. Among 32,826 healthy women, the multivariable relative risks (adjusted for hsCRP, homocysteine, and other traditional cardiac risk factors) for the highest quintiles of lipid variables were as follows: apolipoprotein B: RR, 4.1 (2-8.3); low levels of HDL-C: RR, 2.6 (1.4-5); LDL-C: RR, 3.1 (1.7-5.8); and TG: RR, 1.9 (1-3.9). Adverse changes in lipid profile accompany menopause. Perimenopausal TG levels are the most erratic but follow roughly the same pattern of increased TC and LDL-C on average by ~10% from levels 6 months before menopause. Menopause can influence HDL-C less dramatically, with mild declines noted.
Dyslipidemia is strongly predictive of IHD risk in older women. Women in the Framingham study with TC >265 mg/dL were at two to three times greater risk for experiencing an IHD event compared with women with TC <205 mg/dL. Overall, a 1% increase in TC translated to a 2% increase in IHD incidence. Elevated TG levels and low HDL-C levels are more closely associated with the risk of IHD in women, especially in those at least 65 years old. Lower levels of HDL-C are associated with an increased risk of IHD in the Lipid Research Clinics Follow-up Study. HDL-C was second to age in predicting IHD risk. The ratio of TC and HDL-C was a more accurate marker of IHD risk than either level alone. The NCEP guidelines call for measurement of TC as well as of HDL-C as part of the initial cholesterol screening after the age of 20 years. The TC/HDL-C ratio is typically lower in women than in men through middle age but then increases and parallels that of men by 75 years of age. After the age of 55 years, elevated TC and TC/HDL-C ratio significantly increase IHD risk.
The protective role of lipid-lowering therapy in women, especially with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins), is well established by numerous randomized clinical trials noting consistent reductions in CVD risk ranging from 11% to 54% ( Table 24-2 ). Although the representation of women in most trials is relatively low (averaging <20% of the population), a positive trend for benefit was consistent across all trials. Importantly, the protective effect of statins based on these trials appeared equivalent to or greater than that observed for men. The reduction in risk of major cardiovascular events in women ranged from 11% in the Long-term Intervention with Pravastatin Ischaemic Disease (LIPID) study to 54% in the Greek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) trial. There was no significant effect in the subgroup of women in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) or in the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). There was no significant effect in the total cohort (men or women) in the lipid-lowering arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ; however, Treating to New Targets (TNT), a trial of high-dose (80 mg) versus low-dose (10 mg) atorvastatin, showed equal protection against major cardiovascular events with more intensive therapy in women, statistically similar to that of men, without a sex difference in serious adverse events. There was modestly higher frequency of discontinuation of statins (10% versus 6.5%) and liver function test abnormalities (2.5% versus 1%) in women than in men. Likewise, in patients with acute coronary syndromes (n = 4162 patients, 22% women), more intensive lipid treatment with atorvastatin 80 mg versus pravastatin 40 mg also yielded similar benefits for women and men.
| Study | Patients (n) | Women, n (%) | Prevention Category | Drug | Year | Risk Reduction in Major CHD Events in Women (%) |
|---|---|---|---|---|---|---|
| 4S | 4444 | 827 (19) | Secondary | Simvastatin | 1994 | 35 |
| CARE | 4159 | 576 (14) | Secondary | Pravastatin | 1996 | 46 |
| LIPID | 9014 | 1516 (17) | Secondary | Pravastatin | 1998 | 11 |
| AFCAPS/TexCAPS | 6605 | 997 (15) | Primary | Lovastatin | 1998 | 46 |
| PROSPER | 5804 | 3000 (52) | Both | Pravastatin | 2002 | NS benefit for women |
| HPS | 20,536 | 5082 (25) | Primary | Simvastatin | 2002 | 19 |
| ALLHAT-LLT | 10,355 | 5051 (49) | Primary (hypertension) 14% CHD | Pravastatin | 2002 | Sex-specific data not reported; NS in total cohort |
| GREACE | 1600 | 344 (21) | Secondary | Atorvastatin | 2002 | 54 |
| ASCOT-LLA | 10,305 | 1942 (19) | Primary (hypertension) | Atorvastatin | 2003 | NS benefit for women |
In aggregate, these trials demonstrate the efficacy and safety of statin therapy, including more intensive treatments, for protection against major cardiovascular events in women. In addition to significant reductions of LDL-C and moderate improvements in HDL-C and TG, other potential beneficial effects of statins include improvements in endothelial function, plaque stabilization, anti-inflammatory effects, and antiplatelet effects, among others. Higher risk patients, such as secondary prevention, offer the best short-term efficacy targets. Whereas it has been argued that treatment of dyslipidemic young women is not cost-effective, recent prevention guidelines focused on longer term lifetime risk question this rationale. In addition, women carry a high short-term mortality rate associated with first IHD events (more than twice that for men), providing further support for consideration of statin therapy for both primary and secondary prevention of IHD in women ( Table 24-3 ).
