Better outcomes sought for women with CVD

Recent data are making something very clear: CVD in women is not necessarily the same as CVD in men.

It follows, then, that CVD prevention strategies for women might need to differ from CVD prevention strategies for men. Clinicians are working to implement strategies to better identify risk factors and improve the management of and outcomes for CVD in women.

The good news is that advancements have been made for women with CVD. According to the American Heart Association and CDC Heart Disease and Stroke Statistics, there was a 30% decline in mortality in 2014 compared with a decade ago.

“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,” Jennifer H. Mieres, MD, FACC, FASNC, FAHA, professor of cardiology and population health, Hofstra North Shore-LIJ School of Medicine, said in an interview.

The bad news is that CVD remains underdetected in women, and outcomes lag behind for women with CVD compared with men.

Experts interviewed by Cardiology Today said efforts are being made to close the gender gap, including better understanding of the risk factors unique to or more prevalent in women, better understanding of how atherosclerosis develops and manifests itself in women, and paying more attention to imaging results that may not indicate classic symptoms of CAD but may signal a problem that needs to be treated.

Challenges for women

Women were underdiagnosed and undertreated for CVD for many years because the knowledge base was primarily derived from research in men, experts told Cardiology Today. But that is now changing, they said.

“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,” Mieres said. “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. 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 underdiagnosed, as their disease was not detected.”

In addition, many 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,” 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, told Cardiology Today. “Also, with prophylactic aspirin in the right population, it tends to prevent MI in men; 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.”

Claire Boccia Liang, MD, director of the Women’s Heart Program at Morristown Medical Center in New Jersey, agreed: “The challenge is in identifying more women who may benefit from them by traditional risk models.”

Reliance on the Framingham Risk Score may have contributed to the gender gap, as it “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%,” Boccia Liang said. “For this reason, newer risk calculators have been devised, including the Reynolds Risk Score and the pooled-cohort risk-assessment tool.”

The imbalance in practice also extends to the MI setting, experts said.

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

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

Managing female-specific risk factors

A key to closing the gender gap in prevention and treatment of CVD is a better understanding of risk factors that are unique to women or disproportionately affect them compared with men.

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, Gulati said.

“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 at 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.”

“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, BP, cholesterol, diet, smoking, blood glucose and weight,” Sandra Tsai, MD, MPH, clinical assistant professor of medicine and an internist focused on preventive cardiology who is part of a team of multidisciplinary experts at Stanford University, said.

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

“Women at increased risk for developing diabetes include those with a predisposition toward diabetes, such as 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.”

There is also evidence that depression and anxiety are more linked with CV events in women than in men, Abha Khandelwal, MD, MS, clinical assistant professor of cardiovascular medicine at Stanford University, said in an interview.

“When not treated, outcomes [in women] 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.

The interaction between obesity and CVD in women is also a challenge, experts said. Women lose more muscle mass over their lifetime compared with men, making it particularly difficult for women to maintain normal weight with diet, and women require more exercise as they age to maintain a normal BMI.

“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, said. “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.”

Presentation of disease

It is because of these differences that women require a unique approach to evaluation, experts said.

“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,” Mieres said. “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.”

In fact, clinicians may need to think about the pathophysiology of heart disease in women in a completely different way from that in men, she said.

“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.

Symptom presentation can be quite different in women compared with men, and clinicians and patients need to be aware of these differences, she said.

“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,” Mieres said. “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. Determination of a woman’s risk status for ischemic heart disease (low, intermediate or high) 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.”

Further differences arise after women reach menopause, according to C. Noel Bairey Merz, MD, FACC, FAHA, the Women’s Guild Endowed Chair in Women’s Health; director of the Barbra Streisand Women’s Heart Center; 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, said.

“Menopausal women with CVD carry a greater burden of risk factors, are more often symptomatic and have a higher mortality after MI relative to men,” Bairey Merz, a member of the Cardiology Today Editorial Board, said. “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.”

Special diagnosis considerations

CV imaging in women also presents unique challenges and considerations.

“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,” Khandelwal said.

“The stress myocardial perfusion scans have different imaging artifacts based on whether you have breast attenuation, which is more common in women, or attenuation from the diaphragm, which is 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 men and women.

“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 mechanisms for the absence of significant coronary disease in these patients includes rapid clot lysis, vasospasm and coronary microvascular disease,” Touza said.

Recent gender-specific data regarding the female pattern of ischemic heart disease has resulted in a change in the interpretation of a false-positive stress test in symptomatic women, Mieres said. She noted that a 2014 consensus statement from the AHA offers gender-specific, evidence-based guidance for 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.”

Gulati noted that as a result, interpretations of coronary disease patterns are changing.

“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 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,” she said.

Recent evidence refutes the benign prognosis of nonobstructive 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 MI 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,” she said.

Cardiac magnetic resonance angiography and rubidium-82 PET have been evaluated as new modalities to enhance the stratification of women with cardiac symptoms, Boccia Liang said.

Positive steps

With more knowledge about how women present with CVD and their risk factors, steps are being taken on a number of fronts to better prevent, diagnose and treat CVD in women.

A prominent move was the release of a new risk calculator as part of the Clinical Guidelines on Cardiovascular Risk Reduction in Adults from the American College of Cardiology and the AHA, which the guideline authors say is better suited than the Framingham Risk Score to predict CVD in women.

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-factor levels.

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

More research continues to be conducted and published on women and heart disease, as evidenced by a number of presentations given at the 2014 AHA Scientific Sessions (see Sidebar below). In addition, Boston Scientific recently announced the launch of a trial to evaluate the clinical performance of a drug-eluting stent specifically in women and minorities.

Another area of research interest is whether hormone therapy can help prevent CVD in women.

“While it is clear that the risks of hormone therapy 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,” she said. “Whether hormone therapy 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.”

Institutions have taken a number of initiatives to improve CVD outcomes in women. At The Ohio State University, plans are underway to 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 University 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 underscreened and not as aware of the risks,” Gulati said.

Road to better outcomes

More change is needed before the gender gap is closed, however. For example, Gulati said, women are traditionally treated less aggressively than men.

“We are seeing a decline in mortality from MI in women 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 also noted that 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.”

There is room for improvement regarding CV outcomes in women, Touza said.

“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 to close the gap.” – by Suzanne Bryla