Decline in sudden death in heart failure over last two decades

11-7-2017 • Shen L, et al, NEJM 2017

Declining Risk of Sudden Death in Heart Failure

Shen L, Jhund PS, Petrie MC, et al.
N Engl J Med 2017; 377:41-51

Introduction and Methods

ACE-inhibitors, ARBs, beta-blockers and MRAs reduce the risk of sudden death in heart failure (HF) with reduced ejection fraction (HFrEF) [1-4]. Also, implantable cardioverter–defibrillators (ICDs) reduce the risk of sudden death in these patients, but are costly and have adverse effects [5]. If sudden death rates decrease over time due to the increasing use of evidence-based medications, the added value of ICDs might be diminished.
In this study, the first part of this hypothesis was tested. The risk of sudden death was evaluated during follow-up in 12 randomized, controlled trials, including symptomatic HFrEF patients. The studies were conducted between 1995 and 2014, enrolled more than 1.000 patients each, with NYHA class II, III or IV and EF ≤40%, included adjudication of cause of death and provided patient-level data. Trials in which all patients of each treatment group had an ICD, were excluded. In total, 42 trials were identified and 22 were eligible for inclusion in this analysis, but data could be obtained from only 12 trials (RALES, BEST, CIBIS-II, MERIT-HF, Val-HeFT, SCD-HeFT, CHARM-Alternative, CHARM-Added, CORONA, GISSI-HF, EMPHASIS,HF, PARADIGM-HF).

Main results

  • Out of 40,195 eligible patients, 77% were men, 62% had an ischemic cause of HF and 8.9% died suddenly.
  • The annual rate of sudden death fell over time, from 6.5% in the earliest trial (RALES, completed in 1998) to 3.3% in the most recent trial (PARADIGM-HF, completed in 2014). The P value for trend was 0.02.
  • An exception to the fall of sudden death rates over time was the CORONA trial (completed in 2007), with a rate of sudden death of 5.2%. In this study the rate of death from any cause was also outside the declining trend for other trials, probably because only patients ≥60 years with ischemic HF were enrolled.
  • The rate of sudden death was lower in the experimental-therapy groups than in the control groups in all the trials, with the exceptions of Val-HeFT and GISSI-HF. With adjustment for randomized group, with the trial as a random effect, there was a decline in risk of sudden death of 44% over the 19 years (HR 0.56, 95% CI 0.33-0.93, P=0.03).
  • The reduction in risk over time was attenuated with further adjustment for baseline covariates (adjusted HR 0.90, 95% CI 0.61-1.32, P=0.60), although the randomized group remained associated with a lower risk of sudden death (HR 0.86, 95% CI 0.81-0.92, P<0.001).
  • At 90 days after randomization, the cumulative incidence rates of sudden death ranged from 2.4% (95% CI 1.6-3.1) in RALES to 1.0% (95% CI 0.8-1.3) in the PARADIGM-HF trial. In each trial, the cumulative incidence of sudden death at 180 days was approximately double that at 90 days, with a similar general trend towards lower rates in more recent trials.
  • The cumulative risk of sudden death during follow-up increased significantly according to the length of time between the diagnosis of HF and randomization in the nine trials that had this information available (31,866 patients; 79% of the total study sample).
  • In each trial, a higher rate of sudden death was observed in the subgroup of patients with a lower ejection fraction.


In a meta-analysis of 12 randomized trials, the rate of sudden death in HFrEF patients has fallen over the past two decades and the absolute rate of sudden death was lower among patients with a more recent diagnosis of HF. These findings suggest that there is a cumulative benefit of evidence-based medications on sudden death.
Find this article online at NEJM


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2. Solomon SD, Wang D, Finn P, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 2004;110: 2180-3.
3. Al-Gobari M, El Khatib C, Pillon F, et al. β-Blockers for the prevention of sudden cardiac death in heart failure patients: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2013; 13: 52.
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