Compelling First-Line Drug and Device Therapies for the Prevention of Sudden Death in Patients With Chronic Heart Failure and a Reduced Ejection Fraction Who Are Candidates for an Implantable Cardioverter-Defibrillator

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 12, No. 6Compelling First-Line Drug and Device Therapies for the Prevention of Sudden Death in Patients With Chronic Heart Failure and a Reduced Ejection Fraction Who Are Candidates for an Implantable Cardioverter-Defibrillator Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCompelling First-Line Drug and Device Therapies for the Prevention of Sudden Death in Patients With Chronic Heart Failure and a Reduced Ejection Fraction Who Are Candidates for an Implantable Cardioverter-Defibrillator Milton Packer, MD Milton PackerMilton Packer Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email E-mail Address: [email protected] Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX. Imperial College, London, United Kingdom. Originally published4 Jun 2019https://doi.org/10.1161/CIRCEP.119.007430Circulation: Arrhythmia and Electrophysiology. 2019;12:e007430Sudden unexpected death is a devastating event in patients with chronic heart failure and a reduced ejection fraction, accounting for 30% to 50% of all deaths in this disorder. In 50% to 70% of sudden deaths, the abrupt circulatory collapse results from a sustained ventricular tachyarrhythmia, typically in a patient who had not experienced the rhythm disturbance previously. However, in the remaining 30% to 50%, sudden death appears to result from acute mechanical failure of the left ventricle, which is reflected on the surface ECG as asystole, bradyarrhythmia, or electromechanical dissociation.The former event (ie, sustained ventricular tachycardia or fibrillation) is typically seen in patients with mild symptoms and underlying coronary artery disease, and once detected, can be treated with an implantable cardioverter-defibrillator (ICD). In contrast, the latter event is primarily hemodynamic rather than electrical in nature, is seen disproportionately in those with advancing symptoms or with a nonischemic cardiomyopathy, and is not responsive to an ICD. The existence of 2 distinct pathways for sudden cardiac death explains why ICDs do not prevent all episodes of sudden death in patients with chronic heart failure. Depending on the population studied, ICDs reduce the risk of an abrupt demise by 30% to 70%.1 The effect of ICDs on all-cause mortality depends on the prevalence of sudden deaths in the population. In patients with class III–IV symptoms or meaningful comorbidities, sudden death represents a smaller proportion of all deaths, and ICDs do not significantly decrease all-cause mortality.Whether the terminal event is primarily electrical or mechanical in nature, the common underlying substrate for sudden cardiac death is a severely remodeled left ventricle, which is markedly dilated, replete with interstitial fibrosis, and distended by elevated cardiac filling pressures. The worsening of remodeling not only contributes to repeated hospitalizations for heart failure and death from circulatory insufficiency, but it also creates the structural and pathophysiological prerequisites for acute electrical and mechanical instability. The myocardial substrate is highly vulnerable to tiny shifts in the interactions of cardiomyocytes that normally act to maintain structural and functional integrity. Yet, if the limits of these compensatory mechanisms are breached, the ventricle is subject to cascading failure, leading to electrical storm or mechanical collapse.The placement of an ICD does not ameliorate the severe abnormalities in the underlying substrate, and it addresses the consequences of only one of the 2 types of cascading events (ie, the electrical storm). Therefore, it is reasonable to first use interventions that can reverse the causal process of ventricular remodeling. Specific drug and device strategies can each reduce the risk of sudden death to a meaningful degree, and their combined use yields substantial cumulative advantages. Four interventions for heart failure are effective in preventing sudden death: (1) β-adrenergic receptor blockers; (2) mineralocorticoid receptor antagonists; (3) angiotensin receptor neprilysin inhibitors; and (4) cardiac resynchronization therapy.