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Fewer ventricular arrhythmias with angiotensin-neprilysin vs angiotensin inhibition in HF
Literature - de Diego C, González-Torres L, Núñez JM, et al. - Heart Rhythm 2017; published online ahead of print


For HFrEF patients, ACEis, ARBs, MRAs, and beta-blockers (BBKs) are of clinical benefit, whereas the ARNI sacubitril-valsartan decreases morbidity and mortality, including sudden death, with greater efficacy compared to enalapril [1-3]. Data suggest that natriuretic peptide levels, which reflect myocardial wall stress, are independent strong predictors for sustained ventricular arrhythmias and appropriate ICD shocks [4]. It is speculated that various mechanisms, such as ventricular arrhythmias, asystole, electromechanical dissociation, and cardiogenic shock lead to sudden death, however, the precise mechanism of sudden cardiac death remains unclear.

In this study, arrhythmia markers were analyzed with remote monitoring of HFrEF patients with an ICD, for the duration of 9 months under angiotensin inhibition and subsequently for another 9 months under sacubitril-valsartan, in order to evaluate the effect of ARNI on ventricular arrhythmias and appropriate ICD shocks as compared to angiotensin inhibition.

For this purpose, 120 consecutive HFrEF patients with an ICD or ICD-CRT were prospectively recruited (symptomatic HF with NYHA ≥II despite optimal medical therapy, LVEF ≤40%, patient received and tolerated ARNI). The following arrhythmia markers were monitored:

  • appearance of appropriate ICD shocks, due to ventricular tachycardia
  • sustained ventricular tachycardia (VT) with a duration of ≥30 secs or treated by the device
  • non-sustained ventricular tachycardia (NSVT) with ≥4 beats for <30 seconds
  • premature ventricular contractions (PVCs) per hour (on average)
  • the percentage of biventricular pacing
  • sustained atrial tachycardia (AT) at an atrial rate of >190 bpm, or atrial fibrillation (AF) for ≥30 secs, and inappropriate shocks due to AT/AF episodes

Main results

  • ARNI was associated with an improvement in NYHA functional class (P<0.0002), a decrease of pro-BNP levels from 1971±1530 pg/ml to 1172±955 pg/ml (P<0.01), an increase of LVEF from 30.4±4 to 35.1±8% (P<0.01), and a decrease in LV diastolic diameter of 61±5 mm vs. 58±6 mm (P<0.01).
  • ARNI therapy was also associated with a significant increase in potassium levels (from 4.4±0.5 to 4.7±0.5 mEq/l; P <0.03), significant decreases in HR and BP, while GFR was not significantly changed.
  • Compared to angiotensin inhibition alone, patients on ARNI had significantly fewer ICD shocks at 9 months (99.2% survival free from appropriate ICD shocks with ARNI vs. 93.3% with angiotensin inhibition alone; P<0.02).
  • Sustained VT was significantly decreased with ARNI as compared to angiotensin inhibition, from 6.7 % to 0.8% at 9 months (P <0.02). A Kaplan-Meier curve also showed significant reduction of NSVT with ARNI as compared to angiotensin inhibition.
  • ARNI was associated with a significant decrease of NSVT episodes/patient as compared to angiotensin inhibition (15 ±1.7 vs. 5.4±0.5; P <0.002). The number of patients with ≥1 episode of NSVT were significantly reduced from 71 to 45 with ARNI (P<0.0001).
  • Compared to angiotensin inhibition, ARNI was associated with a significant reduction of the PVC burden at 9 months (P<0.0003), driven by an increase of biventricular pacing percentage from 95±6 % to 98.8±1.3 % (P <0.02).
  • Based on repeated measures analyses, patients with ventricular arrhythmia ICD events had significantly higher levels of pro-BNP. Particularly in this patient subgroup, ARNI significantly decreased pro-BNP levels.


In HFrEF patients with an ICD under remote control, angiotensin-neprilysin inhibition as compared to angiotensin inhibition alone decreased ventricular arrhythmias, leading to a reduction of appropriate ICD shocks.


1. Ponikowski P, Voors AA, Anker SD, et al. 2016. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.

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

3. Hubers SA and Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016;133:1115-24.

4. Levine YC, Rosenberg MA, Mittleman M, et al. B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias. Heart Rhythm. 2014;11:1109-16.

Find this article online at Heart Rhythm

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