Coronary Atherosclerosis, Cardiac Troponin, and Interleukin-6 in Patients With Chest Pain: The PROMISE Trial Results.

BACKGROUND: Increased inflammation and myocardial injury can be observed in the absence of myocardial infarction or obstructive coronary artery disease (CAD). OBJECTIVES: The authors determined whether biomarkers of inflammation and myocardial injury-interleukin (IL)-6 and high-sensitivity cardiac troponin (hs-cTn)-were associated with the presence and extent of CAD and were independent predictors of major adverse cardiovascular events (MACEs) in stable chest pain. METHODS: Using participants from the PROMISE trial, the authors measured hs-cTn I and IL-6 concentrations and analyzed computed tomography angiography (CTA) images in the core laboratory for CAD characteristics: significant stenosis (≥70%), high-risk plaque (HRP), Coronary Artery Disease Reporting and Data System (CAD-RADS) categories, segment involvement score (SIS), and coronary artery calcium (CAC) score. The primary endpoint was a composite MACE (death, myocardial infarction, or unstable angina). RESULTS: The authors included 1,796 participants (age 60.2 ± 8.0 years; 47.5% men, median follow-up 25 months). In multivariable linear regression adjusted for atherosclerotic cardiovascular disease (ASCVD) risk, hs-cTn was associated with HRP, stenosis, CAD-RADS, and SIS. IL-6 was only associated with stenosis and CAD-RADS. hs-cTn above median (1.5 ng/L) was associated with MACEs in univariable analysis (HR: 2.1 [95% CI: 1.3-3.6]; P = 0.006), but not in multivariable analysis adjusted for ASCVD and CAD. IL-6 above median (1.8 ng/L) was associated with MACEs in multivariable analysis adjusted for ASCVD and HRP (HR: 1.9 [95% CI: 1.1-3.3]; P = 0.03), CAC (HR: 1.9 [95% CI: 1.0-3.4]; P = 0.04), and SIS (HR: 1.8 [95% CI: 1.0-3.2]; P = 0.04), but not for stenosis or CAD-RADS. In participants with nonobstructive CAD (stenosis 1%-69%), the presence of both hs-cTn and IL-6 above median was strongly associated with MACEs (HR: 2.5-2.7 after adjustment for CAD characteristics). CONCLUSIONS: Concentrations of hs-cTn and IL-6 were associated with CAD characteristics and MACEs, indicating that myocardial injury and inflammation may each contribute to pathways in CAD pathophysiology. This association was most pronounced among participants with nonobstructive CAD representing an opportunity to tailor treatment in this at-risk group. (PROspective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

Non-invasive fractional flow reserve derived from coronary computed tomography angiography in patients with acute chest pain: Subgroup analysis of the ROMICAT II trial.

BACKGROUND: Non-invasive fractional flow reserve (FFRCT) derived from coronary computed tomography angiography (CTA) permits hemodynamic evaluation of coronary stenosis and may improve efficiency of assessment in stable chest pain patients. We determined feasibility of FFRCT in the population of acute chest pain patients and assessed the relationship of FFRCT with outcomes of acute coronary syndrome (ACS) and revascularization and with plaque characteristics. METHODS: We included 68 patients (mean age 55.8 ±â€¯8.4 years, 71% men) from the ROMICAT II trial who had ≥50% stenosis on coronary CTA or underwent additional non-invasive stress test. We evaluated coronary stenosis and high-risk plaque on coronary CTA. FFRCT was measured in a core laboratory. RESULTS: We found correlation between anatomic severity of stenosis and FFRCT ≤0.80 vs. FFRCT >0.80 (severe stenosis 84.8% vs. 15.2%; moderate stenosis 33.3% vs. 66.7%; mild stenosis 33.3% vs. 66.7% patients). Patients with severe stenosis had lower FFRCT values (median 0.64, 25th-75th percentile 0.50-0.75) as compared to patients with moderate (median 0.84, 25th-75th percentile, p < 0.001) or mild stenosis (median 0.86, 25th-75th percentile 0.78-0.88, p < 0.001). The relative risk of ACS and revascularization in patients with positive FFRCT ≤0.80 was 4.03 (95% CI 1.56-10.36) and 3.50 (95% CI 1.12-10.96), respectively. FFRCT ≤0.80 was associated with the presence of high-risk plaque (odds ratio 3.91, 95% CI 1.55-9.85, p = 0.004) after adjustment for stenosis severity. CONCLUSION: Abnormal FFRCT was associated with the presence of ACS, coronary revascularization, and high-risk plaque. FFRCT measurements correlated with anatomic severity of stenosis on coronary CTA and were feasible in population of patients with acute chest pain.

