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• W2947344183 abstract "In 30–50% of patients with chronic heart failure, the mode of demise is sudden cardiac death. Because many (but not all) of these events are related to a sustained ventricular tachyarrhythmia, implantable cardioverter-defibrillators (ICD) have been recommended to prevent these serious rhythm disturbances, and their use reduces the risk of sudden death by 50–70%, depending on the patient population studied.1-3 However, these devices address the lethality of a life-threatening arrhythmia; they do not interfere with the critical pathophysiological mechanisms that cause the structural remodelling that is responsible for disease progression. Neurohormonal antagonists and cardiac resynchronization can reduce the risk of heart failure hospitalizations and pump failure deaths, but the effect of these interventions on sudden death is not well appreciated, especially the potential for a cumulative benefit when they are used in combination (Table 1).4-11 Minimal effect on the risk of sudden death in patients not receiving beta-blockers; 20% reduction in sudden death in post-infarction patients treated with beta-blockers In patients with heart failure and a reduced ejection fraction not treated with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors primarily act to prevent pump failure deaths and heart failure hospitalizations. The effect of these drugs on the risk of sudden death is modest (<10%),4 and in direct comparator trials, this benefit is smaller than with beta-blockers.6 A larger (i.e. 15–20%) reduction in sudden death has been seen with angiotensin receptor blockers in chronic heart failure5 and with ACE inhibitors in post-infarction left ventricular systolic dysfunction,12 but interestingly, in these studies, patients were commonly receiving background therapy with a beta-blocker. Beta-blockade with carvedilol, bisoprolol and metoprolol succinate reduces the risk of sudden death by 35–50% in patients with New York Heart Association class II, III and IV symptoms with a reduced ejection fraction, who are already receiving ACE inhibitors but do not have an ICD.6-8 This favourable effect is likely related to (i) an action to minimize the consequences of circadian catecholamine surges; (ii) the prevention of new myocardial infarctions in patients with an underlying ischaemic cardiomyopathy; and (iii) a marked effect to cause reversal of cardiac remodelling, and thereby, minimize the development of a vulnerable substrate that is prone to electrical instability. Spironolactone and eplerenone reduce the risk of sudden death both in patients with chronic heart failure and a reduced ejection fraction as well as in post-infarction patients with systolic dysfunction. Interestingly, this benefit is largely seen in those who are already receiving concomitant therapy with ACE inhibitors and beta-blockers, but without an ICD.8 Mineralocorticoid receptor antagonists reduce the risk of sudden death by 35% in patients receiving beta-blockers, but they have negligible effects in those not treated with beta-blockers. The synergism of mineralocorticoid receptor antagonists with beta-blockers may be related to the fact that the two classes of drugs act on different pro-arrhythmic mechanisms and different aspects of ventricular structure. Specifically, beta-blockers blunt catecholamine surges and reduce cardiac volumes, whereas aldosterone antagonists prevent hypokalaemia and minimize fibrosis with little effect on ventricular geometry.13, 14 The addition of a neprilysin inhibitor to an angiotensin receptor blocker potentiates the effects of the latter on ventricular remodelling.15 Although conventional inhibitors of the renin–angiotensin system have only a modest effect to prevent sudden death, sacubitril/valsartan provides an incremental 20% decrease in the risk of sudden death in patients already receiving ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists.10 Interestingly, the magnitude of the benefit of neprilysin inhibition may be enhanced (i.e. increasing to a 50% reduction in risk) in patients who already have an ICD. Such a finding supports earlier observations that the efficacy of ICDs to prevent sudden death may be attenuated in patients with markedly remodelled left ventricles and advancing symptoms.16 In patients with heart failure and a reduced ejection fraction who have meaningful electrical conduction system delay (particularly, left bundle branch block), cardiac resynchronization can produce striking reversal of ventricular remodelling. The resulting improvement in wall stress is translated into a meaningful amelioration of the substrate for unstable electrical activity.17 Following cardiac resynchronization, the risk of sustained ventricular tachyarrhythmias and sudden death declines by 50% in patients who are receiving combinations of neurohormonal antagonists, including ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists.11 By contrast, such pronounced antiarrhythmogenic effects have not been observed in patients who have a persistently severely remodelled ventricle and advancing symptoms of heart failure following the resynchronization procedure.17 Drugs and devices that have favourable effects on ventricular structure and geometry have remarkable effects to reduce the risk of sudden death, and the available evidence demonstrates the incremental value of each intervention in patients already receiving treatments that were previously shown in earlier