Impact of Sacubitril/Valsartan on Sudden Cardiac Death as per ICD Use and HF Cause

23 Nov, 20

Introduction

Despite advances in pharmacological and device-based strategies for heart failure (HF) management, sudden cardiac death (SCD) accounts substantially for overall mortality in patients with HF with reduced ejection fraction (HFrEF). The PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study has already demonstrated the benefits of sacubitril/valsartan in cutting down the risk of death and worsening of HF irrespective of the use of implantable cardioverter-defibrillator (ICD).

Aim

To determine the impact of sacubitril/valsartan therapy on SCD as per the use of and eligibility for an ICD, as stratified by the cause of HF

Patient Profile

Ambulatory or hospitalized HFrEF patients (New York Heart Association [NYHA] class II-IV, ejection factor [EF] ≤35%) either treated with a low dose of angiotensin converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker (ARB) (on a stable dose for last 2 weeks) or ACEI/ARB-na?ve (must not have taken ACEI/ARB for at least 4 weeks) (age ≥18 years; n = 8,399)
All patients had elevated levels of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP)

Methods

Study Design

Subgroup analysis of the PARADIGM-HF study
PARADIGM-HF was randomized, double-blind, prospective study, conducted in 3 phases

Treatment Strategy

Patients were randomized 1:1 to receive enalapril, 10 mg twice daily, or sacubitril/valsartan, 200 mg twice daily

Outcomes

SCD and all-cause mortality

Results

At baseline, 7,145 patients (85%) were eligible for ICD implantation, but only 1,243 (15%) had an ICD. Of the 1243 patients who had ICD implantation, 780 had an ischemic etiology and 376 had non-ischemic etiology.
As per a propensity score-adjusted analysis, use of an ICD was associated with a 56% reduction in the risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and non-ischemic cardiomyopathy (p = 0.02) (Table 1).

Table 1: Risk reduction for SCD with use of ICD

	Hazard ratio (HR) (95% CI)	Risk reduction	P value
Overall	0.44 (0.30 to 0.64 )	56%	< 0.001
Ischemic etiology	0.43 (0.27 to 0.67)	57%	< 0.001
Non-ischemic etiology	0.45 (0.23 to 0.88)	55%	0.02

Sacubitril/valsartan treatment was associated with a greater reduction in the risk of SCD in patients with an ICD vs. those who were eligible for but did not receive an ICD (Table 2). This effect was more prominent in non-ischemic cardiomyopathy (p < 0.05), though interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers).

Table 2: Impact of sacubitril/valsartan on SCD as per ICD use

	HR (95% CI)	Risk Reduction	P value
ICD use	0.49 (0.25-0.99)	51%	0.047
Eligible for ICD but no ICD usage	0.81 (0.67-0.98)	19	0.03

Sacubitril/valsartan treatment also associated with reduced all-cause mortality across subgroups identified by ICD use and eligibility, although the magnitude of protection was attenuated in the ICD user subgroup (HR: 0.81; 95% CI: 0.61 to 1.06; p = 0.13; p_interaction =0.77)

Conclusions

Amongst patients with HFrEF, use of an ICD reduced the rates of SCD, irrespective of HF cause. Nevertheless, ICD was underused in most regions of the world in the PARADIGM-HF study.
Treatment with sacubitril/valsartan reduced SCD risk irrespective of use of an ICD or eligibility. This was particularly true for ICD users and for patients with non-ischemic cardiomyopathy.

J Am Coll Cardiol HF 2020;8:844–55.