β-Adrenergic Receptor Blockersβ-Blockers have decreased the risk of sudden cardiac death by 35% to 45% of patients with chronic heart failure and a reduced ejection fraction in large-scale trials,2 in whom ICDs were rarely used. This benefit appears to have been primarily driven by a remarkable action of these drugs to reverse the ventricular remodeling process. Long-term treatment with β-blockers can produce striking increases in ejection fraction and decreases in cardiac volumes, thus minimizing the vulnerable myocardial substrate for the development of electrical and mechanical cascading failure. β-blockers may also prevent ventricular tachyarrhythmias precipitated by circadian catecholamine surges, by hypokalemia due to β2-receptor activation, and by acute coronary thrombo-occlusive events.Mineralocorticoid Receptor AntagonistsIn large-scale trials, spironolactone and eplerenone have been shown to reduce the risk of sudden cardiac death by ≈20% in patients with chronic heart failure, who generally did not have an ICD. The magnitude of the risk reduction was particularly striking in patients who were receiving β-blockers,3 and was incremental to the benefits on sudden death produced by the β-blockers themselves. This favorable effect seems to be related to an improvement in cardiac fibrosis, and potentially, the prevention of hypokalemia-related ventricular tachyarrhythmias.Angiotensin Receptor Neprilysin InhibitorsConventional inhibitors of the renin-angiotensin system alone have only modest effects on ventricular remodeling and little effect to prevent sudden cardiac death. However, in a large-scale clinical trial, the addition of neprilysin inhibition to angiotensin receptor blockade potentiated both benefits. Sacubitril/valsartan reduced the risk of sudden death by 20% when compared with high doses of enalapril; this incremental benefit was seen in patients already receiving β-blockers and mineralocorticoid receptor antagonists. Interestingly, the magnitude of the reduction in sudden death with neprilysin inhibition was particularly striking in patients with an ICD, whose risk was decreased by 50%.4 This effect may be related to an action of neprilysin inhibitors to retard the progression of cardiac remodeling, and thereby, prevent the abrupt mechanical cascading collapse that can lead to sudden death, but is not amenable to treatment with an ICD.Cardiac Resynchronization TherapyIn patients with meaningful electromechanical delay and ventricular dyssynchrony (especially with left bundle branch block), cardiac resynchronization produces striking effects to improve ventricular remodeling, and this benefit is accompanied by a marked amelioration of the underlying arrhythmogenic substrate. In a large-scale trial, cardiac resynchronization in appropriate patients reduced the risk of sudden deaths by 50%,5 particularly in those who experienced reversal of the ventricular remodeling process. The risk reduction was seen in patients already receiving angiotensin-converting enzyme inhibitors, β-blockers, and mineralocorticoid receptor antagonists, but not an ICD.It is currently recommended that treatment with β-blockers, mineralocorticoid receptor antagonists, angiotensin receptor neprilysin inhibitors, and cardiac resynchronization be combined in all appropriate patients who have heart failure and a reduced ejection fraction. The cumulative benefits on sudden death with the use of combination therapy are likely to be large, but are difficult to estimate with precision, since the trials that demonstrated their individual effects on sudden death evaluated target doses, and compliance with the assigned treatment was high; such conditions do not typify those in clinical practice. Nevertheless, it is intriguing to note that the annual rate of sudden death has been reduced by 45% to 60% over a period of 10 to 15 years in patients with heart failure and a reduced ejection fraction who were receiving combination treatments in the community; this benefit was unrelated to treatment with an ICD.6 Therefore, the cumulative magnitude of the reduced risk of sudden death with combination antiremodeling therapies appears to rival that attributable to an ICD. Importantly, these drugs and devices have the added advantage of addressing the underlying myocardial disease, and thereby