You’ve Come a Long Way, Baby
Cardiovascular Health and Disease in Women: Problems and Prospects
Heart disease is the leading cause of death for women both in the United States and in most of the industrialized world. Whereas cardiovascular deaths in US men have declined, the number of cardiovascular deaths in women remains unchanged or is increasing.1
The onset of clinical manifestations of coronary heart disease (CHD) in women lags behind men by about 10 years and by as much as 20 years for more ominous events such as myocardial infarction and sudden cardiac death. Despite this age disparity in coronary events for women, with the aging of the US population and with elderly US women outnumbering elderly men, each year since 1984, more US women than men have died of cardiovascular disease. The sex gap in mortality continues to widen.
But CHD is not solely a problem for elderly women. More than 9000 US women younger than 45 years sustain a myocardial infarction each year. The question of why women younger than 65 years of age are more than twice as likely to die from an acute myocardial infarction than comparably aged men is intriguing. Among survivors, 25% of men versus 38% of women die within a year after an initial myocardial infarction. Within 6 years after myocardial infarction, 18% of men but 35% of women will have a recurrent infarction. Women with unstable angina have a survival advantage compared with men, in contrast to their more lethal outcomes after myocardial infarction. Can the more favorable prognosis with unstable angina be exploited by interventions designed to avert myocardial infarction? CHD accounts for almost 250 000 female deaths annually. Almost every minute, a US woman dies of cardiovascular disease.2
Recent reports from the National Heart, Lung, and Blood Institute (NHLBI) Dynamic PTCA Registry indicate that, despite their persistent high-risk characteristics, women who undergo percutaneous coronary interventions have improved procedural success rates and outcomes. Nonetheless, women continue to have more anginal symptoms than do men after percutaneous coronary intervention, with resultant limitations on their activities and quality of life.
Women have a mortality rate from coronary artery bypass graft (CABG) surgery that is almost double that of their male peers, with women younger than age 50 years 3 times more likely to die at CABG surgery than comparably aged men. Recent sex-based analyses of CABG surgery suggest that diabetes and urgent or emergency presentations accounted for the predominance of this doubled fatality risk.2
An excess of bleeding complications, with their pathogenesis as yet unexplained, is reported for women who undergo all interventional procedures (eg, coronary thrombolysis, percutaneous coronary interventions, CABG surgery), likely contributing to the adverse outcomes for women.
For many years, the medical community has viewed women’s health with a bikini approach, focusing essentially on the breast and reproductive system. The rest of the woman was virtually ignored in considerations of women’s health; the tacit assumption was that women and men reacted comparably to diseases and drugs. Although the concept of sex-specific medicine is predominantly one of the past decade, relevant information about CHD and cardiovascular disease in women is rapidly escalating.
Both women and their healthcare providers have traditionally considered cardiovascular disease and CHD as a male problem. Where did this misperception arise? The viewpoint that CHD was a man’s disease dates back as early as the writings from the Ebers papyrus in 2600 BC, translated as, “If you find a man with cardiac discomfort, with pain in his arms, at the side of his heart, death is near.” The ensuing 5000 years likely have ensured more advantageous outcomes for both men and women. William Heberden, in his classic 1768 treatise on angina pectoris, wrote, “I have seen nearly a hundred people under this disorder, of which number there have been three women… . All the rest were men near or past, the fiftieth year of their age.” Far more recently, a 1960s American Heart Association conference in Oregon on women and cardiovascular disease was titled “How Can I Help My Husband Cope with Heart Disease?” In addition, the initial presentation of the American Heart Association’s Prudent Diet was a public education pamphlet titled “The Way to a Man’s Heart.”
Favorable advances have been notable, however. The landmark 2001 Institute of Medicine (IOM) Report Exploring the Biological Contributions to Human Health: Does Sex Matter?3 articulated the pervasive sex bias in medical research and advocated better understanding of the differences in human diseases between the sexes, with translation of these differences into clinical practice. As noted in the IOM report, women have been traditionally underrepresented in clinical research studies. A recent systematic review of research on the diagnosis and treatment of CHD in women concluded that much of the evidence supporting contemporary recommendations for prevention, testing, and treatment is extrapolated from studies conducted predominantly in middle-aged men.
