The American Heart Association’s (AHA) CVD prevention guidelines for women, updated in 2011,53 highlighted that substantially different approaches were needed to assure adequate preventive interventions for women. This relates both to nontraditional atherosclerotic CVD risk factors that are unique to, or predominant in, women and to the fact that traditional atherosclerotic CVD risk factors impart differential risk for women and men. The importance of prevention is highlighted by the information that two of three US women have at least one major coronary risk factor, with that percentage increasing with age.9 Additionally, for women aged 35 to 54 years, in contrast to the total population of women, CHD mortality has increased, reversing the favorable trend of the past four decades. In this population, increasing Framingham risk scores over the past two decades are likely the result of the epidemic of obesity and sedentary lifestyle.35,78 These characteristics support the importance of providing preventive CVD screening for women.
Although women represent 46% of the US population with CHD, they constituted only 25% of participants in CHD prevention trials, with sex-specific data cited in only 31% of primary trial publications.79 It must be appreciated that women are not a homogeneous group. Almost half of African American women have some form of CVD, with a 44% prevalence of hypertension (which is earlier in onset), an increase in metabolic syndrome, higher CVD rates, and higher mortality than their white counterparts, and in all studies, they receive less guideline-directed therapies. Black women have the greatest risk factor burden at hospitalization for an acute MI.34 By contrast, Hispanic women have double the occurrence of diabetes compared with non-Hispanic white women (12.6% vs 6.5%), yet have the paradox of lower mortality and increased life expectancy compared with non-Hispanic white women.80,81,82
Risk Factors Unique to, or Predominant in, Women
Pregnancy complications, including preeclampsia, gestational diabetes, pregnancy-induced hypertension, preterm delivery, and small for gestational age at birth, are early indicators of increased CVD risk. Preterm delivery (< 34 weeks of gestation) appears as an independent risk factor for subsequent long-term CVD morbidity and hospitalizations.83A This mandates a detailed pregnancy history as an integral component of risk assessment for all women. It has been suggested that pregnancy is the first “stress test” a woman undergoes, in that the CVD and metabolic stresses of pregnancy have the potential for early prediction of future CVD risk. It is likely that shared risk factors for preeclampsia and CVD are unmasked by the pregnancy, rather than risk being specifically caused by the preeclampsia. Preeclampsia and gestational hypertension increase by three- to six-fold the risk for subsequent hypertension and double the risk for subsequent CVD events, including stroke. Pre-hypertension during a normotensive pregnancy appears as an independent risk factor for predicting postpartum metabolic syndrome.83B An increased later risk of cardiomyopathy has also been reported in women with hypertensive disorders of pregnancy.84A Further, gestational diabetes increases by seven-fold the risk of subsequent development of type 2 diabetes.53,84B,85,86,87
Oral Contraceptive Therapy
Although there is no apparent increase in CVD risk for healthy women with no risk factors receiving oral contraceptive therapy, smoking increases their risk by seven-fold, and there may be an increase in blood pressure for hypertensive women.88,89,90,91 There is also a nearly two-fold increase in stroke risk, which increases with older age at oral contraceptive therapy use. There are differences among the oral contraceptives, with earlier forms, particularly levonorgestrel, increasing MI risk, and more recent oral contraceptives associated with a lesser increase in blood pressure or even a decrease, but all carry an elevated risk of venous thromboembolism. The recommendations are for precise risk factor ascertainment and control in women using oral contraceptive preparations.88,89,90,91
Hormonal Fertility Therapy
A new area of risk is hormonal fertility therapy, best delineated in a Canadian population cohort from 1993 to 2010.92 These women had a decreased risk of all-cause mortality, stroke, thromboembolism, and heart failure with successful fertility therapy that was evident across age and income subsets. However, unsuccessful fertility therapy in the same cohort was associated with an increase in adverse CVD events.93
Menopausal Hormone Therapy
Menopausal hormone therapy is an area where clinical trial data have dramatically altered clinical recommendations and practice. Based on data from the Women’s Health Initiative (in healthy women) and the Heart and Estrogen/Progestin Replacement Study (in women with CHD), menopausal hormone therapy is not recommended for the primary or secondary prevention of CVD. The US Preventive Services Task Force recommendations state that menopausal hormone therapy should not be recommended for the primary prevention of chronic conditions.94,95,96,97,98
Systemic Autoimmune Disorders
Systemic autoimmune disorders are highly prevalent among women and have adverse consequences, increasing the risk of CHD and stroke. CHD is a leading cause of both morbidity and mortality in women with systemic lupus erythematosus. There is a two- to three-fold increase in MI and CVD mortality among women with rheumatoid arthritis, and increased CVD risk has also been reported among women with psoriasis.53,99,100 The recommendation is that precise screening for CVD risk factors and risk intervention is warranted for women with systemic autoimmune disorders.