| Lifestyle Interventions |
| Cigarette Smoking |
| Women should not smoke and should avoid environmental tobacco smoke. Provide counseling, nicotine replacement, and other pharmacotherapy as indicated in conjunction with a behavioral program or formal smoking cessation program (Class I, Level B) . |
| Physical Activity |
| Women should accumulate a minimum of 30 minutes of moderate-intensity physical activity (e.g., brisk walking) on most and preferably all days of the week (Class I, Level B) . |
| Women who need to lose weight or sustain weight loss should accumulate a minimum of 60 to 90 minutes of moderate-intensity physical activity (e.g., brisk walking) on most and preferably all days of the week (Class I, Level C) . |
| Rehabilitation |
| A comprehensive risk reduction regimen, such as cardiovascular or stroke rehabilitation or a physician-guided home- or community-based exercise training program, should be recommended to women with a recent acute coronary syndrome or coronary intervention, new-onset or chronic angina, recent cerebrovascular event, peripheral arterial disease (Class I, Level A) , or current/prior symptoms of heart failure and LVEF <40% (Class I, Level B) . |
| Dietary Intake |
| Women should consume a diet rich in fruits and vegetables; choose whole-grain, high-fiber foods; consume fish, especially oily fish, * at least twice a week; limit intake of saturated fat to <10% of energy and if possible to <7%, cholesterol to <300 mg/day, alcohol intake to no more than 1 drink per day, † and sodium intake to <2.3 g/day (approximately 1 tsp salt). Consumption of trans –fatty acids should be as low as possible (e.g., <1% of energy) (Class I, Level B). |
| Weight Maintenance or Reduction |
| Women should maintain or lose weight through an appropriate balance of physical activity, calorie intake, and formal behavioral programs when indicated to maintain or to achieve a BMI between 18.5 and 24.9 kg/m 2 and a waist circumference ≤35 inches (Class I, Level B) . |
| Omega-3 Fatty Acids |
| As an adjunct to diet, omega-3 fatty acids in capsule form (approximately 850 to 1000 mg of EPA and DHA) may be considered in women with CHD, and higher doses (2 to 4 g) may be used for treatment of women with high triglyceride levels (Class IIb, Level B) . |
| Depression |
| Consider screening women with CHD for depression and refer or treat when indicated (Class IIa, Level B) . |
| Major Risk Factor Interventions |
| Blood Pressure—Optimal Level and Lifestyle |
| Encourage an optimal blood pressure of <120/80 mm Hg through lifestyle approaches such as weight control, increased physical activity, alcohol moderation, sodium restriction, and increased consumption of fresh fruits and vegetables and low-fat dairy products (Class I, Level B) . |
| Blood Pressure—Pharmacotherapy |
| Pharmacotherapy is indicated when blood pressure is ≥140/90 mm Hg or at an even lower blood pressure in the setting of chronic kidney disease or diabetes (≥130/80 mm Hg). Thiazide diuretics should be part of the drug regimen for most patients unless contraindicated or if there are compelling indications for other agents in specific vascular diseases. Initial treatment of high-risk women ‡ should be with beta blockers and/or ACE inhibitors or ARBs, with addition of other drugs such as thiazides as needed to achieve goal blood pressure (Class I, Level A) . |
| Lipid and Lipoprotein Levels—Optimal Levels and Lifestyle |
| The following levels of lipids and lipoproteins in women should be encouraged through lifestyle approaches: LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL, and non–HDL-C (total cholesterol minus HDL cholesterol) <130 mg/dL (Class I, Level B) . If a woman is at high risk ‡ or has hypercholesterolemia, intake of saturated fat should be <7% and cholesterol intake <200 mg/day (Class I, Level B) . |
