Clinicians seek better outcomes for women with CVD

As emerging data focused on considerations for women with cardiovascular disease compared with men is increasing, clinicians are working to implement strategies to better identify risk factors and improve the management and outcomes for these women.

Advancements have been made for women with CVD, as demonstrated by the 30% decline in mortality in 2014 compared with a decade ago, which was recently reported in the American Heart Association and CDC 2014 heart disease and stroke statistics. Yet, CVD — and more specifically coronary artery disease, or ischemic heart disease — remains under-detected in women, and outcomes lag behind for women with CVD compared with men, clinicians said.

Clinicians discussed with Endocrine Today the unique challenges they face in prevention, detection and treatment of CVD in women and what they are doing to combat the issues, as clinicians must consider a distinct relationship between cardiometabolic health and endocrine health in women.

“Marked reductions in CV mortality in women have occurred for the first time this decade partly as a result of an increase in awareness, greater focus on women and their CV risk, and the application of evidence-based treatments for established CAD,” said Jennifer H. Mieres, MD, FACC, FASNC, FAHA, professor of cardiology and population health, Hofstra North Shore-LIJ School of Medicine.

Based on recent data, Mieres states that the use of the term ischemic heart disease when referring specifically to CV pathology in women is more appropriate, as it covers the full spectrum of the female pattern of coronary atherosclerosis “The evolving evidence concerning the sex-specific aspects of coronary atherosclerotic disease supports a multifactorial pathophysiology of coronary atherosclerosis that includes obstructive CAD and dysfunction of the coronary microvasculature and endothelium. The term ischemic heart disease best encompasses this varied pathophysiology in women,” Mieres said.

Guidelines, identifying CVD risk in women

Because of these differences in the sexes, women require a unique evaluation approach.

“It is important for clinicians to appreciate that although women have a higher atherosclerotic burden, are more symptomatic, and have a worse clinical outcome, they have a lower prevalence of obstructive coronary disease than men. The pathophysiology of heart disease in women is a spectrum and, therefore, the clinician must consider a unique evaluation approach, which in some cases will extend beyond the detection of obstructive coronary stenosis to include evaluation of the atherosclerotic burden, as well as an evaluation of coronary reactivity of the microvasculature and endothelium,” Mieres said.

Along with the traditional risk factors for CVD, women have a unique set of pregnancy-related risk factors such as gestational diabetes, pregnancy-induced hypertension and preeclampsia. Inflammatory diseases such as rheumatoid arthritis and lupus are highly associated with CVD and disproportionately affect women compared with men, said Martha Gulati, MD, MS, FACC, FAHA, Sarah Ross Soter Chair in Women’s Cardiovascular Health and section director for preventive cardiology and women’s cardiovascular health at The Ohio State University Wexner Medical Center.

“We have learned that while men and women share similar modifiable risk factors for heart disease, the risk factors of diabetes, sedentary lifestyle and obesity are more potent in women and that certain unique risk factors, such as early onset of menopause before age 50; inflammatory diseases, such as lupus and rheumatoid arthritis; and complications of pregnancy, such as preeclampsia, gestational diabetes and birth of a preterm infant are associated with an increased incidence of heart disease,” Mieres said.

According to Mariana Garcia Touza, MD, assistant professor of clinical medicine, University of Missouri Health System, School of Medicine, “After menopause, the incidence and severity of coronary disease increases to rates three times of those women the same age who are premenopausal.”

The American Heart Association’s guidelines updated in 2011 and the American College of Cardiology (ACC) and the AHA clinical practice guidelines released in 2013 apply to the specific question of identifying women who are at risk for CVD, Gulati said, adding that ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, released in November 2013, may be added to the CVD guidelines in the future.

“There is no debate that the cornerstone for treating CVD risk factors is through lifestyle modification and, when needed, medication. In addition, there has been no debate about which modifiable risk factors people should focus on: exercise, blood pressure, cholesterol, diet, smoking, blood glucose and weight,” according to Sandra Tsai, MD, MPH, clinical assistant professor of medicine, an internist focused on preventive cardiology who is part of a team of multidisciplinary experts at Stanford University.

