By Joshua D. Moss, MD

Associate Professor of Clinical Medicine, Cardiac Electrophysiology, Division of Cardiology, University of California, San Francisco

Dr. Moss reports no financial relationships relevant to this field of study.

SYNOPSIS: In patients with congestive heart failure due to reduced ejection fraction who underwent remote arrhythmia monitoring via an implantable cardioverter defibrillator (ICD), both ventricular arrhythmias and appropriate ICD shocks were reduced while on sacubitril-valsartan compared to an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker alone.

SOURCE: de Diego C, González-Torres L, Núñez JM, et al. Effects of angiotensin-neprilysin inhibition as compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm 2017 Nov 14. pii: S1547-5271(17)31331-0. doi: 10.1016/j.hrthm.2017.11.012. [Epub ahead of print].

The authors of the PARADIGM-HF trial1 discontinued the study early after noting clear superiority of the angiotensin-neprilysin inhibitor (ARNI) LCZ696, now FDA-approved as sacubitril-valsartan (Entresto), over enalapril in the treatment of heart failure. There were significant reductions in mortality, hospitalization for heart failure, and sudden death with ARNI therapy, although relatively few patients with sudden death had an implanted device to facilitate adjudication of ventricular arrhythmias (vs. other modes of sudden cardiac death such as asystole, electromechanical dissociation, and cardiac shock).

To further investigate the effects of ARNI therapy on ventricular arrhythmias, de Diego et al enrolled 120 consecutive patients with congestive heart failure (New York Heart Association [NYHA] class II or greater despite optimal medical therapy), reduced ejection fraction (EF) ≤ 40%, and an implanted defibrillator with home monitoring capability. Patients were followed for 18 months: nine months while on therapy with angiotensin inhibition alone (ramipril or valsartan), then nine more months on sacubitril-valsartan. Patients were treated concurrently with beta-blockers and a mineralocorticoid antagonist, if tolerated.

The enrolled population had a mean age around 70 years and were predominantly male (76%), with an ischemic etiology of their cardiomyopathy (82%). Mean EF at the time of enrollment was 30%. In 35% of patients, the implantable cardioverter defibrillator device (ICD) or implantable cardiac resynchronization therapy defibrillator (CRT-D) had been implanted for secondary prevention, and 30% of patients were on antiarrhythmic drug therapy.

Not surprisingly, therapy with the ARNI was associated with multiple statically significant changes compared with angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy: improvement in NYHA functional class, decrease in brain natriuretic peptide (BNP) levels, increase in EF, decrease in left ventricular diastolic diameter, decrease in blood pressure, and increase in heart rate. However, there also was significantly higher survival free from ICD shocks; patients on ARNI therapy experienced one appropriate and one inappropriate ICD shock over nine months, while patients on angiotensin inhibition alone demonstrated eight appropriate and three inappropriate ICD shocks. Significant reductions also were noted in incidence of sustained ventricular tachycardia (VT) (0.8% vs. 6.7%), nonsustained VT (NSVT) episodes (mean 5.4 vs. 15 episodes per patient), and premature ventricular complex (PVC) burden. The decline in PVC burden in turn was associated with a significant increase in biventricular pacing percentage, from a mean of 95% to 98.8%. There was a nonsignificant decrease in episodes of paroxysmal atrial tachycardia or fibrillation. The authors concluded that in patients with congestive heart failure due to reduced ejection fraction who had an ICD, ventricular arrhythmias and appropriate ICD shocks were reduced on sacubitril-valsartan compared with an ACE inhibitor or ARB.


This study adds to our understanding of how ARNI therapy may alter the mode of death in patients with advanced heart failure. In this population with predominantly ischemic cardiomyopathy and congestive heart failure, angiotensin-neprilysin inhibition decreased the burden of ventricular arrhythmia, which in turn reduced the number of appropriate ICD shocks, compared with angiotensin inhibition alone. The authors did not report any mortality data, so, presumably, there were few or no deaths over the 18-month study period. However, it is plausible that a reduction in ventricular arrhythmias is a primary driver of reduction in sudden cardiac death with ARNI therapy.

The potential mechanisms of this arrhythmia reduction are not immediately clear. The most plausible explanation simply may be the reduction in heart failure (with improved filling pressures and decreased volume overload) and improvement in left ventricular systolic function afforded by inhibition of neprilysin, the enzyme responsible for degradation of natriuretic peptides and several other vasoactive substances. Resultant decreases in cardiac fibrosis, myocardial wall stress, and sympathetic tone all may play a role. A direct electrophysiological effect is possible, but prior studies have shown no effect of sacubitril-valsartan on the ECG, including QTc. Notably, potassium levels were significantly higher with ARNI therapy, but there were no significant differences in potassium levels between patents with or without ventricular arrhythmias.

The principal weakness of this study is the sequential design of therapeutic intervention. All patients first were treated with an ACE inhibitor alone, after which all were transitioned to sacubitril-valsartan. Thus, the improvement in both heart failure parameters and burden of ventricular arrhythmias could be attributable in part simply to therapeutic optimization over time in a closely followed cohort of patients referred to a heart failure clinic. Ideally, a cohort of patients would have continued with angiotensin inhibition alone as a control. That said, it is clearly feasible that ARNI therapy could have driven the clinical benefits, given the corroborating knowledge from the PARADIGM-HF trial. It is unknown whether similar reductions in arrhythmia burden would be achieved in a cohort of patients with non-ischemic cardiomyopathy.

The data and results should serve to reinforce what we already know: For patients with a cardiomyopathy and increasing arrhythmia burden (whether manifesting as PVCs, NSVT, or sustained VT), aggressive medical therapy to optimize heart failure management should be the first step in management. Only one appropriate ICD shock was recorded in 120 patients over nine months on ARNI therapy. Whether routine addition of an angiotensin-neprilysin inhibitor to our patients’ standard heart failure regimen ultimately might shift the risk-benefit analysis for primary prevention ICD implant will be an intriguing and controversial question worth further investigation.


  1. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.