| Lipids—Pharmacotherapy for LDL Lowering, High-Risk Women |
| Use LDL-C–lowering drug therapy simultaneously with lifestyle therapy in women with CHD to achieve an LDL-C <100 mg/dL (Class I, Level A) and similarly in women with other atherosclerotic CVD or diabetes mellitus or 10-year absolute risk >20% (Class I, Level B) . |
| A reduction to <70 mg/dL is reasonable in very-high-risk women § with CHD and may require an LDL-lowering drug combination (Class IIa, Level B) . |
| Lipids—Pharmacotherapy for LDL Lowering, Other At-Risk Women |
| Use LDL-C–lowering therapy if LDL-C level is ≥130 mg/dL with lifestyle therapy and there are multiple risk factors and 10-year absolute risk 10% to 20% (Class I, Level B) . |
| Use LDL-C–lowering therapy if LDL-C level is ≥160 mg/dL with lifestyle therapy and multiple risk factors even if 10-year absolute risk is <10% (Class I, Level B) . |
| Use LDL-C–lowering therapy if LDL ≥190 mg/dL regardless of the presence or absence of other risk factors or CVD on lifestyle therapy (Class I, Level B) . |
| Lipids—Pharmacotherapy for Low HDL or Elevated Non-HDL, High-Risk Women |
| Use niacin || or fibrate therapy when HDL-C is low or non–HDL-C is elevated in high-risk women ‡ after LDL-C goal is reached (Class IIa, Level B) . |
| Lipids—Pharmacotherapy for Low HDL or Elevated Non-HDL, Other At-Risk Women |
| Consider niacin || or fibrate therapy when HDL-C is low or non–HDL-C is elevated after LDL-C goal is reached in women with multiple risk factors and a 10-year absolute risk 10% to 20% (Class IIb, Level B) . |
| Diabetes Mellitus |
| Lifestyle and pharmacotherapy should be used as indicated in women with diabetes (Class I, Level B) to achieve HbA1c <7% if this can be accomplished without significant hypoglycemia (Class I, Level C) . |
| Preventive Drug Interventions |
| Aspirin, High Risk |
| Aspirin therapy (75 to 325 mg/day) ¶ should be used in high-risk ‡ women unless contraindicated (Class I, Level A) . |
| If a high-risk ‡ woman is intolerant of aspirin therapy, clopidogrel should be substituted (Class I, Level B) . |
| Aspirin—Other At-Risk or Healthy Women |
| In women ≥65 years of age, consider aspirin therapy (81 mg daily or 100 mg every other day) if blood pressure is controlled and benefit for ischemic stroke and MI prevention is likely to outweigh risk of gastrointestinal bleeding and hemorrhagic stroke (Class IIa, Level B) and in women <65 years of age when benefit for ischemic stroke prevention is likely to outweigh adverse effects of therapy (Class IIb, Level B) . |
| Beta Blockers |
| Beta blockers should be used indefinitely in all women after MI, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated (Class I, Level A) . |
| ACE Inhibitors/ARBs |
| ACE inhibitors should be used (unless contraindicated) in women after MI and in those with clinical evidence of heart failure or LVEF ≤40% or with diabetes mellitus (Class I, Level A) . In women after MI and in those with clinical evidence of heart failure or LVEF ≤40% or with diabetes mellitus who are intolerant of ACE inhibitors, ARBs should be used instead (Class I, Level B) . |
| Aldosterone Blockade |
| Use aldosterone blockade after MI in women who do not have significant renal dysfunction or hyperkalemia who are already receiving therapeutic doses of an ACE inhibitor and beta blocker and have LVEF ≤40% with symptomatic heart failure (Class I, Level B) . |
* Pregnant and lactating women should avoid eating fish potentially high in methylmercury (e.g., shark, swordfish, king mackerel, or tile fish) and should eat up to 12 oz/wk of a variety of fish and shellfish low in mercury and check the Environmental Protection Agency and the U.S. Food and Drug Administration’s websites for updates and local advisories about safety of local catch.
