By Cara Pellegrini, MD
Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division; Electrophysiology Section, San Francisco VA Medical Center
Dr. Pellegrini reports no financial relationships relevant to this field of study.
SYNOPSIS: Prophylactic implantable cardioverter defibrillator implantation was not associated with an all-cause mortality benefit among patients presenting with nonischemic symptomatic systolic heart failure in DANISH, a randomized, controlled trial in Denmark.
SOURCE: Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016 Aug 27. [Epub ahead of print].
Implantable cardioverter defibrillator (ICD) implantation for primary prevention of sudden cardiac death (SCD) in patients presenting with symptomatic systolic heart failure carries a class Ia recommendation in the American Heart Association guidelines, regardless of heart failure etiology. The rationale for that recommendation extending to the nonischemic heart failure population largely rests on data from SCD-HeFT, a randomized, controlled trial that enrolled 2,521 patients between 1997 and 2001, and was comprised of nonischemic and ischemic heart failure patients in nearly equal proportion. Medical therapy has improved greatly since then, and cardiac resynchronization therapy (CRT) now is used widely in this population, raising the question of whether nonischemic patients truly benefit from the addition of ICD implantation to current standards of clinical care.
The Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic Heart Failure on Mortality (DANISH) was an investigator-initiated, randomized, unblinded, controlled trial that was conducted at all centers in Denmark that implant ICDs. Patients presenting with symptomatic systolic heart failure with left ventricular ejection fraction ≤ 35% and left ventricular dysfunction out of proportion to coronary artery disease (> 95% of patients had undergone a cardiac catheterization; those with one-vessel to two-vessel coronary artery disease could be included, if the extent of disease was not considered sufficient to explain cardiac dysfunction) were eligible for enrollment. Poorly rate-controlled permanent atrial fibrillation or a requirement for dialysis were exclusions. Primary outcome was death from any cause. Secondary outcomes included SCD, cardiovascular death, aborted SCD or sustained ventricular tachycardia, and change from baseline in quality of life.
The authors randomized 1,116 patients to ICD implantation or usual clinic care and followed the patients for a mean of 5.6 years. There was approximately 5% crossover between groups. The average age was 63.5 years, about 25% of patients were female, about 75% presented with an idiopathic etiology of their heart failure, and a slight majority of patients featured New York Heart Association class II symptoms vs. class III symptoms. Medical therapy was excellent, with 92% of patients receiving beta-blocker therapy, 96.5% receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and 58% on a mineralocorticoid-receptor antagonist. More than half the patients presented with a CRT device. Although ICD therapy halved the risk of SCD from 8.2% to 4.3%, the effect on overall mortality was not significant (hazard ratio for death from any cause = 0.87; 95% confidence interval, 0.68-1.12; P = 0.28). There was an interaction with age, suggesting ICD implantation may provide survival benefits for younger patients. A similar differential effect was not seen for presence of CRT device. The authors concluded that prophylactic ICD implantation does not provide mortality benefit for nonischemic heart failure patients.
ICDs are very specific in what they target: prevention of arrhythmic death. Non-cardiovascular death and even non-arrhythmic cardiovascular death are beyond the scope of the ICD, unlike pharmacologic therapy for heart failure, which can affect both arrhythmic mortality and events due to pump failure. Thus, to see a benefit in overall mortality from ICD implantation, the contribution of arrhythmic death to overall death must be sizable in the population studied. This trial provides additional evidence that the competing mortality risks among the nonischemic heart failure population together with the smaller risk of SCD, as compared to that in ischemic heart failure, minimizes the overall mortality benefit from ICD implantation in this population.
There are several potential explanations for the differences in outcome between this study and SCD-HeFT. The much higher use of beta-blockers and other pharmacologic agents for heart failure management in DANISH decreased the overall cardiovascular death rate as well as the contribution of SCD to overall mortality. Additionally, no patients in SCD-HeFT were treated with CRT, which was highly prevalent in the DANISH population. The etiology of the nonischemic cardiomyopathy may have differed as well; certainly, the percentages of patients suffering from hypertension and diabetes were much less in DANISH. Also, DANISH patients were on average 3.5 years older than SCD-HeFT patients, again contributing to a larger competing risk of non-arrhythmic mortality. Finally, it remains possible that DANISH, at half the size of SCD-HeFT, was underpowered to detect a truly present, but small, mortality benefit.
DANISH should prompt cardiologists to consider who among the large nonischemic heart failure population is most likely to benefit from ICD therapy. One consistent message is that younger patients with less competing mortality risk have a greater likelihood of benefit. Whether there is a U-shaped curve similar to that proposed for ischemic cardiomyopathy patients, where not only the sickest, but also the most healthy, are unlikely to benefit from ICD implantation, is as yet unclear. Interestingly, both DANISH and SCD-HeFT showed no benefit of ICDs in women, a population that really deserves greater study. It is really good news that with improving medical therapy, ICDs might not be warranted across the board for heart failure patients. However, it may be premature to conclude that they provide no benefit to the population of nonischemic heart failure patients as a whole.