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Prevention of Cardiovascular Disease in Women Marian C. Limacher, MD1
1 Department of Medicine, University of Florida, Gainesville, Florida
Semin Reprod Med 2014;32:447–453
Abstract
Keywords
► ► ► ► ►
aspirin primary prevention women cardiovascular disease myocardial infarction
Address for correspondence Anthony A. Bavry, MD, MPH, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 10277, Gainesville, FL 32610-0277 (e-mail: [email protected]fl.edu).
Cardiovascular disease is the leading cause of death among women. In fact, the cardiovascular disease mortality rate among women exceeds the rate in men. Unfortunately, many minority women are still unaware of the importance of this disease. All women, including those with no history of cardiovascular disease, should have an accurate estimate of the probability of a cardiovascular disease event (death, myocardial infarction, or stroke) usually within the next decade. Such an estimate will help determine if women are candidates for preventive measures and specific therapies such as aspirin. Data from the Framingham Heart Study were used to construct a risk score, which is now widely used; however, other risk scores are available. To prevent cardiovascular disease, women should refrain from smoking, maintain a healthy weight, eat a heart-healthy diet, be physically active, and have normal blood pressure and cholesterol levels. Aspirin can be considered for primary prevention, with expected benefit to prevent ischemic stroke; however, this needs to be balanced against potential bleeding risk. Hormone therapy is no longer recommended due to an increase in adverse events (most consistently seen as increased ischemic stroke risk). Folic acid is also no longer recommended due to lack of benefit.
Before 1985, cardiovascular disease was predominantly viewed as a “man’s disease.” In fact, this premise was largely true since more men died from cardiovascular disease during the mid-20th century.1 However, cardiovascular disease and mortality became increasingly recognized as the leading chronic disease and cause of death among women over the last several decades. Among a random survey of women during a 15-year period from 1997 to 2012, awareness that cardiovascular disease is the leading killer of women had increased significantly.2 However, over 40% of women were still unaware of the importance of cardiovascular disease during the most recent sampling, with most of this disparity seen in black and Hispanic women. Among women, deaths due to cardiovascular disease modestly increased until 2000, outpacing the death rate in men, then experienced a sharp decline thereafter. Approximately half of this reduction has been attributed to risk factor modification and approximately half to evidence-based medical therapies.3 There are still excess deaths from cardiovascular disease in women compared with men (►Fig. 1).1
Issue Theme Women’s Health Initiative: Lessons Learned 20 Plus Years After; Guest Editor, Robert Bryzski, MD
Increasingly, authorities are concerned that the decline in deaths due to cardiovascular disease may reverse over the next several decades as the epidemic of overweight/obesity now affects approximately two-thirds of adult women.1 Due to the importance of the topic, the American Heart Association published their first women-specific recommendations on the prevention of cardiovascular disease in 1999,4 which have been updated frequently.5–7 We focus this review on the primary prevention of cardiovascular disease in healthy women. Secondary prevention, which is beyond the scope of this review, applies to women who have already suffered a cardiovascular event and addresses measures to prevent a recurrent myocardial infarction or stroke. Primordial prevention is a term used to describe the prevention of the risk factors that lead to the development of asymptomatic atherosclerosis, even before the first cardiovascular event. Effective primordial prevention would require implementing population-wide practices that lower the rates of developing hypertension, diabetes, hypercholesterolemia, smoking, and physical inactivity. These
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DOI http://dx.doi.org/ 10.1055/s-0034-1384628. ISSN 1526-8004.
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Anthony A. Bavry, MD, MPH1
Prevention of Cardiovascular Disease in Women
Bavry, Limacher
Figure 1 Trend in deaths due to cardiovascular disease for men and women from 1979 to 2008. (Reprinted with permission from Roger et al.1)
steps are considered the ultimate goals for reducing cardiovascular disease in women. However, effective strategies are still being developed. Therefore, this review addresses steps to assess and manage cardiovascular risk through primary prevention, that is, optimizing behaviors and risk factor levels.