† A drink equivalent is equal to a 12-oz bottle of beer, a 5-oz glass of wine, or a 1.5-oz shot of 80-proof spirit.
‡ Criteria for high risk include established CHD, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, end-stage or chronic renal disease, diabetes mellitus, and 10-year Framingham risk >20%.
§ Criteria for very high risk include established CVD plus any of the following: multiple major risk factors, severe and poorly controlled risk factors, diabetes mellitus.
|| Dietary supplement niacin should not be used as a substitute for prescription niacin.
¶ After percutaneous intervention with stent placement or coronary artery bypass grafting within previous year and in women with noncoronary forms of CVD, use current guidelines for aspirin and clopidogrel.
On the basis of a number of trials in high-risk subjects, the 2004 revision of the NCEP ATP III guidelines introduced a new LDL-C goal of <70 mg/dL for patients at very high risk, which includes women with established CVD and multiple other cardiovascular risk factors. A meta-analysis of primary prevention trials (excluding the recent JUPITER trial) concluded that pharmacologic lipid lowering, primarily with statins, does not reduce mortality or events in women without known CVD. Caution, however, is warranted in the interpretation of this finding because of the relatively small number of cardiovascular events and the relatively young age of the female enrollees. As young women have a lower absolute risk than that of men in a limited observational period, it is conceivable that the number needed to treat is significantly higher for women than for men. As statins primarily affect LDL-C reduction, one can speculate whether targeting of HDL-C or TGs may be more promising in women compared with men. The documented benefits of lipid-lowering therapy in high-risk women, on the other hand, are convincing and robust. It is therefore important to implement aggressive pharmacotherapy to new lipid targets in high-risk women. A 2003 national survey highlighted that women remain undertreated compared with men and that significantly fewer high-risk women achieved their LDL-C goal compared with men.
From the recent JUPITER trial, 17,802 apparently healthy men and women with LDL-C levels of <130 mg/dL and hsCRP levels of > 2.0 mg/L were randomized to 20 mg of rosuvastatin daily versus placebo. The trial was stopped early after a median follow-up of 1.9 years, with rosuvastatin reducing LDL-C levels by 50% and hsCRP levels by 37%. Rosuvastatin significantly reduced the primary endpoint, a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and CVD death, by 44% compared with individuals treated with placebo. This reduction was observed across nearly all of the endpoints, including a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of “hard” cardiac events (a composite of MI, stroke, and CVD death). Consistent effects were observed in all subgroups including women. Among the 6801 women (38%) included in JUPITER, rosuvastatin significantly reduced the primary composite end point by 46%, a magnitude similar to that observed in men.
Women are often concerned about stroke more than MI. Data from statin trials such as JUPITER, which showed a 48% reduction in the risk of nonfatal stroke with rosuvastatin, might help physicians provide a more convincing argument for women who may be reluctant about taking statins, especially if familial risk of stroke is great relative to that of MI.
Smoking
Cigarette smoking is the most preventable IHD risk factor in women and men and increases the risk of MI in women relatively greater than in men. More than 60% of MIs in women younger than 50 years are attributable to smoking, as are 21% of all deaths from IHD. For women smokers, a dose-dependent relationship between consumption and risk has been described. Rosenberg and colleagues cited an increased risk of nonfatal MI from 2.4 in women who smoke 15 to 24 cigarettes/day to 7 for those who smoke >25 cigarettes/day. In addition, smoking increases the IHD risk when other cardiac risk factors are present or when oral contraceptive pills are being taken. Women not taking oral contraceptive pills who smoke >25 cigarettes/day have a 4.8-fold relative risk of nonfatal MI compared with a 23-fold relative risk in female smokers taking oral contraceptives.
In the United States, fewer women than men currently smoke, and the prevalence of smoking among women has declined during the past three decades. However, tobacco use has decreased more dramatically in men than in women. More worrisome is the increased prevalence of female adolescents who are smoking. Compared with male smokers, women more often smoke to relieve stress, anger, boredom, or depression. Women are more likely than men to cite smoking as a strategy for weight loss, and they more often give weight gain as a major reason for relapsing. All women benefit from smoking cessation, regardless of age at cessation, which should provide a tremendous incentive for elderly smokers to quit. In the Nurses’ Health Study, women who stopped smoking experienced an immediate benefit as well as a further long-term decline in IHD risk to levels comparable to those of women who never smoked. Total mortality risk among former smokers decreases nearly to that of never-smokers within 10 to 14 years of cessation. The risk of an index MI in women declines soon after the cessation of smoking and is largely dissipated after 2 to 3 years.
