Letters

RESEARCH LETTER
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 dis-
ease (CAD) is not benign.1-3 The Women’s Ischemia Syndrome
Evaluation (WISE)4 demonstrated that the WISE CAD sever-
ity 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 ische-
mia and nonobstructive CAD enrolled from 1996 to 2000 and
followed up for up to 8.5 years.
Methods | The Women’s Ischemia Syndrome Evaluation is a Na-
tional Heart, Lung, and Blood Institute–sponsored, multicenter
study of 936 women undergoing clinically ordered coronary an-
giography 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 in-
stitutional review board at each WISE clinical site including the
Figure. Freedom From All-Cause Mortality Grouped By Stress Test Result
100
80
60
Survival, %
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 cat-
egorized 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 ex-
ercise; a dipyridamole stress technetium Tc 99m sestamibi
with at least mild reversible defect; or a dobutamine stress ech-
ocardiography 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 echocardi-
ography with more than 1 of 16 segments with fixed hypoki-
nesis or akinesis; resting electrocardiogram evidence of sig-
nificant 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 devel-
oped: adjusting only for stress test result (model 1) and addi-
tionally adjusting for CAD severity score, selected based on its
known importance as a predictor for mortality4 (model 2). Sta-
tistical analyses were carried out using SAS, version 9.4 (SAS
Institute Inc).
Results | Women in the ischemic group had lower rates of hyper-
lipidemia 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.

Log-rank P value = .05 Over the follow-up period, there were 8 deaths in the is-
40 chemic group, 11 deaths in the nonischemic group, and 12 deaths
Nonischemic in the prior infarct group. Survival curves were significantly dif-
Ischemic
20 Infarct ferent by stress test result, with the poorest survival in the in-
farct group (log-rank P = .05, Figure). Women with prior in-
0 farct had a significantly worse prognosis compared with women
0 1 2 3 4 5 6 7 8 9 with a nonischemic stress test, which persisted even after ad-
Time to Death, y
No. at risk justing for CAD severity scores (Table). There were no differ-
Nonischemic 169 166 165 165 165 164 163 162 159 ences in prognosis for women in the ischemic group compared
Ischemic 103 102 102 102 100 100 99 97 96
Infarct 75 73 73 71 71 71 69 67 64 with women in the nonischemic group, either before or after ad-
justment for CAD severity score (Table).

Table. Hazard Ratios (HRs) (95% CIs) for All-Cause Mortality

HR (95% CI)
a
Outcome Factor Model 1a Model 2b Adjusted for stress test result.
b
All-cause mortality Infarct vs nonischemic 2.58 (1.14, 5.84) 2.84 (1.24, 6.54) Adjusted for stress test result and
coronary artery disease severity
All-cause mortality Ischemic vs nonischemic 1.20 (0.48, 2.98) 1.35 (0.53, 3.40)
score.

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 Letters
Discussion | 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. Ische-
mia 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 sen-
sitivity and specificity for ischemia and/or infarct. Our find-
ings underscore the need for heightened recognition of an ad-
verse event profile in these women.
Tara L. Sedlak, MD
Meijiao Guan, PhD
May Lee, MSc
Karin H. Humphries, DSc
B. Delia Johnson, PhD
Carl J. Pepine, MD
C. Noel Bairey Merz, MD
Author Affiliations: Vancouver General Hospital, Vancouver, British Columbia,
Canada (Sedlak); Department of Medicine, University of British Columbia,
Vancouver, British Columbia, Canada (Sedlak, Humphries); British Columbia
Centre for Improved Cardiovascular Health, Vancouver, British Columbia,
Canada (Guan, Lee, Humphries); Department of Cardiovascular Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania (Johnson); Department of
Epidemiology, University of Florida, Gainesville (Pepine); Barbra Streisand
Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
(Merz).
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.
492 JAMA Cardiology July 2016 Volume 1, Number 4 (Reprinted)
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1. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no
obstructive coronary artery disease is associated with increased risks of major
adverse cardiovascular events. Eur Heart J. 2012;33(6):734-744.
2. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary
artery disease and risk of myocardial infarction. JAMA. 2014;312(17):1754-1763.
3. Sedlak TL, Lee M, Izadnegahdar M, Merz CN, Gao M, Humphries KH. Sex
differences in clinical outcomes in patients with stable angina and no
obstructive coronary artery disease. Am Heart J. 2013;166(1):38-44.
4. Sharaf B, Wood T, Shaw L, et al. Adverse outcomes among women
presenting with signs and symptoms of ischemia and no obstructive coronary
artery disease: findings from the National Heart, Lung, and Blood
Institute–sponsored Women’s Ischemia Syndrome Evaluation (WISE)
angiographic core laboratory. Am Heart J. 2013;166(1):134-141.
5. Merz CN, Kelsey SF, Pepine CJ, et al. The Women’s Ischemia Syndrome
Evaluation (WISE) study: protocol design, methodology and feasibility report.
J Am Coll Cardiol. 1999;33(6):1453-1461.
6. Sharaf BL, Pepine CJ, Kerensky RA, et al; WISE Study Group. Detailed
angiographic analysis of women with suspected ischemic chest pain (pilot phase
data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation [WISE]
Study Angiographic Core Laboratory). Am J Cardiol. 2001;87(8):937-941, A3.
Risk of Premature Cardiovascular Disease vs the
Number of Premature Cardiovascular Events
The risk of new-onset cardiovascular disease (CVD) is low be-
fore the age of 40 years, increases steadily between 40 and 60
years, but jumps sharply thereafter.1 Consequently, treat-
ment guidelines, which are based on risk, recommend pre-
ventive therapy most commonly for individuals older than 60
years.2 However, the distribution of the population is not uni-
form across the age spectrum and therefore risk does not nec-
essarily reflect the absolute number of cardiovascular events
at different ages. Accordingly, we have estimated the ex-
pected number of new-onset cardiovascular events per de-
cade across the age spectrum beginning at age 45 years.
Methods | This study was conducted from November 1, 2015, to
January 19, 2016. To estimate the sex-specific incidence of total
new-onset cardiovascular events per age decade, we used the av-
erage event rates included in the American Heart Association 2015
heart disease and stroke statistical update.1 We also estimated
the number of US residents free of clinical atherosclerotic CVD
as defined by the 2013 American College of Cardiology/American
Heart Association cholesterol guidelines,2 applying the 2005-
2010 National Health And Nutrition Examination Survey as pre-
viously described.3 We then applied the average annual incidence
rates to the populations at risk by age decade and sex. As the study
used published results and publicly available survey data from
the National Health And Nutrition Examination Survey, no in-
stitutional review board approval was necessary. The National
Health And Nutrition Examination Survey does not contain any
identifiable patient data, so no deidentification was needed.
Results | In both women and men, the absolute rate of new-onset
cardiovascular events increases sharply after 65 years (Figure, A).
By contrast, the population at risk steadily decreases as age in-
creases (Figure, B). As a result, in men, the number of new-onset
cardiovascular events per age decade is roughly constant until age
85 years. About one-fourth of all new-onset cardiovascular events
in men occur before age 55 years and half occur before age 65 years
(Figure, C). In women, there is a progressive increase in the num-
ber of new-onset cardiovascular events such that about one-
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