trials to reduce the risk of an abrupt unexpected demise. Because of the sequencing of these studies, it is possible to estimate the cumulative advantages of combination therapy on the risk of sudden death in patients with heart failure. In a hypothetical cohort of 1000 patients with chronic heart failure and a reduced ejection fraction, ≈400 patients would be expected to die suddenly in the absence of modern-day treatment with neurohormonal antagonists. If implantation of an ICD reduced the risk of sudden death by 60–70%, i.e. 120–160 patients would die suddenly. However, if an ICD were not implanted, the use of beta-blockers in patients receiving an ACE inhibitor would be expected to decrease the risk of abrupt circulatory collapse by ≈40%, i.e. 240 patients would die suddenly. If these patients were also treated with a mineralocorticoid receptor antagonist and a neprilysin inhibitor, the risk of sudden death would be progressively reduced by an additional 35%, and then by 20%, thereby lowering the number of sudden deaths to 156 (with the addition of a mineralocorticoid receptor antagonist), and then to 125 patients (with the addition of a neprilysin inhibitor). Therefore, a modern-day target-dose combination of neurohormonal antagonists administered to 1000 patients would be expected to prevent 275 sudden deaths (400 events decreased to 125 events), and these drugs would also produce favourable effects on pump failure deaths as well as hospitalizations for worsening heart failure. By contrast, the placement of an ICD administered to 1000 patients would be expected to prevent 240–280 sudden deaths (400 events decreased to 120–160 events), but without any effect on events related to worsening heart failure. Therefore, the magnitude of the cumulative benefit of the combination of neurohormonal antagonists on sudden cardiac death is meaningful and rivals that of an ICD, even though the effect size estimates were derived under different set of circumstances. Obviously, this juxtaposition of the benefits of different strategies is provided for illustrative purposes; ideally, patients should receive all appropriate drug and device treatments used in conjunction with each other. It should be emphasized that the estimates of the effect size of a combination of neurohormonal antagonists are exaggerated, since they assume that all patients with chronic heart failure and a reduced ejection fraction are receiving all appropriate neurohormonal antagonists at target doses, a state of affairs that does not realistically occur in clinical practice. Nevertheless, these calculations do not consider the additional benefits on heart failure events and sudden deaths that would accrue to patients who were candidates for and would be treated with a cardiac resynchronization device. In patients with left bundle branch block, the addition of synchronized biventricular pacing would be expected to decrease the number of sudden death by an additional 50%.11 Direct support for the validity of these estimates has recently been provided by longitudinal analyses showing that — with the advent and widespread adoption of modern drugs and devices for heart failure — the annual rate of sudden cardiac death in patients with a reduced ejection fraction has declined by 45–60% over the last two decades, in the absence of the utilization of an ICD.18 In these analyses, it is important to note that patients were not receiving all appropriate neurohormonal antagonists at target doses, and thus, the effect size estimate reflects a far more realistic scenario that the hypothetical set of calculations presented in the previous paragraphs. Nevertheless, by producing favourable effects on heart failure events as well as comparable effects on sudden deaths, it is possible that a strategy of combining neurohormonal antagonists might minimize the need for ICD placement in many patients. Although such a proposal should be considered judiciously, it might represent a welcome development, given the considerable expense of ICDs and their lack of easy availability to many populations. However, even when access to ICDs is not limited, a cautious approach to their use may be warranted, particularly in individual patients who demonstrate meaningful reversal of ventricular remodelling with the use of broad-based neurohormonal antagonism and cardiac resynchronization therapy. Such an approach is consistent with current guidelines, but physicians should recognize that it may require 6–12 months of intensive drug and device therapy before the full benefits on cardiac structure are realized, so as to allow for appropriate assessment for suitability of a patient for ICD placement. Further studies should determine the degree of reverse remodelling that might forestall the necessity of an ICD, thereby redefining the role of ICDs in preventing sudden death in the modern era. Conflict of interest: M.P. has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Gilead, Johnson & Johnson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics and Theravance." @default.
• W2947344183 created "2019-06-07" @default.
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• W2947344183 date "2019-05-29" @default.
• W2947344183 modified "2023-10-01" @default.
• W2947344183 title "Major reduction in the risk of sudden cardiac death in patients with chronic heart failure with the use of drug and device combinations that favourably affect left ventricular structure" @default.
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