Abstract
Background
Sacubitril/valsartan reduced the occurrence of sudden cardiac death in the PARADIGM-HF trial. However, limited information is available about the mechanism.
Methods
Heart failure (HF)-patients receiving sacubitril/valsartan for a class-I indication equipped with an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) with remote tele-monitoring were retrospectively analyzed. Device-registered arrhythmic-events were determined [ventricular tachycardia/fibrillation (VT/VF), appropriate therapy, non-sustained VT (NsVT; > 4beats and < 30 s), hourly premature ventricular contraction (PVC)-burden], following sacubitril/valsartan initiation (incident-analysis) and over an equal time period before initiation (antecedent-analysis). Reverse remodeling to sacubitril/valsartan was defined as an improvement of left ventricular ejection fraction of ≥ 5% between baseline and follow-up.
Results
A-total of 151 HF-patients with reduced LVEF (29 ± 9%) were included. Patients were switched from ACE-I or ARB to equal doses of sacubitril/valsartan (expressed as %-target-dose; before = 58 ± 30% vs. after = 56 ± 27%). The mean follow-up of both the incident and antecedent analysis was 364 days. Following the initiation, VT/VF-burden dropped (individual patients with VT/VF pre_n = 19 vs. post_n = 10, total-episodes of VT/VF pre_n = 51 vs. post_n = 14, both p < 0.001), resulting in reduced occurrence of appropriate therapy (pre_n = 16 vs. post_n = 6; p < 0.001). NsVT-burden per patient also dropped (mean episodes pre_n = 7.7 ± 11.8 vs. post_n = 3.7 ± 5.4; p < 0.001). There was no impact on atrial-fibrillation burden. PVC-burden dropped significantly which was associated with an improvement in BiV-pacing in patients with < 90% BiV-pacing at baseline. A higher degree of reverse remodeling was associated with a lower burden of NsVT and PVCs (both p < 0.05).
Conclusion
Initiation of sacubitril/valsartan is associated with a lower degree of VT/VF, resulting in less ICD-interventions. This beneficial effect on ventricular arrhythmias might be related to cardiac reverse remodeling.
Similar content being viewed by others
References
Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, Granger CB, Kjekshus J, Kober L, Latini R, Maggioni AP, Packer M, Pitt B, Solomon SD, Swedberg K, Tavazzi L, Wikstrand J, Zannad F, Zile MR, McMurray JJV (2017) Declining risk of sudden death in heart failure. N Engl J Med 377(1):41–51
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004
Virmani R, Burke AP, Farb A (2001) Sudden cardiac death. Cardiovasc Pathol 10(6):275–282
Sinha SK, Crain B, Flickinger K, Calkins H, Rickard J, Cheng A, Berger R, Tomaselli G, Marine JE (2016) Clinical inferences of cardiovascular implantable electronic device analysis at autopsy. J Am Coll Cardiol 68(12):1255–1264
Chung MK, Szymkiewicz SJ, Shao M, Zishiri E, Niebauer MJ, Lindsay BD, Tchou PJ (2010) Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 56(3):194–203
Kober L, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, Eiskjaer H, Brandes A, Thogersen AM, Gustafsson F, Egstrup K, Videbaek R, Hassager C, Svendsen JH, Hofsten DE, Torp-Pedersen C, Pehrson S (2016) Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 375(13):1221–1230
Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE (2013) 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 15(8):1070–1118
Martens P, Verbrugge FH, Nijst P, Dupont M, Nuyens D, Herendael HV, Rivero-Ayerza M, Tang WH, Mullens W (2017) Incremental benefit of cardiac resynchronisation therapy with versus without a defibrillator. Heart 103(24):1977–1984
Wilkoff BL, Fauchier L, Stiles MK, Morillo CA, Al-Khatib SM, Almendral J, Aguinaga L, Berger RD, Cuesta A, Daubert JP, Dubner S, Ellenbogen KA, Mark Estes NA, Fenelon G, Garcia FC, Gasparini M, Haines DE, Healey JS, Hurtwitz JL, Keegan R, Kolb C, Kuck KH, Marinskis G, Martinelli M, McGuire M, Molina LG, Okumura K, Proclemer A, Russo AM, Singh JP, Swerdlow CD, Teo WS, Uribe W, Viskin S, Wang CC, Zhang S (2016) 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 13(2):e50–e86