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

BACKGROUND: People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown. METHODS: REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40-75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally. RESULTS: To date the Mechanistic Substudy has completed planned enrollment, with 805 participants. CONCLUSION: This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin's effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.

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.

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.

Safety of coronary CT angiography and functional testing for stable chest pain in the PROMISE trial: A randomized comparison of test complications, incidental findings, and radiation dose.

BACKGROUND: Coronary computed tomography angiography (CTA) and functional testing strategies for stable chest pain yield similar outcomes; one aspect that may guide test choice is safety. METHODS: We compared test safety (test complications, incidental findings, and effective radiation dose) between CTA and functional testing as-tested in PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain). In the subgroup whose physicians intended nuclear stress over other functional tests if randomized to the functional arm, we compared radiation dose of CTA versus nuclear stress and identified characteristics associated with dose. RESULTS: Of 9470 patients, none had major and <1% had minor complications (CTA: 0.8% [37/4633] vs. functional: 0.6% [27/4837]). CTA identified more incidental findings (11.6% [539/4633] vs. 0.7% [34/4837], p < 0.001), most commonly pulmonary nodules (9.4%, 437/4633). CTA had similar 90-day cumulative radiation dose to functional testing. However, in the subgroup whose physicians intended nuclear stress (CTA 3147; nuclear 3203), CTA had lower median index test (8.8 vs. 12.6 mSv, p < 0.001) and 90-day cumulative (11.6 vs. 13.1 mSv, p < 0.001) dose, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing ≥500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv). CONCLUSION: Complications were negligibly rare for both CTA and functional testing. CTA detects more incidental findings. Compared to nuclear stress testing, CTA's lower radiation dose, independent of patient characteristics, makes it an attractive test choice. Radiation dose varies with imaging protocol, indicating opportunities to further reduce dose. (ClinicalTrials.gov number, NCT01174550).

Noninvasive FFR Derived From Coronary CT Angiography: Management and Outcomes in the PROMISE Trial.

OBJECTIVES: The purpose of this study was to determine whether noninvasive fractional flow reserve derived from computed tomography (FFRCT) predicts coronary revascularization and outcomes and whether its addition improves efficiency of referral to invasive coronary angiography (ICA) after coronary computed tomography angiography (CTA). BACKGROUND: FFRCT may improve the efficiency of an anatomic CTA strategy for stable chest pain. METHODS: This observational cohort study included patients with stable chest pain in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial referred to ICA within 90 days after CTA. FFRCT was measured at a blinded core laboratory, and FFRCT results were unavailable to caregivers. We determined the agreement of FFRCT (positive if ≤0.80) with stenosis on CTA and ICA (positive if ≥50% left main or ≥70% other coronary artery), and predictive value for a composite of coronary revascularization or major adverse cardiac events (death, myocardial infarction, or unstable angina). We retrospectively assessed whether adding FFRCT ≤0.80 as a gatekeeper could improve efficiency of referral to ICA, defined as decreased rate of ICA without ≥50% stenosis and increased ICA leading to revascularization. RESULTS: FFRCT was calculated in 67% (181 of 271) of eligible patients (mean age 62 years; 36% women). FFRCT was discordant with stenosis in 31% (57 of 181) for CTA and 29% (52 of 181) for ICA. Most patients undergoing coronary revascularization had an FFRCT of ≤0.80 (91%; 80 of 88). An FFRCT of ≤0.80 was a significantly better predictor for revascularization or major adverse cardiac events than severe CTA stenosis (HR: 4.3 [95% confidence interval [CI]: 2.4 to 8.9] vs. 2.9 [95% CI: 1.8 to 5.1]; p = 0.033). Reserving ICA for patients with an FFRCT of ≤0.80 could decrease ICA without ≥50% stenosis by 44%, and increase the proportion of ICA leading to revascularization by 24%. CONCLUSIONS: In this hypothesis-generating study of patients with stable chest pain referred to ICA from CTA, an FFRCT of ≤0.80 was a better predictor of revascularization or major adverse cardiac events than severe stenosis on CTA. Adding FFRCT may improve efficiency of referral to ICA from CTA alone.