Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort

Abstract

Aims: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients.

Methods and results: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract).

Conclusion: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS.

Clinical trial registration: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

Keywords: Acute coronary syndrome; Biomarkers; Prognosis; Repeated measurements; Risk assessment.

Structured Graphical Abstract

Figure 1

Biomarker level of each measurement per patient during follow-up for high-sensitivity cardiac troponin T (A), N-terminal-pro-B-type natriuretic peptide (B), high-sensitivity C-reactive protein (C), growth differentiation factor 15 (D). On the x-axis is the relative position of each individual patient ranked according to their average biomarker level across several repeated measurements during follow-up. The patient with the lowest average level is depicted on the far left of the x-axis, while the highest is depicted on the far right. Each of the measurements during follow-up belonging to an individual patient are shown vertically with the corresponding levels. All measurements are shown on the left side (blue circles) and the same measurements highlighted for patients who reached the primary endpoint (red circles) vs. those who did not (small grey dots) on the right side. mg/L, milligram per litre; pg/mL, picogram per millilitre; pmol/L, picomole per litre.

Figure 2

Longitudinal evolution of the average estimated biomarker levels (back-transformed to the original linear scale) of hs-cTnT (A), N-terminal-pro-B-type natriuretic peptide (B), high-sensitivity C-reactive protein (C), growth differentiation factor 15 (D) according to linear mixed effects models of the biomarker on log2-scale as dependent variable adjusted for time-to-sample with GRACE risk score category interaction during follow-up post-acute coronary syndrome. Categories were defined according to the cut-off values provided in the online GRACE risk table, additionally taking into account whether there was ST-elevation at the index event. Solid green (low risk), orange (intermediate risk), and red (high risk) lines denote the mean values of each biomarker according to the appropriate category. Dashed lines denote the corresponding 95% confidence intervals. mg/L, milligram per litre; pg/mL, picogram per millilitre; pmol/L, picomole per litre.

Figure 3

Longitudinal evolution of the average estimated biomarker level (back-transformed to the original linear scale) of hs-cTnT (A), N-terminal-pro-B-type natriuretic peptide (B), high-sensitivity C-reactive protein (C), growth differentiation factor 15 (D) leading up to the event in patients who reached the primary endpoint or end-of-follow-up in patients who did not, according to linear mixed effects models of the biomarker on log2-scale as dependent variable adjusted for time-to-event with primary endpoint status interaction. The x-axis is reversed. Solid red (primary endpoint patients) and black (primary endpoint-free patients) lines denote the mean biomarker values, while the dashed lines denote the 95% confidence intervals. Dots represent the individual measurements. mg/L, milligram per litre; pg/mL, picogram per millilitre; pmol/L, picomole per litre.