Use of Neprilysin Inhibitors in Chronic Heart Failure

Introduction^1-3

Heart failure (HF) contributes to significant morbidity and mortality in the United States. Despite a variety of mainstay medications, such as angiotensin I converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), aldosterone antagonists, and beta-blockers, HF is associated with 1 in 9 deaths in the United States. Approximately 50% of patients given a diagnosis of HF will die within 5 years. Sacubitril/valsartan (Entresto; by Novartis) was approved by the FDA in July 2015 under the priority review program, and was granted fast-track designation. Sacubitril is the first FDA-approved neprilysin inhibitor (NI).

Pharmacology^1,4-6

Neprilysin catalyzes the degradation of natriuretic peptides. Natriuretic peptides are produced in response to volume overload and cardiac dysfunction, and exert a beneficial response in HF. Sacubitril is a prodrug, and its active metabolite inhibits neprilysin, thus allowing natriuretic peptides to persist longer and promote vasodilation, diuresis, and natriuresis, as well as prevent cardiac hypertrophy. Sacubitril is combined with valsartan, an ARB that acts on the renin-angiotensin-aldosterone system and prevents vasoconstriction and decreases both aldosterone secretion and renal reabsorption of sodium.

Therapeutic Use, Dosing, and Administration^1,7

Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization in patients with chronic HF (NYHA class II-IV) with reduced ejection fraction. Sacubitril/valsartan is used in place of an ACE inhibitor or ARB. The initial dose is 24/26 mg twice daily if a patient is not currently taking an ACE inhibitor or ARB, and 49/51 mg twice daily if a patient is converting from either of these classes. Allow at least 36 hours after the last ACE inhibitor dose before initiating therapy. The dose should be increased every 2 to 4 weeks to achieve a target dose of 97/103 mg twice daily.

Adverse Reactions^1,7

Sacubitril/valsartan carries a boxed warning for fetal toxicity; therefore, discontinue when pregnancy is detected. Discontinue immediately if angioedema occurs, and do not readminister. The most common adverse reactions of sacubitril/valsartan compared with those of enalapril are hypotension (18% vs 12%, respectively), hyperkalemia (12% vs 14%, respectively), and cough (9% vs 13%, respectively).

Drug Interactions^1,8

NIs should not be used with ACE inhibitors. A clinical trial studying a combination ACE inhibitor/NI demonstrated an increase in angioedema frequency associated with this combination compared with use of an ACE inhibitor alone (2.17% vs 0.68%; P <.005). Both ACE inhibitors and NIs interrupt the degradation of bradykinin, and high levels of bradykinin are associated with angioedema. Do not use sacubitril/valsartan in combination with an ARB, because one is already contained in the formulation. In addition, serum potassium may be increased when used with potassium-sparing diuretics or potassium supplements. Elderly patients should not use sacubitril/valsartan with nonsteroidal anti-inflammatory drugs, as this may worsen renal function. Monitor the serum lithium level, as increased concentrations have been reported.

Clinical Efficacy⁹

FDA approval was based on a double-blind, randomized, multinational trial (PARADIGM-HF) comparing sacubitril/valsartan with enalapril in patients with NYHA class II-IV HF with left ventricular ejection fraction ≤40%. Patients were previously taking an ACE inhibitor or ARB and a beta-blocker at a maximally tolerated dose and had a systolic blood pressure of at least 100 mm Hg. During a run-in period, patients were exposed to enalapril twice daily for 2 weeks, and then sacubitril/valsartan for 4 to 6 weeks. There was a 1-day washout period between the enalapril and sacubitril/valsartan run-in, as well as before randomization. Patients who tolerated both medications during this run-in period were randomized to sacubitril/valsartan 97/103 mg twice daily (n = 4187) or enalapril 10 mg twice daily (n = 4212). All patients randomized were included in the analysis.

Death from cardiovascular causes or hospitalization for HF (the composite primary end point) occurred in 21.8% and 26.5% of patients in the sacubitril/valsartan and enalapril groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.73-0.87; P <.001; number needed to treat,22). Death from cardiovascular causes occurred in 13.3% of the sacubitril/valsartan group and 16.5% of the enalapril group (HR, 0.80; 95% CI, 0.71-0.89; P <.001). Hospitalizations for HF occurred in 12.8% and 15.6% of patients in the sacubitril/valsartan and enalapril groups, respectively (HR, 0.79; 95% CI, 0.71-0.89; P <.001). Median follow-up was 27 months; the trial was discontinued after a preplanned interim analysis showed overwhelming benefit with sacubitril/valsartan. The authors concluded that sacubitril/valsartan was superior to enalapril in reducing death and hospitalization due to HF.

Place in Therapy^10,11

The American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) Guidelines for the Management of Heart Failure were updated in May 2016 to include a recommendation for ARB/NI combination therapy. This class is recommended to replace an ACE inhibitor or ARB in patients with chronic symptomatic HF with reduced ejection fraction (NYHA class II or III) in order to further reduce morbidity and mortality. This is a class I, level B-R strong recommendation, defined by ACC/AHA/HFSA as the benefit greatly outweighs the risk and is based on moderate-quality evidence from at least 1 RCT. To further investigate the utilization of sacubitril/valsartan, Novartis recently announced FortiHFy, an umbrella clinical program encompassing more than 40 trials. These trials will study use in different populations and settings, and will promote a better understanding of HF.

Conclusion¹²

NIs combined with ARBs are novel agents recommended in the ACC/AHA/HFSA HF guidelines to reduce hospitalizations and death. However, the only currently available medication in this class, sacubitril/valsartan, is notably more expensive than other mainstay medications. The average wholesale price for a 30-day supply is $450, and the wholesale acquisition cost is $375. Studies in the FortiHFy program are designed to provide further insight regarding exactly when and how this therapy should be used.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

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