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Published on: January 28, 2020
Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials
Jonathan D Newman1, Rebecca Anthopolos2, Kelly V Ruggles1
1Department of Medicine, NYU Grossman School of Medicine, New York, NY.
Insights
Biomarkers for inflammation and myocyte injury significantly improve cardiovascular event prediction in stable coronary artery disease (CAD) patients. These markers enhance risk stratification beyond traditional clinical assessments and ischemia severity.
Area of Science:
- Cardiovascular Medicine
- Biomarker Discovery
- Clinical Risk Stratification
Background:
- Predicting cardiovascular events in stable coronary artery disease (CAD) can be improved with biomarkers.
- The added prognostic value of biomarkers alongside clinical tests for ischemia and CAD severity is not well-established.
Purpose of the Study:
- To assess the prognostic significance of multiple biomarkers in stable outpatients with obstructive CAD.
- To determine if biomarkers improve risk prediction in patients with moderate to severe inducible ischemia.
Main Methods:
- Analysis of 757 participants from the ISCHEMIA biorepository with stable CAD.
- Assessed baseline levels of 10 biomarkers including interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP).
- Utilized Cox proportional hazards models and receiver operating characteristic curves (AUC) to evaluate prediction improvements.
Main Results:
- A multimarker model including hsTnT, growth differentiation factor 15 (GDF-15), NT-proBNP, and soluble CD 40 ligand (sCD40L) significantly predicted cardiovascular events (adjusted HRs ranging from 1.46 to 1.61 per interquartile increase).
- The multimarker model substantially improved prediction accuracy (AUC increased from 0.710 to 0.792 for the primary outcome) compared to a clinical model.
- These improvements were consistent even after adjusting for computed cardiac tomographic angiography (CCTA)-assessed atherosclerosis severity.
Conclusions:
- Biomarkers reflecting myocyte injury/distension, inflammation, and platelet activity enhance cardiovascular event prediction in stable CAD.
- These biomarkers offer added value beyond traditional risk factors, left ventricular ejection fraction (LVEF), ischemia, and atherosclerosis severity.
- The findings suggest that incorporating these biomarkers can improve risk stratification for patients with stable CAD.
Importance:
Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown.
Objectives:
To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia.
Design And Setting:
The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository.
Main Outcome Measures:
Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA).
Exposures:
Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3).
Results:
Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity.
Conclusions And Relevance:
Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.
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