Martens P, Verbrugge FH, Nijst P, Bertrand PB, Dupont M, Tang WH, Mullens W (2017) Feasibility and association of neurohumoral blocker up-titration after cardiac resynchronization therapy. J Card Fail 23(8):597–605
Martens P, Belien H, Dupont M, Vandervoort P, Mullens W (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
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 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 Heart J 37(27):2129–2200
Mullens W, Martens P (2018) Exploiting the natriuretic peptide pathway to preserve glomerular filtration in heart failure. JACC Heart Fail 6(6):499–502
Landstrom AP, Dobrev D, Wehrens XHT (2017) Calcium signaling and cardiac arrhythmias. Circ Res 120(12):1969–1993
Zile MR, Claggett BL, Prescott MF, McMurray JJ, Packer M, Rouleau JL, Swedberg K, Desai AS, Gong J, Shi VC, Solomon SD (2016) Prognostic implications of changes in N-terminal Pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol 68(22):2425–2436
Levine YC, Rosenberg MA, Mittleman M, Samuel M, Methachittiphan N, Link M, Josephson ME, Buxton AE (2014) B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias. Heart Rhythm 11(7):1109–1116
Wang Z, Taylor LK, Denney WD, Hansen DE (1994) Initiation of ventricular extrasystoles by myocardial stretch in chronically dilated and failing canine left ventricle. Circulation 90(4):2022–2031
de C Diego, L Gonzalez-Torres, Nunez JM, Centurion IR, Martin-Langerwerf DA, Sangio AD, Chochowski P, Casasnovas P, Blazquez JC, Almendral J (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. Heart Rhythm 15(3):395–402
Chin KL, Collier T, Pocock S, Pitt B, McMurray JJV, van Veldhuisen DJ, Swedberg K, Vincent J, Zannad F, Liew D (2019) Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1410-4
Kobayashi M, Rossignol P, Ferreira JP, Aragao I, Paku Y, Iwasaki Y, Watanabe M, Fudim M, Duarte K, Zannad F, Girerd N (2018) Prognostic value of estimated plasma volume in acute heart failure in three cohort studies. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1385-1
Rossello X, Ariti C, Pocock SJ, Ferreira JP, Girerd N, McMurray JJV, van Veldhuisen DJ, Pitt B, Zannad F (2018) Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1378-0
Mogensen UM, Jhund PS, Abraham WT, Desai AS, Dickstein K, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, Kober L, McMurray JJV (2017) Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 70(20):2490–2500
Lakkireddy D, Di BL, Ryschon K, Biria M, Swarup V, Reddy YM, Verma A, Bommana S, Burkhardt D, Dendi R, Dello RA, Casella M, Carbucicchio C, Tondo C, Dawn B, Natale A (2012) Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders. J Am Coll Cardiol 60(16):1531–1539
Boveda S, Marijon E, Jacob S, Defaye P, Winter JB, Bulava A, Gras D, Albenque JP, Combes N, Pavin D, Delarche N, Teubl A, Lambiez M, Chevalier P (2009) Incidence and prognostic significance of sustained ventricular tachycardias in heart failure patients implanted with biventricular pacemakers without a back-up defibrillator: results from the prospective, multicentre, Mona Lisa cohort study. Eur Heart J 30(10):1237–1244
Gracieux J, Sanders GD, Pokorney SD, Lopes RD, Thomas K, Al-Khatib SM (2014) Incidence and predictors of appropriate therapies delivered by the implantable cardioverter defibrillator in patients with ischemic cardiomyopathy: a systematic review. Int J Cardiol 177(3):990–994
Acknowledgements
Pieter Martens is supported by a doctoral fellowship by the Research Foundation—Flanders (FWO, Grant number: 1127917N). Pieter Martens and Wilfried Mullens are researchers for the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Martens, P., Nuyens, D., Rivero-Ayerza, M. et al. 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 (2019). https://doi.org/10.1007/s00392-019-01440-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00392-019-01440-y