"Women with clinical findings suggestive of ischemia but without findings of obstructive...CAD on angiography represent a frequent clinical problem; predicting prognosis is challenging," write Martha Gulati, MD, MS, from Northwestern University in Chicago, Illinois, and colleagues.
In the Women's Ischemia Syndrome Evaluation (WISE) study, women with ischemic symptoms were referred for clinically indicated coronary angiography. Mean duration of follow-up was 5.2 years. In the St. James Women Take Heart (WTH) Project, asymptomatic, community-dwelling women with no history of heart disease at baseline were observed for 10 years.
The investigators compared rates of cardiovascular events, including myocardial infarction, stroke, hospitalization for heart failure, and mortality in 540 women from WISE who had suspected ischemia but no angiographic evidence of obstructive CAD vs those in a cohort of 1000 women from WTH who were matched for age and race.
Baseline prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus were lower in asymptomatic women from WTH vs the matched sample from WISE (P < .001). After adjustment for risk factors for CAD at baseline, 5-year annualized cardiovascular event rates were 16.0% in women from the WISE study with nonobstructive CAD (defined as stenosis in any coronary artery of 1% to 49%) vs 7.9% in the women from WISE with normal coronary arteries (defined as 0% stenosis in all coronary arteries) and 2.4% in asymptomatic women from WTH (P = .002).
Women with 4 or more cardiac risk factors had the highest rate of cardiovascular events. Five-year annualized cardiovascular event rate was 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women (P = .003).
"Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women," the study authors write.
"Based on our findings reported herein and the findings of others linking endothelial dysfunction and future cardiovascular events, we recommend that all women with symptoms suggestive of ischemia undergo initial evaluation for obstructive CAD. If there is no evidence of obstructive CAD, such women need further assessment for endothelial dysfunction."
Limitations of this study include the referral pattern of the symptomatic women from WISE, because women were referred for a coronary angiogram only if clinically indicated based on signs and symptoms suggesting myocardial ischemia. Women in this group had access to healthcare and volunteered for exercise stress testing, creating other possible bias in this group. Self-report of cardiovascular events in both cohorts creates the potential for recall bias.
Furthermore, cause of death was confirmed by medical records only for deaths in the WISE cohort, and the WTH cohort was reevaluated for cardiovascular events only at 10 years vs annually, again increasing the risk for recall bias. In both cohorts, women came from different geographic regions with different rates of cardiovascular disease, creating possible confounding. Electrocardiography was not available for the full WISE cohort, preventing adjustment for left ventricular hypertrophy.
"Given that CAD remains the leading cause of death in women in the United States and that this clinical scenario of cardiac symptoms in the absence of obstructive CAD is relatively common, future investigations need to expand on the mechanisms and pathophysiologic processes of vascular dysfunction in symptomatic women," the study authors conclude.
"In addition, future research needs to focus on randomized clinical trials to determine the effectiveness of treatment both for symptoms and for endothelial dysfunction. Nonetheless, symptomatic women with normal coronary arteries or nonobstructive CAD do not have a benign prognosis and, as such, should have cardiac risk factors aggressively treated and possibly should be considered for further testing for endothelial dysfunction."
The National Heart, Lung, and Blood Institute; the Gustavus and Louis Pfeiffer Research Foundation; the Women's Guild of Cedars-Sinai Medical Center; and the Ladies Hospital Aid Society of Western Pennsylvania supported this study. The study authors have disclosed no relevant financial relationships.
Arch Intern Med. 2009;169:843-850.
Clinical Context
Women with angina or other symptoms suggesting cardiac ischemia are sometimes not found to have clinically significant CAD on angiography, and management may be problematic. Although these women were originally thought to have a benign prognosis, recent evidence suggests that they may be increased risk for future cardiac events.
No previous prospective studies have evaluated the prognosis of women who have chest pain without obstructive CAD vs the prognosis in symptomatic women. Even in the absence of obstructive CAD, chest pain and similar symptoms may have important functional ramifications for affected women and economic repercussions for society.
Study Highlights
- The goal of this prospective study was to determine the prognostic implications of cardiac symptoms in women with nonobstructive CAD vs community-dwelling women without cardiac symptoms.
- Women with ischemic symptoms who were referred for clinically indicated coronary angiography in the WISE study (n = 540) were compared with an age-matched and race-matched cohort from the WTH Project.
- The WTH comparison group consisted of 1000 asymptomatic, community-dwelling women free of known CAD at baseline.
- Mean duration of follow-up was 5.2 years in WISE and 10 years in WTH.
- In both cohorts, the cardiovascular endpoint included myocardial infarction, hospitalization for heart failure, stroke, cardiac mortality, and all-cause mortality.
- The primary composite endpoint was cardiovascular events, defined as myocardial infarction, hospitalization for heart failure, stroke, or cardiac death.
- The secondary composite endpoint was myocardial infarction, hospitalization for heart failure, stroke, or all-cause mortality.
- Compared with the matched sample from WISE, the asymptomatic women from WTH had lower prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus (P < .001).
- Nonobstructive CAD was defined as stenosis in any coronary artery of 1% to 49%, and normal coronary arteries were defined as 0% stenosis in all coronary arteries.
- 5-year annualized cardiovascular event rates were 16.0% in women from WISE with nonobstructive CAD, 7.9% in women from WISE with normal coronary arteries, and 2.4% in asymptomatic women from WTH, after adjustment for risk factors for CAD at baseline (P ≤ .002),
- The highest 5-year annualized cardiovascular event rates occurred in women with ≥ 4 cardiac risk factors at baseline: 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women (P = .003).
- The investigators concluded that women without obstructive CAD but with symptoms and signs suggesting ischemia are at higher risk for cardiovascular events vs asymptomatic, community-based women.
- Therefore, the investigators recommend that all women with symptoms suggesting ischemia be evaluated for obstructive CAD, with further workup for endothelial dysfunction if results of workup for obstructive CAD are negative.
- Limitations of the study include potential referral bias, volunteer bias, and recall bias, as well as possible confounding.
- Cause of death was confirmed by medical records only for deaths in the WISE cohort, but electrocardiography was not available for the full WISE cohort, preventing adjustment for left ventricular hypertrophy.
Clinical Implications
- Community-dwelling women with symptoms suggesting myocardial ischemia but without findings of obstructive CAD are at greater risk for future cardiovascular events than asymptomatic women. Five-year risk for cardiovascular events in symptomatic women with nonobstructive CAD is almost twice that in symptomatic women with normal coronary arteries.
- The highest 5-year annualized cardiovascular event rates occurred in women with 4 or more cardiac risk factors at baseline: 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women.
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