PROMISE Trial: High-Sensitivity Troponins May Assist in Detecting Obstructive CAD in Symptomatic Outpatients

Increasing concentrations of hsTnI are significantly associated with the presence and severity of coronary artery disease (CAD) among stable outpatients with chest pain, an analysis of PROMISE trial indicates.  The study, conducted by Prof. James Januzzi et al., is recently published in the June 1, 2019, issue of the Journal of the American College of Cardiology: Cardiovascular Imaging.

Chest discomfort in the outpatient setting has always been a major challenge faced by health care providers. Recently, there has been a growing interest in using coronary computed tomography angiography (CTA) for the evaluation of patients with suspected CAD. High sensitivity and negative predictive value of coronary CTA for detecting obstructive CAD and its ability to detect non-obstructive CAD, make it a promising diagnostic test in the evaluation of patients with chest discomfort. In addition to imaging modalities, serum biomarkers have diagnostic value in the evaluation of patients with suspected obstructive CAD. Currently, high-sensitivity troponin I (hsTnI) is considered the gold standard test to diagnose acute cardiac injury in acute settings. However, its clinical utility in the evaluation of the stable chest discomfort in outpatient encounters is not clear.

The current PROMISE sub-study addresses an important unanswered question: Could hsTnI be used to detect underlying CAD among symptomatic patients in a less acute, office-based setting?

The PROMISE trial was a multicenter, pragmatic comparative effectiveness study enrolling 10,003 stable symptomatic outpatients without known CAD referred for non-invasive, non-urgent cardiac testing at 193 sites in North America. The participants were randomly allocated to undergo either functional stress testing versus coronary CTA. Baseline hsTnI concentration was measured in 4,022 participants who consented. For the present analysis, the authors focused on subjects who were allocated to undergo coronary CTA and had available baseline hsTnI measurements. HsTnI concentrations were measured using a very highly sensitive single-molecule counting assay. The presence and extent of obstructive CAD as either CAD₅₀ (≥50% stenosis in any vessels ≥ 2.0 mm in diameter) or CAD₇₀ (≥70% stenosis in any vessel ≥2.0 mm in diameter or 50% stenosis involving the left main coronary artery) were assessed. Coronary artery calcium (CAC) was also quantified. Using a multivariable logistic regression model, independent predictors of obstructive CAD₅₀ and CAD₇₀ were identified.

Overall, 1,844 subjects were included in the analysis. HsTnI was measurable in nearly all (98.5%) subjects, with 6.1% having hsTnI concentrations of ≥99^th percentile for the normal population (6 ng/l). The PROMISE Investigators observed higher prevalence and number of CAD risk factors in the higher hsTnI quartiles. In higher concentrations of hsTnI, there were also more prevalent and more extensive obstructive CAD with higher CAC scores. In multivariable analyses that adjusted for demographic characteristics and traditional risk factors, log-transformed concentrations of hsTnI were independent predictors of CAD50 (odds ratio: 1.15 per IQR of log hsTnI; p = 0.02) and CAD70 (odds ratio: 1.25 per IQR of log hsTnI; p = 0.001).

A notable finding was the graded association between hsTnI and CAD within the normal range for the used assay. Although the 99^th percentile value of the assay was 6 ng/l, the authors observed a monotonic rise in CAC scores and prevalence of obstructive CAD from the lowest (<1.0 ng/l) to the highest (≥2.5 ng/l) hsTnI quartile.

Several caveats should be considered when interpreting the results. First, the hsTnI assay used in the PROMISE study had a higher sensitivity than the currently available methods, these findings may not be readily generalized to clinical practice. Second, it is noteworthy that the positive predictive value (PPV) and negative predictive value (NPV) were inadequate to be applied as a stand-alone test for decision-making (PPV 35% and NPV 76% for CAD₅₀; PPV 22% and NPV 88% for CAD₇₀). Last, the study participants were from a clinical trial with specific inclusion and exclusion criteria and may not represent the real-world outpatients with suspected CAD.