Compared with men, women find it more difficult to quit smoking with and without treatment and are also more likely to relapse. Simple encouragement to stop smoking should be part of every follow-up encounter with an active smoker. In women who are unable to quit without assistance, use of nicotine replacement and other pharmacotherapy (e.g., bupropion, varenicline) in conjunction with behavioral therapy or a formal smoking cessation program is warranted.
Physical Inactivity
Sedentary lifestyle is a common risk factor for IHD in women and men. Data from the National Center for Health Statistics indicate that 39% of white women and 57% of women of color do not exercise regularly. Rates of physical inactivity are highest among poor women. Increased levels of physical activity are associated with lower blood pressure, lower cholesterol levels, improved glucose metabolism, higher bone density, and improved mental health variables. Physical inactivity contributes to obesity and is an independent risk factor for MI. Even modest exercise has been strongly associated with risk reduction in observational studies. Investigators in the Nurses’ Health Study found that 30 to 45 minutes of walking three times weekly reduces the risk of MI by 50% in women across the ages. Exercise has also been found to reduce the risk of type 2 diabetes mellitus, even in obese women and those with a family history of diabetes.
Physical activity has an even more beneficial role in women after MI or coronary artery bypass surgery. However, despite improved health outcomes associated with cardiac rehabilitation, fewer women than men enroll. A variety of reasons, including referral bias, difficulty with transportation, and elder and child care responsibilities, often prevent women from participating in cardiac rehabilitation programs. According to the 2007 prevention guidelines for women, women should accumulate a minimum of 30 minutes of moderate-intensity physical activity (e.g., brisk walking) daily (Class I recommendation) (see Table 24-3 ).
Diet
In the Nurses’ Health Study, the dietary score, based on intake of cereal fiber, marine-3 fatty acids, folate, glycemic load, and ratio of polyunsaturated to saturated fat, acted as an independent factor for IHD. A second report from the Nurses’ Health Study evaluated the relationship between diet and cardiovascular events during 1980-1994 in 85,941 apparently healthy women. Improvement in dietary score consisting of reduced consumption of red meat, trans- fats, and high-fat products during the study was associated with a significant 16% decline in IHD incidence. Current recommendations suggest that women should consume a diet rich in fruits and vegetables, whole-grain high-fiber foods, and fish at least twice a week, with limited intake of saturated fat (<7% to 10%) and cholesterol (<300 mg/day). Alcohol intake should be limited to no more than one drink per day and sodium intake to <2.3 g/day. Consumption of trans –fatty acids should be as low as possible (see Table 24-3 ). Nutrition intervention trials have demonstrated reductions in CVD and mortality, although sex-stratified trial results are typically not available.
Obesity
Between 1988 and 1991, the Third National Health and Nutrition Examination Survey (NHANES III) reported that one third of U.S. adults (35% of the women and 31% of the men) were overweight. Obesity was defined by a body mass index (BMI) of 27.8 kg/m 2 in men and 27.3 kg/m 2 in women (120% of desirable weight). Obesity is associated with glucose intolerance (or pre–diabetes mellitus), hypertension, and hypercholesterolemia and is also considered an independent risk factor for IHD. In the Nurses’ Health Study, obesity was strongly associated with an increased incidence of cardiovascular events even after control for older age and smoking. Women who were > 30% of ideal body weight had an increased risk ratio of 3.3 for nonfatal MI and IHD death. Recent data suggest that regional fat distribution, particularly a waist-to-hip ratio of >0.88 (android body type), may be more of an accurate marker for chronic ischemic IHD risk than obesity. Several studies have reported an increased risk of MI and IHD or CVD death in women with increased truncal adiposity even after adjustment of other cardiac risk factors.
