ISSUE1623
- Mark Abramowicz, M.D., President: no disclosure or potential conflict of interest to report
- Jean-Marie Pflomm, Pharm.D., Editor in Chief: no disclosure or potential conflict of interest to report
- Brinda M. Shah, Pharm.D., Consulting Editor: no disclosure or potential conflict of interest to report
- Corinne Z. Morrison, Pharm.D., Associate Editor: has disclosure that her spouse is an employee of Pfizer, Inc.
- Explain the evidence supporting the expanded indication for sacubitril/valsartan (Entresto) to patients with heart failure and any ejection fraction.
The oral fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan (Entresto – Novartis) was approved by the FDA in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF; LVEF <40%).1 The indication has now been expanded to include patients with chronic heart failure with any LVEF; the label specifies that benefits are most clearly evident in patients with LVEF below normal. Entresto is the first drug to be approved in the US for this indication.
TYPES OF HF — Almost half of all patients with heart failure have HFrEF, almost half have heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%), and the rest have heart failure with mid-range ejection fraction (HFmrEF; LVEF 41-49%).
CLINICAL STUDY — FDA approval of the expanded indication for Entresto was based on the results of a double-blind trial (PARAGON-HF) in 4822 patients with NYHA class II-IV heart failure, LVEF ≥45%, elevated levels of natriuretic peptides, and structural heart disease. The primary endpoint was a composite of total hospitalizations for heart failure and cardiovascular death. After a median follow-up of 35 months, there were 894 primary events in 526 patients randomized to receive sacubitril/valsartan 97/103 mg twice daily and 1009 primary events in 557 patients randomized to receive valsartan 160 mg twice daily (RR 0.87; 95% CI 0.75-1.01).2 Although statistical significance was narrowly missed, subgroup analyses suggested that sacubitril/valsartan showed benefit in patients with LVEF 45-57% and in women.
DOSAGE — The recommended starting dosage of sacubitril/valsartan in adults is 49/51 mg twice daily. The dose should be doubled every 2-4 weeks as tolerated to reach a final dose of 97/103 mg. ACE inhibitor treatment should be discontinued 36 hours before starting Entresto. In patients who had not been taking an ACE inhibitor or an ARB, or in those with severe renal impairment (eGFR <30 mL/min/1.73 m2) or moderate hepatic impairment, the recommended starting dosage of Entresto is 24/26 mg twice daily. Entresto is not recommended for patients with severe hepatic impairment. One month's treatment at the target dosage costs $583.00.3
Additional Content Available: Comparison Table: Some Drugs for HFrEF
- Sacubitril/valsartan (Entresto) for heart failure. Med Lett Drugs Ther 2015; 57:107.
- SD Solomon et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019; 381:1609.
- Approximate WAC. WAC = wholesale acquisition cost, or manufacturer's published price to wholesalers; WAC represents published catalogue or list prices and may not represent actual transactional prices. Source: Analysource® Monthly. March 5, 2021. Reprinted with permission by First Databank, Inc. All rights reserved. ©2021. www.fdbhealth.com/policies/drug-pricing-policy.
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