From 1965 to 1998, 54% of participants in NHLBI clinical cardiovascular trials were women.4 However, when single-sex trials were excluded, participation by women was 38%. Since 1990, the National Institutes of Health (NIH) has required inclusion of women in all NIH-sponsored research, and since 1994, the NIH has required analysis of outcomes by sex. Over time, there has been a significant increase in the participation of women in CHD trials but no increased participation over time in trials of hypertension, arrhythmia, or heart failure. Female representation has been excellent in trials of hypertension (≈50%) but has hovered at or below 20% in clinical trials of arrhythmia and heart failure. In monitoring adherence to the NIH policy of inclusion of women and minorities as subjects in clinical research, a December 2002 report identified that when male-only and female-only studies were excluded, the proportion of women and men in all NIH extramural studies was equal: 50.2% versus 49.3%.5
With regard to drug therapy, a 2001 General Accounting Office report6 stated that the US Food and Drug Administration (FDA) had allowed industry to ignore 1998 regulations for the reporting of data about sex differences in clinical trials of new drugs. For more than one third of drugs approved by the FDA between 1998 and 2000, information was lacking on sex-related responses; 22% of reports failed to provide separate efficacy data for women and men, and 17% omitted sex-based safety data in their New Drug Applications. There is a compelling need for the FDA to monitor inclusion of women in all stages of drug research and to improve oversight of analyses and of the presentation of sex differences in clinical drug trials. From 1992 to 2000, female participation in phase III pharmaceutical trials conducted for FDA submissions increased from 44% to 56%; however, included in these numbers are trials for clinical issues involving only women.
Public information and education about women and heart disease is emerging, as well. The cover story for TIME magazine (April 28, 2003) addresses women and heart disease, a major reversal of the prior androcentric focus of cardiovascular reporting. The NHLBI Heart Truth Campaign currently underway is a national effort to highlight that the female heart is vulnerable to heart disease.
Recent evidence-based delineation that the simplistic application of estrogen/progestin menopausal hormone therapy failed to provide cardiac protection for women has refocused attention on lifestyle and pharmacological interventions of documented efficacy for the prevention of cardiovascular disease and CHD in women. Sentinel studies have indicated that menopausal hormone therapy currently has no evidence-based role in the primary or secondary prevention of CHD. Evidence-based guidelines for cardiovascular disease prevention in women appear in the present issue of Circulation.7 This statement derives from the contributions of more than a dozen cosponsoring professional organizations (with double that number providing endorsement) and is designed to promote the delivery of optimal preventive care for women.
Challenges to the Research Sector
It is imperative that women be included in all aspects of biomedical and health-related research. Researchers must devote increased attention to the different ways in which women and men are affected both by diseases and by treatments of disease.
The IOM report further pointed out that little research has been done on sex differences at the cellular level and the possibility of whether such differences may help explain why diseases affect women and men differently. Previously, only epidemiological data from whole organisms (humans or animal models) were examined with regard to sex differences. The IOM report should serve to encourage more sex-based research by both clinical trial investigators and research scientists at the molecular, genetic, and cellular levels. As examples, are there sex-based pathophysiological differences in coronary plaque characteristics, in coronary vasoactivity, or in endothelial function that may contribute to the adverse outcomes for women? Are there sex-based differences in drug absorption, metabolism, or excretion and resultant drug concentrations? Also unaddressed are implications of hormone variability in the menstrual cycle and of effects of menopausal status. Derivation of sex-specific information has the potential to remedy undertreatment, curtail inappropriate treatment, and improve clinical outcomes for women. Worthy of note is that 8 of the 10 prescription drugs withdrawn from the market since 1997 caused more adverse events in women than men.
Arguably, sex must be considered in the design and analysis of most research studies. As noted in the IOM report, sex-based analysis in clinical trials is requisite to delineate risks and benefits unique to women. Earlier clinical trials often were underpowered for sex-based analyses because of the inadequate numbers of women recruited into such trials. Notably, elderly age–based exclusions from cardiovascular clinical trials doubly disadvantaged women because of their prominent representation in elderly age populations.
Sex-based differences in cardiovascular disease provide a compelling reason for inclusion of women in cardiovascular clinical trials. Well-designed and well-conducted clinical research studies are needed: both single-sex trials (for issues specific to women) and adequate representation of women in other trials with sex-specific comparisons. This approach will provide a reliable database to guide clinical decision-making for health professionals and for women, as well as to support public health recommendations for women.
Challenges to the Clinical Sector
Once clinical trial evidence defines differences in the way women and men react to diseases and drugs, these data must be incorporated by clinicians in their preventive, diagnostic, and therapeutic practices.