Data from the Framingham study indicate a doubling in the incidence of diabetes for both sexes during the past 30 years; most of this increase occurred in individuals with a BMI of 30 kg/m 2 and above. The Coronary Artery Risk Development in Young Adults (CARDIA) study illustrated that young adults who maintained a stable BMI over time had minimal progression of risk factors and lower incidence of metabolic syndrome, regardless of baseline BMI. However, among 1358 men and 1321 women, only 16.3% maintained a stable BMI, and 73.9% had an increased BMI. The increasing prevalence of obesity and diabetes in the population, despite a reduction of dietary fat intake during the past decades, highlights the importance of dietary recommendations for exercise and carbohydrate and fat intake. The Nurses’ Health Study reported a positive association between dietary glycemic load and IHD in women, which was even more pronounced in overweight and obese women. Thus, reducing the glycemic load in the diet should be as much of a priority as replacing saturated fats by unsaturated fats. Avoidance of refined sugars and restriction of sugar-sweetened beverages may particularly help reduce dietary glycemic load. A diet high in fruits and vegetables may reduce the risk of diabetes; however, high consumption of fruit juices may be associated with an increased diabetes hazard among women.
Diabetes and the Metabolic Syndrome
Diabetes is a relatively greater risk factor in women than in men, increasing IHD risk by threefold to sevenfold in diabetic women compared with a twofold to threefold increase in risk for diabetic men. Furthermore, the risk of IHD death is higher in diabetic women than in diabetic men. Whereas angiographic CAD is generally more prevalent in men than in women, diabetes eliminates this difference by increasing risk disproportionately in women. Large-scale prospective studies, including the Framingham study and the Nurses’ Health Study, report diabetes mellitus as an independent risk factor; diabetic women were six to seven times more likely to experience nonfatal MI and CVD death. In addition, the risk of CVD morbidity and mortality in women with diabetes is minimally affected by the duration of diabetes, and a significant risk for cardiovascular events is still noted in patients with diabetes of less than 4 years in duration.
Diabetic women have not experienced a decrease in IHD mortality during the past three decades compared with their male counterparts. In fact, there was an increase in IHD mortality in the subgroup of diabetic women. As diabetes is considered a CHD risk equivalent by the NCEP, all diabetic women are classified as high or very high risk. A history of diabetes in women was associated with a 37% increased IHD-related mortality. Diabetes appears to have a greater adverse effect on TG, HDL-C, and LDL-C concentrations in diabetic women than in diabetic men.
Milder forms of glucose intolerance and asymptomatic hyperglycemia may still place women at risk for IHD events. Type 2 diabetes or milder forms of glucose intolerance tend to cluster in women with visceral obesity, hypertension, and dyslipidemia. This clinical pattern confers a much higher IHD risk in diabetic women, depending on the accompanying risk factor profile. Because other risk factors, such as hypertension, smoking, and obesity, act synergistically with diabetes, control of these other risk factors attenuates the risk of MI in diabetic women.
According to the American Diabetes Association, diabetes screening should be considered for women and men older than 45 years and repeated every 3 years, if results are normal. Women with a history of gestational diabetes or polycystic ovarian syndrome should be screened earlier. History of gestational diabetes doubles the risk of diabetes within 4 months post partum, and it remains a lifelong risk factor for the development of diabetes, which is largely risk of type 2 diabetes. Fasting plasma glucose levels of ≥121 mg/dL during pregnancy increase the risk for diabetes in the early puerperium by 21-fold. Expert panels recommend fasting glucose testing or oral glucose tolerance tests 6 to 12 weeks post partum, then every 1 to 2 years in women with gestational diabetes. To prevent the development of diabetes in high-risk women, pre-pregnancy weight should be reached within 6 to 12 months post partum, and physical activity should be recommended.
Furthermore, it is reasonable to screen for diabetes earlier if obesity, hypertension, and dyslipidemia are present because these characteristics frequently co-occur as the metabolic syndrome. The prevalence of metabolic syndrome is similar for both sexes after adjustment for age. A hallmark of the metabolic syndrome is insulin resistance, defined as impaired fasting glucose (100 to 125 mg/dL), which is considered to be a prediabetic state. For women in the Framingham study, impaired fasting glucose was associated with increased IHD risk to a similar degree as established diabetes, a finding that was not seen in the men.
