clinicaltrials.gov Indentifier: NCT01174550.

Background Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However limited data exist as to how CAC compares to functional testing (FT) in estimating prognosis in symptomatic patients. Methods In the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial, patients with stable chest pain (or dyspnea) and intermediate pre-test probability for obstructive coronary artery disease (CAD) were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4,209) and compared to results of FT (n=4,602). We stratified CAC and FT results as normal or mildly, moderately or severely abnormal (for CAC: 0, 1–99 Agatston Score [AS], 100–400 AS and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia and severe=large ischemic region abnormality). The primary endpoint was all-cause death, myocardial infarction or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios and C-statistic to determine predictive and discriminatory value. Results Overall, the distribution of normal or mildly, moderately or severely abnormal test results was significantly different between FT and CAC (FT = normal 3588 [78.0%], mild 432 [9.4%], moderate 217 [4.7%], severe 365 [7.9%]; CAC = normal 1,457 [34.6%], mild 1340 [31.8%], moderate 772 [18.3%], severe 640 [15.2%], p <0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC HR 3.14, 95% CI 1.81–5.44 and FT HR 2.65, 95% CI 1.46–4.83; severe: CAC HR 3.56, 95% CI 1.99–6.36 and FT HR 3.88, 95% CI 2.58–5.85. In the CAC arm, the majority of events (n=112/133; 84%) occurred in patients with any positive CAC test (score >0) whereas less than half of events occurred in patients with mild, moderate or severely abnormal FT (n=57/132; 43%) (p<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT vs 35.2% for CAC, p<0.001). Overall discriminatory ability in predicting the primary endpoint of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (c-statistic, 0.67 vs. 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared to FT and CAC testing (C-index: 0.72). Conclusion Among stable outpatients presenting with suspected CAD, most patients experiencing clinical events have measurable CAC at baseline while less than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests. Clinical Trial Registration URL: https://clinicaltrials.gov; Unique Identifier: NCT01174550