Definition of a Cardiovascular Disease Event For this review, we will define an atherosclerotic cardiovascular disease event as an acute coronary syndrome (i.e., unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction), stroke, or cardiovascular death. Other cardiovascular disease events which are not the focus of this review include coronary revascularization procedures (i.e., percutaneous coronary intervention and coronary artery bypass grafting) and acquired valve disorders that share the same pathophysiological process as coronary artery disease (i.e., aortic stenosis). The broadest characterization of cardiovascular diseases also includes all other conditions affecting the heart and blood vessels, which are beyond the scope of this article. Stroke requires special mention since women have a higher lifetime risk for stroke than men, resulting in approximately 55,000 excess strokes in women compared with men every year.1 The higher rates may be related to a higher prevalence of hypertension in older age1 and, until recently, the use of hormone replacement therapy.8,9
Risk Assessment All adult women should be assessed for their risk of a cardiovascular disease event, most notably cardiovascular death, myocardial infarction, or stroke. The Adult Treatment Panel (ATP) III of the National Cholesterol Education Program used the risk factors identified from the Framingham Heart Study to create a risk score according to age, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking status, and systolic blood pressure.10,11 Diabetes is excluded from the ATP III risk score since it is considered a coronary heart Seminars in Reproductive Medicine
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disease risk equivalent. The ATP III risk score is available at http://hp2010.nhlbihin.net/atpiii/calculator.asp. A 10-year risk of a cardiovascular disease event > 20% carries the same risk as established coronary heart disease,11 while high-risk status is defined as a 10-year risk of a cardiovascular disease event 10%.7 While this score is easy to use, it has several important limitations. (1) The Framingham Heart Study predominantly enrolled Caucasians; therefore, extrapolating risk estimates to minority women is less accurate. Black women have higher rates of cardiovascular disease and therefore different risk prediction than white women.1 (2) Framingham excluded participants with known coronary heart disease; thus, risk estimates from this dataset cannot be directly applied to women with established coronary heart disease. (3) Up to one-quarter of women can have a myocardial infarction despite having no identifiable risk factors,12 leaving a significant number of women unidentifiable by the ATP III risk score and other scales based on traditional risk factors. In addition to calculation of an elevated score from the ATP III risk score or another validated instrument, high-risk status is also defined as women with clinically established coronary heart disease, cerebrovascular disease, peripheral arterial disease (including abdominal aortic aneurysm), diabetes, or chronic kidney disease.7,11 At-risk women are defined by at least one of the criteria listed in ►Table 1, while ideal cardiovascular health is defined by all the criteria listed in ►Table 2. Given the inherent limitations in the ATP III risk score, an alternative means to risk stratify women is with the Reynolds risk score (http://www.reynoldsriskscore.org/).13 This tool is similar to ATP III risk score, but also considers high-sensitivity C-reactive protein and family history. The Reynolds risk score has demonstrated improved accuracy at correctly classifying intermediate-risk women compared with the ATP III risk score. The Women’s Health Initiative (WHI) added 18 biomarkers to the traditional risk score and also demonstrated a moderate improvement in risk prediction.14 Other options include the Systematic Coronary Risk Evaluation Project (SCORE), which is endorsed by the European Society of Cardiology (www.heartscore.org).15,16 SCORE derived data from 12 European cohort studies and stratified patients into high-risk and low-risk countries. This risk score is potentially applicable to Americans of European background.
Lifestyle Interventions The first approach to preventing cardiovascular disease is through adherence to healthy lifestyle choices. Unfortunately, only a minority of women eats a heart-healthy diet, gets regular exercise, and maintains a healthy weight. According to the American Heart Association,7 the following behaviors are necessary components for preventing cardiovascular disease.
Smoking Cessation All women should be screened for tobacco use, including environmental exposure. Women who report exposure to
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Criteria for determining high-risk status Treated hypertension, or untreated SBP 120 mm Hg (or DBP 80 mm Hg) Treated dyslipidemia, or untreated total cholesterol 200 mg/dL (or HDL cholesterol < 50 mg/dL) Family history of premature heart disease (< 55 y for first degree male relatives and < 65 y for first degree female relatives) Metabolic syndrome (requires three of five criteria): (1) waist > 35 inches, (2) fasting glucose > 100 mg/dL, (3) HDL < 50 mg/dL, (4) triglycerides > 150 mg/dL, and (5) SBP > 130 mm Hg Physical inactivity Obesity Tobacco use Unhealthy diet Subclinical atherosclerosis (i.e., coronary calcification, carotid plaque, or thickened carotid intima-media thickness) Poor functional capacity (i.e., < 5 min duration on an exercise treadmill test) and/or abnormal heart rate recovery Autoimmune disorder (i.e., lupus or rheumatoid arthritis) History of preeclampsia, gestational diabetes, or pregnancy-induced hypertension Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein; SBP, systolic blood pressure.
Table 2 Ideal cardiovascular health is defined by meeting all criteria7 Criteria for determining ideal cardiovascular health Untreated SBP < 120 mm Hg (and DPB < 80 mm Hg) Untreated total cholesterol < 200 mg/dL Untreated fasting blood glucose < 100 mg/dL Body mass index < 25 kg/m2 No smoking 150 min/wk of moderate intensity exercise or 75 min/wk of vigorous intensity exercise Healthy diet (see ►Table 3) Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
tobacco should be informed about its harmful effects and encouraged to undergo smoking cessation. Support can include counseling, referral to a smoking cessation program, nicotine replacement therapy, and pharmacotherapy (i.e., bupropion).
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Physical Activity Healthy women should be encouraged to accumulate regular physical activity of moderate intensity at least 150 minutes per week or vigorous exercise at least 75 minutes per week. Exercise duration should be increased as tolerated, and each episode of physical activity should be at least 10 minutes. It is also recommended that women participate in weight-bearing exercises at least twice per week.
