Research Article

Effects of highest dose of sacubitril/valsartan association compared to lower doses on mortality and ventricular arrhythmias

Florent Allain*, Damien Legallois*, Katrien Blanchart*, Laure Champ-Rigot, Arnaud Pellissier, Pierre Ollitrault, Mathieu Chequel, Rémi Sabatier , Alain Lebon, Sophie Gomes, Olivier Citerne, Paul Milliez, Paul Milliez*, Florent Allain, Damien Legallois, Katrien Blanchart, Laure Champ-Rigot, Arnaud Pellissier, Pierre Ollitrault, Mathieu Chequel, Rémi Sabatier, Alain Lebon, Sophie Gomes, Olivier Citerne and Farzin Beygui

Published: 24 April, 2020 | Volume 5 - Issue 1 | Pages: 089-094

Background: Sudden cardiac death is a major healthcare issue in reduced ejection fraction heart failure (HFrEF) patients. Recently, the new association of sacubitril/valsartan showed a reduction of both ventricular arrhythmias (VA) and mortality even at low dose compared to enalapril in HF patients. The purpose of our study was to assess whether the highest dose of sacubitril/valsartan compared to lower doses may improve the rate of death and VA in a population of patients with HFrEF and with an implantable cardiac defibrillator (ICD).

Methods: 104 HF patients with reduced EF under sacubitril/valsartan with an ICD were divided in 2 groups: the first one with the lower doses of sacubitril/valsartan (24/26 mg or 49 mg/51 mg twice daily) and the second with the maximal dose (97mg/103mg twice daily). The primary outcome was a composite of death or appropriate ICD therapy for VA.

Results: After a median follow-up of 14 months, 39 patients were treated with lower doses and 65 patients with the highest dose. Patients from the lower doses group were older (70 [60-80] vs. 66 [60-70]; p = 0,03), more symptomatic at initiation (NYHA 3: 44% vs. 19%; p < 0,01) and more often in atrial fibrillation (31% vs. 12%; p = 0,04). The primary composite endpoint occurred in 14 patients (36%) in the low doses group versus 7 patients (11%) in high dose group (p < 0,01). This difference was particularly observed in the subgroup of patients with ischemic cardiomyopathy. In a multivariable analysis, the higher dose was independently associated with the primary outcome with an HR = 2,934 [IC 95% 1,147 – 7,504]; p = 0,03. Kaplan-Meier curve showed an early effect of the highest dose of sacubitril/valsartan association.

Conclusion: Patients with HFrEF under the highest dose of sacubitril/valsartan showed better clinical outcomes with a decrease of both mortality or appropriated ICD therapies related to ventricular arrhythmias.

Read Full Article HTML DOI: 10.29328/journal.jccm.1001092 Cite this Article Read Full Article PDF


Sacubitril/valsartan; Dose; Mortality; Ventricular arrhythmia; Implantable cardiac defibrillator


  1. Kong MH, Fonarow GC, Peterson ED, Curtis AB, Hernandez AF, et al. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol. 2011; 57: 794-801. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21310315
  2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, 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). Eur J Heart Fail. 2016; 18: 891-975. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27207191
  3. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, et al; PARADIGM-HF Investigators and Committees.Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014; 371: 993–1004. PubMed : https://www.ncbi.nlm.nih.gov/pubmed/25176015
  4. Vardeny O, Claggett B, Packer M, Zile MR, Rouleau J, et al. Efficacy of sacubitril/valsartan vs.. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. European Journal of Heart Failure, 2016; 18: 1228–1234. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27283779
  5. de Diego C, González-Torres L, Núñez JM, Centurión Inda R, Martin-Langerwerf DA, et al. Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm. 2018; 15: 395–402. PubMed : https://www.ncbi.nlm.nih.gov/pubmed/29146274
  6. Wilkoff BL, Fauchier L, Stiles MK, Morillo CA, Al-Khatib SM, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Europace. 2016; 18: 159–183. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26585598
  7. Webb RL, de Gasparo M. Role of the angiotensin II receptor blocker valsartan in heart failure. Exp Clin Cardiol. 2001; 6: 215-221. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859003/
  8. Young JB. Mortality and Morbidity Reduction with Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction: Results of the CHARM Low-Left Ventricular Ejection Fraction Trials. Circulation. 2004; 110: 2618–2626. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15492298
  9. Hubers SA, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016; 133: 1115–1124. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26976916
  10. Iborra-Egea O, Gálvez-Montón C, Roura S, Perea-Gil I, Prat-Vidal C, et al. Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. Npj Systems Biology and Applications. 2017; 3.
  11. Sarrias A, Bayes-Genis A. Is Sacubitril/Valsartan (Also) an Antiarrhythmic Drug? Circulation. 2018; 138: 551–553. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30354612
  12. Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological Effects of Myocardial Stretch and Mechanical Determinants of Stretch-Activated Arrhythmias. Circulation. 1992; 86: 968-978. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1381296


Figure 1

Figure 1

Figure 1

Figure 2

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More