Cardiovascular disease (CVD) remains the most common cause of death in women and men in the developed world, despite the multiple epidemiologic and interventional studies that demonstrate significant declines in CVD incidence and prevalence with adherence to a healthy lifestyle and identification and treatment of risk factors.¹ Women account for more than one half of the almost 1 million deaths caused by CVD in the United States annually²; yet historically, CVD risk factors in women have been insufficiently recognized, diagnosed, and treated.^3–9

The basis for this lack of recognition and less aggressive management of cardiovascular risk in women has largely been a result of the misperception by women and physicians that women are at an inherently low risk for developing heart disease.^10,11 A 2003 American Heart Association (AHA) survey found that only 13 percent of U.S. women (7 percent in 1997) believe heart disease is their major health threat.¹⁰ 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 physician¹⁰; and women receive fewer preventive recommendations, such as lipid-lowering therapy, aspirin, and lifestyle advice, than do men with similar Framingham risk scores.^11,12

In 2004, the AHA published evidence-based guidelines for CVD prevention in women.¹ Several factors led to the development of these guidelines. First, much of the data used to develop previous prevention guidelines came from trials that enrolled few or no women, making it difficult to perform a meaningful analysis of results by sex. In practice, the response to this evidence gap has been to withhold preventive therapies from women because of the lack of sex-specific proof of benefit, or to provide “gender-blind” preventive care using data from studies involving men to guide treatment in women. Neither approach is evidence based and both have the potential for harm. In addition, new guidelines were necessitated by the publication of results from several large CVD prevention trials, most notably the Women’s Health Initiative trial, which confirmed the lack of cardiovascular protection afforded by estrogen use in women after menopause.^13–15 Finally, acceptance of the concept of “global risk,” codified by the National Cholesterol Eduction Program – Adult Treatment Program III (NCEP– ATP III) report as a mechanism to assign CVD risk levels and guide the aggressiveness of preventive interventions using the Framingham risk score,¹⁶ provided a validated framework for the recommendations.

Methods of the AHA Guidelines

Systematic review topics of the AHA guidelines included dietary modification; physical activity; tobacco cessation; management of hyperlipidemia, blood pressure, weight, and diabetes; cardiac rehabilitation; angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), antiplatelet, and beta-blocker therapy; warfarin (Coumadin) for atrial fibrillation; aspirin for primary prevention; treatment for depression; hormone therapy; and antioxidant, omega-3 fatty acid, and folic acid supplementation.¹ Recent guidelines for treating hypertension,^17,18 diabetes,¹⁹ hyperlipidemia,¹⁶ obesity,²⁰ tobacco dependence,²¹ and atrial fibrillation²² were incorporated where applicable.

Each major topic was reviewed for content, strength of recommendation, level of evidence, and generalizability to women (where data in women were insufficient). The classification of efficacy and level of evidence rating systems (Table 1¹) were based on methods used in AHA and American College of Cardiology (ACC) clinical practice guidelines.²³ Class I and IIa interventions are generally recommended and have adequate levels of evidence to support their implementation; class IIb interventions typically have potential benefit but are supported by weaker or conflicting data. The final recommendations were divided into five main categories: lifestyle interventions, major risk factor interventions, preventive drug interventions, atrial fibrillation and stroke prevention, and contraindicated (potentially harmful) interventions.

Dissemination and use of the guidelines was recognized as critical. Most women who could benefit from CVD preventive measures are not cared for by cardiovascular subspecialists until they develop symptoms or signs of CVD. Previous guidelines were published primarily in cardiology journals, which limited knowledge and adoption of preventive practices by family physicians, gynecologists, and internists, who care for most women at risk.

Cardiovascular Risk Assessment

The first step in applying the guidelines to individual women is the assessment of overall CVD risk. The Framingham 10-year coronary heart disease (CHD) risk score is central to making appropriate CHD preventive recommendations.¹⁶ Risk level can be calculated using age, sex, total and high-density lipoprotein (HDL) cholesterol levels, smoking history, and blood pressure (Figure 1).¹ An online calculator is available athttp://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof. Persons at high risk have a greater than 20 percent 10-year CHD risk, and include women with established CVD as well as those with CHD equivalents such as diabetes and chronic renal disease (Table 2).¹ Persons at intermediate risk have a 10 to 20 percent 10-year CHD risk, and persons at lower risk have a less than 10 percent 10-year CHD risk. “Optimal risk” is defined as optimal levels of all risk factors and adherence to a heart-healthy lifestyle. The guidelines or recommendations for each risk category based on a person’s risk score determine the intensity of intervention.

Final AHA Recommendations

The AHA CVD prevention recommendations for women are outlined in Tables 3 through 6.¹ Interventions categorized as ineffective and potentially harmful, including prophylactic aspirin use in women at low risk, anti-oxidants,²⁴ and hormone therapy, are listed in Table 7.¹ A framework for applying the recommendations based on individual risk is given in Table 8,¹ which lists the recommended interventions for each level of CVD risk.

HEALTHY LIFESTYLE

Counseling on lifestyle interventions, including smoking cessation, physical activity, a heart-healthy diet, and weight maintenance, is important for all women, regardless of risk level, even if only to reinforce established healthy behaviors (Table 3).¹ Women at higher risk may need additional consultation with a dietitian and prescription of a therapeutic diet or professional guidance in designing an exercise program. All women should be encouraged to perform at least 30 minutes of moderate-intensity physical activity (e.g., brisk walking) every day; to maintain or achieve a healthy weight; and to eat a diet low in saturated fat, cholesterol, trans-fatty acids, and sodium, and one that is rich in a variety of fruits, vegetables, whole grains, low-fat and nonfat dairy products, legumes, and fish.

RISK FACTOR MANAGEMENT

Risk factor interventions such as control of blood pressure and treatment of hyperlipidemia apply to all risk groups. The treatment targets and intensity of interventions are based on established guidelines as outlined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the NCEP–ATP III report (Table 4¹).^16,17 Ideal blood pressure is defined as less than 120/80 mm Hg. If weight loss, dietary modification, and exercise are insufficient to control blood pressure, pharmacologic therapy should be considered when blood pressure is 140/90 mm Hg or greater, or 130/80 mm Hg or greater in women with diabetes or chronic kidney disease.¹⁷

The ideal low-density lipoprotein (LDL) cholesterol level in women is less than 100 mg per dL (2.59 mmol per L), and the ideal HDL cholesterol level is greater than 50 mg per dL (1.29 mmol per L). The primary target for lipid-lowering therapy is LDL cholesterol. Women at high risk whose LDL cholesterol level is greater than 100 mg per dL should receive statin therapy to reach the goal level, and those at very high risk (e.g., multiple uncontrolled risk factors) should be considered for a target LDL cholesterol level of less than 70 mg per dL (1.81 mmol per L).^25,26 Consideration also should be given to initiating pharmacologic therapy in women at high risk whose LDL cholesterol level is less than 100 mg per dL, because these women may benefit from further reduction. Pharmacologic therapy should be considered in women at intermediate risk whose LDL cholesterol levels are 130 mg per dL (3.36 mmol per L) or greater and in those at lower risk whose LDL cholesterol levels are 160 mg per dL (4.14 mmol per L) or greater. In women who have no more than one risk factor, a treatment threshold of LDL cholesterol 190 mg per dL (4.91 mmol per L) or greater should be used. Triglyceride levels should be less than 150 mg per dL (1.69 mmol per L), and combination therapy with niacin or a fibrate should be considered in women whose triglyceride levels remain elevated after LDL cholesterol level goals have been met.

Tight control of diabetes (i.e., normalized A1C level) is associated with a reduction in CVD events compared with less-stringent glucose control.²⁷ Although the current A1C goal for most persons with diabetes is less than 7 percent, recent data suggest that normalization of A1C level (i.e., less than 6 percent) is associated with better outcomes and should be considered in patients who do not experience frequent hypoglycemic episodes.²⁸

Women at high risk, especially those with overt CHD, should be screened and treated for depression (Table 3).¹ Depression confers a significantly increased risk of adverse outcome after a diagnosis of heart disease and is a major barrier to adoption of healthy lifestyle behaviors. It is associated with a higher risk for first and recurrent myocardial infarction and is more prevalent in women than in men. Diagnosing and treating depression is critical, because treatment with selective serotonin reuptake inhibitors is safe and effective and may be associated with a reduced risk of adverse outcomes in women and men with heart disease.^29,30

Except for generally higher levels of evidence to support CVD risk-lowering interventions in men, differences in treatment goals and recommendations for men and women are slight. For example, the desirable level of HDL cholesterol for men is 40 mg per dL (1.0 mmol per L) or greater. As in women, the goal levels of lipids, blood pressure, and diabetes control for men are dependent on estimated CVD risk, calculated using a separate Framingham risk table to reflect sex-based differences in risk intensity.

PHARMACOTHERAPY

In addition to pharmacologic therapy for hyperlipidemia, hypertension, and diabetes, all women at high risk for CVD should receive aspirin, beta blockers, and an ACE inhibitor or ARB unless contraindicated (Table 5¹).^31,32 The use of omega-3 fatty acid and folic acid supplementation also should be considered in women at high risk, but there is insufficient evidence to support universal recommendations (Table 3).¹

Aspirin has proven benefit and is recommended for all women at high risk without contraindications and for select women at intermediate risk (Table 5).¹ Previously, there were few data on the use of aspirin for primary prevention of CVD in women. Earlier recommendations were based on extrapolation from large, men-only studies that demonstrated a reduction in risk for myocardial infarction but not stroke in men of middle age or older at intermediate or high risk. Data from the aspirin arm of the Women’s Health Initiative, released subsequent to the AHA guidelines, support the practice of not recommending aspirin to women at lower risk.³³ In that study, almost 40,000 women were randomized to receive low-dose aspirin (100 mg every two days) or placebo. The overall risk of significant bleeding complications was increased by 40 percent in those taking aspirin, whereas ischemic stroke incidence was reduced by 24 percent. In contrast to the effects of aspirin for primary prevention of CVD in men, the risks of fatal and nonfatal myocardial infarction were not reduced in women except in those older than 65 years. A meta-analysis of five major aspirin primary prevention trials had similar findings.³⁴ As a result, widespread use of aspirin is not recommended for women at low risk because of the excess risk of cerebral and gastrointestinal hemorrhage and the lack of definite benefit for prevention of CVD (Table 7).¹

STROKE PREVENTION IN ATRIAL FIBRILLATION

Women with atrial fibrillation, paroxysmal or permanent, are at significantly increased risk for stroke; although systemic anticoagulation, particularly in older women, reduces this risk,²² women are less likely than men to receive it.^35–37 As with other interventions, the decision to treat depends on risk level, and treatment guidelines are similar for women and men (Table 6).¹ Women with atrial fibrillation who are at low risk for stroke (i.e., less than 1 percent per year) should be treated with aspirin at a dosage of 325 mg per day. Women at low risk include those younger than 60 years without heart disease or risk factors (e.g., hypertension, congestive heart failure, left ventricular dysfunction) and select older women with no risk factors for thromboembolism.²² Those at high or intermediate risk (i.e., 1 percent per year or greater) should receive warfarin anticoagulation with a goal International Normalized Ratio of 2 to 3. Persons with contraindications to warfarin anticoagulation should receive aspirin.

MANAGING HEALTH

Women must become more actively informed and work with physicians to manage their health, not just their illnesses. The mnemonic ALOHA can help physicians and women use the new guidelines effectively (Table 9).^1,38 Several useful patient education pieces also have been developed.^38,39 With wider dissemination and adoption of the AHA guidelines,¹ CVD prevention practices in women may be enhanced, and CVD incidence and prevalence may decline. The gaps in sex-specific data identified in the systematic review process serve as a guide for researchers of future clinical trials to identify opportunities for reducing CVD risk in women.