simultaneously ameliorating the symptoms of heart failure and reducing the risk of hospitalizations and death due to heart failure.Since combination antiremodeling therapy is mandated for patients with chronic heart failure and left ventricular systolic dysfunction regardless of their risk of sudden death, its ability to reduce the likelihood of abrupt circulatory collapse is an important added benefit. Some individuals who have a striking benefit on ejection fraction and ventricular volumes from combination treatment have a very low likelihood of sudden cardiac death, but others remain at risk. Until the thresholds for adequacy of the remodeling benefits are established, it may be difficult to identify those in whom use of an ICD may be obviated.DisclosuresDr Packer has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. None of these relationships have any bearing to the topic of this article.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email milton.[email protected]eduReferences1. Packer DL, Prutkin JM, Hellkamp AS, Mitchell LB, Bernstein RC, Wood F, Boehmer JP, Carlson MD, Frantz RP, McNulty SE, Rogers JG, Anderson J, Johnson GW, Walsh MN, Poole JE, Mark DB, Lee KL, Bardy GH. Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial.Circulation. 2009; 120:2170–2176. doi: 10.1161/CIRCULATIONAHA.109.853689LinkGoogle Scholar2. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.Circulation. 2002; 106:2194–2199.LinkGoogle Scholar3. Rossello X, Ariti C, Pocock SJ, Ferreira JP, Girerd N, McMurray JJV, Van Veldhuisen DJ, Pitt B, Zannad F. 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. 2019; 108:477–486. doi: 10.1007/s00392-018-1378-0CrossrefMedlineGoogle Scholar4. Desai AS, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Chen F, Gong J, Rizkala AR, Brahimi A, Claggett B, Finn PV, Hartley LH, Liu J, Lefkowitz M, Shi V, Zile MR, Solomon SD. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients.Eur Heart J. 2015; 36:1990–1997. doi: 10.1093/eurheartj/ehv186CrossrefMedlineGoogle Scholar5. Uretsky BF, Thygesen K, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, Cleland JG. Predictors of mortality from pump failure and sudden cardiac death in patients with systolic heart failure and left ventricular dyssynchrony: results of the CARE-HF trial.J Card Fail. 2008; 14:670–675. doi: 10.1016/j.cardfail.2008.06.001CrossrefMedlineGoogle Scholar6. Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, Granger CB, Kjekshus J, Køber L, Latini R, Maggioni AP, Packer M, Pitt B, Solomon SD, Swedberg K, Tavazzi L, Wikstrand J, Zannad F, Zile MR, McMurray JJV. Declining risk of sudden death in heart failure.N Engl J Med. 2017; 377:41–51. doi: 10.1056/NEJMoa1609758CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByLeyva F, Israel C and Singh J (2023) Declining Risk of Sudden Cardiac Death in Heart Failure: Fact or Myth?, Circulation, 147:9, (759-767), Online publication date: 28-Feb-2023. Pascual-Figal D, Bayés-Genis A, Beltrán-Troncoso P, Caravaca-Pérez P, Conde-Martel A, Crespo-Leiro M, Delgado J, Díez J, Formiga F and Manito N (2021) Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.754499, 8 Packer M and McMurray J (2021) Rapid evidence‐based sequencing of foundational drugs for heart failure and a reduced ejection fraction, European Journal of Heart Failure, 10.1002/ejhf.2149, 23:6, (882-894), Online publication date: 1-Jun-2021. Wong J, Roberts J and Healey J (2021) The Optimal Timing of Primary Prevention Implantable Cardioverter-Defibrillator Referral in the Rapidly Changing Medical Landscape, Canadian Journal of Cardiology, 10.1016/j.cjca.2021.01.024, 37:4, (644-654), Online publication date: 1-Apr-2021. Boriani G, De Ponti R, Guerra F, Palmisano P, Zanotto G, D'Onofrio A and Ricci R (2020) Sinergy between drugs and devices in the fight against sudden cardiac death and heart failure, European Journal of Preventive Cardiology, 10.1093/eurjpc/zwaa015, 28:1, (110-123), Online publication date: 23-Mar-2021. June 2019Vol 12, Issue 6 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.119.007430PMID: 31159583 Originally publishedJune 4, 2019 Keywordsheart failureneprilysinbeta-blockersspironolactonecardiac resynchronization therapyPDF download Advertisement SubjectsHeart FailureSudden Cardiac DeathVentricular Fibrillation

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