Commentaries. Primary Prevention of Coronary Heart Disease in Men and Women: Does 1 Size Fit All? Yes!

Transcription

1 Commentaries Primary Prevention of Coronary Heart Disease in Men and Women: Does 1 Size Fit All? Yes! Address for correspondence: Ezra A. Amsterdam, MD UC Davis Medical Center Ambulatory Care Center 4860 Y Street, Suite 2820 Sacramento, CA eaamsterdam@ucdavis.edu Ezra A. Amsterdam, MD Division of Cardiovascular Medicine, University of California, Davis Medical Center, Sacramento, California Cardiovascular disease remains the leading cause of mortality in both women and men in the industrialized nations. Coronary heart disease (CHD) accounts for the single largest share of this toll in both sexes. Although it had long been known that the number 1 cause of death in men is CHD, it was determined only relatively recently that this was also true in women. Identification of the traditional risk factors (RFs) for CHD by the Framingham Heart Study and other investigations during the last 5 decades has provided the basis of preventive cardiology. These RFs can be considered as fixed or modifiable. Numerous epidemiologic and clinical studies have demonstrated that, with few exceptions, the major RFs that increase the hazard for CHD are the same for both men and women, whether fixed (age, sex, family history) or modified (lipids, blood pressure, smoking). A number of other RFs are under investigation and await confirmation in rigorous prospective studies. Even those conditions unique to women, which can predispose patients to CHD, such as polycystic ovaries and complications of pregnancy, act through provocation of the traditional RFs. Thus, the large body of evidence that supports the similarity of RFs for CHD in men and women provides a rational foundation for similar strategies of prevention in the 2 sexes. Introduction The question is whether prevention of coronary heart disease (CHD) in healthy men and women requires different or fundamentally similar strategies. As will be shown in this brief review, the answer is a resounding Yes! to the latter strategy, based on an abundance of evidence. It has been recognized for over half a century that cardiovascular disease (CVD) is the leading cause of mortality in our society. 1 The grim toll of CVD in men has long been noted, but more recently, CVD has received increased attention as the leading cause of death in women. 2 By the end of the last decade, CVD deaths in this country totaled over /yr. 3 Within this scourge, atherosclerotic CHD accounted for the highest toll in both sexes. 3 The number of CHD deaths in women actually exceeded that in men; however, this may be related to the greater number of women in the elderly population, the group in which CHD incidence is highest. 4 The demographic disparity between elderly women and men is reflected by their numbers in the population over age 75 years, which included 10.5 million women and 6.0 million men in It is also of interest that only after age 75 years does CHD exceed cancer as the number 1 cause of mortality in women, at which point it becomes the leading cause of mortality over the lifetime. 5 These grave statistics for women and men have resulted in major programs to reduce the CHD epidemic by preventive approaches based The author has no funding, financial relationships, or conflicts of interest to disclose. 658 on favorable modification of atherosclerotic risk factors (RFs) through lifestyle alterations, nonpharmacologic therapy, and drug treatment. The encouraging results of these efforts are reflected by the sharp reductions of CVD deaths in both sexes during the last decade. 3 The thesis of this presentation is that the major traditional RF for atherosclerotic CHD are, with modest exceptions, the same in men and women. It is, therefore, reasonable to conclude that preventive strategies should be fundamentally the same in both sexes. These concepts are supported by the following statement of Mosca, in the recent American Heart Association s Evidence-Based Guidelines for the Prevention of Cardiovascular Disease in Women-2011 Update : Evolving science suggests that the overwhelming majority of recommendations to prevent CVD are similar for women and men, with few exceptions. 2 Furthermore, it was noted in the National Cholesterol Education Program Adult Treatment Panel III that, Although the magnitude of risk factors on average may vary between women and men, all of the major risk factors raise the risk of CHD in women. 6 CHD RFs in Men and Women Epidemiologic Data The Table lists the CHD RFs that are recognized as (1) fixed, (2) modifiable, and (3) unique to women. However, it is essential to understand that even the latter conditions act primarily through provocation of the traditional RFs. 7 Although the focus of this review is the modifiable CHD RFs, attention to the fixed risk variables is essential because their presence should provide further incentive for improvement of Received: August 2, 2011 Accepted: September 11, 2011

