Heart Failure Guideline Update Puts Trust in Entresto

The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) recently updated guidelines for pharmacological heart failure (HF) treatment, focusing specifically on 2 new agents: sacubitril/valsartan (Entresto) and ivabradine (Corlanor).

Entresto is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker (ARB). Neprilysin is an endopeptidase that degrades several vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin.¹ Inhibition of neprilysin leads to elevated levels of these compounds, countering the vasoconstriction and sodium retention that occurs during neurohormonal overactivation.² In experimental studies, inhibition of the renin-angiotensin and neprilysin had effects superior to either approach alone.³

The PARADIGM-HF study was designed to determine whether Entresto was superior to enalapril in reducing mortality and frequency of hospitalizations in HF patients with reduced ejection fraction (HFrEF). It was a multicentered, parallel group, double-blind, phase 3, randomized, controlled trial that included 10,521 patients at 1043 clinical institutions in 47 countries over a 3-year period (2009-2012).⁴

The study included the following patients:

• ≥18 years with a diagnosis of chronic HF NYHA class II-IV and reduced ejection fraction
• BNP ≥150 pg/mL or pro-BNP ≥600 pg/mL, or BNP ≥100 pg/mL or pro-BNP ≥400 pg/mL and hospitalized for HF within the previous year
• Patients taking any dose of an angiotensin-converting enzyme (ACE) inhibitor or ARB
• At least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and ACE inhibitor or ARB equivalent to at least enalapril 10 mg daily

Patients with hypotension, impaired renal function (eGFR <30/min/1.73m²), hyperkalemia, or history of angioedema were excluded from the study.

Patients were randomized to Entresto 200 mg twice-daily (n=4187) or enalapril 10 mg twice-daily (n=4212) in addition to standard HF therapy: beta-blockers (93%), diuretics (80%), aldosterone antagonists (56%), and digoxin (30%). The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF.

Notably, the study was terminated early after the third efficacy interim analysis because Entrestro treatment duration of about 27 months was associated with significant reductions in death from CV causes and first hospitalization secondary to HF. Regarding safety, patients in the Entresto group were more likely to have symptomatic hypotension. This rarely lead to discontinuation of therapy but did require dose modification.

The results of PARADIGM-HF led to Entresto’s FDA approval and was a major reason why the ACC, AHA, and HFSA updated the 2013 HF guidelines. Prior to that, only the Canadian Cardiovascular Society had published a focused update on recent therapeutic trials in HF. It gave a conditional recommendation of “high-quality evidence” to Entresto, stating “patients with mild-to-moderate HF and an EF of <40%, elevated BNP, or hospitalizations for HF in the past 12 months on appropriate doses of guideline-directed medical therapy should receive the combination over an ACE inhibitor or ARB.”⁵

Based on the results of PARADIGM-HF, the ACC, AHA, and HFSA now endorse Entresto for stage C, HFrEF patients. The groups have provided the following recommendations regarding the place of Entresto in HF management:

• The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence A), ARBs (Level of Evidence A), or ARNIs (Level of Evidence B-R) in conjunction with evidence-based beta-blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality.
• In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.

Key Points Regarding Entresto

• Entresto is considered superior to enalapril in reducing mortality and decreasing hospitalizations in HF patients. Recommended for use in symptomatic patients on stable doses of ACE inhibitors or ARBs
• Entresto should be used in patients with stage C HF and NYHA class II or III The FDA-approved indication includes NYHA class IV, but these patients weren’t represented well in PARADIGM-HF.
• Entresto was primarily tested in Caucasians, and African-Americans were severely under-represented in PARADIGM-HF (5% in each treatment arm) Use caution in generalizing results to this population
• Patients with an eGFR <30/min/1.73m² were excluded from PARADIGM-HF Package insert for Entresto recommends dose reduction in this group
• Use caution in patients with hypotension Patients should be on stable doses of an ACE inhibitor or ARB with no hypotension prior to switching to Entresto.
• Angioedema is still a concern, so patients on ACE inhibitors require a washout period of 36 hours before beginning Entresto

References

• Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci (Lond). 1996;91: 283-291.
• Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol. 2004;99: 76-82.
• Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Combined neutral endopeptidase and angiotensin- converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol. 1998;31: 116-125.
• McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371: 993-1004.
• Moe GW, Ezekowitz JA, O’Meara E et al. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol. 2015;15: 3-16.