Risk stratification for sudden cardiac death: is there a clinical role for T wave alternans?

Abstract

The proportion of cardiovascular deaths attributable to sudden cardiac death (SCD) is on the rise. Herein lies the rationale for developing risk stratification strategies to predict who will benefit from prophylactic implantable cardioverter-defibrillator (ICD) implantation. Current guidelines recommend prophylactic ICD therapy in patients with reduced left ventricular ejection fraction (LVEF). However, there are clear limitations in using LVEF alone to decide who should receive an ICD. There is mounting evidence that microvolt-level T-wave alternans (TWA) is an important marker of arrhythmic risk. TWA is appealing because it noninvasively probes the underlying electrophysiological substrate and has been linked to cellular mechanisms for arrhythmias. This review considers the clinical role of TWA for risk stratification of SCD.

Figure 1

Prediction of events depends on definition of “events”. Comparison of prospective clinical trials evaluating T-wave alternans (TWA) measured using the spectral analytic method in primary prevention populations in which (1) few patients had implantable cardioverter defibrillators (ICD) and as a result none or a small fraction (≤ 15%) of the reported endpoint ventricular tachyarrhythmic events (VTEs) were ICD-detected (Low ICD Group) or (2) many of the patients had implanted ICDs and the majority of the reported endpoint VTEs were ICD-detected (High ICD Group). In the Low ICD Group comprising 3,682 patients, the hazard ratio associated with a TWA + vs TWA - was 13.6 (8.5 - 30.4) and the annual event rate (AER) among the TWA - patients was 0.3% (0.1% - 0.5%). In contrast, in the High ICD Group comprising 2,234 patients, the hazard ratio was only 1.6 (1.2 - 2.1) and the AER among the TWA - patients was elevated to 5.4% (4.1% - 6.7%). Adapted from Hohnloser et al.

Figure 2

T-wave alternans (TWA) is a marker of the sudden cardiac death phenotype. Upper Panel: Mortality rates from the main SCD Heart Failure Trial (SCD-HeFT). This plot shows that the beneficial effect of ICD therapy in SCD-HeFT begins to emerge between 18 and 24 months (dashed line). Lower Panel: Event rates from the TWA substudy of SCD-HeFT. The time base is scaled to match the survival curves from the main SCD-HeFT trial (upper), permitting comparison of the time course of an apparent prognostic TWA signal (i.e. separation of TWA + and TWA - curves) and the emergence of a detectable SCD phenotype in the same population. These data show that the TWA begins to develop at the same time as the SCD phenotype becomes detectable.

Figure 3

Implantable cardioverter defibrillators (ICD) do not benefit all patients with low left ventricular ejection fraction: Hitting the “sweet spot”. Based on recent primary and secondary prevention trials, patients achieve the greatest benefit from ICD therapy for primary prevention guided by a combined risk stratification strategy (i.e. LVEF + invasive EP testing), even better than secondary prevention. In other words, you are more likely to benefit from an ICD if you have never had an arrhythmia but have a positive risk marker, than if you have had a cardiac arrest.

Figure 4

Delivering implantable cardioverter defibrillator (ICD) therapy to those who need it. This figure demonstrates analysis of data from the ABCD trial testing various risk stratification scenarios asking how a patient would do with prophylactic ICD therapy in terms of the tradeoff between therapeutic efficiency (i.e. ICD treated patients without an event) and therapeutic risk (i.e. patients who did not receive an ICD, yet had an event). If a reduced LVEF alone is the only marker used to guide prophylactic ICD implantation 93% of patients receiving an ICD will never use their device. In contrast, the addition of TWA reduced the number of ICD treated patients without an event to 65% with only a 1.8% risk that a patient with a VTE is not treated. Addition of EPS in all patients, a strategy which has been largely abandoned by clinicians, decreases the number of ICD recipients without events to 35%, but increases the risk of having a VTE and not being protected to 2.7%. Taken together, risk stratification strategies using multiple risk markers improve therapeutic efficiency 25 times more than it increases risk of under treatment, as evidenced by the steep slot of the plot.