Use of High-Risk Coronary Atherosclerotic Plaque Detection for Risk Stratification of Patients With Stable Chest Pain: A Secondary Analysis of the PROMISE Randomized Clinical Trial

Abstract

Importance: Coronary computed tomographic angiography (coronary CTA) can characterize coronary artery disease, including high-risk plaque. A noninvasive method of identifying high-risk plaque before major adverse cardiovascular events (MACE) could provide practice-changing optimizations in coronary artery disease care.

Objective: To determine whether high-risk plaque detected by coronary CTA was associated with incident MACE independently of significant stenosis (SS) and cardiovascular risk factors.

Design, setting, and participants: This prespecified nested observational cohort study was part of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial. All stable, symptomatic outpatients in this trial who required noninvasive cardiovascular testing and received coronary CTA were included and followed up for a median of 25 months.

Exposures: Core laboratory assessment of coronary CTA for SS and high-risk plaque (eg, positive remodeling, low computed tomographic attenuation, or napkin-ring sign).

Main outcomes and measures: The primary end point was an adjudicated composite of MACE (defined as death, myocardial infarction, or unstable angina).

Results: The study included 4415 patients, of whom 2296 (52%) were women, with a mean age of 60.5 years, a median atherosclerotic cardiovascular disease (ASCVD) risk score of 11, and a MACE rate of 3% (131 events). A total of 676 patients (15.3%) had high-risk plaques, and 276 (6.3%) had SS. The presence of high-risk plaque was associated with a higher MACE rate (6.4% vs 2.4%; hazard ratio, 2.73; 95% CI, 1.89-3.93). This association persisted after adjustment for ASCVD risk score and SS (adjusted hazard ratio [aHR], 1.72; 95% CI, 1.13-2.62). Adding high-risk plaque to the ASCVD risk score and SS assessment led to a significant continuous net reclassification improvement (0.34; 95% CI, 0.02-0.51). Presence of high-risk plaque increased MACE risk among patients with nonobstructive coronary artery disease relative to patients without high-risk plaque (aHR, 4.31 vs 2.64; 95% CI, 2.25-8.26 vs 1.49-4.69). There were no significant differences in MACE in patients with SS and high-risk plaque as opposed to those with SS but not high-risk plaque (aHR, 8.68 vs. 9.31; 95% CI, 4.25-17.73 vs 4.21-20.61). High-risk plaque was a stronger predictor of MACE in women (aHR, 2.41; 95% CI, 1.25-4.64) vs men (aHR, 1.40; 95% CI, 0.81-2.39) and younger patients (aHR, 2.33; 95% CI, 1.20-4.51) vs older ones (aHR, 1.36; 95% CI, 0.77-2.39).

Conclusions and relevance: High-risk plaque found by coronary CTA was associated with a future MACE in a large US population of outpatients with stable chest pain. High-risk plaque may be an additional risk stratification tool, especially in patients with nonobstructive coronary artery disease, younger patients, and women. The importance of findings is limited by low absolute MACE rates and low positive predictive value of high-risk plaque.

Trial registration: clinicaltrials.gov Indentifier: NCT01174550.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ferencik reports receiving a grant from the American Heart Association. Dr Bittner was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (grant 5K24HL113128). Dr Lu reports receiving grant support from the American Roentgen Ray Society Scholarship during the conduct of the study and personal fees from PQBypass outside the submitted work. Dr Meyersohn was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (grant T32 HL076136). Dr Patel reports receiving grants from HeartFlow Technologies, AstraZeneca, Bayer, and Janssen and personal fees from Bayer, outside the submitted work. Dr Mark reports receiving grants from the National Institutes of Health during the conduct of the study, as well as personal fees from Medtronic, Inc, CardioDx, and St. Jude Medical, and grants from Eli Lilly and Company, Bristol-Myers Squibb, Gilead Sciences, Inc, AGA Medical Corporation, Merck & Company, Oxygen Therapeutics, and AstraZeneca outside the submitted work. Dr Udelson reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Lee reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Douglas reports receiving grant support from HeartFlow and service on a data and safety monitoring board for GE HealthCare outside the submitted work. Dr Hoffmann reports receiving grants from the American College of Radiology Imaging Network and HeartFlow Technologies, Medimmune, Kowa Ltd, Siemens Healthcare, and HeartFlow Inc. outside the submitted work. No other disclosures are reported.

Figures

Figure 1.. Patient Inclusion and Exclusion

This flowchart outlines patient selection. CTA indicates computed tomography angiography; PROMISE, the Prospective Multicenter Imaging Study for Evaluation of Chest Pain.

Figure 2.. Kaplan-Meier Estimates of the Composite Primary End Point as a Function of Time After Randomization

A, Kaplan-Meier estimates stratified by the presence of high-risk plaque (HRP), adjusted for significant stenosis [SS], defined as 70% or greater stenosis in any coronary artery or 50% or greater stenosis in the left main coronary artery and for atherosclerotic cardiovascular disease risk score. B, Kaplan-Meier estimates stratified by both the presence of HRP and SS with adjustment for atherosclerotic cardiovascular disease risk score. The absolute number of patients with high relative risk of major adverse cardiovascular events (MACE) was low. Only 105 patients (2.3%) had SS without high-risk plaque, and 171 patients (3.9%) had both SS and HRP.

Figure 3.. Multivariable Cox Proportional Analyses in Patient Subgroups

The analyses demonstrate the predictive value of high-risk plaque for the outcome of major adverse cardiovascular events (death, nonfatal myocardial infarction, or hospitalization for unstable angina) adjusted for significant stenosis (≥70% stenosis in any coronary artery or ≥50% in the left main coronary artery) and atherosclerotic cardiovascular disease risk score. Error bars show adjusted hazard ratios with 95% CIs, adjusted for atherosclerotic cardiovascular disease risk score and significant stenosis. Wide and overlapping 95% CIs were present. The median age of participants was 59.6 years; median body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), 29.5.