Traditional Cardiovascular Disease Risk Factors
Misperception among physicians of lower CVD risk status for women correlates with suboptimal application of CVD risk interventions for women.
Hypertension is the leading cause of CVD worldwide, with a doubled population-adjusted risk for CVD mortality in women compared with men (29.0% vs 14.9%). Hypertension is more strongly associated with MI in women than men.101 Although women are less likely than men to have hypertension before 45 years of age, hypertension predominates among women compared with men after the age of 65 years. Of concern is that 80% of US women aged 75 years and older have hypertension. Importantly, only 29% of elderly women in the United States have adequate control of their blood pressure compared with 41% of men.81,101,102,103,104 Important is the impressive correlation of body mass index and elevated systolic blood pressure in women, indicating another potential intervention to control hypertension.
Controversy remains as to blood pressure targets, with recommendations varying from 150/90 to 140/90 mm Hg. In the Systolic Blood Pressure Intervention Trial (SPRINT), a systolic blood pressure of < 120 mm Hg compared with < 140 mm Hg resulted in a 25% lower risk of fatal and nonfatal major CVD events and deaths from any cause.105 However, women were underrepresented in this trial and the age range of 50 to 80 years excluded young as well as elderly women with hypertension; in addition, by the trial design, diabetic patients were excluded.106
Smoking is the most important preventable cause of MI in women.107 Although cigarette smoking rates have decreased globally, the decline is less for women than men; in fact, the number of female smokers is increasing, particularly in developing countries. Nearly one in five women in the United States smoke cigarettes, with smoking among younger women more common than in younger men. The CVD risk for female smokers is 25% higher than for male smokers, with cigarette smoking tripling the MI risk for women. Moreover, smoking in association with oral contraceptive use increases the risk of acute MI, stroke, and venous thromboembolism.108 Smoking cessation is the most cost-effective risk-modifying program.81,109
Diabetes confers greater risk for CVD death in women compared with men, and the rate of diabetes in Hispanic women is more than double that of non-Hispanic white women. Women with diabetes have a three-fold excess risk of CAD mortality as compared with nondiabetic women, and a higher adjusted hazard for CAD death when compared to men. A meta-analysis of 850,000 individuals showed that the relative risk of CVD was 44% greater in diabetic women than diabetic men.110 Diabetic women have a more adverse CVD risk factor status than their male peers, including impaired endothelium-dependent vasodilation, a hypercoagulable state, dyslipidemia, and the metabolic syndrome.111
The 2015 AHA Scientific Statement on Sex Differences in the CVD Consequences of Diabetes Mellitus noted that the prevalence of diabetes is increasing rapidly in the United States, with 9.3% of the population being diabetic.111 Overall, the prevalence of type 2 diabetes is similar for women and men, with about 12.6 million women over the age of 20 years estimated to have type 2 diabetes. At hospitalization for acute MI, women are more likely than men to have diabetes mellitus (25.5% vs 16.2%). CVD is the leading cause of morbidity and mortality among type 2 diabetics, accounting for more than 75% of the hospitalizations and 50% of all deaths.112 Although nondiabetic women have fewer CVD events than comparably aged nondiabetic men, this sex-specific advantage is lost once type 2 diabetes develops.113,114 Diabetes confers a greater CVD risk for women than men (19.1% vs 10.1%). Diabetic women have a 40-fold increase in the risk of incident CHD and a 25-fold increase in the risk of stroke.
