C-Terminal-Pro-Endothelin-1 Adds Incremental Prognostic Value for Risk Stratification After Ischemic Stroke

Abstract

Background and Aims: Endothelins have shown to play a role in the pathophysiology of ischemic stroke. We aimed at evaluating the incremental prognostic value of C-terminal-pro-endothelin-1 (CT-pro-ET-1) in a well-described cohort of acute stroke patients. Methods: We performed serial measurements of CT-pro-ET-1 in 361 consecutively enrolled ischemic stroke patients and assessed functional outcome and mortality after 90 days. As we found peak levels of CT-pro-ET-1 and the most prominent association with mortality on day 1 after admission (n = 312), we focused on this time point for further outcome analyses. We calculated logistic regression and cox proportional hazards models to estimate the association of CT-pro-ET-1 with our outcome measures after adjusting for demographic and clinical risk factors. To evaluate the incremental value of CT-pro-ET-1, we calculated the area under the receiver operating characteristics (AUC) curve and the continuous net reclassification index (cNRI) comparing the model with and without the biomarker CT-pro-ET-1. Results: In the univariate analysis CT-pro-ET-1 with a peak on day 1 after admission was associated with unfavorable outcome with an OR of 1.32 (95% CI, 1.16-1.51, p < 0.001) and with mortality with a HR of 1.45 (95% CI, 1.29-1.63, p < 0.001). After adjusting, CT-pro-ET-1 remained an independent predictor of mortality with an adjusted HR of 1.50 (95% CI, 1.29-1.74, p < 0.001), but not for functional outcome. Adding CT-pro-ET-1 to the cox-regression model for mortality, the discriminatory accuracy improved from 0.89 (95% CI, 0.84-0.94) to 0.92 (95% CI, 0.88-0.96) p < 0.001, and the cNRI was 0.72 (95% CI, 0.17-1.13). Conclusion: CT-pro-ET-1 with a peak level on day 1 was an independent predictor of mortality adding incremental prognostic value beyond traditional risk factors.

Keywords: C-terminal-pro-endothelin-1; biomarker; mortality; outcome; risk stratification; stroke.

Figure 1

CT-pro-ET-1 levels over time. Circles indicate median CT-pro-ET-1 levels, squares lower 95%-confidence interval limits and arrows upper confidence interval limits, respectively.

Figure 2

Receiver Operator Characteristic (ROC)-curves based on regression models for mortality within 3 months after stroke with and without CT-pro-ET-1. Model 1 represents the cox proportional hazards model for mortality within 3 months after stroke including the risk factors age and NIHSS on admission. Model 2 represents the analysis adding CT-pro-ET-1 on day 1 after admission to the model.

Figure 3

Kaplan-Meier survival estimates of patients stratified by CT-pro-ET-1 on day 1 after admission. Kaplan-Meier survival curves of patients stratified per CT-pro-ET-1 cut-off levels <8.80 and ≥8.80 pg/ml differed significantly (p = <0.001, log-rank test).