A combined anatomic and electrophysiologic substrate based approach for sudden cardiac death risk stratification

Abstract

Background: Although left ventricular ejection fraction (LVEF) is the primary determinant for sudden cardiac death (SCD) risk stratification, in isolation, LVEF is a sub-optimal risk stratifier. We assessed whether a multi-marker strategy would provide more robust SCD risk stratification than LVEF alone.

Methods: We collected patient-level data (n = 3355) from 6 studies assessing the prognostic utility of microvolt T-wave alternans (MTWA) testing. Two thirds of the group was used for derivation (n = 2242) and one-third for validation (n = 1113). The discriminative capacity of the multivariable model was assessed using the area under the receiver-operating characteristic curve (c-index). The primary endpoint was SCD at 24 months.

Results: In the derivation cohort, 59 patients experienced SCD by 24 months. Stepwise selection suggested that a model based on 3 parameters (LVEF, coronary artery disease and MTWA status) provided optimal SCD risk prediction. In the derivation cohort, the c-index of the model was 0.817, which was significantly better than LVEF used as a single variable (0.637, P < .001). In the validation cohort, 36 patients experienced SCD by 24 months. The c-index of the model for predicting the primary endpoint was again significantly better than LVEF alone (0.774 vs 0.671, P = .020).

Conclusions: A multivariable model based on presence of coronary artery disease, LVEF and MTWA status provides significantly more robust SCD risk prediction than LVEF as a single risk marker. These findings suggest that multi-marker strategies based on different aspects of the electro-anatomic substrate may be capable of improving primary prevention implantable cardioverter-defibrillator treatment algorithms.

Figure 1

Predicted 24 month probability of sudden cardiac death (SCD) based on left ventricle ejection fraction and microvolt T-wave alternans status. The inflection point in the risk of SCD associated with an indeterminate MTWA test is highlighted with the arrow.

Figure 2

Receiver-operating characteristic (ROC) curves for predicting sudden cardiac death at 24 months for the multivariable model based on three clinical parameters (presence of coronary artery disease, left ventricle ejection fraction [LVEF] & microvolt T-wave alternans status) versus either LVEF or MTWA as single variables. In the derivation cohort, the area under the ROC curve (c-index) for the multivariate model (0.817) is significantly greater than both LVEF (0.637) and MTWA (0.716) (p < 0.001 for both comparisons). In the validation cohort, the c-index of the model (0.774) is also significantly better than LVEF (0.671, p = 0.020), and non-significantly greater than MTWA as a lone variable (0.729, p = 0.170).

Figure 3

Kaplan-Meier event-free survival curves for the primary endpoint of sudden cardiac death, stratified by predicted SCD risk based on the multivariable model. Using the multivariate model, patients in the validation cohort with left ventricle ejection fraction (LVEF) ≤ or > 35% were further stratified into one of three groups based on predicted SCD risk at 24 months: <1%, 1-6% and >6%. The survival curves demonstrate that even among patients stratified by LVEF, there is still significant heterogeneity in SCD risk, which can be accurately predicted by the multivariable model. The number of patients (n) in each predicted risk group is listed. Of note, there were no patients in the LVEF ≤ 35% cohort with predicted SCD risk of <1% at 24 months, and therefore, only 5 curves are plotted. The p value by log-rank test is <0.001, suggesting a significant difference in survival across subgroups.