The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, published in September 2014, demonstrated significant reductions in mortality and heart failure (HF) hospitalization with use of the composite angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril/valsartan (LCZ696) compared with enalapril in patients with heart failure with reduced ejection fraction (HFrEF).¹ These data have supported an update to current ACC/AHA treatment guidelines that encourages clinicians to consider substitution of an ARNi for patients with chronic HFrEF who tolerate an ACE inhibitor or angiotensin-receptor blocker (ARB).² In this brief review, we discuss key findings from analyses of the PARADIGM-HF data subsequent to publication of the principal trial results that provide insight into the use of sacubitril/valsartan clinical practice.

To recap, PARADIGM-HF randomized 8399 subjects with chronic HF, NYHA class II-IV functional capacity, left ventricular ejection fraction ≤40%, and elevated natriuretic peptide levels who were stable on guideline-directed medical therapy including a beta-blocker and an ACE inhibitor or ARB at a dosage equivalent to enalapril ≥10mg/d for at least 4 weeks. Patients were not eligible for study inclusion if they had a history of angioedema, an eGFR <30 ml/min/1.73m², serum potassium >5.2 mmol/L, symptomatic hypotension or a SBP <100 mmHg, or were in the midst of a heart failure exacerbation. At median follow up of 27 months, subjects assigned to sacubitril/valsartan experienced a 20% reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization which occurred in 26.5% of patients taking enalapril compared with 21.8% in patients taking sacubitril/valsartan (HR 0.80, 95% CI 0.73-0.87, p<0.001). Similar reductions were seen in the individual components of the primary endpoint, and importantly, there was also an associated reduction of 16% in all-cause mortality (17.0% with sacubitril/valsartan vs. 19.8% with enalapril, HR 0.84, 95% CI 0.76-0.93, p <0.001). A subsequent analysis of mode of death in the trial suggested that among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, p = 0.008) and death due to worsening HF (HR 0.79, 95% CI 0.64-0.98, p = 0.034) were reduced by treatment with sacubitril/valsartan compared with enalapril. The effect on sudden death (which accounted for 36.3% of all deaths that occurred during the trial) was apparent in patients with and without an implantable defibrillator and was apparent within months of randomization.³ Leveraging the PARADIGM-HF data using actuarial methods to project the impact on life expectancy suggests that use of sacubitril/valsartan in preference to enalapril in appropriate patients may be result in a 1 to 2 year prolongation of survival free from HF.⁴ Assuming similar safety, tolerability, and efficacy in clinical practice as seen during the trial, it is estimated that more than 28,000 deaths among HF patients in the United States might be prevented by transition of eligible patients with HF and reduced EF from an ACE inhibitor or ARB to ARNi.⁵

The study design of PARADIGM-HF included sequential run-in periods designed to ensure the tolerability of both study drugs at target doses. The run-period has raised some concerns about the generalizability of the study results, since the randomized population was a subset of those initially eligible based on screening criteria. Rates of study drug discontinuation were roughly 10% during each of the run in periods, half of these for adverse effects of either enalapril or sacubitril/valsartan. In multivariable models, lower systolic blood pressure, lower estimated GFR, higher NT-proBNP, and ischemic HF etiology were associated with higher risk for run-in noncompletion during either period. However, patients who were unable to complete the run-in period shared many characteristics with patients who were successfully randomized, and overweighting the experience of patients similar to those who dropped out did not alter the hazard ratio favoring LCZ696 over enalapril for the primary composite endpoint or all-cause mortality. Accordingly, the size of the treatment effect of LCZ696 over enalapril during the randomized phase does not appear to have been influenced by the pattern of discontinuations during the run-in period.⁶

The benefits of sacubitril/valsartan in the PARADIGM-HF trial were robust in all subgroups examined. Notably, subsequent analyses of effects according to ejection fraction suggest no variation in benefit by the EF at the time of enrollment despite the modification of the trial inclusion criteria from an EF ≤40% to EF ≤35% one year into the trial.⁷ Benefits were also consistent in patients treated and not treated with a mineralocorticoid receptor antagonist (MRA) at baseline, and the risk of hyperkalemia with MRAs was actually reduced by use of sacubitril/valsartan in lieu of enalapril.⁸ As well, the safety, tolerability, and efficacy appear to be consistent in subgroups defined by age, including those over the age of 75, suggesting that the drug may be appropriate even for elderly patients who meet the study inclusion criteria.⁹ Although the trial enrolled predominantly patients with NYHA Class 2 heart failure symptoms, the study population actually reflected a broad spectrum of HF severity as defined by more granular risk stratification algorithms such as the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) or EMPHASIS-HF (Epleronone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk scores. Importantly, rates of important clinical outcomes including cardiovascular death and HF hospitalization were consistently lower among patients taking sacubitril/valsartan compared to those taking enalapril across all quintiles of these risk score, indicating consistent benefits across a wide range of disease severity.¹⁰ Although some have argued for deferring initiation of sacubitril/valsartan in clinically stable patients treated with an ACE-inhibitor or ARB (such as those without recent HF exacerbation), the data from PARADIGM suggest that even 'stable' NYHA 2-3 patients may remain at high risk for cardiovascular death and HF hospitalization (17% of those with no prior HF hospitalization died during the course of the trial); in analyses comparing outcomes by treatment assignment in relation to the time since the most recent HF hospitalization, those with a remote HF hospitalization or no prior HF hospitalization (more 'stable') were equally likely to benefit from sacubitril/valsartan treatment as those with more recent hospitalization (less 'stable').¹¹ Since a large proportion of deaths among the apparently 'stable' patients were sudden deaths occurring prior to any clinical heart failure exacerbation, a strategy of waiting for clinical deterioration to initiate sacubitril/valsartan may be inadvisable.

