Skip to main content

Advertisement

SpringerLink
Log in

Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Sacubitril/valsartan has been associated with a positive reverse left ventricular remodelling in patients with heart failure with reduced ejection fraction (HFrEF). These patients may also benefit from an ICD implant. We aimed to assess EF improvement after 6 months of treatment with sacubitril/valsartan, evaluating when ICD as primary prevention was no longer indicated.

Methods

Multicentre, observational, prospective study enrolling all consecutive patients with HFrEF and EF ≤ 35% with an ICD as primary prevention and starting treatment with sacubitril/valsartan (NCT03935087). Resynchronization therapy and patients experiencing appropriate ICD therapies before sacubitril/valsartan were excluded.

Results

Two-hundred-and-thirty patients were enrolled (73.9% males, mean age 64.3 ± 12.1 years) After 6 months of treatment, a reduction in left ventricular end-diastolic and end-systolic volumes was noted and LVEF increased from 28.3 ± 5.6% to 32.2 ± 6.5% (p < 0.001). At 6 months, a non-ischemic aetiology of cardiomyopathy and a final dose of sacubitril/valsartan > 24/26 mg twice daily were associated with a higher probability of an absolute increase of > 5% in LVEF. A total of 5.3% of primary prevention patients still had an arrhythmic event in the first 6 months after treatment with sacubitril/valsartan started.

Conclusions

Sacubitril/valsartan improves systolic function in HFrEF, mainly due to reverse left ventricular remodelling. Improvement in EF after 6 months of treatment could help prevent ICD implantation in nearly one out of four patients, with important clinical and economic implications. However, the risk of sudden cardiac death in this recovered HFrEF population has not been thoroughly studied, and the present data should be interpreted only as hypothesis-generating.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data

Data will be available upon request to the corresponding author.

References

  1. Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 37:2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  2. Bui AL, Horwich TB, Fonarow GC (2011) Epidemiology and risk profile of heart failure. Nat Rev Cardiol 8:30–41

    Article  PubMed  Google Scholar 

  3. McMurray JJV, Packer M, Desai AS et al (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004. https://doi.org/10.1056/NEJMoa1409077

    Article  CAS  PubMed  Google Scholar 

  4. Almufleh A, Marbach J, Chih S et al (2017) Ejection fraction improvement and reverse remodeling achieved with Sacubitril/Valsartan in heart failure with reduced ejection fraction patients. Am J Cardiovasc Dis 7:108–113

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Januzzi JL, Prescott MF, Butler J et al (2019) Effects of angiotensin receptor/neprilysin inhibitor therapy on amino-terminal Pro-B-Type natriuretic peptide and cardiac remodeling in heart failure with reduced ejection fraction: the PROVE-HF Study. J Card Fail 25:937. https://doi.org/10.1016/j.cardfail.2019.11.004

    Article  Google Scholar 

  6. Vasan RS, Larson MG, Benjamin EJ et al (2002) Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med 336:1350–1355. https://doi.org/10.1056/nejm199705083361903

    Article  Google Scholar 

  7. Martens P, Beliën H, Dupont M et al (2018) The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther 36:e12435. https://doi.org/10.1111/1755-5922.12435

    Article  CAS  PubMed  Google Scholar 

  8. de Diego C, González-Torres L, Núñez JM et al (2018) 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. Hear Rhythm 15:395–402. https://doi.org/10.1016/j.hrthm.2017.11.012

    Article  Google Scholar 

  9. Chandra A, Lewis EF, Claggett BL et al (2018) Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 3:498–505. https://doi.org/10.1001/jamacardio.2018.0398

    Article  PubMed  PubMed Central  Google Scholar 

  10. Norberg H, Bergdahl E, Ängerud KH, Lindmark K (2020) A systematic approach for introduction of novel treatments to a chronic patient group: sacubitril-valsartan as a case study. Eur J Clin Pharmacol 77(1):125–131. https://doi.org/10.1007/s00228-020-02979-w

    Article  PubMed  PubMed Central  Google Scholar 

  11. Senni M, McMurray JJV, Wachter R et al (2016) Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 18:1193–1202. https://doi.org/10.1002/ejhf.548

    Article  CAS  PubMed  Google Scholar 

  12. Priori SG, Blomström-Lundqvist C, Mazzanti A et al (2015) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europe. Europace 17:1601–1687. https://doi.org/10.1093/europace/euv319

    Article  PubMed  Google Scholar 

  13. Desai AS, McMurray JJV, Packer M et al (2015) Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 36:1990–1997. https://doi.org/10.1093/eurheartj/ehv186

    Article  CAS  PubMed  Google Scholar 

  14. Guerra F, Palmisano P, Dell’Era G et al (2018) Cardiac resynchronization therapy and electrical storm: results of the OBSERVational registry on long-term outcome of ICD patients (OBSERVO-ICD). Europace 20:979–985. https://doi.org/10.1093/europace/eux166

    Article  PubMed  Google Scholar 

  15. Januzzi JL, Prescott MF, Butler J et al (2019) Association of change in N-terminal Pro–B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 322:1085. https://doi.org/10.1001/jama.2019.12821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alter P, Rupp H, Rominger MB et al (2007) Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy. Can J Physiol Pharmacol 85:790–799. https://doi.org/10.1139/Y07-076

    Article  CAS  PubMed  Google Scholar 

  17. Chang P-C, Wo H-T, Lee H-L et al (2020) Sacubitril/valsartan therapy ameliorates ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model. J Card Fail. https://doi.org/10.1016/j.cardfail.2020.03.007