Clinical trials demonstrate the value of risk factor management in diabetics. The Collaborative Atorvastatin Diabetes Study (CARDS) trial, which used atorvastatin 10 mg every day versus placebo in more than 3000 diabetic patients, was terminated early because of a 37% risk reduction with the statin. In the Diabetes Control and Complications Trial, type 1 diabetics receiving conventional therapy observed for 6.5 years had fewer microvascular and neurologic complications with no impact on major cardiovascular events ; however, in the follow-up trial, Epidemiology of Diabetes Interventions and Complications (EDIC), a 42% risk reduction for any cardiovascular event and 57% reduction for major cardiovascular events (including fatal or nonfatal MI or stroke) was observed in the intensively treated subjects. In addition, the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive) study of 5238 type 2 diabetics, which randomized patients to the PPARγ agonist pioglitazone or placebo, produced a nonsignificant reduction in the primary endpoint (all-cause mortality, nonfatal MI, stroke, leg amputation, and cardiovascular or leg revascularization). There was, however, a significant 20% reduction in the secondary endpoint of all-cause mortality, nonfatal MI, and stroke. Finally, the Diabetes Prevention Program demonstrated efficacy with both lifestyle interventions and metformin; high-risk individuals who exercised to goal had the lowest development of diabetes, whereas the addition of metformin significantly reduced diabetes development by 31% in those receiving the drug. Overall, these intervention trial results aimed at CVD risk in diabetes and metabolic syndrome subjects are not available stratified by sex.
Hypertension
The overall prevalence of hypertension is higher among women than among men, although it varies by age. Until the age of 45 years, the prevalence of hypertension is higher in men than in women. In older individuals, hypertension is more prevalent in women, with a much higher prevalence in women aged 65 years and older. Hypertension is two to three times more common in women taking oral contraceptives. Of note, incidence rates for black individuals are approximately twice the rates for white women and men across the ages.
The association of hypertension and IHD has been reported in many prospective studies in both men and women. Hypertension is also the leading risk factor for congestive heart failure. The Systolic Hypertension in the Elderly Program evaluated pharmacologic intervention with a thiazide diuretic in the treatment of systolic hypertension. This study included a study population of 57% women and demonstrated reductions in stroke and IHD incidence by 36% and 25%, respectively. A second trial tested the benefit of beta blockers and thiazide diuretics in decreasing target organ damage from hypertension and demonstrated similar risk reduction in women and men; however, in absolute terms, the benefit in women was seen primarily for stroke, whereas in men, treatment prevented as many IHD events as strokes.
Blood pressure treatment recommendations, based on the Seventh Report of the Joint National Committee on the Prevention, Detection, and Treatment of High Blood Pressure (JNC 7), do not differ between women and men. An optimal blood pressure of below 120/80 mm Hg should be encouraged through lifestyle modifications, such as weight control, physical activity, alcohol moderation, sodium restriction, and increased consumption of fruits and vegetables and low-fat dairy products (see Table 24-3 ). Pharmacotherapy is indicated if the blood pressure remains higher than 140/90 mm Hg or 130/80 mm Hg in women with diabetes or chronic kidney disease. Once medications are initiated, thiazide diuretics should be part of the regimen unless contraindicated or if another drug has a compelling indication and achieves sufficient blood pressure control. Thiazide diuretics have a favorable effect on calcium excretion and thus may be especially appropriate for use in women who are at risk for osteoporosis. Despite similar treatment rates throughout different age groups, hypertension control is especially poor in older women, with only 29% of hypertensive women aged 70 to 79 years reaching their blood pressure target.
Although some studies have shown that the treatment of hypertension among women conferred relatively less benefit against cardiac events compared with antihypertensive treatment among men, the national guidelines recommend the same approach for treatment of hypertensive men and women. A recent publication based on data from the National Nutrition and Health Examination Survey 1999-2004 showed that hypertensive women are significantly more likely to be treated than are men but less likely to have achieved blood pressure control.