Healthy Diet Many diet patterns have been promoted for weight loss or to enhance cardiovascular health. The WHI Dietary Modification Trial examined a diet of low-fat content with increased consumption of fruits and vegetables in over 48,000 postmenopausal women between the ages of 50 and 79 years. To be eligible for this study, women had to obtain more than 32% of their calories from fat.17 Women were randomly assigned to a low-fat diet intervention or control condition. Participants in the low-fat diet group received behavior modification to reduce total fat intake to < 20% of calories through increased intake of fruits, vegetables, and grains. Although it was assumed that the proportion of saturated fat in the diet would decrease, there was no formal intervention to accomplish this goal. The control group received diet-related educational materials. At 6 years, the low-fat diet group experienced an absolute 8.2% reduction in total fat intake, a 2.9% reduction in saturated fat, a 3.3% reduction in monounsaturated fat, and a 1.5% reduction in polyunsaturated fat compared with the control group. At a mean follow-up of 8.1 years, there was no difference in the incidence of coronary heart disease death or nonfatal myocardial infarction: 0.35% in the low-fat diet group compared with 0.36% in the control group. There was also no difference in stroke or coronary revascularizations between intervention groups. The low-fat diet also failed to reduce the incidence of invasive breast cancer or colorectal cancer.18,19 A Mediterranean-type diet was evaluated by randomized trial design in the Lyon Diet Heart Study.20,21 In this study, 605 patients who suffered a first myocardial infarction were randomized to the Mediterranean-type diet versus a control diet. Themes of the Mediterranean diet include generous portions of fruits, vegetables, whole grains, fish, and canola-oil margarine, while avoiding meat and refined sugars. Adherence to the Mediterranean diet was associated with an approximate 70% reduction in cardiovascular death or nonfatal myocardial infarction at a follow-up of 27 months.20 This benefit was sustained to 46 months.21 Unfortunately, fewer than 10% of those enrolled in this study were women. The recently reported Prevención con Dieta Mediterránea (PREDIMED) study expanded the role of a Mediterraneantype diet to patients with no known cardiovascular disease (i.e., for primary prevention).22 Eligible participants were men 55 to 80 years of age or women 60 to 80 years of age with diabetes or at least three of the following risk factors: smoking, hypertension, elevated low-density lipoprotein (LDL) cholesterol, low HDL cholesterol, overweight/obese, or family history of premature coronary heart disease. Patients were randomly assigned to a Mediterranean diet plus Seminars in Reproductive Medicine
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Table 1 At-risk women are defined by at least one of these criteria7
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Table 3 Recommended healthy diet for women Nutrient
Serving
Comments
Fruits and vegetables
4.5 cups/d
Serving size considered one cup of raw leafy vegetables, half cup of cut raw or cooked vegetables, one medium fruit, one-fourth cup dried fruit, half cup vegetable/fruit juice, half cup fresh/frozen/canned fruit
Fish
Twice/wk
Preferably oily fish
Fiber
30 g/d
Bran cereal, berries, avocado, etc.
Whole grains
Three times/d
Includes bread, cereal, rice, and pasta
Sugar
Limited
Nuts, legumes, and seeds
At least four times/wk
Avoid macadamia and salted nuts
Saturated fat
Limited, < 7% of total energy intake
Found in fried foods, meat, or chicken skin, packaged desserts, butter, cheese, sour cream
Trans fats
None
Cholesterol
< 150 mg/d
Sodium
< 1,500 mg/d
Alcohol
1 drink/d
Source: Adapted with permission from Mosca et al (2011).7
extra olive oil (n ¼ 2,543), a Mediterranean diet plus extra nuts (n ¼ 2,454), or a control low-fat diet (n ¼ 2,450). Nearly two-thirds of participants were women. At a median followup of 4.8 years, a Mediterranean diet was associated with an approximate 30% reduction in cardiovascular death, myocardial infarction, or stroke compared with a control diet. Therefore, randomized trials conducted in thousands of participants have demonstrated that a low-fat diet does not confer cardiovascular protection, but rather a liberal intake of healthy fats (i.e., monounsaturated fats found in olive oil) with reduction in saturated fats is beneficial. The diet currently recommended for women by the American Heart Association closely resembles a Mediterranean diet (►Table 3). Pregnant women should be advised to avoid fish with the highest content of mercury (i.e., tuna, swordfish, etc.).
Ideal Body Weight Although not a perfect measure, body mass index (BMI) can be easily calculated from height and weight (kg/m2) and provides a standardized assessment of body size. BMI 25 kg/m2 is considered overweight, while BMI 30 kg/m2 is considered obese, and BMI 40 kg/m2 is morbidly obese. The target BMI for overweight/obese individuals is < 25 kg/m2. Evidence suggests that central obesity may be a better marker for adverse outcomes. Waist circumference for women should be < 35 inches. A healthy weight can be achieved and maintained through regular physical activity and caloric modification.23
Risk Factor Modification
sodium restriction, alcohol restriction, exercise, and maintaining a healthy weight. Blood pressure that is repeatedly 140/ 90 mm Hg (or 130/80 mm Hg among patients with chronic kidney disease and/or diabetes) despite the lifestyle interventions mentioned above should be considered for antihypertensive therapy.24 A thiazide diuretic has been considered a first-line agent for most women. However, recent studies suggest caution in selecting thiazides and β-blockers because of the potential of increasing the risk of diabetes.25,26 Angiotensin-converting-enzyme inhibitors are contraindicated in pregnancy or in women that may become pregnant.24
Lipids Optimal cholesterol levels among healthy women are defined by LDL cholesterol < 100 mg/dL, HDL cholesterol > 50 mg/dL, and triglycerides < 150 mg/dL. Similar to blood pressure, the first-line approach to achieving these targets is through lifestyle modification. LDL-cholesterol lowering therapy using an HMG co-A reductase inhibitor (statin) for primary prevention is recommended among women with a 10-year risk of a cardiovascular disease event > 20%, or women > 60 years of age with a 10-year risk of a cardiovascular disease event > 10% and high-sensitivity C-reactive protein > 2 mg/dL.7 This restrictive recommendation for the use of statins for primary prevention is due to lack of proven benefit. A meta-analysis of over 65,000 participants (35% women) found no reduction in all-cause mortality from the use of statin therapy.27 Moreover, the use of statin therapy in postmenopausal women has been associated with an increased hazard for diabetes.28
