FDA approves sacubitril/valsartan to treat heart failure

Jennifer Marshall

Kevin ChamberlinOn July 7, FDA announced its approval of sacubitril/valsartan (Entresto; Novartis) for the treatment of heart failure with reduced ejection fraction. FDA had earlier given the drug fast-track designation and priority review.

It is estimated that more than 5 million people in the United States suffer from heart failure, which affects both health and quality of life. Patients diagnosed with heart failure have significant morbidity and mortality, resulting from exacerbations that lead to frequent hospitalizations. For patients with heart failure, Entresto is the first treatment available that has been shown to decrease hospitalizations and reduce the risk of cardiovascular-related death.

See also: New first-in-class drug therapy for heart failure

Efficacy

Sacubitril is a neprilysin inhibitor, an endopeptidase that degrades multiple vasoactive peptides involved in remodeling, vasoconstriction, and sodium retention. In previous studies, the combination of sacubitril and ACE (angiotensin converting enzyme) inhibitors resulted in effects superior to either approach alone; however, the association of serious angioedema with this combination in clinical trials led to the substitution of the ACE inhibitor with an ARB (angiotensin receptor) blocker.

See also: FDA approves eluxadoline to treat IBS-D in adults

The approval of Entresto was based on the clinical trial PARADIGM-HF, a multi-phase study that included a double-blind 1:1 randomized assignment of more than 8,000 patients to receive either enalapril 10 mg twice daily or Entresto 200 mg twice daily.

Death from cardiovascular causes or hospitalization for heart failure, the primary endpoint of the study, occurred in 21.8% of patients in the Entresto group and 26.5% of patients in the enalapril group (HR 0.8, 95% CI, 0.73-0.87, P<0.001). Specifically, deaths due to cardiovascular causes occurred in 13.3% of the Entresto arm and 16.5% of the enalapril arm (HR 0.8, 95% CI, 0.71-0.89, P<0.001). In addition, 12.8% of patients in the Entresto arm were hospitalized for heart failure, compared with 15.6% in the enalapril arm (HR 0.79, CI 0.71-0.89, P<0.001). The number needed to treat to prevent one death from cardiovascular causes was 32; for one hospitalization for heart failure it was 21. The study concluded that Entresto was superior to enalapril in reducing hospitalization and cardiovascular-related death in heart failure.

Safety

The most common adverse effects associated with Entresto include hypotension, hyperkalemia, dizziness, increased serum creatinine, decreased hemoglobin and hematocrit, renal failure, cough, and angioedema. Caution should be used in patients who have a history of angioedema.

Because of its effects on the renin-angiotensin system, Entresto carries a boxed warning for pregnant women, whose use of the drug may lead to injury and death of the developing fetus. Entresto should not be used concomitantly with ACE inhibitors, other ARB agents, or aliskiren in patients with renal impairment. Transition of therapy from an ACE inhibitor to Entresto should allow for a 36-hour washout period before initiation of Entresto.

Dosing

It is important to note that while dosing in clinical trials employed a combined dosage strength of the two components (e.g., 200 mg), Entresto should be prescribed by with the strength of each individual ingredient denoted, as described below.

The starting dose of Entresto is determined by the patient’s current use of an ACE inhibitor or ARB. Patients not currently receiving an ACE inhibitor or ARB therapy or taking low doses of these agents should be initiated with sacubitril 24 mg/valsartan 26 mg orally twice daily after a 36-hour washout period between agents. Patients currently taking standard doses of an ACE inhibitor or ARB should be initiated on sacubitril 49 mg/valsartan 51 mg orally twice daily after a 36-hour washout period between agents. Regardless of previous use of an ACE inhibitor or ARB, the dose should be doubled every 2-4 weeks as tolerated, to a target dose of sacubitril 97 mg/valsartan 103 mg orally, taken twice daily.

Patients with severe renal impairment (eGRF < 30 mL/min/1.73 m²) or moderate hepatic impairment (Child-Pugh class B) should be initiated and titrated in the same manner as patients who are not currently receiving an ACE inhibitor or ARB therapy. Entresto is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).

Jennifer L. Marshall, PharmD is a PGY-1 pharmacy resident at John Dempsey Hospital/UConn Health, Farmington, Conn. 
Kevin W. Chamberlin, PharmD is associate clinical professor and assistant department head, pharmacy practice, UConn School of Pharmacy, Storrs, Conn.