    Article  PubMed  PubMed Central  Google Scholar 

  18. Langenickel TH, Jordaan P, Petruck J et al (2016) Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. Eur J Clin Pharmacol 72:917–924. https://doi.org/10.1007/s00228-016-2062-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martens P, Nuyens D, Rivero-Ayerza M et al (2019) Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction. Clin Res Cardiol 108:1074–1082. https://doi.org/10.1007/s00392-019-01440-y

    Article  CAS  PubMed  Google Scholar 

  20. Thomas CJ, McAllen RM, Salo LM, Woods RL (2008) Restorative effect of atrial natriuretic peptide or chronic neutral endopeptidase inhibition on blunted cardiopulmonary vagal reflexes in aged rats. Hypertension 52:696–701. https://doi.org/10.1161/HYPERTENSIONAHA.108.111302

    Article  CAS  PubMed  Google Scholar 

  21. Okumura N, Jhund PS, Gong J et al (2016) Effects of sacubitril/valsartan in the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) according to background therapy. Circ Hear Fail 9:e003212. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003212

    Article  CAS  Google Scholar 

  22. Boriani G, De Ponti R, Guerra F et al (2020) Sinergy between drugs and devices in the fight against sudden cardiac death and heart failure. Eur J Prev Cardiol. https://doi.org/10.1093/eurjpc/zwaa015

    Article  PubMed  Google Scholar 

  23. Buxton AE, Lee KL, Hafley GE et al (2007) Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease. J Am Coll Cardiol 50:1150–1157. https://doi.org/10.1016/j.jacc.2007.04.095

    Article  PubMed  Google Scholar 

  24. Barbier P, Mirea O, Cefalù C et al (2015) Reliability and feasibility of longitudinal AFI global and segmental strain compared with 2D left ventricular volumes and ejection fraction: intra- and inter-operator, test-retest, and inter-cycle reproducibility. Eur Heart J Cardiovasc Imaging 16:642–652. https://doi.org/10.1093/ehjci/jeu274

    Article  PubMed  Google Scholar 

  25. Guerra F, Malagoli A, Contadini D et al (2020) Global longitudinal strain as a predictor of first and subsequent arrhythmic events in remotely monitored ICD patients with structural heart disease. JACC Cardiovasc Imaging 13:1–9. https://doi.org/10.1016/j.jcmg.2018.12.020

    Article  PubMed  Google Scholar 

  26. Nichol G, Sayre MR, Guerra F, Poole J (2017) Defibrillation for ventricular fibrillation. J Am Coll Cardiol 70:1496–1509. https://doi.org/10.1016/j.jacc.2017.07.778

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital “Umberto I – Lancisi – Salesi,”, Ancona, Italy

    Federico Guerra, Giulia Stronati & Antonio Dello Russo

  2. Cardiology Department, Università Della Campania, Monaldi Hospital, Naples, Italy

    Ernesto Ammendola & Gerardo Nigro

  3. Cardiology Department, Università Di Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy

    Matteo Ziacchi & Pasquale Paolisso

  4. Cardiology Unit, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy

    Vittorio Aspromonte & Giampiero Maglia

  5. Department of Cardiology, Policlinico Ospedali Riuniti, Foggia, Italy

    Pier Luigi Pellegrino & Natale Daniele Brunetti

  6. Cardiology Unit, “Maria Ss Addolorata” Hospital, Eboli, Italy

    Giuseppe Del Giorno & Angelo Carbone

  7. Cardiology Unit, “Maggiore Della Carità” Hospital, Novara, Italy

    Gabriele Dell’Era & Miriam Gravellone

  8. Cardiology Unit-CCU, Italian National Reserch Centre On Aging, Ancona, Italy

    Lorenzo Pimpini & Roberto Antonicelli

  9. Department of Cardiology, Bonomo Hospital, Andria, Italy

    Francesco Santoro & Michele Cannone

  10. Department of Medical and Surgery Sciences, University of Foggia, Foggia, Italy

    Francesco Santoro

  11. Cardiology Unit, “Nostra Signora Di Bonaria” Hospital, San Gavino Monreale, Italy

    Roberto Floris

  12. Cardiology Unit, “Card. G. Panico” Hospital, Tricase, Italy

    Alessandro Guido, Michele Accogli & Pietro Palmisano

Authors
  1. Federico Guerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ernesto Ammendola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matteo Ziacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vittorio Aspromonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pier Luigi Pellegrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuseppe Del Giorno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriele Dell’Era
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lorenzo Pimpini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francesco Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberto Floris
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giulia Stronati
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gerardo Nigro
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pasquale Paolisso
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alessandro Guido
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Giampiero Maglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Natale Daniele Brunetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Angelo Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Miriam Gravellone
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Roberto Antonicelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michele Cannone
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Michele Accogli
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Antonio Dello Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Pietro Palmisano
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FG and PP conceived and designed the study, performed research, analysed data, contributed to methods, and wrote the paper. All other authors performed research, collected data, and critically revised the paper.

Corresponding author

Correspondence to Federico Guerra.

Ethics declarations

Ethics approval

The present protocol was approved by the ethics committee of the proposing centre.

Consent to participate and consent for publication

Written informed consent was obtained by all patients.

Conflict of interest

FG reported consultancy fees of small amount from Novartis. All other authors declare they have no conflict of interests related to the present manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guerra, F., Ammendola, E., Ziacchi, M. et al. Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study. Eur J Clin Pharmacol 77, 1835–1842 (2021). https://doi.org/10.1007/s00228-021-03189-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-021-03189-8

Keywords

Search

Navigation