Ischemic Predictors of Outcomes in Women With Signs and Symptoms of Ischemia and Nonobstructive Coronary Artery Disease

Studies suggest that the prognosis of women with signs and symptoms of ischemia and nonobstructive coronary artery disease (CAD) is not benign.^1-3 The Women’s Ischemia Syndrome Evaluation (WISE)⁴ demonstrated that the WISE CAD severity score, a measure of coronary atherosclerotic burden, is a useful predictor of mortality in women with nonobstructive CAD. However, the prognostic value of ischemia variables is less well described. We evaluated the associaton of ischemia and prior infarct with outcomes using the WISE database, which consisted of women with signs and symptoms of ischemia and nonobstructive CAD enrolled from 1996 to 2000 and followed up for up to 8.5 years.

The Women’s Ischemia Syndrome Evaluation is a National Heart, Lung, and Blood Institute–sponsored, multicenter study of 936 women undergoing clinically ordered coronary angiography for suspected myocardial ischemia.⁵ The 4 clinical sites, study design, and protocols were described previously.^5,6 All women provided signed informed consent in accordance with institutional guidelines and the study was approved by the institutional review board at each WISE clinical site including the University of Pittsburgh Medical Center and the Allegheny County General Hospital (both located in Pittsburgh, Pennsylvania), the University of Florida (Gainesville), and the University of Alabama at Birmingham. Three hundred forty-seven women, classified with nonobstructive CAD on angiography (defined as <50% CAD in any epicardial artery) and an available clinically ordered stress test performed at baseline before entry into the WISE, were categorized into ischemic, nonischemic, or prior infarct.

Ischemia was defined as one of the following: an exercise stress test with at least 1 mm of horizontal or downsloping ST segment depression in 2 or more contiguous leads during exercise; a dipyridamole stress technetium Tc 99m sestamibi with at least mild reversible defect; or a dobutamine stress echocardiography with at least 1 of 16 segments with stress-induced hypokinesis or akinesis. Prior infarct was defined as one of the following: a technetium Tc 99m sestamibi with at least mild irreversible defect; a dobutamine stress echocardiography with more than 1 of 16 segments with fixed hypokinesis or akinesis; resting electrocardiogram evidence of significant Q waves in 2 or more contiguous leads; or history of myocardial infarction on medical record review.

Kaplan-Meier curves by stress test result with up to 8.5 years of follow-up for all-cause mortality were compared by the log-rank test. Two Cox regression models were developed: adjusting only for stress test result (model 1) and additionally adjusting for CAD severity score, selected based on its known importance as a predictor for mortality⁴ (model 2). Statistical analyses were carried out using SAS, version 9.4 (SAS Institute Inc).

Women in the ischemic group had lower rates of hyperlipidemia and statin use. Women in the prior infarct group had lower rates of a family history of premature CAD. Otherwise, there were no other differences in baseline characteristics.

Over the follow-up period, there were 8 deaths in the ischemic group, 11 deaths in the nonischemic group, and 12 deaths in the prior infarct group. Survival curves were significantly different by stress test result, with the poorest survival in the infarct group (log-rank P = .05, Figure). Women with prior infarct had a significantly worse prognosis compared with women with a nonischemic stress test, which persisted even after adjusting for CAD severity scores (Table). There were no differences in prognosis for women in the ischemic group compared with women in the nonischemic group, either before or after adjustment for CAD severity score (Table).

In women with signs and symptoms of ischemia and nonobstructive CAD, those with prior infarct had a 2.84-fold increased risk of death for up to 8.5 years of follow-up. Ischemia on stress testing was not associated with an increase in risk of mortality in this population of women. Our results may not be generalizable to nonangiographic populations of women or to men. A second limitation is that our classification of women is based on a mixture of stress testing results with different sensitivity and specificity for ischemia and/or infarct. Our findings underscore the need for heightened recognition of an adverse event profile in these women.

Corresponding Author: Tara L. Sedlak, MD, 2775 Laurel St, Level 9, Vancouver, BC V5Z 1M9, Canada (tara.sedlak@vch.ca).

Published Online: May 11, 2016. doi:10.1001/jamacardio.2016.0740.

Author Contributions: Dr Sedlak had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Sedlak, Pepine, Merz.

Acquisition, analysis, or interpretation of data: Sedlak, Guan, Lee, Humphries, Johnson, Merz.

Drafting of the manuscript: Sedlak, Guan, Lee.

Critical revision of the manuscript for important intellectual content: Sedlak, Humphries, Johnson, Pepine, Merz.

Statistical analysis: Sedlak, Guan, Lee, Johnson, Merz.

Administrative, technical, or material support: Sedlak, Humphries.

Study supervision: Sedlak, Pepine, Merz.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by grants N01-HV-68161, N01-HV-68162, N01-HV-68163, and N01-HV-68164 from the National Heart, Lung, and Blood Institutes; grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, UL1TR000124, and 1R03AG032631 from the National Institute on Aging; GCRC grant MO1-RR00425 from the National Center for Research Resources; and National Center for Advancing Translational Sciences grant UL1TR000124. It was also supported by grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey; the Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California; the Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh; QMED Inc, Laurence Harbor, New Jersey; the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California; the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, California; the Society for Women’s Health Research, Washington, DC; the Linda Joy Pollin Women’s Heart Health Program; and the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.