2 Table 1. Major Coronary Heart Disease Risk Factors Fixed Modifiable Unique to Women Age HTN Pregnancy-related HTN Sex Dyslipidemia Pregnancy-related diabetes Family history Smoking Polycystic ovaries Abbreviation: HTN, hypertension. the modifiable factors. A large, potentially important number of emerging or novel RFs have been proposed, but few have received adequately rigorous investigation to be included in current, standard risk assessment models. 8 The foundation for preventive therapy is identification and modification of the traditional CHD RFs (Table 1). These were established by the Framingham Heart Study (FHS) and still serve as primary therapeutic targets for preventive cardiology. 6,9 Subsequent large epidemiologic trials have corroborated the classic findings of the FHS. 10,11 This large body of evidence has demonstrated that the traditional RFs for CHD tend to cluster, apply to both men and women, account for the great majority of risk in both sexes, and confer a continuous and graded hazard for incidence of CHD. These relationships are illustrated in Figure 1 for men and women in the Framingham study. 12 The primacy of the traditional RFs in predisposing both women and men to CHD was most recently confirmed in a landmark study (INTERHEART) by Yusuf and colleagues. 13 This investigation included approximately men and women in 52 countries of all inhabited continents. The results demonstrated that abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, diet, and physical activity accounted for 90% of the risk of a first myocardial infarction (MI) in men and 94% in women. These findings were consistent at all ages and in both sexes worldwide. The odds ratios for MI in women and men were similar for smoking and dyslipidemia; however, the increased risk associated with hypertension and diabetes was higher in women (Figure 2). Figure 1. Increasing risk of coronary heart disease (CHD) with increasing number of risk factors. 12 Abbreviations: Chol, total cholesterol (mg/dl); HBP, hypertension (mm Hg), HDL, high-density lipoprotein cholesterol (mg/dl). Adapted with permission from Kannel. 12 Figure2. Association of risk factors with first acute myocardial infarction in women and men after adjustment for age, sex and geographic region. 13 Abbreviations: ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; CI, confidence interval. Adapted with permission from Yusuf et al. 13 The following sections briefly review the evidence for the impact of the traditional RFs on the incidence of CHD in men and women from numerous studies preformed over the last several decades. Specific CHD RFs Cholesterol Serum Cholesterol and Low-Density Lipoprotein Cholesterol: The cholesterol hypothesis, which focused on elevated serum cholesterol as a crucial factor in atherogenesis, was based on a large body of evidence acquired over the last century from epidemiologic, pathologic, biochemical, and clinical studies. Epidemiologic investigations demonstrated a direct relationship between total serum cholesterol (TC), a surrogate for low-density lipoprotein cholesterol (LDL-C), and CHD in both men and women 9 11 (Figure 1). The cholesterol hypothesis was ultimately confirmed in both men and women in the therapeutic trials of statins, in which decreases in TC and LDL-C significantly reduced CHD events in both. For example, in the Scandinavian Simvastatin Survival Study, simvastatin produced equivalent reductions in TC and LDL-C, which were associated with comparable decreases in major CHD events in men and women. 14 In the Cholesterol and Recurrent Coronary Events (CARE) study, in which patients were treated with pravastatin, LDL-C reduction was again associated with significant decreases in coronary events in both women and men. 15 High-Density Lipoprotein Cholesterol: Risk of CHD is inversely related to serum high-density lipoprotein cholesterol (HDL-C). Thus, in the FHS it was found that the probability of MI rose by 25% for each 5-mg/dL decline below the median values for men and women. 16 In contrast, high serum HDL-C (>60 mg/dl) was associated with a decrease in CHD risk. Ratio of TC to HDL-C: Studies of the ratio of TC to HDL-C have indicated that this ratio has greater predictive power for CHD than serum TC or LDL-C for men and women