Novel Risk Factors
Traditional risk factors and the Framingham risk score underestimate IHD risk in women, and novel risk markers may improve risk detection. Women have, on average, higher hsCRP measures compared with men, a sex difference apparent at the time of puberty. This difference in inflammatory markers is consistent with the higher frequency of inflammation-mediated autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, observed in women compared with men and suggests a more prominent role for inflammation in IHD in women. The relative risk of IHD events increases proportionally with rising levels of hsCRP and acts synergistically with other risk factors to accelerate IHD risk in women. A number of inflammatory markers, including hsCRP, are related to other IHD risk markers, such as the metabolic syndrome, type 2 diabetes, and heart failure. The use of multiple biomarkers appears to improve IHD risk assessment in women.
Antiplatelet Therapy
An overview of randomized trials from the Antiplatelet Trialists’ Collaboration found that aspirin (75 to 162 mg/day) was beneficial in women for secondary prevention of IHD. Among patients with an acute coronary syndrome, aspirin should be part of preventive management for women and men.
Although the benefits of aspirin therapy in reducing the risk of MI, stroke, and vascular death among men and women with preexisting CVD are well established, the role of aspirin in primary prevention in women is less established, primarily because of a lack of inclusion of women in clinical trials. Aspirin has proven benefit and is recommended for all women at high risk without contraindications and for select at-risk women (see Table 24-3 ). Previously, there were few data on the use of aspirin for primary prevention of IHD in women. Earlier recommendations were based on extrapolation from large studies primarily done in men demonstrating a reduction in risk for MI but not stroke in men of middle age or older at intermediate or high risk. Investigators in the Nurses’ Health Study observed a decreased risk of first MI and death in women who took one to six aspirins per week. In the Hypertension Optimal Treatment (HOT) study, men (53%) and women (47%) were randomized to receive 75 mg of aspirin per day or placebo, in addition to hypertension treatment. The HOT study showed an association between aspirin use and reductions in major CVD and MI.
A sex-specific meta-analysis conducted by Berger and coworkers found that aspirin therapy reduced cardiovascular events by 12% in a group of 51,342 women and by 14% in a group of 44,114 men. Aspirin therapy reduced MI by 32% in men and had no significant impact on stroke; it had no significant impact on MI in women but reduced stroke by 17%. The decrease in stroke in women was due to reductions in ischemic stroke out of proportion to a small increase in hemorrhagic stroke. There was no significant effect on CVD mortality for either sex. Whereas the study found that aspirin therapy was effective in lowering the occurrence of cardiovascular events, the differences found between men and women suggest differences in mechanisms of benefit.
The use of aspirin for primary prevention in women was evaluated in the Women’s Health Study with the same dosing strategy as in the Physicians’ Health Study (100 mg every other day), which had shown a striking reduction in the risk of index MI among 22,071 healthy men. In the Women’s Health Study (n = 39,876 women aged 45 years or older), aspirin lowered the risk of stroke by 17%, including a 24% reduction in the risk of ischemic stroke with a nonsignificant increase in the risk of hemorrhagic stroke, with no reduction in fatal or nonfatal MI except for those older than 65 years. Importantly, there was a significant increase (40%) in gastrointestinal bleeding. Thus, a woman who is at risk is treated differently from those at high risk with regard to platelet inhibition. All high-risk women should be prescribed a daily aspirin (75 to 325 mg) unless it is contraindicated. If the woman is aspirin intolerant, clopidogrel should be used (see Table 24-3 ). Women classified as at risk who are younger than 65 years should not take aspirin for primary MI prevention but may consider it when the benefit of stroke prevention outweighs the increased bleeding risk associated with aspirin. In women at risk aged 65 years or older, daily aspirin reduces MI and stroke significantly; however, there was an almost comparable occurrence of gastrointestinal bleeding. Therefore, weighing of the individual risk of gastrointestinal or cerebral hemorrhage versus benefit in preventing ischemic stroke is preferred in at-risk women of all ages because aspirin has no effect on cardiovascular mortality. Aspirin resistance was found to be four times more prevalent in women than in men in a study by Dorsch and coworkers, although the validity of this phenomenon remains unknown.
The U.S. Preventive Services Task Force (USPSTF) recommends the use of aspirin for women aged 55 to 79 years when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of an increase in gastrointestinal hemorrhage. The USPSTF concluded that the current evidence is insufficient to assess the balance of benefits and harms of aspirin for CVD prevention in men and women 80 years or older. The USPSTF recommended against the use of aspirin for stroke prevention in women younger than 55 years and for MI prevention in men younger than 45 years.
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