ISCHEMIA, to revascularize or not to revascularize
ISCHEMIA, to revascularize or not to revascularize
Faraz Kureshi 0
Mouin S. Abdallah 0
0 Reprint requests: Mouin S. Abdallah, MD, MSc, Saint Luke's Mid America Heart Institute, University of Missouri Kansas City , Kansas City, MO
1 Saint Luke's Mid America Heart Institute, University of Missouri Kansas City , Kansas City, MO
Management of patients with coronary artery
disease is focused on preventing cardiovascular events,
improving survival, and control of anginal symptoms,
and the cornerstone of treatment is optimal medical
therapy with or without coronary revascularization.1
When these options of therapy have been compared
among patients with stable ischemic heart disease, the
benefits of coronary revascularization in addition to
optimal medical therapy is not as clear as among
patients with acute coronary syndrome. This is based on
the results of several large randomized clinical trials that
have failed to show a consistent superiority of one
treatment strategy compared to the other. However,
some results from observational studies have suggested
that coronary revascularization may be superior to
optimal medical therapy among patients with significant
ischemia.2,3,4-7 The above-mentioned hypothesis served
as the nidus behind the ongoing National Heart, Lung,
and Blood Institute-funded ISCHEMIA trial
(International Study of Comparative Health Effectiveness With
Medical and Invasive Approaches; NCT01471522). In
this trial, patients with stable ischemic heart disease and
at least moderate ischemia will be randomized to
optimal medical therapy with or without coronary
revascularization to definitively answer the ongoing
dilemma whether an invasive strategy with
revascularization improves long-term outcomes in a randomized
Although ischemia can be detected and quantified
through multiple modalities, the richest data confirming
the role of myocardial ischemia as a strong prognostic
factor come from nuclear imaging.8-12 In this issue of
the journal, Nudi et al reports a single-center,
retrospective observational study evaluating the impact of
coronary revascularization as compared to medical
therapy on ischemia in patients undergoing serial
stress- and rest-gated single-photon emission computed
tomography (SPECT) myocardial perfusion imaging
(MPI) studies. In order to better evaluate a cohort of
patients with stable ischemic heart disease, patients
were excluded if they had unstable angina in the prior 6
months, prior myocardial infarction, reduced left
ventricular ejection fraction (\45%), or a left ventricular
end diastolic volume index [ 130 ml/m2. Ischemia was
semi-quantified by 2 experienced unblinded readers
based on previously published (but not widely adopted)
seven-region segmentation approach for left ventricular
myocardium corresponding to a maximal ischemia
score (MIS) group (no, minimal, mild, moderate, or
severe ischemia).13 The authors identified a total of
3631 patients who underwent serial SPECT MPI
between the years of 2004-2014 with 27% (n = 967)
undergoing coronary revascularization and 73%
(n = 2664) receiving only medical therapy at baseline.
Multivariable adjustment and propensity score
methodologies were used to minimize the effect of
confounders. Unadjusted analyses revealed that
revascularization was more effective than medical therapy in
reducing myocardial ischemia in those patients with
baseline moderate or greater MIS scores. All adjusted
and propensity-matched analyses suggested a lower
odds of a unit increase in MIS scores of patients who
underwent revascularization as compared to medical
Given the observational nature of this study, several
limitations should be noted. First, the study is subject to
selection biases based on inclusion criteria and treatment
assignment. Although the authors attempted to control
for confounding using adjustment methods and
propensity matching, there were several notable
differences between those who were placed on medical
therapy and those who received revascularization. This
is clearly demonstrated in the propensity-matched
analysis where the analytic cohort was reduced from 3631 to
732 patients, and the statistical significance of the results
was less pronounced (P dropped from \0.001 for
multivariable-adjusted analysis to 0.042 for
propensitymatched analysis). Second, there were several important
factors associated with management strategies that were
not accounted for (chronic kidney disease, baseline
angina status, prior revascularization by type, peripheral
arterial disease, financial status, medication compliance),
neither in the adjustment or propensity-matched groups.
Third, when using propensity methodology, prior work
has discouraged the use of statistical significance testing
and suggested the use of standardized differences to assess
the balance in propensity matching as this measure of
distribution is not as sensitive to sample size as traditional
testing.14,15 Fourth, there was no definition of optimal
medical therapy or report of medication dosing, and it is
certainly plausible that suboptimal medical therapy could
have contributed to changes in ischemic burden on
In spite of the above-mentioned limitations, the
results from this analysis are similar to the prior reported
sub-studies from the COURAGE and BARI-2D, which
evaluated the effects of medical therapy and
revascularization on ischemic burden.6,7 In the COURAGE
substudy, patients underwent baseline and follow-up
SPECT MPI, and it was found that revascularization in
addition to optimal medical therapy resulted in a greater
proportion of patients achieving the primary end point of
C5% reduction in ischemic myocardium at follow-up
(33% vs 19%, P = 0.0004), especially patients among
those with moderate-to-severe baseline ischemia (78%
vs 52% P = 0.007). However, no differences were
noted in adjusted death or myocardial infarction rates
based on ischemia reduction.7 In the BARI-2D sub
study, 1-year follow-up SPECT MPI was performed in
1505 diabetic patients with stable ischemic heart
disease. It was found that a greater proportion of patients
who received revascularization had no ischemia as
compared with those assigned to optimal medical
therapy (59% vs 49%, P \ 0.001). Similar to COURAGE,
myocardial ischemic severity was not an independent
predictor of death or MI after adjustment.6
As the ISCHEMIA trial is progressing in a slow
fashion, having recruited only 3020 patients out of a
goal of 8000 patients as of May 17th, 2016 (https://
www.ischemiatrial.org; accessed on May 17, 2016), we
will have to wait for several more years to better
understand the complex interaction between ischemic
burden, optimal medical therapy, and coronary
revascularization, and how these factors impact patient
outcomes. In the interim, we should continue to follow
current practice guidelines1 along with the Appropriate
Use Criteria16 that have been vetted by the leaders in our
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2. Hachamovitch R. Does Ischemia Burden in Stable Coronary Artery Disease Effectively Identify Revascularization Candidates?: Ischemia Burden in Stable Coronary Artery Disease Effectively Identifies Revascularization Candidates . Circulation 2015 ; 8 : e000352 .
3. Reynolds HR , Picard MH , Hochman JS . Does Ischemia Burden in Stable Coronary Artery Disease Effectively Identify Revascularization Candidates?: Ischemia Burden in Stable Coronary Artery Disease Does Not Effectively Identify Revascularization Candidates. Circulation 2015 ; 8 : e000362 .
4. Hachamovitch R , Hayes SW , Friedman JD , Cohen I , Berman DS . Comparison of the Short-Term Survival Benefit Associated With Revascularization Compared With Medical Therapy in Patients With No Prior Coronary Artery Disease Undergoing Stress Myocardial Perfusion Single Photon Emission Computed Tomography . Circulation 2003 ; 107 : 2900 - 7 .
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6. Shaw LJ , Cerqueira MD , Brooks MM , Althouse AD , Sansing VV , Beller GA , et al. Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk reduction in diabetic patients with coronary artery disease: Results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial . J Nucl Cardiol 2012 ; 19 : 658 - 69 .
7. Shaw LJ , Berman DS , Maron DJ , Mancini GB , Hayes SW , Hartigan PM , et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: Results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy . Circulation 2008 ; 117 : 1283 - 91 .
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