3 Thus, for men, a ratio 6.4 was associated with a 2% to 14% greater risk of CHD than predicted by serum TC or LDL-C; in women, a ratio of 5.6 conferred a 25% to 45% greater risk than predicted by either TC or LDL-C. More recently, the INTERHEART study assessed risk based on the ratio of apolipoprotein B:apolipoprotein A (surrogates for LDL-C + very low-density lipoprotein cholesterol and HDL-C, respectively) (Figure 2). 13 For men and women, the odds ratios of MI for dyslipidemia based on this ratio were 4.42 and 3.76, respectively. Triglycerides Epidemiologic data reveal an association of hypertriglyceridemia with CHD in both men and women. This was shown in a meta-analysis of 16 prospective studies that included a total of over men and almost women. 18 In univariate analysis, men with elevated triglycerides had an increased relative risk of 32% and women had an increased relative risk of 76%. 17 The frequent occurrence of elevated triglycerides with low levels of HDL-C may contribute to the risk conferred by the triglycerides. Hypertension Numerous studies have observed a powerful risk of hypertension for CHD. 12,13,19 Early results of the FHS demonstrated that this well-established RF produced a similar relative increase in risk for MI in women and men (Figure 1), 12 and both systolic and diastolic hypertension increased this risk. 9,13 In the INTERHEART study, hypertension accounted for 18% of the risk for a first MI. As had been previously found, 20 hypertension was a stronger RF in women than men. The odds ratios of hypertension for a first MI were 2.95 for women and 2.32 for men (Figure 2). Additionally, it has been shown that hypertension is associated with up to a 10-fold increase in CHD mortality in women. 21 Cigarette Smoking Cigarette smoking is the most important RF for CHD in men and women in terms of its elevation of risk and potential for risk reversal. Risk increases with the number of cigarettes smoked and has been reported to increase the incidence of MI 6-fold in women and 3-fold in men compared to nonsmokers of both sexes. 22 In the INTERHEART study, cigarette smoking accounted for 36% of the risk for a first MI (Figure 2). 13 Odds ratios of cigarette smoking for MI in this study were 2.86 and 3.05 for women and men, respectively. The entire spectrum of insulin resistance, impaired glucose tolerance, and diabetes is associated with increased risk for CHD, which is augmented 2 to 3 times in type 2 diabetes. 23 In the INTERHEART study, diabetes accounted for 10% of the risk for MI (Figure 2). 13 Impaired glucose tolerance in the absence of overt diabetes is also associated with a graded risk of CHD related to increasing levels of hemoglobin A1c. 24 Consistent with previous findings, 25 relative risk was higher for women than men: 4.26 and 2.67, respectively. 13 The metabolic syndrome, which comprises a cluster of RFs, significantly increases the hazard for CHD in both men and women. 26 Pregnancy-Related Factors Pregnancy may be associated with the new onset of several cardiac RFs. Even the transient occurrence of a RF may be a harbinger of late reappearance. It is emphasized that the impact on CHD risk of the following gestational syndromes is through the traditional RFs they may induce. Hypertension The frequency of hypertension during pregnancy is 5%, but this varies widely because of disparities in definition and the population studied. These numbers may include both preexisting and pregnancy-induced elevation of blood pressure. If the hypertension is severe, evaluation for secondary etiologies should be pursued. Prognosis is usually good, with mild blood pressure elevations that do not progress to preeclampsia or eclampsia. 27 However, because gestational elevation of blood pressure may be associated with the late development of chronic hypertension, all women who develop hypertension during pregnancy should be monitored for the chronic disease. 28 Gestational diabetes occurs in 1% to 14% of pregnancies with an estimated average of 7%. 29 The risk for developing subsequent type 2 diabetes was over 9-fold in women with gestational diabetes compared to those with normoglycemic pregnancies. 30 Furthermore, gestational diabetes increased the risk of subsequently developing CHD. 31 Polycystic Ovary Syndrome It is reported that 20% of young women have polycystic ovaries, which can produce a constellation of cardiac RFs, including obesity, metabolic syndrome, type 2 diabetes, and dyslipidemia. 32 Although these abnormalities increase the CHD risk profile, long-term outcomes in women with this syndrome have not shown an actual increase in CHD in this group. 