Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time

Abstract

Background: Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker-based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short-term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short-term risk estimate.

Methods and results: According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide were measured with high-sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N-terminal pro-B-type natriuretic peptide +13.5%) and within-subject correlation was high (all ≥0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person-years of follow-up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65-0.76) as compared with 0.70 (95% CI, 0.65-0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes.

Conclusions: In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker-based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Keywords: atrial fibrillation; cardiac biomarkers; natriuretic peptide; risk score; stroke; troponin.

© 2017 The Authors and Bristol Myers Squibb Co. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1

CONSORT flow diagram of the number of participants included in the serial biomarker substudy and total number of patients with events after 2 months stratified for each biomarker. ARISTOTLE indicates Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; cTnI, cardiac troponin I; cTnT, cardiac troponin T; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; SE, systemic embolism.

Figure 2

Bland‐Altman plot of the ratio between the 2‐month level and the baseline level against the geometric mean of the 2 observations for cardiac troponin I (cTnI) (A), cardiac troponin T (cTnT) (B), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (C). The dotted lines represent mean and 95% CI. A, Association between continuous cTnI levels at baseline (x axis) and cardiovascular mortality by group according to changes of cTnI at 2 months (lines). B, Association between continuous cTnT levels at baseline (x axis) and cardiovascular mortality by group according to changes of cTnT at 2 months (lines). C, Association between continuous NT‐proBNP levels at baseline (x axis) and cardiovascular mortality by group according to changes of NT‐proBNP at 2 months (lines).

Figure 3

Association between continuous biomarker levels at baseline (x‐axis) and cardiovascular mortality by group according to increase of each biomarker at 2 months (red lines) for (A) cTnI, (B) cTnT, and (C) NT‐proBNP. NT‐proBNP indicates N‐terminal pro‐B‐type natriuretic peptide.

Figure 4

Bland‐Altman plot of the log ratio (difference in log‐predicted ABC [age, biomarkers, and clinical history of prior stroke] risk) between the 2‐month and baseline estimates of the 1‐year risk of stroke or systemic embolism against the geometric mean of the 2 estimates. The dashed lines indicate the mean and the 2‐SDs distance from the mean. The red line indicates locally weighted scatterplot smoothing. Cardiac troponin T was used in the ABC stroke score.

Figure 5

Cumulative event rate of stroke or systemic embolism by predicted 1‐year ABC (age, biomarkers, and clinical history of prior stroke) risk (cardiac troponin T) group (green=0–1%, blue=1–2%, and red >2%) for the baseline (dashed lines) and temporal validation (solid lines) data. The figure shows the cumulative event rate within risk classes for the ABC stroke model evaluated independently at the 2 time points. It illustrates that the model performs equally well when it is applied using biomarker values at baseline as when it is applied using biomarker values at 2 months. SE indicates systemic embolism.

Figure 6

Decision curve analysis for the ABC stroke score (age, biomarkers, and clinical history of prior stroke) (cardiac troponin T) applied at baseline (red) and at 2 months (blue).