What is the role of Angiotensin-Receptor Neprilysin Inhibitors (ARNI) in Heart Failure with Preserved Ejection Fraction (HFpEF)?

From the Guidelines

Angiotensin-Receptor Neprilysin Inhibitors (ARNI) are recommended for patients with Heart Failure with Preserved Ejection Fraction (HFpEF) who have elevated natriuretic peptides and meet specific criteria, particularly women and those with ejection fractions in the lower range of HFpEF (45-57%). The recommended starting dose is 24/26 mg twice daily, which can be titrated to a target dose of 97/103 mg twice daily as tolerated 1. Before initiating ARNI therapy, ACE inhibitors should be discontinued at least 36 hours prior to prevent angioedema. Patients should be monitored for hypotension, hyperkalemia, and renal dysfunction.

Key Considerations

• The PARAGON-HF trial showed that sacubitril/valsartan may reduce heart failure hospitalizations in certain HFpEF subgroups, particularly women and those with ejection fractions in the lower range of HFpEF (45-57%) 1.
• The benefit of ARNIs in HFpEF is thought to be due to the enhancement of natriuretic peptide activity, which promotes vasodilation, natriuresis, and reduces cardiac fibrosis and hypertrophy.
• Additionally, ARNIs block the harmful effects of the renin-angiotensin-aldosterone system.
• While the evidence for ARNIs in HFpEF is not as robust as in heart failure with reduced ejection fraction, they represent an important therapeutic option for appropriately selected HFpEF patients.

Monitoring and Safety

• Patients on ARNI therapy should be closely monitored for hypotension, hyperkalemia, and renal dysfunction 1.
• The occurrence of hyperkalemia and the composite outcome of decline in renal function favored sacubitril-valsartan, but it was associated with a higher incidence of hypotension and angioedema 1.
• In prespecified subgroup analyses, a differential effect by LVEF and sex was noted, with a benefit of sacubitril-valsartan compared with valsartan observed in patients with LVEF below the median (45%–57%) and in women 1.

From the FDA Drug Label

The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF greater than or equal to 45% comparing 97/103 mg of sacubitril and valsartan (n=149) to 160 mg of valsartan (n =152) twice-daily, sacubitril and valsartan decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0. 005). In PARAGON-HF, sacubitril and valsartan decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively.

The role of Angiotensin-Receptor Neprilysin Inhibitors (ARNI) in Heart Failure with Preserved Ejection Fraction (HFpEF) is to decrease NT-proBNP levels, which is a marker of heart failure, by increasing the levels of peptides degraded by neprilysin and inhibiting the effects of angiotensin II. Key points include:

• Decrease in NT-proBNP: Sacubitril and valsartan decreased NT-proBNP levels by 17% in the PARAMOUNT study and by 24% in the PARAGON-HF study.
• Increased natriuretic peptides: The drug increases the levels of natriuretic peptides, which are degraded by neprilysin.
• Inhibition of angiotensin II: Sacubitril and valsartan inhibit the effects of angiotensin II, which contributes to the cardiovascular and renal effects of the drug 2.

From the Research

Role of Angiotensin-Receptor Neprilysin Inhibitors (ARNI) in Heart Failure with Preserved Ejection Fraction (HFpEF)

• The efficacy of ARNI in HFpEF patients is not well established, with most studies showing little benefit in this population 3, 4.
• Sacubitril/valsartan, an ARNI, has been shown to be effective in reducing mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but its effects in HFpEF patients are unclear 5, 6.
• Some studies suggest that sacubitril/valsartan may have a beneficial effect in patients with mid-range or preserved ejection fraction, but more research is needed to confirm this 6.
• The safety and tolerability of ARNI in HFpEF patients are similar to those of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), but the risk of hypotension may be higher 3, 7.
• Overall, the current evidence suggests that ARNI may not be effective in HFpEF patients, but more research is needed to fully understand its role in this population 3, 4, 6.

Key Findings

• A systematic review and meta-analysis found no evidence of an effect of sacubitril/valsartan in HFpEF patients 4.
• A review of the efficacy and safety of sacubitril/valsartan in heart failure patients found that it had little benefit in HFpEF patients 3.
• A perspective viewpoint on current evidence suggested that sacubitril/valsartan may have a beneficial effect in patients with mid-range or preserved ejection fraction, but more research is needed to confirm this 6.
• A retrospective study found that ARNI resulted in a greater improvement in heart failure than ACEIs/ARBs in patients with HFrEF and moderate-to-severe chronic kidney disease, but this study did not focus on HFpEF patients 7.