The reasons for the sex differences are not well delineated, but likely are contributed to by inherent physiologic differences, including the impact of sex hormones, differences in CVD risk factors, and differences between the sexes in the treatment of diabetes and CVD.115 It remains uncertain whether differences are related to increased adiposity, increased abdominal adiposity, and/or possibly insulin resistance among diabetic women. In all studies, diabetic women receive less treatment and reduced control of their CVD risk factors than diabetic men.116,117,118,119,120 Women with diabetes are less likely to be appropriately treated than are men, which is contributory to worsening outcomes.121 Diabetic women are the sole group without a documented mortality reduction, based on recent population surveys. These surveys showed a decreased mortality among men with and without diabetes and women without diabetes (13%, 36%, and 27.1%, respectively). Conversely, mortality has increased in diabetic women (23%).
Hypercholesterolemia imparts the highest population-adjusted risk for women (47%), with all studies showing similar statin benefit for women and men. In the US population, fewer than half of adults eligible for cholesterol medications actually took them,122 with women less likely to be prescribed statin therapy123,124 and with variable compliance.125 The 2013 American College of Cardiology (ACC)/AHA guidelines for cholesterol management promulgated significant change in the management of dyslipidemia.126 First, the new pooled cohort risk equations were to be used, and these include sex-specific calculations.127 Lifestyle guidelines are offered for diet and physical activity for low-density lipoprotein (LDL) lowering. Fixed-dose statin therapy for women is based on their risk categorization by the new pooled cohort risk equations, without use of target LDL cholesterol levels. Lifestyle modifications, particularly diet and exercise, are important for primary and secondary prevention of atherosclerotic CVD, with the use of pharmacologic therapy for secondary prevention being equally effective among women and men for the reduction of recurrent CAD events and mortality. Nonstatin therapies are generally not recommended. Moderate-dose statins are recommended after the age of 75 years, as a result of altered statin metabolism in the elderly.128,129,130,131,132 The outcome of these new guidelines will likely increase statin use for women, decrease inappropriate statin use, decrease the use of nonstatin therapies, and decrease the use of LDL-cholesterol laboratory testing. Recommendations for ezetimibe and PCSK9 inhibitors were not included in these guidelines, because the clinical trial results were not available by 2013. Ezetimibe added to statin therapy decreases LDL-cholesterol by approximately 15% and has been associated with a decrease in CVD events,133 and although there are no clinical trial outcome results to date, the recently approved PCSK9 inhibitors have resulted in dramatic lowering of LDL-cholesterol.134,135 Women appeared to have a greater likelihood than men of developing diabetes on statins.136
Two out of three US women are either obese or overweight; obesity is closely associated with hypertension, dyslipidemia, physical inactivity, and insulin resistance. In the Framingham Heart Study, obesity increased CAD risk by 64% in women compared with 46% in men.137 Obesity is a major risk factor for MI in women, increasing their risk nearly three-fold.138 Overall, the prevalence of obesity is double in women compared with men in low-to-middle-income nations, although it is equivalent among women and men in higher income countries.101,139 Detailed guidelines released by the ACC/AHA in 2013 are available for the management of obesity.139
Nearly one-third of adults in the United States are physically inactive (32.2% of women vs 29.9% of men). In the INTERHEART study (Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries), the protective effects of exercise were more prominent for women than for men. Physical inactivity is the most prevalent risk factor for women, with one-quarter of US101 women reporting no regular physical activity and three-quarters reporting less than the recommended amount of activity. Moreover, the development of diabetes and risk of CVD events are decreased for women who exercise regularly. For secondary prevention, exercise-based rehabilitation is a Class IA recommendation in all coronary guidelines, yet women are 55% less likely to participate than men.101,130,140,141 The recommended levels in the physical activity guidelines for adult Americans are at least 150 minutes per week of moderate-intensity aerobic activity, such as walking, 75 minutes per week of vigorous-intensity aerobic activity, such as jogging, or a combination of both, with muscle strength training activity recommended on 2 or more days of the week.28 Higher levels of physical activity are associated with lower rates of CVD.142,143
