Prediction of sudden and non-sudden cardiac death in post-infarction patients with reduced left ventricular ejection fraction by periodic repolarization dynamics: MADIT-II substudy

Abstract

Aims: To test the value of Periodic Repolarization Dynamics (PRD), a recently validated electrocardiographic marker of sympathetic activity, as a novel approach to predict sudden cardiac death (SCD) and non-sudden cardiac death (N-SCD) and to improve identification of patients that profit from ICD-implantation.

Methods and results: We included 856 post-infarction patients with left-ventricular ejection fraction (LVEF) ≤30% of the MADIT-II trial in sinus rhythm. Of these, 507 and 348 patients were randomized to ICD or conventional treatment. PRD was assessed from multipolar 10-min baseline ECGs. Primary and secondary endpoints were total mortality, SCD and N-SCD. Multivariable analyses included treatment group, QRS-duration, New York Heart Association classification, blood-urea nitrogen, diabetes mellitus, beta-blocker therapy and LVEF. During follow-up of 20.4 months, 119 patients died (53 SCD and 36 N-SCD). On multivariable analyses, increased PRD was a significant predictor of mortality (standardized coefficient 1.37[1.19-1.59]; P < 0.001) and SCD (1.40 [1.13-1.75]; P = 0.003) but also predicted N-SCD (1.41[1.10-1.81]; P = 0.006). While increased PRD predicted SCD in conventionally treated patients (1.61[1.23-2.11]; P < 0.001), it was predictive of N-SCD (1.63[1.28-2.09]; P < 0.001) and adequate ICD-therapies (1.20[1.03-1.39]; P = 0.017) in ICD-treated patients. ICD-treatment substantially reduced mortality in the lowest three PRD-quartiles by 53% (P = 0.001). However, there was no effect in the highest PRD-quartile (mortality increase by 29%; P = 0.412; P < 0.001 for difference) as the reduction of SCD was compensated by an increase of N-SCD.

Conclusion: In post-infarction patients with impaired LVEF, PRD is a significant predictor of SCD and N-SCD. Assessment of PRD is a promising tool to identify post-MI patients with reduced LVEF who might benefit from intensified treatment.

Keywords: Electrocardiography; Implantable cardioverter defibrillator; Risk prediction; Sudden cardiac death; Sympathetic nervous system.

Figure 1

Consort flow-diagram for the MADIT-II population.

Figure 2

Cumulative 3-year mortality rates in the MADIT-II population. Patients are stratified by PRD quartiles (PRD Q1 ≤4.09 deg², PRD Q2 4.10–7.27 deg², PRD Q3 7.28–11.51 deg², PRD Q4 ≥11.52 deg²). Because of low number of patients with follow-up time greater than 3 years, Kaplan–Meier curves were right-censored at year 3.

Figure 3

Effect of ICD therapy on mortality- and sudden cardiac death- reduction (SCD) for different levels of periodic repolarization dynamics (PRD). (A) In the lowest three quartiles, ICD-treatment was associated with a mortality reduction from 30 to 16% (P = 0.003). (B) In the highest quartile no significant effect of ICD-treatment was observed (P = 0.853). ICD-therapy was associated with a reduction of SCD in all PRD quartiles (C) In the lowest three quartiles SCD was reduced from 15 to 5% (P <0.001) and (D) in the highest quartile from 18 to 8% (P = 0.049).

Figure 4

Effect of ICD therapy on mortality- and sudden cardiac death- reduction (SCD) for different levels of periodic repolarization dynamics (PRD). Hazard ratios are calculated from multivariable models adjusted for left-ventricular ejection fraction (cont.), New York Heart Association classification ≥ II, diabetes mellitus, blood urea nitrogen >25 mg/dL, treatment with beta-blockers and QRS-duration.