Cysteine-Rich Angiogenic Inducer 61 Improves Prognostic Accuracy of GRACE (Global Registry of Acute Coronary Events) 2.0 Risk Score in Patients With Acute Coronary Syndromes

Roland Klingenberg, Soheila Aghlmandi, Lorenz Räber, Alexander Akhmedov, Baris Gencer, David Carballo, David Nanchen, Heiner C Bucher, Nicolas Rodondi, François Mach, Stephan Windecker, Ulf Landmesser, Arnold von Eckardstein, Christian W Hamm, Thomas F Lüscher, Christian M Matter, Roland Klingenberg, Soheila Aghlmandi, Lorenz Räber, Alexander Akhmedov, Baris Gencer, David Carballo, David Nanchen, Heiner C Bucher, Nicolas Rodondi, François Mach, Stephan Windecker, Ulf Landmesser, Arnold von Eckardstein, Christian W Hamm, Thomas F Lüscher, Christian M Matter

Abstract

Background It remains unclear whether the novel biomarker cysteine-rich angiogenic inducer 61 (CCN1) adds incremental prognostic value to the GRACE 2.0 (Global Registry of Acute Coronary Events) risk score and biomarkers high-sensitivity Troponin T, hsCRP (high-sensitivity C-reactive protein), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in patients with acute coronary syndromes. Methods and Results Patients referred for coronary angiography with a primary diagnosis of acute coronary syndromes were enrolled in the Special Program University Medicine - Acute Coronary Syndromes and Inflammation cohort. The primary/secondary end points were 30-day/1-year all-cause mortality and the composite of all-cause mortality or myocardial infarction as used in the GRACE risk score. Associations between biomarkers and outcome were assessed using log-transformed biomarker values and the GRACE risk score (versions 1.0 and 2.0). The incremental value of CCN1 beyond a reference model was assessed using Harrell's C-statistics calculated from a Cox proportional-hazard model. The P value of the C-statistics was derived from a likelihood ratio test. Among 2168 patients recruited, 1732 could be analyzed. CCN1 was the strongest single predictor of all-cause mortality at 30 days (hazard ratio [HR], 1.77 [1.31, 2.40]) and 1 year (HR, 1.81 [1.47, 2.22]). Adding CCN1 alone to the GRACE 2.0 risk score improved C-statistics for prognostic accuracy of all-cause mortality at 30 days (0.87-0.88) and 1 year (0.81-0.82) and when combined with high-sensitivity Troponin T, hsCRP, NT-proBNP for 30 days (0.87-0.91), and for 1-year follow-up (0.81-0.84). CCN1 also increased the prognostic value for the composite of all-cause mortality or myocardial infarction. Conclusions CCN1 predicts adverse outcomes in patients with acute coronary syndromes adding incremental information to the GRACE risk score, suggesting distinct underlying molecular mechanisms. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01000701.

Keywords: acute coronary syndrome; biomarkers; inflammation; risk.

Conflict of interest statement

The authors have no conflicts of interest to report beyond the stated funding institutions and companies.

Figures

Figure 1. Flow diagram.
Figure 1. Flow diagram.
The flow diagram shows patient enrollment and follow‐up throughout the study. T1 signifies blood drawn performed at coronary angiography. ACS indicates acute coronary syndromes; CCN1, cysteine‐rich angiogenic inducer 61; hsCRP, high‐sensitivity C‐reactive protein; hsTnT, high‐sensitivity Troponin T; and NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.
Figure 2. Forrest plot illustration of the…
Figure 2. Forrest plot illustration of the relative prognostic accuracy of GRACE risk scores (version 1.0 in blue color and 2.0 in red color) and biomarkers for short‐term (A and B) and long‐term (C and D) adverse outcomes (n=1732).
For GRACE 2.0 scores, and the biomarkers, natural logarithm was used, and hazard ratios were reported per 1 log‐unit increase. CCN1 indicates cysteine‐rich angiogenic inducer 61; GRACE, Global Registry of Acute Coronary Events; hsCRP, high‐sensitivity C‐reactive protein; hsTnT, high‐sensitivity Troponin T; MI, myocardial infarction; and NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.

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