Age and Effect of ICD in the DANISH Trial

Study Questions:

What is the relationship between age and outcome of a primary prevention implantable cardioverter-defibrillator (ICD) in patients with nonischemic systolic heart failure?

Methods:

This was a prespecified subgroup analysis of the 1,116 patients from the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality) study, which randomized patients with nonischemic cardiomyopathy to ICD or no ICD. The relationship between ICD and mortality was assessed by age, and an optimal age cut-off was estimated nonparametrically using selection impact curves. Modes of death were divided into sudden cardiac death (SCD) and nonsudden death and compared between patients younger and older than this age cut-off with the use of χ2-analysis.

Results:

Median age of the study population was 63 years (range 21-84 years). There was a linearly decreasing relationship between the ICD and mortality with age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.003-1.06; p = 0.03). An optimal age cut-off for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and the ICD in patients ≤70 years (HR, 0.70; 95% CI, 0.51-0.96; p = 0.03), but not in patients >70 years (HR, 1.05; 95% CI, 0.68-1.62; p = 0.84). For patients ≤70 years, SCD rate was 1.8 (1.3-2.5) and nonsudden death rate was 2.7 (2.1-3.5) events/100 patient-years, whereas for patients >70 years, SCD rate was 1.6 (0.8-3.2) and nonsudden death rate was 5.4 (3.7-7.8) events/100 patient-years. This difference in modes of death between the two age groups was statistically significant (p = 0.01).

Conclusions:

In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cut-off for ICD implantation at ≤70 years yielded the highest survival for the population as a whole.

Perspective:

Despite over three decades of ICD therapy, there has not been a single study of exclusively primary prevention nonischemic cardiomyopathy patients demonstrating mortality reduction with ICD implantation, although a meta-analysis of patients with nonischemic cardiomyopathy did show this benefit. Food and Drug Administration (FDA) approval of ICDs for primary prevention in this population was made based on the SCD-HeFT trial, which included patients with both ischemic and nonischemic cardiomyopathy, and randomized them to ICD versus amiodarone. The DANISH study found no reduction in all-cause mortality. The present report is a prespecified subgroup analysis based on age. It shows that younger patients (up to the age of 70 years), who more often die of SCD, derive benefit from ICDs, while older patients do not. The lessening of benefits of ICDs with increasing age, of course, is not limited to patients with nonischemic cardiomyopathy. Of relevance is also the fact that DANISH had an exceedingly high percentage of patients who underwent cardiac resynchronization therapy (CRT). CRT was implanted in 58% of the patients in the trial (and in 68% of patients >70 years), and this has impacted the outcomes. High prevalence of CRT would be expected to attenuate the benefits of an ICD.


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