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 ?1 mm. 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.

Public Health Relevance

Each year almost 120,000 Veterans and several million Americans complete heart blood flow (nuclear imaging) stress tests costing up to 6 billion dollars annually. Many of these Veterans cannot perform treadmill exercise and hence undergo chemical stress test nuclear imaging, which requires injection of radioactivity, is several times more expensive and time?consuming than exercise testing without imaging and precludes access to powerful prognostic and clinically important exercise data. To address this problem, we obtained previous evidence that non-imaging arm exercise stress test results strongly predict mortality and clinical outcome but no prospective trials have compared arm exercise to chemical stress test imaging or treadmill exercise testing. Thus, our goal is to perform a trial comparing arm and treadmill exercise without imaging with chemical stress testing with imaging, all without and with coronary artery calcium scoring, to detect coronary artery blockages and predict clinical outcome.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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St. Louis VA Medical Center
St. Louis
United States
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