However, Tsai said, “The current guidelines for CV risk factors, which include hypertension, cholesterol and obesity, have stirred up quite a controversy because there are significant shifts in the previous way we identified and treated cholesterol and hypertension.”

In 2013, the AHA and ACC released a CV risk calculator and prevention guidelines. Clinicians discussed the newer pooled cohort equation risk calculators that help identify women with CVD and shifts in identifying risks related to cholesterol and hypertension.

“Our most commonly used CV risk calculator, the Framingham risk score, generally underestimates CV risk in women, misidentifying too many women into a low CV risk category who may ultimately suffer from CAD (up to 40%),” said Claire Boccia Liang, MD, director of the Women’s Heart Program at Morristown Medical Center in New Jersey. “For this reason, newer risk calculators have been devised, including the Reynolds risk score and the pooled cohort risk assessment tool.”

Touza said these pooled cohorts estimate 10-year absolute risk for atherosclerotic CVD, giving clinically relevant thresholds from age 40 to 79 years, while specific coefficients permit identification of at-risk African-American and non-Hispanic white women at younger ages and lower risk factors levels.

“We finally have a risk calculator that does more than [evaluate] the white population,” Gulati said.

Mieres said, in June, an AHA consensus statement on the noninvasive diagnostic evaluation of ischemic heart disease in women expanded the traditional diagnostic testing algorithm to include evaluation of all components of the full spectrum of the female-specific patterns of coronary atherosclerosis.

“Women with ischemic heart disease have a more diverse symptom presentation than do men, with pain not only in the chest but in the arms, jaw, neck and interscapular area; associated epigastric discomfort and nausea; and often nonpain symptoms such as excessive dyspnea and fatigue. Women’s ischemic symptoms may often relate to emotional or mental stress and are less frequently precipitated by physical activity compared to ischemic symptoms in men,” Mieres said. “Determination of a woman’s risk status (low, intermediate or high risk for ischemic heart disease) should guide the discussion and shared decision-making between the woman and her health care provider as to the need for and appropriate selection of diagnostic tests.”

Imaging, ‘false-positive’ stress tests

Clinicians work with unique challenges and considerations daily when imaging women, experts said.

“Our measurements are adjusted for gender when describing the left ventricular cavity size or thickness. When measuring chamber sizes in our lab, we adjust for body surface area as well, which sometimes can be lower in women and result in missing enlarged cavity sizes if not adjusted,” Abha Khandelwal, MD, MS, clinical assistant professor of cardiovascular medicine at Stanford University told Endocrine Today.

“The stress myocardial perfusion scans have different imaging artifacts based on whether you have breast attenuation (more common in women) or attenuation from the diaphragm (more common in men). Finally, when looking at CT or calcium scanning, there are different reference ranges for men vs. women. More importantly, the implications of these studies often can affect women more as the radiation exposures with nuclear imaging or CT scan imaging are significant. Cumulatively, they can affect rates of future malignancy specifically in the area of the breast for our female patients,” Khandelwal said.

Touza said treadmill stress tests have higher rates of false positives in women, although stress imaging appears similarly accurate between the sexes.

“The diagnostic accuracy in women is low due to older age at presentation with comorbidities and lower exercise capacity. In the case of the stress echo and nuclear test, the values are similar to men but lower for stress ECG. Second, in the case of coronary angiography, a higher rate of absence of significant coronary stenosis has been noted in women with a non-ST elevation acute coronary syndrome. Possible mechanism for the absence of significant coronary disease in these patients includes rapid clot lysis, vasospasm and coronary microvascular disease,” Touza said.

The recent sex-specific data regarding the female pattern of ischemic heart disease has resulted in a change in clinicians interpretation of a false positive stress test in symptomatic women, Mieres said.

“Often an abnormal stress test in a man followed by a cardiac catheterization would result in finding some degree of obstructive coronary disease. We may not find any obstructive disease in women with the same type of testing. We used to label those tests as false positives,” Gulati said. “What is changing now is the whole focus that maybe those tests are not false positives, but rather a different pattern of coronary disease in women. Maybe what we are seeing would be described as ischemic heart disease. It might not be obstructive coronary disease that we typically see in men; it’s a more of a diffused disease process in women.”

Gulati said her institution often performs a traditional treadmill stress test with MRI imaging when a woman has a false-positive stress test and there are clear symptoms and signs of ischemia.