33 Estimation of Global Risk for Coronary Heart Disease Several tools for estimating the risk of CHD have been developed, of which the Framingham risk score (FRS) is the most widely employed. 6 It is applied in persons without evidence of CVD or diabetes and incorporates 6 of the traditional RFs (age, sex, TC, HDL-C, cigarette smoking, and systolic blood pressure), which are assigned weighted points from which the FRS is calculated to estimate absolute 10-year risk for a fatal or nonfatal MI. Risk is categorized as high (>20%), intermediate (10% 20%), or low (<10%); <5%, which is considered very low risk, is sometimes included. Application of the FRS is indicated by the following comparison of a 50- year-old man and woman and a 70-year-old man and woman, all of whom have the following RFs: TC, 250 mg/dl; systolic blood pressure, 140 mm Hg; HDL-C, 40 mg/dl; and nonsmoker. The 10-year risk of CHD (fatal or nonfatal MI) is 16% in the 50-year-old man and 2% in the 50-year-old woman. However, the 10-year risk for the 70-year-old man is 20%, but for the 70-year-old woman it has risen to 17%, more than 8-fold from her risk 20 years before. These calculations indicate the importance of sex and age in determining coronary 660

4 artery disease risk. Furthermore, they demonstrate the gradient of risk between the younger man and woman and the decrease in this disparity between the 2 older individuals. The FRS has recognized limitations, which include absence of family history and prediction of risk for only a decade. In addition, its utility in women has been criticized for underestimating risk in this group. 2,34 To enhance risk prediction, additional strategies have been developed, including the Reynolds Risk Score (RRS), which was used to predict risk in almost initially healthy women followed for over 10 years in the Women s Health Initiative. 35 The investigators developed a model comprising 7 RFs, including family history and C-reactive protein. Validation of the method was based on clinical follow-up for incidence of CVD. The study demonstrated that reclassification of FRS-based risk occurred mainly in the group considered at intermediate risk; 12.1% were reclassified to high risk and 17.3% were reclassified to low risk. Predictive information in women at very low risk by FRS (<5% 10-year risk) was not altered in the RRS. These findings, in a very large study cohort, demonstrated overall lower risk prediction for women by the RRS than by the FRS. To provide comprehensive risk assessment, the Framingham formulation was updated to establish a general cardiovascular risk profile. 36 This method estimates risk for all major CVD, including MI, stroke, heart failure, and peripheral arterial disease and is now the preferred approach for risk estimation. Calculation of risk is similar to that of the older FRS exemplified above, but the estimates differ considerably because of inclusion of all major CVDs. For example, 10-year CVD risk for the 50-year-old man and woman in the above example is 18.4% and 11.7%, respectively. At 70 years of age, their risks are >30.0% and 21.5%, respectively. Conclusion The review of CHD RFs in women and men, as shown by the forgoing analysis, clearly demonstrates the similarity of these RFs in both sexes. Appreciation of these relationships provides a sound basis for preventive cardiology in these populations. Acknowledgment The author acknowledges the skilled assistance of Brittany Chatterton, BS. References 1. Centers for Disease Control and Prevention/National Center for Health Statistics. Leading cause of death cdc.gov/nchs/data/dvs/lead1900_98.pdf. Accessed July 27, Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women 2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011;57: Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics 2011 update: a report from the American Heart Association. Circulation. 2011;123:e18 e Spraggins R. We the people: men and women in the United States. Census 2000 special report. U.S. Census Bureau Web site. January Accessed March 4, Centers for Disease Control and Prevention/National Center for Health Statistics. Leading cause of death by age group, all female United States, _all_females.pdf. Accessed March 4, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106: Wilson PWF. Cardiovascular disease risk factors in women. Chapter 2. In: Wenger NK, Collins P, eds. Women and Heart Disease. 2nd ed. London, UK: Taylor & Francis; 2005, p Greenland P, Alpert JS, Beller GA, et al ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122:e584 e Kannel WB. Bishop lecture. Contribution of the Framingham Study to preventive cardiology. J Am Coll Cardiol. 