Blood Pressure
Aspirin
Optimal blood pressure is considered to be < 120/80 mm Hg and should be achieved primarily through a healthy diet,
A recent study queried over 200,000 women at 127 U.S. health care centers for aspirin use according to primary or
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Postmenopausal Hormone Therapy The strongest evidence for recommendations about postmenopausal hormone therapy is derived from WHI, which conducted two randomized trials that tested the hypothesis that hormone therapy would be beneficial for preventing certain chronic diseases among postmenopausal women. In one trial, 16,608 women with an intact uterus were randomly assigned to conjugated equine estrogen plus medroxyprogesterone acetate versus placebo.34 At a mean follow-up of 5.2 years, the trial was terminated early due to evidence of harm. Women who received hormone therapy had excess coronary heart disease deaths and nonfatal myocardial infarction, stroke, venous thromboembolic disease, and invasive breast cancer. A complementary trial examined 10,739 postmenopausal women with prior hysterectomy who were randomly assigned to conjugated equine estrogen alone versus placebo.35 This trial was also terminated early (mean follow-up of 6.8 years) due to lack of benefit. Therefore, despite numerous observational studies suggesting a significant cardiovascular benefit for long-term use of postmenopausal hormone therapy, this practice is no longer recommended.7,36
Folic Acid The Women’s Antioxidant and Folic Acid Cardiovascular Study enrolled 5,442 women with cardiovascular disease or
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three or more risk factors and randomly assigned them to a combination pill that consisted of folic acid, vitamin B6, and vitamin B12 versus placebo. At 7.3 years of follow-up there was no difference in the composite outcome of cardiovascular death, myocardial infarction, stroke, or coronary revascularization for combination vitamins versus placebo. In addition, no evidence for effect modification was seen when patients with and without existing cardiovascular disease were considered separately.37
Future Research As described, women have a greater risk of stroke than men and respond differently to certain treatments. For example, when used for primary prevention, aspirin is effective at preventing a first myocardial infarction in men, but not in women. On the contrary, aspirin is effective at preventing a first stroke in women.30 Risk estimation has largely been derived from datasets that are comprised both men and women; therefore, some clinical decision rules (i.e., ATP III risk score) have inherent limitations when estimating the risk of a cardiovascular disease event in women. Accordingly, enhanced risk estimation may need to be derived from women-only datasets. With a better knowledge of future cardiovascular risks, research can be conducted to study the role of certain medications. For example, the use of statin therapy for primary prevention in women remains understudied. Additional research is also need to establish safe and effective weight loss programs, including surgeries, as overweight/obesity remains a top public health priority. Finally, widespread promotion and adoption of heart-healthy diets and increased physical activity are needed.
Summary In the last several decades, great progress has been made regarding increased awareness of the importance of cardiovascular disease among women; however, gaps remain in the awareness of cardiovascular disease, especially in minority women. There are many ways to stratify cardiovascular risk for women, although there are important limitations in each of the available risk scores. Through control of risk factors and application of evidenced-based therapies, the United States has seen a steady reduction in the cardiovascular death rates for women. Overweight/obesity is the current epidemic which could increase the mortality rate due to cardiovascular disease. WHI reinforced the importance of randomized trials as the hormone therapy trials disproved the expectations from widely accepted observational data. Overall, the decline in the cardiovascular death rate among women is testament to significant progress that has been made, but there are many questions left to answer.
References 1 Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Associa-
tion Statistics Committee and Stroke Statistics Subcommittee. Seminars in Reproductive Medicine
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secondary prevention.29 The criteria for aspirin use were based on 2007 guidelines,6 which recommended the use of aspirin for primary prevention in women 65 years and with no indication for secondary prevention. For secondary prevention, aspirin use was recommended with a history of myocardial infarction, stroke, abdominal aortic aneurysm, coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), carotid endarterectomy, or diabetes. Only 41% of women eligible to take aspirin for primary prevention and 48% of the women eligible for secondary prevention reported daily aspirin use.29 Currently, the use of aspirin for primary prevention requires a careful assessment of risks and benefits. A metaanalysis of randomized trials, including the Women’s Health Study, revealed that aspirin does not reduce the incidence of first myocardial infarction. However, aspirin is effective at reducing the rate of first ischemic stroke from 1.1 to 0.8%.30,31 Women are disproportionately at risk of stroke than men and this risk can be estimated using data derived from Framingham (www.westernstroke.org/PersonalStrokeRisk1.xls). The American Heart Association currently recommends aspirin for primary prevention among women 65 years of age if blood pressure is controlled and the risk of myocardial infarction and ischemic stroke outweighs anticipated gastrointestinal bleeding and hemorrhagic stroke risk.7 Aspirin can also be considered for younger women for stroke prevention, albeit with a weaker (IIB) recommendation.7 The United States Preventive Services Task Force also recommends balancing the stroke risk against gastrointestinal bleeding risk in deciding whether to use daily aspirin therapy.32,33 For example, if a 55-year-old woman’s 10-year risk of stroke exceeds 3%, aspirin would be recommended.