“We have actually been able to better delineate the area of microvascular disease in those women, better enhancing that reduced blood flow to the endocardium,” Gulati said.

Recent evidence refutes the benign prognosis of non-obstructive coronary atherosclerosis in women and supports the fact that women with coronary microvascular disease may have plaque rupture and plaque ulceration, which can lead to myocardial infarctions in the absence of demonstrable obstructive coronary disease, Mieres said. This is more commonly seen in younger women.

“Myocardial ischemia with adverse outcomes, in the absence of obstructive coronary disease, is an emerging paradigm for women. For several decades, the male model of coronary disease ­— obstructive atherosclerosis of the epicardial coronary arteries — constituted the basis for most diagnostic and treatment strategies for both sexes. As a result, many women who did not have classic obstructive coronary atherosclerosis were not diagnosed with ischemic heart disease and did not receive appropriate treatment,” Mieres said. “The male model of testing was designed to detect only the obstructive coronary atherosclerosis. Therefore, women who had symptoms and microvascular coronary disease or dysfunction of the coronary endothelium were under-diagnosed, as their disease was not detected.”

The 2014 consensus statement from the AHA offers gender-specific, evidence-based guidance in the use of diagnostic procedures and focuses on the role of noninvasive testing for women with suspected ischemic heart disease.

“Contemporary testing techniques must be used to evaluate the components of the full spectrum of coronary atherosclerosis in women beyond obstructive coronary disease. The prognosis is not benign in the women with microvascular disease and dysfunction of the coronary endothelium,” Mieres said. “Clinicians need to be aware of the diagnostic strategies to detect all components of ischemic heart disease in women.”

Boccia Lang said cardiac magnetic resonance angiography and rubidium-82 PET are being evaluated as new modalities to enhance the stratification of women with cardiac symptoms.

Atherosclerotic disease, medications

Women are equally vulnerable to coronary atherosclerosis as men and are at risk for CV events, Mieres said, and the Stanford team said the sexes experience this diagnosis differently.

“We have found that rates of depression and anxiety are higher with these events in women. When not treated, their outcomes are worse than their male counterparts. That is why we focus on a multidisciplinary approach to CAD from aggressive risk reduction, to post-event management including a team with providers focused on prevention, a dietitian, a behavioral psychologist, an advanced practice nurse practitioner, an imaging cardiologist and an interventional cardiologist,” Khandelwal said.

Yet, Gulati said, “Based on our knowledge right now, we should be treating men and women with atherosclerosis equally. The biggest issue is that we don’t always give women the treatment that they need.”

Additionally, the drug trials often did not include many women.

“In some of the older drug trials where drugs were proven to be life-saving medications, fewer women were included in the trials. And that is the case for even some of the newer drugs such as statins,” Gulati said. “Also, with prophylactic aspirin in the right population, it tends to prevent MI in men, but for women, it doesn’t seem reduce the risk of MI, but it does reduce the risk for stroke. We have to be studying all the drugs that we use in both men and women.”

Boccia Lang agreed: “The challenge is in identifying more women who may benefit from them by traditional risk models.”

Gulati further said in the setting of MI, women are less likely to receive “the life-saving medication,” such as statins, beta-blockers or aspirin.

“We see it both immediately, in the first 24 hours of the MI and at discharge. I would say that is the first thing that we need to correct,” she said.

Bleeding complication rates also are higher in women, experts said.

“As drugs are emerging, we should be a little more cognizant that women have more bleeding complications after an MI, and bleeding tends to be a bigger risk for our women patients compared with men,” Gulati said.

Boccia Liang said: “Particular attention is being focused on women’s higher bleeding complication rates with cardiac catheterization. For this reason, radial arterial approach is preferred to femoral approach, when feasible, particularly for women. Doses of platelet inhibitors have been modified for average smaller body mass indices in women.”

Diabetes as a risk factor

Tsai said diabetes is “a major risk factor” for CVD in women.

“Women at increased risk for developing diabetes include women with a predisposition toward diabetes, such as women with gestational diabetes, lower socioeconomic status, certain ethnic subgroups such as Southeast Asians and Latinos, and a family history of diabetes. Gestational diabetes occurs in 7% of all pregnancies (200,000 cases annually), and 5% of women with gestational diabetes will have type 2 diabetes within 6 months of postpartum; their long-term risk of developing type 2 diabetes is increased sevenfold,” Tsai said.