1990;15: The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251: Stamler J, Neaton JD. The Multiple Risk Factor Intervention Trial (MRFIT) importance then and now. JAMA. 2008;300: Kannel WB. Clinical misconceptions dispelled by epidemiological research. Circulation. 1995;92: Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364: Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997;96: Lewis SJ, Moye LA, Sacks FM, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129: Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62: Kinosian B, Glick H, Garland G. Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med. 1994;121: Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3: MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335: Rich-Edwards JW, Manson JE, Hennekens CH, et al. The primary prevention of coronary heart disease in women. N Engl J Med. 1995;332: Cornoni-Huntley J, LaCroix AZ, Havlik RJ. Race and sex differentials in the impact of hypertension in the United States. The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Intern Med. 1989;149: Prescott E, Hippe M, Schnohr P, et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316: Almdal T, Scharling H, Jensen JS, et al. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med. 2004;164: Singer DE, Nathan DM, Anderson KM, et al. Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study ;41: Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332:

5 26. Ninomiya JK, L Italien G, Criqui MH, et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109: Ferrazzani S, De Carolis S, Pomini F, et al. The duration of hypertension in the puerperium of preeclamptic women: relationship with renal impairment and week of delivery. Am J Obstet Gynecol. 1994;171: Robbins CL, Dietz PM, Bombard J, et al. Gestational hypertension: a neglected cardiovascular disease risk marker. Am J Obstet Gynecol. 2011;204:336 e1 e The Expert Committee on the Diagnosis and Classification of Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Mellitus. Care. 2011;34:S Bellamy L, Casas JP, Hingorani AD, et al. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373: Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Care. 2008;31: Clayton RN, Ogden V, Hodgkinson J, et al. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin Endocrinol (Oxf). 1992;37: Wild RA. Polycystic ovary syndrome: a risk for coronary artery disease? Am J Obstet Gynecol. 2002;186: Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009;54: Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297: D Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117: Rebuttal Before beginning my rebuttal, I wish to emphasize that I strongly agree that it is important that all clinicians recognize that coronary heart disease (CHD) is the leading cause of mortality in both women and men, and all efforts and resources should be expended to continue to close the gender gap in the diagnosis and treatment of CHD in women. My rebuttal comprises reemphasis of several points made in my initial presentation. They are: (1) The major premise of my brief review, which was that risk factors are essentially the same in women and men, is supported by epidemiologic evidence and underscored by the lead author of Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease In Women 2011 Update, 1 as quoted in my initial presentation. (2) It is after age 75 years that CHD exceeds cancer as the number 1 cause of mortality in women, at which point it becomes the leading cause of mortality over the lifetime. 2 (3) Although the number of CHD deaths in women exceeds that in men, this may be related to the greater number of women in the elderly population, the group in which CHD incidence is highest. 3 (4) Risk factors associated with some cases of pregnancy are the traditional ones, such as hypertension, rather than any that are unique to women. Similarly, polycystic ovary syndrome is associated with traditional risk factors. 4 (5) Concerns for the underestimation of risk in women have been allayed by development of the updated Framingham formulation for global estimation of total cardiovascular risk in women and men. 5 References 1. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women 2011 update: a guideline from the American Heart Association. JAmColl Cardiol. 2011;57: Centers for Disease Control and Prevention/National Center for Health Statistics. Leading cause of death by age group, all female United States, _all_females.pdf. Accessed March 4, Spraggins R. We the people: men and women in the United States. Census 2000 special report. U.S. Census Bureau Web site. January Wild RA. Polycystic ovary syndrome: a risk for coronary artery disease? Am J Obstet Gynecol. 2002;186: D Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117: