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Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction

03 Aug 2021 11:41 AM | MSHP Office (Administrator)

By: Michelle Tulchinskaya, Elena Stroman, and Katherine Nguyen; PharmD. Candidates

Mentor: Anastasia L. Armbruster Pharm.D., FACC, BCPS, BCCP

Since 2017, new therapies for Heart Failure with Reduced Ejection Fraction (HFrEF) have emerged reducing both mortality and hospitalizations for heart failure in this population. In particular, two drug therapies have emerged: angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2s). Overall, ARNIs, SGLT2s, and other guideline directed medical therapy (GDMT) are underutilized. CHAMP-HF has exhibited the underutilization of these medications.1 Specifically sacubitril/valsartan (Entresto®), has been underutilized even after the 2016 ACC/AHA/HFSA Focused Update on HF included it as a Class I recommendation for patients with HFrEF.2 In outpatient settings, 86.1% of patients without contraindications did not receive sacubitril/valsartan. Patients with the following characteristics were less likely to receive treatment; older age, Hispanic ethnicity, chronic insufficiency, and higher EF (p ≤ 0.009). Patients with higher systolic blood pressure and a history of hypertension were associated with achieving a ≥50% target dose (all p ≤ 0.037).1

Traditionally, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have been first line therapies for patients with Stage C HFrEF. The 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment is the first document to prefer the usage of ARNIs for patients with Stage C HFrEF over ACE-Is/ARBs.2 Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, such as natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF.2 As demonstrated in the PARADIGM-HF trial, sacubitril/valsartan was associated with reduced hospitalizations, morbidity, and mortality in these patients compared to enalapril.3 The composite of death from cardiovascular causes or hospitalization for heart failure occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (HR in LCZ696 group: 0.80; 95% CI 0.73 - 0.87; P<0.001).4 Due to this pivotal trial and following guideline recommendations, the preference is to start patients on an ARNI at the diagnosis of Stage C HFrEF, transition patients from an ACE-I or an ARB, or start patients that have not been given an ARNI, ACE-I, or ARB. Recent data from clinical studies, along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACE-I/ARBs, is a safe and effective strategy.2 In the PIONEER-HF trial, it was concluded that sacubitril/valsartan’s efficacy and safety was consistent across dose levels in hemodynamically stable patients with advanced decompensated heart failure. In the randomized, double-blind, active-controlled trial sacubitril/valsartan versus enalapril, there was no heterogeneity across dose levels in the effects of sacubitril/valsartan on the reduction of NT-proBNP, reduction of cardiovascular death, rehospitalization, or pre-specified adverse events.5

Although it is recommended to use an ARNI, ideal timing of initiation and rate of titration are frequently discussed. Many providers are concerned that patients will not be able to tolerate target dose due to adverse effects such as hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure. A randomized, multicenter, open-label study comparing two different treatment initiation regimens of sacubitril/valsartan, concluded that it was feasible for about half of the patients to achieve target dose within 10 weeks. In the TRANSITION trial, about half of the HF patients reached the recommended target dose in 10 weeks (relative RR 0.90; 95% CI 0.79 - 1.02), and over 86% were able to maintain any dose for at least  2 weeks leading to week 10 (relative RR 0.96; 95% CI 0.92 - 1.01).6 When obtaining full dose, it was noted that adverse effects of hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure were low. These adverse events were reasons for patients’ discontinuation of sacubitril/valsartan as well.6 It was found that a better tolerability profile was obtained when the uptitration was done gradually and that patient’s tolerability was higher when baseline adverse effects and labs of the patients were taken into account. Another multicenter, randomized, open-label, parallel‐group study found that a more gradual/conservative uptitration can increase the chance of attaining the target dose of sacubitril/valsartan in patients transitioning from lower doses of ACEI/ARBs.7 Additionally, it was found that the majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually.8 A gradual dose increase included patients on a low dose of 24 mg/26 mg twice per day, followed by a titration up to 97 mg/103 mg twice per day over a 3 or 6 week period.8 These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.

The mortality benefit of sacubitril/valsartan for HFrEF patients is notable as described in the PARADIGM-HF trial, but many patients struggle with access to the life-saving medication due to the high cost. Sacubitril/valsartan is covered by Medicare Part D, but the out-of-pocket cost can be more than $1,600 a year for patients. In a study conducted by DeJong, et al., more than 2,000 Medicare Part D plans were analyzed. While all plans fully covered sacubitril/valsartan, the results concluded that the average cost-sharing for a 30-day supply of an ARNI during the coverage period was $57, as opposed to a range of $2 - 5.00 for other heart failure medications such as ARBs, beta-blockers, and loop diuretics. The study estimated the subjects’ projected annual out-of-pocket costs to be $1,685, of which $1,632 of $1,685 (96.9%) would be attributable to the ARNI.9  Although Medicare Part D provides coverage for sacubitril/valsartan, patients would still be left with a considerable amount of out-of-pocket costs.

An additional analysis of the effectiveness and value of sacubitril/valsartan, conducted by Ollendorf, et al., looked at the lifetime cost-effectiveness of sacubitril/valsartan relative to ACE-I therapy. The analysis showed that the ACE-I had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123,578, while sacubitril/valsartan produced an additional 0.57 QALY and an additional $29,138 in costs.10 This shows that cost-effectiveness would exceed $100,000 per QALY gained if the benefits of sacubitril/valsartan over enalapril persist for 3.3 years.10 Another study by Gaziano, et al. examined the cost-effectiveness of sacubitril/valsartan in comparison to enalapril in HFrEF patients. The study estimated that there would be 220 fewer hospital admissions per 1000 patients with heart failure treated with sacubitril/valsartan vs. enalapril over 30 years and calculated sacubitril/valsartan’s incremental cost-effectiveness ratio of US $45,017 per QALY gained.11 These findings concluded that utilization of sacubitril/valsartan could result in more QALYs gained, prevention of premature death, as well as significant cost-savings through avoided hospitalizations.

There is sufficient evidence that exhibits sacubitril/valsartan’s benefit in HFrEF therapy, and updated guidelines now prefer the usage of ARNI. Sacubitril/valsartan has demonstrated a decrease in hospitalizations due to HFrEF in comparison to ACE-I/ARBs, in addition to cost-savings. Though there are concerns for tolerability of sacubitril/valsartan, it can potentially be avoided with a gradual uptitration to target dose. It would be beneficial to use sacubitril/valsartan over ACE-I/ARBs unless limited by contraindications, tolerability or cost limitations.


  1. Greene SJ, Butler J, Albert NM, DeVore AD, et al. Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018 Jul 24;72(4):351-366.
  2. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the american college of cardiology solution set oversight committee. J Am Coll Cardiol 2021;Jan 11
  3. Myhre PL, Vaduganathan M, Claggett B, et al. B-type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol. 2019;73:1264–72.
  4. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
  5. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548.
  6. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019;21(8):998-1007.
  7. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202.
  8. Senni M, McMurray JJV, Wachter R, et al. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail. 2018;20(3):491-500.
  9. DeJong C, Kazi DS, Dudley RA, Chen R, Tseng CW. Assessment of national coverage and out-of-pocket costs for sacubitril/valsartan under Medicare Part D. JAMA Cardiol. 2019;4(8):828-830.
  10. Ollendorf DA, Sandhu AT, Pearson SD. Sacubitril-valsartan for the treatment of heart failure: effectiveness and value. JAMA Intern Med. 2016;176(2):249–250.
  11. Gaziano TA, Fonarow GC, Claggett B, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1(6):666–672.

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