Clinicians must make women aware of coronary risk factors and CHD symptoms and enable their appropriate access to care, diagnosis, and proven therapies. Better cardiovascular education of women during office visits warrants priority. Earlier and more aggressive control of coronary risk factors is requisite. There must be a higher index of suspicion for CHD, inasmuch as appropriate prompt evaluation for chest pain may reverse the trend of late referral and late intervention. Because angina is most likely to be the initial and subsequent presentation of CHD in women, objective confirmatory testing with risk stratification and subsequent intervention has the potential to improve outcomes. There is need to refocus patterns of clinical practice to address the unique diagnostic and management needs of women with CHD.
Clinicians should heed the new FDA labeling requirements for all estrogen and estrogen/progestin products. These iterate that these products are not approved for heart disease prevention and advise that women discuss with their healthcare providers other approaches to reducing heart disease risk factors—eg, diet, smoking cessation, and blood pressure control. To these, I would add exercise, weight control, and lipid management, among others.
Challenges to the Public/Patient Sector
Few women appreciate that cardiovascular disease is their major health problem. This gap between fact and perception highlights the need to increase women’s awareness about their vulnerability to CHD. Although 1 of 29 deaths in women is due to breast cancer, in contrast to 1 in 2.4 deaths due to cardiovascular disease, women perceive breast cancer as their major health problem.
Changing the misperception of women about their health problems includes increasing their knowledge that favorable changes in lifestyle can reduce cardiovascular risk factors and prevent cardiovascular disease and CHD. Almost two thirds of women who die suddenly of CHD had no previous symptoms of their illness. The fact that coronary risk factors predict sudden cardiac death provides a further rationale for coronary risk reduction for women.
Emerging data have displayed important sex-based differences in CHD: its pathophysiology, clinical presentation, diagnostic strategies, response to therapies, and adverse outcomes.
Exploration of sex-related differences in CHD provides a basis for clinical strategies to improve outcomes for women. The goal is the lessening of the sex-based disparities in morbidity and mortality rates for women, in particular addressing the excess mortality rate for myocardial infarction and CABG surgery in younger women compared with their male peers.
Addressing the challenges displayed above may help remedy the sex-based disparities in the cardiovascular care and cardiovascular outcomes of women. Behavioral changes by women and reshaping of practice patterns by their healthcare providers may dramatically reduce the number of women who meet with death and disability each year from CHD.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Dr Wenger has received research grants from or entered into contracts with Bristol-Myers Squibb, Eli Lilly and Co, and Astra Zeneca. She has served as a consultant to the Eli Lilly Raloxifene Advisory Committee; Heart Disease in Women, MED-ED, Pfizer, Inc; Aventis Pharmaceuticals; Women First Healthcare, Inc; and Bristol Myers Squibb. She has served on the advisory boards of Aventis Pharmaceuticals, Merck, and CV Therapeutics. She has served on the speakers bureaus of Aventis Pharmaceuticals, Pfizer, Merck, Bristol Myers Squibb, Wyeth Ayerst, and Eli Lilly and Co. She has served on the Data Safety Monitoring Board of Pfizer, Inc.
↵*“You’ve Come a Long Way, Baby” is a registered trademark of Philip Morris, Inc.
American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex: American Heart Association; 2002. Available at: http://www.americanheart.org/downloadable/heart/1040391091015HDS_Stats_03.pdf. Accessed January 9, 2004.
Wizemann TM, Pardue M-L, eds. Exploring the Biological Contributions to Human Health: Does Sex Matter? Committee on Understanding the Biology of Sex and Gender Differences. Board on Health Sciences Policy, Institute of Medicine. Washington, DC: National Academy Press; 2001.
National Institutes of Health, US Department of Health and Human Services. Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research: Comprehensive Report (Fiscal Year 1999 & 2000 Tracking Data): Blue Report. Bethesda, Md: National Institutes of Health; December 2002. Available at: http://www4.od.nih.gov/orwh/bluerpt.pdf. Accessed January 22, 2004.
US General Accounting Office. Report to Congressional Requesters. Women’s Health: Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement. Washington, DC: US General Accounting Office; July 2001. GAO-01-754. Available at: http://www.gao.gov/new.items/d01754.pdf. Accessed January 22, 2004.
Mosca L, Appel LJ, Benjamin EJ, et al. AHA Scientific Statement: Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004; 109: 573–579.