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Prevention of Cardiovascular Disease in Women Marian C. Limacher, MD1
1 Department of Medicine, University of Florida, Gainesville, Florida
Semin Reprod Med 2014;32:447–453
Abstract
Keywords
► ► ► ► ►
aspirin primary prevention women cardiovascular disease myocardial infarction
Address for correspondence Anthony A. Bavry, MD, MPH, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 10277, Gainesville, FL 32610-0277 (e-mail: [email protected]fl.edu).
Cardiovascular disease is the leading cause of death among women. In fact, the cardiovascular disease mortality rate among women exceeds the rate in men. Unfortunately, many minority women are still unaware of the importance of this disease. All women, including those with no history of cardiovascular disease, should have an accurate estimate of the probability of a cardiovascular disease event (death, myocardial infarction, or stroke) usually within the next decade. Such an estimate will help determine if women are candidates for preventive measures and specific therapies such as aspirin. Data from the Framingham Heart Study were used to construct a risk score, which is now widely used; however, other risk scores are available. To prevent cardiovascular disease, women should refrain from smoking, maintain a healthy weight, eat a heart-healthy diet, be physically active, and have normal blood pressure and cholesterol levels. Aspirin can be considered for primary prevention, with expected benefit to prevent ischemic stroke; however, this needs to be balanced against potential bleeding risk. Hormone therapy is no longer recommended due to an increase in adverse events (most consistently seen as increased ischemic stroke risk). Folic acid is also no longer recommended due to lack of benefit.
Before 1985, cardiovascular disease was predominantly viewed as a “man’s disease.” In fact, this premise was largely true since more men died from cardiovascular disease during the mid-20th century.1 However, cardiovascular disease and mortality became increasingly recognized as the leading chronic disease and cause of death among women over the last several decades. Among a random survey of women during a 15-year period from 1997 to 2012, awareness that cardiovascular disease is the leading killer of women had increased significantly.2 However, over 40% of women were still unaware of the importance of cardiovascular disease during the most recent sampling, with most of this disparity seen in black and Hispanic women. Among women, deaths due to cardiovascular disease modestly increased until 2000, outpacing the death rate in men, then experienced a sharp decline thereafter. Approximately half of this reduction has been attributed to risk factor modification and approximately half to evidence-based medical therapies.3 There are still excess deaths from cardiovascular disease in women compared with men (►Fig. 1).1
Issue Theme Women’s Health Initiative: Lessons Learned 20 Plus Years After; Guest Editor, Robert Bryzski, MD
Increasingly, authorities are concerned that the decline in deaths due to cardiovascular disease may reverse over the next several decades as the epidemic of overweight/obesity now affects approximately two-thirds of adult women.1 Due to the importance of the topic, the American Heart Association published their first women-specific recommendations on the prevention of cardiovascular disease in 1999,4 which have been updated frequently.5–7 We focus this review on the primary prevention of cardiovascular disease in healthy women. Secondary prevention, which is beyond the scope of this review, applies to women who have already suffered a cardiovascular event and addresses measures to prevent a recurrent myocardial infarction or stroke. Primordial prevention is a term used to describe the prevention of the risk factors that lead to the development of asymptomatic atherosclerosis, even before the first cardiovascular event. Effective primordial prevention would require implementing population-wide practices that lower the rates of developing hypertension, diabetes, hypercholesterolemia, smoking, and physical inactivity. These
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DOI http://dx.doi.org/ 10.1055/s-0034-1384628. ISSN 1526-8004.
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Anthony A. Bavry, MD, MPH1
Prevention of Cardiovascular Disease in Women
Bavry, Limacher
Figure 1 Trend in deaths due to cardiovascular disease for men and women from 1979 to 2008. (Reprinted with permission from Roger et al.1)
steps are considered the ultimate goals for reducing cardiovascular disease in women. However, effective strategies are still being developed. Therefore, this review addresses steps to assess and manage cardiovascular risk through primary prevention, that is, optimizing behaviors and risk factor levels.
Definition of a Cardiovascular Disease Event For this review, we will define an atherosclerotic cardiovascular disease event as an acute coronary syndrome (i.e., unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction), stroke, or cardiovascular death. Other cardiovascular disease events which are not the focus of this review include coronary revascularization procedures (i.e., percutaneous coronary intervention and coronary artery bypass grafting) and acquired valve disorders that share the same pathophysiological process as coronary artery disease (i.e., aortic stenosis). The broadest characterization of cardiovascular diseases also includes all other conditions affecting the heart and blood vessels, which are beyond the scope of this article. Stroke requires special mention since women have a higher lifetime risk for stroke than men, resulting in approximately 55,000 excess strokes in women compared with men every year.1 The higher rates may be related to a higher prevalence of hypertension in older age1 and, until recently, the use of hormone replacement therapy.8,9
Risk Assessment All adult women should be assessed for their risk of a cardiovascular disease event, most notably cardiovascular death, myocardial infarction, or stroke. The Adult Treatment Panel (ATP) III of the National Cholesterol Education Program used the risk factors identified from the Framingham Heart Study to create a risk score according to age, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking status, and systolic blood pressure.10,11 Diabetes is excluded from the ATP III risk score since it is considered a coronary heart Seminars in Reproductive Medicine
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disease risk equivalent. The ATP III risk score is available at http://hp2010.nhlbihin.net/atpiii/calculator.asp. A 10-year risk of a cardiovascular disease event > 20% carries the same risk as established coronary heart disease,11 while high-risk status is defined as a 10-year risk of a cardiovascular disease event 10%.7 While this score is easy to use, it has several important limitations. (1) The Framingham Heart Study predominantly enrolled Caucasians; therefore, extrapolating risk estimates to minority women is less accurate. Black women have higher rates of cardiovascular disease and therefore different risk prediction than white women.1 (2) Framingham excluded participants with known coronary heart disease; thus, risk estimates from this dataset cannot be directly applied to women with established coronary heart disease. (3) Up to one-quarter of women can have a myocardial infarction despite having no identifiable risk factors,12 leaving a significant number of women unidentifiable by the ATP III risk score and other scales based on traditional risk factors. In addition to calculation of an elevated score from the ATP III risk score or another validated instrument, high-risk status is also defined as women with clinically established coronary heart disease, cerebrovascular disease, peripheral arterial disease (including abdominal aortic aneurysm), diabetes, or chronic kidney disease.7,11 At-risk women are defined by at least one of the criteria listed in ►Table 1, while ideal cardiovascular health is defined by all the criteria listed in ►Table 2. Given the inherent limitations in the ATP III risk score, an alternative means to risk stratify women is with the Reynolds risk score (http://www.reynoldsriskscore.org/).13 This tool is similar to ATP III risk score, but also considers high-sensitivity C-reactive protein and family history. The Reynolds risk score has demonstrated improved accuracy at correctly classifying intermediate-risk women compared with the ATP III risk score. The Women’s Health Initiative (WHI) added 18 biomarkers to the traditional risk score and also demonstrated a moderate improvement in risk prediction.14 Other options include the Systematic Coronary Risk Evaluation Project (SCORE), which is endorsed by the European Society of Cardiology (www.heartscore.org).15,16 SCORE derived data from 12 European cohort studies and stratified patients into high-risk and low-risk countries. This risk score is potentially applicable to Americans of European background.
Lifestyle Interventions The first approach to preventing cardiovascular disease is through adherence to healthy lifestyle choices. Unfortunately, only a minority of women eats a heart-healthy diet, gets regular exercise, and maintains a healthy weight. According to the American Heart Association,7 the following behaviors are necessary components for preventing cardiovascular disease.
Smoking Cessation All women should be screened for tobacco use, including environmental exposure. Women who report exposure to
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Criteria for determining high-risk status Treated hypertension, or untreated SBP 120 mm Hg (or DBP 80 mm Hg) Treated dyslipidemia, or untreated total cholesterol 200 mg/dL (or HDL cholesterol < 50 mg/dL) Family history of premature heart disease (< 55 y for first degree male relatives and < 65 y for first degree female relatives) Metabolic syndrome (requires three of five criteria): (1) waist > 35 inches, (2) fasting glucose > 100 mg/dL, (3) HDL < 50 mg/dL, (4) triglycerides > 150 mg/dL, and (5) SBP > 130 mm Hg Physical inactivity Obesity Tobacco use Unhealthy diet Subclinical atherosclerosis (i.e., coronary calcification, carotid plaque, or thickened carotid intima-media thickness) Poor functional capacity (i.e., < 5 min duration on an exercise treadmill test) and/or abnormal heart rate recovery Autoimmune disorder (i.e., lupus or rheumatoid arthritis) History of preeclampsia, gestational diabetes, or pregnancy-induced hypertension Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein; SBP, systolic blood pressure.
Table 2 Ideal cardiovascular health is defined by meeting all criteria7 Criteria for determining ideal cardiovascular health Untreated SBP < 120 mm Hg (and DPB < 80 mm Hg) Untreated total cholesterol < 200 mg/dL Untreated fasting blood glucose < 100 mg/dL Body mass index < 25 kg/m2 No smoking 150 min/wk of moderate intensity exercise or 75 min/wk of vigorous intensity exercise Healthy diet (see ►Table 3) Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
tobacco should be informed about its harmful effects and encouraged to undergo smoking cessation. Support can include counseling, referral to a smoking cessation program, nicotine replacement therapy, and pharmacotherapy (i.e., bupropion).
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Physical Activity Healthy women should be encouraged to accumulate regular physical activity of moderate intensity at least 150 minutes per week or vigorous exercise at least 75 minutes per week. Exercise duration should be increased as tolerated, and each episode of physical activity should be at least 10 minutes. It is also recommended that women participate in weight-bearing exercises at least twice per week.
Healthy Diet Many diet patterns have been promoted for weight loss or to enhance cardiovascular health. The WHI Dietary Modification Trial examined a diet of low-fat content with increased consumption of fruits and vegetables in over 48,000 postmenopausal women between the ages of 50 and 79 years. To be eligible for this study, women had to obtain more than 32% of their calories from fat.17 Women were randomly assigned to a low-fat diet intervention or control condition. Participants in the low-fat diet group received behavior modification to reduce total fat intake to < 20% of calories through increased intake of fruits, vegetables, and grains. Although it was assumed that the proportion of saturated fat in the diet would decrease, there was no formal intervention to accomplish this goal. The control group received diet-related educational materials. At 6 years, the low-fat diet group experienced an absolute 8.2% reduction in total fat intake, a 2.9% reduction in saturated fat, a 3.3% reduction in monounsaturated fat, and a 1.5% reduction in polyunsaturated fat compared with the control group. At a mean follow-up of 8.1 years, there was no difference in the incidence of coronary heart disease death or nonfatal myocardial infarction: 0.35% in the low-fat diet group compared with 0.36% in the control group. There was also no difference in stroke or coronary revascularizations between intervention groups. The low-fat diet also failed to reduce the incidence of invasive breast cancer or colorectal cancer.18,19 A Mediterranean-type diet was evaluated by randomized trial design in the Lyon Diet Heart Study.20,21 In this study, 605 patients who suffered a first myocardial infarction were randomized to the Mediterranean-type diet versus a control diet. Themes of the Mediterranean diet include generous portions of fruits, vegetables, whole grains, fish, and canola-oil margarine, while avoiding meat and refined sugars. Adherence to the Mediterranean diet was associated with an approximate 70% reduction in cardiovascular death or nonfatal myocardial infarction at a follow-up of 27 months.20 This benefit was sustained to 46 months.21 Unfortunately, fewer than 10% of those enrolled in this study were women. The recently reported Prevención con Dieta Mediterránea (PREDIMED) study expanded the role of a Mediterraneantype diet to patients with no known cardiovascular disease (i.e., for primary prevention).22 Eligible participants were men 55 to 80 years of age or women 60 to 80 years of age with diabetes or at least three of the following risk factors: smoking, hypertension, elevated low-density lipoprotein (LDL) cholesterol, low HDL cholesterol, overweight/obese, or family history of premature coronary heart disease. Patients were randomly assigned to a Mediterranean diet plus Seminars in Reproductive Medicine
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Table 1 At-risk women are defined by at least one of these criteria7
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Table 3 Recommended healthy diet for women Nutrient
Serving
Comments
Fruits and vegetables
4.5 cups/d
Serving size considered one cup of raw leafy vegetables, half cup of cut raw or cooked vegetables, one medium fruit, one-fourth cup dried fruit, half cup vegetable/fruit juice, half cup fresh/frozen/canned fruit
Fish
Twice/wk
Preferably oily fish
Fiber
30 g/d
Bran cereal, berries, avocado, etc.
Whole grains
Three times/d
Includes bread, cereal, rice, and pasta
Sugar
Limited
Nuts, legumes, and seeds
At least four times/wk
Avoid macadamia and salted nuts
Saturated fat
Limited, < 7% of total energy intake
Found in fried foods, meat, or chicken skin, packaged desserts, butter, cheese, sour cream
Trans fats
None
Cholesterol
< 150 mg/d
Sodium
< 1,500 mg/d
Alcohol
1 drink/d
Source: Adapted with permission from Mosca et al (2011).7
extra olive oil (n ¼ 2,543), a Mediterranean diet plus extra nuts (n ¼ 2,454), or a control low-fat diet (n ¼ 2,450). Nearly two-thirds of participants were women. At a median followup of 4.8 years, a Mediterranean diet was associated with an approximate 30% reduction in cardiovascular death, myocardial infarction, or stroke compared with a control diet. Therefore, randomized trials conducted in thousands of participants have demonstrated that a low-fat diet does not confer cardiovascular protection, but rather a liberal intake of healthy fats (i.e., monounsaturated fats found in olive oil) with reduction in saturated fats is beneficial. The diet currently recommended for women by the American Heart Association closely resembles a Mediterranean diet (►Table 3). Pregnant women should be advised to avoid fish with the highest content of mercury (i.e., tuna, swordfish, etc.).
Ideal Body Weight Although not a perfect measure, body mass index (BMI) can be easily calculated from height and weight (kg/m2) and provides a standardized assessment of body size. BMI 25 kg/m2 is considered overweight, while BMI 30 kg/m2 is considered obese, and BMI 40 kg/m2 is morbidly obese. The target BMI for overweight/obese individuals is < 25 kg/m2. Evidence suggests that central obesity may be a better marker for adverse outcomes. Waist circumference for women should be < 35 inches. A healthy weight can be achieved and maintained through regular physical activity and caloric modification.23
Risk Factor Modification
sodium restriction, alcohol restriction, exercise, and maintaining a healthy weight. Blood pressure that is repeatedly 140/ 90 mm Hg (or 130/80 mm Hg among patients with chronic kidney disease and/or diabetes) despite the lifestyle interventions mentioned above should be considered for antihypertensive therapy.24 A thiazide diuretic has been considered a first-line agent for most women. However, recent studies suggest caution in selecting thiazides and β-blockers because of the potential of increasing the risk of diabetes.25,26 Angiotensin-converting-enzyme inhibitors are contraindicated in pregnancy or in women that may become pregnant.24
Lipids Optimal cholesterol levels among healthy women are defined by LDL cholesterol < 100 mg/dL, HDL cholesterol > 50 mg/dL, and triglycerides < 150 mg/dL. Similar to blood pressure, the first-line approach to achieving these targets is through lifestyle modification. LDL-cholesterol lowering therapy using an HMG co-A reductase inhibitor (statin) for primary prevention is recommended among women with a 10-year risk of a cardiovascular disease event > 20%, or women > 60 years of age with a 10-year risk of a cardiovascular disease event > 10% and high-sensitivity C-reactive protein > 2 mg/dL.7 This restrictive recommendation for the use of statins for primary prevention is due to lack of proven benefit. A meta-analysis of over 65,000 participants (35% women) found no reduction in all-cause mortality from the use of statin therapy.27 Moreover, the use of statin therapy in postmenopausal women has been associated with an increased hazard for diabetes.28
Blood Pressure
Aspirin
Optimal blood pressure is considered to be < 120/80 mm Hg and should be achieved primarily through a healthy diet,
A recent study queried over 200,000 women at 127 U.S. health care centers for aspirin use according to primary or
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Postmenopausal Hormone Therapy The strongest evidence for recommendations about postmenopausal hormone therapy is derived from WHI, which conducted two randomized trials that tested the hypothesis that hormone therapy would be beneficial for preventing certain chronic diseases among postmenopausal women. In one trial, 16,608 women with an intact uterus were randomly assigned to conjugated equine estrogen plus medroxyprogesterone acetate versus placebo.34 At a mean follow-up of 5.2 years, the trial was terminated early due to evidence of harm. Women who received hormone therapy had excess coronary heart disease deaths and nonfatal myocardial infarction, stroke, venous thromboembolic disease, and invasive breast cancer. A complementary trial examined 10,739 postmenopausal women with prior hysterectomy who were randomly assigned to conjugated equine estrogen alone versus placebo.35 This trial was also terminated early (mean follow-up of 6.8 years) due to lack of benefit. Therefore, despite numerous observational studies suggesting a significant cardiovascular benefit for long-term use of postmenopausal hormone therapy, this practice is no longer recommended.7,36
Folic Acid The Women’s Antioxidant and Folic Acid Cardiovascular Study enrolled 5,442 women with cardiovascular disease or
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three or more risk factors and randomly assigned them to a combination pill that consisted of folic acid, vitamin B6, and vitamin B12 versus placebo. At 7.3 years of follow-up there was no difference in the composite outcome of cardiovascular death, myocardial infarction, stroke, or coronary revascularization for combination vitamins versus placebo. In addition, no evidence for effect modification was seen when patients with and without existing cardiovascular disease were considered separately.37
Future Research As described, women have a greater risk of stroke than men and respond differently to certain treatments. For example, when used for primary prevention, aspirin is effective at preventing a first myocardial infarction in men, but not in women. On the contrary, aspirin is effective at preventing a first stroke in women.30 Risk estimation has largely been derived from datasets that are comprised both men and women; therefore, some clinical decision rules (i.e., ATP III risk score) have inherent limitations when estimating the risk of a cardiovascular disease event in women. Accordingly, enhanced risk estimation may need to be derived from women-only datasets. With a better knowledge of future cardiovascular risks, research can be conducted to study the role of certain medications. For example, the use of statin therapy for primary prevention in women remains understudied. Additional research is also need to establish safe and effective weight loss programs, including surgeries, as overweight/obesity remains a top public health priority. Finally, widespread promotion and adoption of heart-healthy diets and increased physical activity are needed.
Summary In the last several decades, great progress has been made regarding increased awareness of the importance of cardiovascular disease among women; however, gaps remain in the awareness of cardiovascular disease, especially in minority women. There are many ways to stratify cardiovascular risk for women, although there are important limitations in each of the available risk scores. Through control of risk factors and application of evidenced-based therapies, the United States has seen a steady reduction in the cardiovascular death rates for women. Overweight/obesity is the current epidemic which could increase the mortality rate due to cardiovascular disease. WHI reinforced the importance of randomized trials as the hormone therapy trials disproved the expectations from widely accepted observational data. Overall, the decline in the cardiovascular death rate among women is testament to significant progress that has been made, but there are many questions left to answer.
References 1 Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Associa-
tion Statistics Committee and Stroke Statistics Subcommittee. Seminars in Reproductive Medicine
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secondary prevention.29 The criteria for aspirin use were based on 2007 guidelines,6 which recommended the use of aspirin for primary prevention in women 65 years and with no indication for secondary prevention. For secondary prevention, aspirin use was recommended with a history of myocardial infarction, stroke, abdominal aortic aneurysm, coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), carotid endarterectomy, or diabetes. Only 41% of women eligible to take aspirin for primary prevention and 48% of the women eligible for secondary prevention reported daily aspirin use.29 Currently, the use of aspirin for primary prevention requires a careful assessment of risks and benefits. A metaanalysis of randomized trials, including the Women’s Health Study, revealed that aspirin does not reduce the incidence of first myocardial infarction. However, aspirin is effective at reducing the rate of first ischemic stroke from 1.1 to 0.8%.30,31 Women are disproportionately at risk of stroke than men and this risk can be estimated using data derived from Framingham (www.westernstroke.org/PersonalStrokeRisk1.xls). The American Heart Association currently recommends aspirin for primary prevention among women 65 years of age if blood pressure is controlled and the risk of myocardial infarction and ischemic stroke outweighs anticipated gastrointestinal bleeding and hemorrhagic stroke risk.7 Aspirin can also be considered for younger women for stroke prevention, albeit with a weaker (IIB) recommendation.7 The United States Preventive Services Task Force also recommends balancing the stroke risk against gastrointestinal bleeding risk in deciding whether to use daily aspirin therapy.32,33 For example, if a 55-year-old woman’s 10-year risk of stroke exceeds 3%, aspirin would be recommended.
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