Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease

Abstract

Aims: To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD).

Methods and results: The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009].

Conclusion: For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF.

Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

Keywords: Coronary heart disease; Electrocardiogram; Sudden death.

Figure 1

A pathophysiology-based approach to electrocardiographic prediction of sudden arrhythmic death risk. In this study, we assessed the association between several easily measurable electrocardiographic markers and the risk of sudden of arrhythmic death in patients with coronary heart disease and relatively preserved left ventricular function. Electrocardiographic markers were organized into pathophysiology-based ‘risk domains’ including markers reflecting anatomic risk, autonomic function, as well as depolarization and repolarization abnormalities. In models (1) accounting for the competing risk of non-arrhythmic deaths and (2) adjusted for clinical risk factors associated with arrhythmic death (age, sex, race/ethnicity, hypertension, diabetes mellitus, atrial fibrillation, left ventricular ejection fraction, New York Heart Association functional class, and β-blocker use), four electrocardiographic markers were independently associated with arrhythmic death: left ventricular hypertrophy, contiguous Q waves, QRS duration, and a prolonged JTc interval. ECG, electrocardiographic; LA, left atrial; LVH, left ventricular hypertrophy; NYHA, New York Heart Association functional class.

Figure 2

Univariate association of validated arrhythmic electrocardiographic risk markers with arrhythmic death—stratified by risk domains. Shown is the prevalence and univariate association between several electrocardiographic measures and the risk of arrhythmic death. Association was examined in subdistribution hazard models accounting for the competing risk of non-arrhythmic death. Electrocardiographic markers are organized into pathophysiology-based risk domains including measures reflecting anatomic pathology, autonomic function, as well as depolarization and repolarization abnormalities. Patients with atrial arrhythmias at the time of electrocardiographic assessment were excluded from the PR prolongation model (see Methods section). No., number; BPM, beats per minute; LBBB, left bundle branch block.

Figure 3

Cumulative incidence of sudden arrhythmic death according to risk-based electrocardiographic score. (A) Shown is the distribution of electrocardiographic risk score in the derivation (PRE-DETERMINE; solid blue) and validation (ARTEMIS; blue outline) cohorts. The point score was defined by the presence of contiguous Q waves (+1 point), prolonged QRS duration (80–110: 1 point, >110: 2 points), left ventricular hypertrophy (1 point), and prolonged JTc (1 point). (B) Shown are the 5-year cumulative incidences of sudden arrhythmic death in the derivation cohort (PRE-DETERMINE; solid line) and validation (ARTEMIS; dashed line), accounting for the competing risk of non-arrhythmic deaths, in the total cohort stratified by a risk-based electrocardiographic score. The equivalence of cumulative incidence functions in each cohort was assessed using Gray’s test. ECG, electrocardiographic; LV, left ventricular.

Figure 4

Association of risk-based electrocardiographic score with arrhythmic and non-arrhythmic death: derivation and validation cohorts. In both the derivation (PRE-DETERMINE; solid square) and validation (ARTEMIS; empty square) cohorts, we illustrate the relative increased incidence of arrhythmic and non-arrhythmic death as stratified by the risk-based electrocardiographic score. Relative incidence was assessed using multivariable-adjusted Fine–Gray models accounting for the competing risk of other deaths. Multivariable adjustment included age, sex, race/ethnicity, hypertension, diabetes mellitus, atrial fibrillation, left ventricular ejection fraction, New York Heart Association functional class, and β-blocker use. HR, hazard ratio; NYHA, New York Heart Association.

Figure 5

Five year incidence of sudden and/or arrhythmic death according to electrocardiographic score stratified by clinical risk. In the derivation cohort, 5-year cumulative incidence (with 95% confidence intervals) of sudden and/or arrhythmic death are shown according to electrocardiographic risk score stratified by quartiles of baseline model (clinical risk factors, left ventricular ejection fraction) risk. Subgroup sample size (N) are highlighted.

Take home figure

Simple electrocardiographic markers predict actionable sudden death risk in patients with coronary heart disease. Our study demonstrates that simple electrocardiographic markers, reflecting distinct domains of risk, can specifically identify sudden arrhythmic death risk in patients with coronary heart disease. In combination, these electrocardiographic markers identify clinically actionable sudden death at 5 years in derivation and validation cohorts. The electrocardiographic risk score enriches for sudden death risk across the spectrum of risk defined by clinical risk factors. The highest risk subgroups in our study were estimated to derive significant survival benefit from implantable cardioverter-defibrillator (ICD) therapy. We show that randomized controlled trials (RCT) needed to identify this survival benefit are feasible.