Arm Exercise Versus Pharmacologic Stress Testing for Clinical Outcome

Treadmill exercise capacity and other physiologic responses to leg exercise are powerful
predictors of mortality and provide important clinical and diagnostic information. However,
many Veterans cannot perform treadmill exercise because of lower extremity or other
disabilities. For many years, pharmacologic myocardial perfusion imaging (MPI) has been the
standard of care for their evaluation but fails to provide powerful prognostic and clinically
relevant information of exercise testing, requires exposure to ionizing radiation, and is
several times more expensive than exercise electrocardiography (ECG). With a recently
completed Merit Review award, we obtained substantial retrospective observational evidence
that arm exercise ECG stress testing scores are at least equivalent to pharmacologic MPI for
robust prediction of mortality and other measures of clinical outcome in Veterans who cannot
perform leg exercise. Major hypotheses for the current proposal are: 1) arm exercise ECG
stress testing scores or best fit models without or with coronary artery calcium scoring (-/+
CACS) are non-inferior to the Duke Treadmill Score -/+ CACS, best fit model treadmill ECG and
regadenoson (r) MPI stress testing, all performed in the same Veterans in randomized order,
as an initial evaluation for obstructive coronary artery disease (oCAD), and 2) arm exercise
ECG stress testing scores or best fit models -/+ CACS are non-inferior to the Duke Treadmill
Score -/+ CACS, best fit model treadmill ECG and rMPI stress testing in the same Veterans for
predicting the primary clinical endpoint (composite of cardiovascular (CV) mortality,
myocardial infarction, or 90-day post-stress test coronary revascularization) and secondary
clinical endpoints of all-cause mortality and CV mortality. Our specific aim for all Veterans
referred to the St. Louis Veterans Administration (VA) stress testing laboratory and are
without exclusions for exercise or regadenoson stress testing or cardiac computed tomographic
angiography (CTA), is to perform a single site prospective clinical trial comparing arm
exercise ECG stress test scores and best models -/+ CACS with the Duke Treadmill Score -/+
CACS if able to perform treadmill exercise, and best fit treadmill ECG and rMPI models, all
performed in the same Veterans, for identification of the diagnostic endpoint of oCAD,
defined as a severely ( 70%) occluded epicardial, graft, or 50% left main coronary artery
lumen, determined by cardiac CTA or invasive coronary arteriography, and prediction of the
primary and secondary clinical endpoints described above. The arm exercise scoring system to
be evaluated incorporates the variables arm exercise capacity in resting metabolic
equivalents, 1-minute heart rate recovery and arm exercise-induced ST depression of 1 mm or
greater. Regadenoson MPI variables to be evaluated include an abnormal MPI study and best fit
models of summed stress and difference scores, transient ischemic dilatation, gated left
ventricular ejection fraction, and the heart rate response. We plan to enroll 75 Veterans per
year for 4 years and follow the entire cohort for an additional year. Statistical analyses
will be performed with SAS using univariate and multivariate logistic and Cox regression
models. We will evaluate non-inferiority of arm exercise scores -/+ CACS for their
association with oCAD and prediction of clinical endpoints with a non-inferiority margin of
0.05. A long term goal is to develop a multi-site prospective randomized VA Cooperative Study
to assess generalizability of arm exercise ECG stress testing -/+ CACS for diagnostic and
prognostic evaluation in the VA and United States healthcare systems.

Inclusion Criteria:

- Any veteran referred to the St. Louis VA Healthcare System stress testing laboratory
for a cardiac stress test

Exclusion Criteria:

- Contra-indications to stress testing such as acute coronary syndrome, uncompensated
heart failure, or unstable cardiac dysrhythmias Inability to perform arm exercise
stress testing

- Contra-indications to regadenoson stress testing such as significant reversible airway
disease, heart block, or low blood pressure

- An abnormal baseline ECG (e.g. left bundle branch block, widespread ST segment
depression of at least 1 mm, ventricular paced rhythm) that precludes interpretation
of the stress ECG

- Contra-indications to cardiac computed tomographic angiography (CTA) such as contrast
allergies and renal dysfunction (glomerular filtration rate < 30 ml/min)