“Diabetes seems to confer greater prognostic information in women than any other traditional cardiac risk factors,” Touza said. “We also know that background history of gestational diabetes identifies a very young population of women predisposed for type 2 diabetes and CVD. Endothelial dysfunction might represent a shared precursor of both disorders. Appropriate identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression.”

At Ohio State, plans are underway to particularly address the specific group of women who have increased risk for developing CVD due to a history of certain pregnancy-related disorders such as gestational diabetes, preeclampsia and gestational hypertension. Stanford is enrolling patients in a similar program and is introducing a mobile intervention to improve outcomes.

“One of the things that we are going to do is to actually create a clinic for this population because we feel that this is a group that is specifically under-screened and not as aware of the risks,” Gulati said.

The effect of obesity

Women lose more muscle mass over their lifetime compared with men, making it particularly difficult for women to maintain normal weight with diet. Women require more exercise as they age to maintain normal BMI.

This is particularly challenging for women, Boccia Liang said, and the Stanford team noted that many women with obesity have attempted weight loss and failed.

“Women report a higher amount of psychosocial stress in attempting to meet the demands of multiple roles compared to men. The burden of multiple-role stress (work, family caregiving and household responsibilities) contributes to chronic stress and seems to promote atherosclerosis and CV risk in women,” Katie Edwards, PhD, a behavioral psychologist at Stanford University told Endocrine Today. “Furthermore, it is associated with decreased adherence to behavioral interventions such as cardiac rehabilitation. Women who are overweight or obese are already at higher risk for poor adherence to physical activity interventions, and psychosocial stress may make it even harder for them to benefit from diet and exercise counseling. We address this by offering group and individual stress management counseling to help women clear space in their lives to prepare for effective behavioral change.”

Not only can weight loss be an uncomfortable subject, but translating metabolic risk based on weight or BMI can be difficult, Gulati and Touza said.

“We do measurements of waist circumference, probably more so than weight because it is a better way to translate that a patient with metabolic syndrome typically gains more weight around the hip. We work with a nutritionist in our clinic because we think it is essential, but I can say that probably the hardest thing of all the things we do would be weight loss,” Gulati said.

“We use BMI for clinical assessment of human adiposity, but BMI cannot distinguish between lean mass and different depots of adipose tissue. Depending on the categorical BMI, we sometimes misclassified health risk without taking into account differences related to sex,” Touza said. “This will have an impact in counseling or weight loss strategies in women.”

Boccia Lang said this is where individualized counseling comes into play for women.

“Individualized counseling for women may be helpful for developing an action plan for better health that takes into account many women’s busy and complex schedules,” she said. “More health care organizations are moving to a model of integrated wellness coaching for the communities we serve because implementing lifestyle changes to promote heart health is so challenging.”

CVD outcomes in women

Gulati said women are traditionally treated less aggressively than men.

“We are seeing a decline in mortality in women from MI and that’s great, but we can narrow that gap even further. We could change how we view women when they come in to the emergency room,” she said. “When women have symptoms of stable angina, we are less likely to do any type of testing or invasive procedures, we are less likely to give medications. We are less likely to do revascularization procedures in women compared with men. As a result, women are more likely to die, particularly the ST-elevation MI group.”

Touza said women have a higher incidence of silent MI and myocardial ischemia.

“Reports from the Framingham heart study showed that the infarct was silent in 26% of men and 34% of women. Silent MI is strongly age dependent and we know that for total coronary events women lag behind men by 10 years,” she said. “For the more serious manifestations such as MI and sudden death, women lag behind men by 20 years.”

As always, there is room for improvement, Touza said.

“There is room for improvement in CV outcomes in women. In the last years, the medical community has been able to identify differences in stratifications of risk factors, diagnosis and treatment in CVD between women and men, and we are working solidly in closing the gap.” – by Suzanne Bryla

Does estrogen have a protective cardiovascular effect?

Whether estrogen offers benefit in CVD prevention remains under debate.

