Ms. Valarie Sartan is a 55-year-old woman with a history of HFrEF (EF 35%) and well controlled, non-insulin dependent diabetes mellitus who presents to heart failure clinic for routine follow up. She is currently being treated with metoprolol succinate 200mg daily, lisinopril 10mg daily, empagliflozin 10mg daily, and spironolactone 50mg daily. She notes stable dyspnea with moderate exertion, making it difficult to do her yardwork. On exam she is well appearing, and blood pressure is 115/70 mmHg with normal jugular venous pulsations and trace bilateral lower extremity edema. On labs, her potassium is 4.0 mmol/L and creatinine is 0.7 mg/dL with an eGFR > 60 mL/min/1.73m2. Which of the following options would be the most appropriate next step in heart failure therapy? 

A 

Increase lisinopril to 40mg daily 

B 

Increase spironolactone to 100mg daily 

C 

Add sacubitril-valsartan to her regimen 

D 

Discontinue lisinopril and start sacubitril-valsartan in 36 hours 

E 

No change 

Explanation  

The correct answer is D – transitioning from an ACEi to an ARNi is the most appropriate next step in management.  

The renin-angiotensin aldosterone system (RAAS) is upregulated in patients with chronic heart failure with reduced ejection fraction (HFrEF). Blockade of the RAAS system with ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), or angiotensin receptor neprilysin inhibitors (ARNi) have proven mortality benefit in these patients.  

The PARADIGM-HF trial compared sacubitril-valsartan (an ARNi) with enalapril in symptomatic patients with HFrEF. Patients receiving ARNi incurred a 20% relative risk reduction in the composite primary endpoint of cardiovascular death or heart failure hospitalization. Based on these results, the 2022 heart failure guidelines recommend replacing an ACEi or ARB for an ARNi in patients with chronic symptomatic HFrEF with NYHA class II or III symptoms to further reduce morbidity and mortality (Option D). This is a class I recommendation with level of evidence of B-R and is also of high economic value. Making no changes at this time would be inappropriate (Option E). 

While it would be reasonable to increase the dose of lisinopril to 40mg (Option A), this should be pursued only if ARNi therapy is not tolerated.  

Mineralocorticoid receptor antagonists (MRAs) have a class I (LOE A) recommendation in patients with HFrEF and NYHA class II to IV to reduce morbidity and mortality, provided that eGFR is >30 mL/min/1.73 m2 and serum potassium is <5.0 mEq/L, and there is careful monitoring of potassium, renal function, and diuretic dosing. However, the starting dose of spironolactone (or eplerenone) is 25 mg orally daily, increased to 50 mg daily orally after a month. Higher doses may be appropriate for other indications but are not advocated for HFrEF as the sole indication and so option B is incorrect.  

Guidance on starting an ARNi 

While switching from an ACEi to an ARNi, note that ARNi should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi (Class 3 for Harm, LOE B-R). This recommendation comes largely from studies of omapatrilat—a combination ACEi/neprilysin inhibitor. Patients receiving omapatrilat suffered significantly increased risk of angioedema thought secondary to dual suppression of both ACE and neprilysin leading to high concentrations of bradykinin. The current guidelines therefore recommend a washout period of at least 36 hours between the last ACEi dose and the first ARNi dose. If this patient were being transitioned from an ARB such as valsartan, then the first dose of ARNi could simply be given in lieu of the next anticipated dose of ARB.  

When initiating sacubitril-valsartan, it is important to monitor for signs of hypotension. With this patient’s blood pressure of 115/70 mmHg in clinic, she should have enough blood pressure room to tolerate the new medication; both PARADIGM-HF (ARNi vs ACEi in stable chronic HFrEF) and PIONEER-HF (ARNi vs ACEi in hospitalized patients with ADHF) excluded patients with SBP < 100 mmHg. That said, every patient responds differently, and anticipatory guidance should be given to anybody starting a new drug. In particular, Ms. H.F. should be counseled on symptoms that could reflect low blood pressure, such as lightheadedness or orthostatic syncope, asked to call her provider should she experience anything concerning. Laboratory follow-up should include renal function and potassium levels. ARNis should not be initiated on any patient with a history of angioedema (Class III for Harm, LOE C-LD). While this patient likely does not have this history since she is tolerating and ACEi, it is an important part of any CardioNerd’s checklist when reaching for RAAS inhibitors.  

Main Takeaway 

Patients with symptomatic HFrEF who are tolerating ACEi or ARB therapy should be transitioned to ARNi therapy to further reduce morbidity and mortality. 

Expert Suggestions 

• Offer tips & tricks for initiating and monitoring ARNis in the outpatient setting.  
• Discuss PIONEER-HF & initiation in the inpatient setting.  
• Discuss ACEi & ARB combination therapy. 

Guideline Loc. 

Section 7.3.1