Psychosocial Issues: Depression and Stress
Psychosocial issues, particularly depression, preferentially disadvantage women. In the INTERHEART study, psychosocial factors increased CVD mortality more for women than men (45.2% vs 22.8%).101 These factors include stress at work or home, financial stress, and major life events.101 There is growing evidence that psychological factors and emotional stress influence the onset and clinical course of IHD, particularly for women. From the Variation in Recovery: Role of Gender on Outcomes of Young Acute MI Patients (VIRGO) registry, young women had significantly higher stress scores than young men.144 Depression among women appears to be a powerful predictor of early-onset MI and, in the VIRGO registry, young women were more likely than young men to have a history of depression.145
Depression is associated with a 1.6-fold increase in CVD mortality independent of the severity of the depression. In addition, increased mortality has been reported among depressed young women (< 65 years of age) with established CAD. Depression is also a risk factor for adverse outcomes with ACS.101,146,147,148,149,150 Likely contributors are the high-risk behaviors and nonadherence to therapies associated with depression. Depression after MI occurs with increased frequency in women, with the greatest risk in younger women.151 Depression may be a component of the increased CAD event risk of younger women following both MI and coronary artery bypass graft (CABG) procedures.152,153
The preventive use of aspirin for CVD varies by sex. Aspirin is routinely recommended for primary prevention in men, but not in women, based on the Women’s Health Study.154 In this study, 38,876 healthy low-risk women older than 45 years of age were randomized to either 100 mg of aspirin every other day or placebo. Aspirin prevented stroke, but not MI or CVD death, among those younger than 65 years of age, with a sizeable potential for gastrointestinal bleeding. In women over 65 years of age, aspirin prevented stroke, MI, and CVD death; however, an increased risk of gastrointestinal bleeding was comparable to the preventive benefits, thus mandating treatment individualization. By contrast, in the Physicians’ Health Study, in which men were randomized to the same aspirin regimen, a reduction in MI (but not stroke) was observed.155 Comparable sex-specific recommendations for aspirin use are routine in all clinical practice guidelines for secondary prevention.156,157
Class III Interventions: Not Useful/Effective and May Be Harmful for Cardiovascular Disease Prevention in Women
Menopausal Hormone Therapy
The Heart and Estrogen/Progestin Replacement Study98 and the Women’s Health Initiative hormone trials96 documented that menopausal hormone therapy did not prevent incident or recurrent CVD in women, but increased their risk of stroke. These trials displaced menopausal hormone therapy as the ubiquitous solution to women’s cardiovascular problems, refocusing attention on established cardiovascular preventive therapy. In summary, hormone therapy and selective estrogen receptor modulators should not be used for the primary or secondary prevention of CVD. This is emphasized in recommendations from the US Preventive Services Task Force.94
Antioxidant Supplements and Folic Acid
The Women’s Antioxidant CVD and the Women’s Antioxidant and Folic Acid CVD studies demonstrated that vitamins E, C, and β-carotene and folic acid and B vitamin supplements, respectively, did not prevent incident or recurrent CVD in women. Antioxidant supplements (eg, vitamins E, C, and β-carotene) should not be used for the primary or secondary prevention of CVD.158,159 In addition, folic acid, with or without vitamin B6 and B12 supplementation, should not be used for the primary or secondary prevention of CVD.160