By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The combination of the sacubitril and valsartan has been approved by the FDA for the treatment of heart failure. Sacubitril is a prodrug for the neprilysin inhibitor, LBQ657. Neprilysin is an enzyme that metabolizes natriuretic peptides (NP). Valsartan, an angiotensin II receptor type 1 antagonist (ARB), has been available since 2001. This combination was reviewed under the FDA’s priority review program and was granted fast track designation and expedited review. It is marketed by Novartis as Entresto.
INDICATIONS
Sacubitril/valsartan (SAC/VAL) is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.1
DOSAGE
The recommended initial dose is 49/51 mg twice daily.1 After 2 to 4 weeks, the dose may increase to the target maintenance dose of 97/103 mg twice daily as tolerated. In patients not currently on or previously taking an ARB or angiotensin converting enzyme (ACE) inhibitor, or with severe renal impairment, or moderate hepatic impairment, the starting dose should be reduced to 24/26 mg twice daily. SAC/VAL is available as 24/26 mg, 49/51 mg, and 97/103 mg tablets.
POTENTIAL ADVANTAGES
SAC/VAL provides a new option for heart failure, incorporating two drugs with different mechanisms of action.
POTENTIAL DISADVANTAGES
SAC/VAL is contraindicated in patients who previously experienced angioedema while on ACE inhibitors or ARBs.1
COMMENTS
NPs are a family of hormones that maintain sodium and fluid balance.2 Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are expressed in the atria and ventricles in cases of cardiac hypertrophy and increased stress in the cardiac chamber walls. These peptides cause vasodilation resulting in decreased ventricular preload, systemic vascular resistance, and arterial pressure as well as natriuresis, diuresis, and renin release. NPs are degraded by the neutral endopeptidase neprilysin, and inhibition of neprilysin prolongs the activity of these NPs.
The efficacy of SAC/VAL was established in a randomized, double-blind trial in subjects with symptomatic chronic heart failure with left ejection fraction < 40% (PARADIGM-HF).1,3 The majority of subjects were on beta-blockers, mineralocorticoid receptor antagonists, and diuretics. After showing no unacceptable side effects at the target dose of the study drug, subjects were randomized to SAC/VAL (97/103 mg; n = 4187) or enalapril (10 mg twice daily; n = 4212). The primary composite endpoint was cardiovascular death or first heart failure hospitalization. The median follow-up time was 27 months, and subjects were treated for up to 4.3 years. The composite endpoint occurred in 21.8% of the SAC/VAL group compared to 26.5% of the enalapril group (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73-0.87). The proportions of deaths (cardiovascular or heart failure hospitalization prior to death) or heart failure hospitalization were 13.3% for SAC/VAL vs 16.5% for enalapril and 12.8% vs 15.6%, respectively. Rates for all-cause mortality were 17% vs 19.8%, respectively (HR 0.84; 95% CI, 0.76-0.93). SAC/VAL subjects also required fewer hospital stays or emergency department visits for worsening heart failure and intensification of medical treatment for heart failure.4 Symptomatic hypotension was more frequent with SAC/VAL than enalapril, 14% vs 9.2%, and cough was more frequent with enalapril, 14.3% vs 11.3%.3 Overall, fewer subjects on SAC/VAL discontinued their study medication, 10.7% vs 12.3% (P = 0.03.)3 Discontinuation due to renal impairment was 0.7% vs 1.4% (P = 0.002.) In the run-in period, 12% discontinued their medications at a higher rate in the enalapril group. The wholesale cost for Entresto is $375 for a 30-day supply.
CLINICAL IMPLICATIONS
SAC/VAL combines a first-in-class neprilysin inhibitor with an ARB. The combination demonstrated clinical benefit over enalapril in subjects who experienced heart failure with reduced ejection fraction. The study (PARADIGM-HF) ended early due to clear benefit. Currently, Novartis is recruiting subjects in a clinical trial, evaluating the effect of SAC/VAL on morbidity and mortality in heart failure patients with preserved ejection fraction (PARAGON-HF).
REFERENCES
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Entresto Prescribing Information. Novartis. July 2015.
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Vardeny O, et al. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail 2014;2:663-670.
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McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
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Packer M, 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.