Although these results are compelling, the pathophysiologic mechanisms by which sacubitril/valsartan benefits patients with HF remain unclear. Neprilysin inhibitors are known to potentiate the action of a number of endogenous vasoactive compounds that may be relevant to HF progression, including the natriuretic peptides, but it remains unclear precisely which substrates are principally responsible for the observed benefits. Although data regarding effects on cardiac remodeling are unavailable from PARADIGM-HF (which had no dedicated echocardiographic substudy), the early reduction in time to first HF hospitalization (within the first 30 days after randomization) suggests an acute hemodynamic benefit of sacubitril/valsartan and the improvement in other measures of HF severity may be evidence of a slowing of HF progression. Specifically, patients allocated to sacubitril/valsartan compared with those allocated to enalapril had a lower cumulative burden of HF hospitalizations, emergency department visits for HF, requirement for intensive care unit stay, or requirement for initiation of intravenous inotropes, all surrogates for worsening HF.¹² Moreover, in patients hospitalized for heart failure management during the trial, use of the neprilysin inhibitor was associated with reductions in both heart failure and all-cause readmissions at 30 or 60 days.¹³

Though much has been learned since the introduction of sacubitril/valsartan, many questions remain. Limited data is available to guide use of sacubitril/valsartan in patients on low-dose ACE inhibitors or ARBs or in patients or in those who have not previously been treated with an ACE inhibitor or ARB. Furthermore, no data is yet available regarding the safety or efficacy of sacubitril/valsartan in stage D heart failure, in hospitalized HF patients, in those with HF complicating myocardial infarction, or in heart failure with preserved ejection fraction. Ongoing trials enrolling patients with advanced heart failure (HFN-LIFE [Entresto TM In Advanced Heart Failure]), post-MI heart failure (PARADISE-MI [Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI]), and HFpEF (PARAGON-HF [Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction]) will help to determine whether the benefits of sacubitril/valsartan seen in amongst patients with HFrEF in PARADIGM-HF can be extended to the broader range of patients with heart failure.

References

1. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
2. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476-88.
3. Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36:1990-7.
4. Claggett B, Packer M, McMurray JJ, et al. Estimating the long-term treatment benefits of sacubitril-valsartan. N Engl J Med 2015;373:2289-90.
5. Fonarow GC, Hernandez AF, Solomon SD, Yancy CW. Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol 2016;1:714-7.
6. Desai AS, Solomon S, Claggett B, et al. Factors associated with noncompletion during the run-in period before randomization and influence on the estimated benefit of LCZ696 in the PARADIGM-HF trial. Circ Heart Fail 2016;9:e002735.
7. Solomon SD, Claggett B, Desai AS, et al. Influence of ejection fraction on outcomes and efficacy of sacubitril/valsartan (LCZ696) in heart failure with reduced ejection fraction: the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial. Circ Heart Fail 2016;9:e002744.
8. Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2017;2:79-85.
9. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576-84.
10. Simpson J, Jhund PS, Silva Cardoso J, et al. Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol 2015;66:2059-71.
11. Solomon SD, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan relative to a prior decompensation: the PARADIGM-HF trial. JACC Heart Fail 2016;4:816-22.
12. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54-61.
13. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol 2016;68:241-8.

Keywords: Aminobutyrates, Angioedema, Angiotensin-Converting Enzyme Inhibitors, Benzopyrans, Blood Pressure, Death, Sudden, Cardiac, Defibrillators, Implantable, Heart Failure, Hyperkalemia, Hypotension, Mineralocorticoid Receptor Antagonists, Myocardial Infarction, Natriuretic Peptide, Brain, Neprilysin, Peptide Fragments, Potassium, Receptors, Angiotensin, Stroke Volume, Tetrazoles, Tolonium Chloride

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