Menopausal women with cardiovascular disease carry a greater burden of risk factors, are more often symptomatic, and have a higher mortality after myocardial infarction relative to men (Gulati M. Clin Cardiol. 2012;35:141-148; Anand SS. Eur Heart J. 2008;29:932-940).

Data from the Women’s Ischemia Syndrome Evaluation (WISE) suggest that some of the features of CVD in women that contribute to these differences include susceptibility to small plaque erosion or rupture, distal micro-embolization and microvascular dysfunction (Bairey Merz CN. J Am Coll Cardiol. 2006;47(3 Suppl):S21-29.) Despite a plethora of observational studies and randomized control trials, some of which suggest a beneficial effect of menopausal hormone therapy on the progression of CVD, there has been continued debate about whether the benefits of HT are real, and whether the benefits outweigh the risks. While it is clear that the risks of HT outweigh the benefits in women with established CVD, it appears to be relatively safe for most healthy symptomatic women when initiated within 10 years of menopause. Whether HT can offer relatively more benefit in terms of primary CVD prevention in healthy early menopausal women than risk remains under debate and further data from the KEEPS trial are awaited. Meanwhile, maintenance of a healthy diet and exercise program, blood pressure control and smoking cessation remain the cornerstone of CVD prevention.

C. Noel Bairey Merz, MD, FACC, FAHA, holds the Women’s Guild Endowed Chair in Women’s Health, and is Director of the Barbra Streisand Women’s Heart Center as well as Director of the Linda Joy Pollin Women’s Heart Health Program, Director of the Preventive Cardiac Center and Professor of Medicine at Cedars-Sinai Medical Center. Disclosure: Merz is a consultant for the Research Triangle Institute International and has received research funding in 2014 from the Women’s Ischemia Syndrome Evaluation (WISE CVD and RWISE) and the Flight Attendant Medical Research Institute (FAMRI).

Estrogen therapy provides a safe option for the prevention of several chronic disease processes.

The answer to this question is both yes and no, and depends upon the timing of initiation of estrogen therapy relative to menopause (Hodis HN. J Am Geriatr Soc. 2013;61:1005-1010; Hodis HN. J Am Geriatr Soc. 2013;61:1011-1018). The cumulated data across both randomized trials and observational studies consistently show that when initiated in women within 10 years of menopause, ET reduces both coronary heart disease and total mortality by 30% to 40% (Salpeter SR. J Gen Intern Med. 2006;21:363-366; Salpeter SR. J Gen Intern Med. 2004;19:791-804; Salpeter SR. Am J Med. 2009;12:1016-1022).

Although not designed to specifically study young postmenopausal women, subgroup analyses from the Women’s Health Initiative showed that women who were less than 10 years since menopause when randomized to ET vs. placebo had a reduction in CHD, whereas women at least 10 years since menopause when randomized showed a null effect on CHD (Rossouw JE. JAMA. 2007;297:1465-1477). The Danish Osteoporosis Prevention Study confirmed the beneficial effects of ET on CHD and total mortality over 16 years in a cohort of young women who were on average 6 months postmenopausal when randomized (Schierbeck LL. BMJ. 2012;345:e6409). When initiated at the time of menopause, ET exerts a broad spectrum of effects that simultaneously prevent several chronic diseases such as CHD and bone fractures while reducing total mortality (Lobo RA. Climacteric. 2014; published online ahead of print Aug. 27).

The side effect profile of ET is more than acceptable with risks classified as rare and no greater than other medications used in clinical medicine. Use of ET for the primary prevention of CHD requires consideration of currently used therapies such as lipid-lowering medications and aspirin, which carry comparable risks to those of ET as well as additional risks such as induction of new-onset diabetes mellitus with statin therapy, but have a null effect on the primary prevention of CHD and no effect on total mortality in women (Petretta M. Int J Cardiol. 2010;138:25-31; Brugts JJ. BMJ. 2009;338:b2376; Berger JS. JAMA. 2006;295:306-313).

When initiated in close proximity to menopause, ET provides a safe sex-specific option for the simultaneous prevention of several chronic disease processes in women after the menopause.

Howard N. Hodis, MD, holds the position of Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine and Preventive Medicine, Professor of Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California. Disclosure: Hodis reports no relevant financial disclosures.