Recommended Agents for HFrEF with EF 30%
For a nonpregnant patient with normal renal function and an ejection fraction of 30%, guideline-directed medical therapy (GDMT) consists of four foundational medication classes: an ACE inhibitor (or ARB/ARNI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor. 1
Core Medication Classes
ACE Inhibitors or Angiotensin Receptor-Neprilysin Inhibitors (ARNI)
ACE inhibitors are recommended in all patients with EF ≤40% to reduce the risk of heart failure hospitalization and premature death (Class I, Level A). 1
Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors when feasible, as it has demonstrated superior cardiovascular and all-cause mortality reduction compared to enalapril in the PARADIGM-HF trial. 1
For patients with EF 30%, ARNI therapy provides additional benefit in slowing eGFR decline while reducing heart failure-related hospitalizations. 1
If ACE inhibitors are not tolerated due to cough or angioedema, ARBs should be used as an alternative (Class I, Level A). 1
Beta-Blockers
Beta-blockers are recommended in addition to ACE inhibitors (or ARB/ARNI) for all patients with EF ≤40% to reduce heart failure hospitalization and premature death (Class I, Level A). 1
Evidence-based beta-blockers include bisoprolol, carvedilol, or metoprolol succinate, which have been validated in nearly 9,000 patients across major trials (CIBIS II, COPERNICUS, MERIT-HF). 1
Beta-blockers should be initiated at low doses and gradually up-titrated to maximum tolerated doses or evidence-based target doses. 1
Mineralocorticoid Receptor Antagonists (MRAs)
MRAs (spironolactone or eplerenone) are recommended for all symptomatic patients with EF ≤35% despite treatment with an ACE inhibitor and beta-blocker to reduce mortality and heart failure hospitalization (Class I, Level A). 1, 2
With normal renal function and serum potassium <5.0 mEq/L, this patient meets criteria for MRA therapy. 1, 2
Monitoring requirements include checking potassium and renal function at 3 days, 1 week, and then monthly for the first 3 months after initiation. 2
MRAs should be discontinued or dose-reduced if potassium exceeds 5.5 mEq/L. 2
SGLT2 Inhibitors
SGLT2 inhibitors are recommended as part of GDMT for patients with HFrEF (Class I recommendation in contemporary guidelines). 1
These agents provide cardiovascular and renal benefits independent of diabetes status. 1
Implementation Strategy
Initiation Sequence
All four medication classes can be initiated together once the diagnosis of HFrEF is established, though beta-blockers and ACE inhibitors/ARNI are typically started first. 1
There is no evidence favoring initiation of beta-blockers before ACE inhibitors; they are complementary therapies. 1
Start medications at low doses and titrate gradually to evidence-based target doses or maximum tolerated doses. 1
Target Dosing Goals
The majority of patients in real-world practice receive suboptimal doses of GDMT medications. 1
Achieving at least 50% of target doses for beta-blockers, RAS inhibitors, and MRAs should be a therapeutic goal. 3
Pharmacist-led titration programs have demonstrated superior achievement of target ARNI doses (60.9% vs 18.0% with usual care). 4
Important Considerations
Contraindications to Monitor
ACE inhibitors should only be used with adequate renal function (eGFR ≥30 mL/min/1.73 m²) and normal serum potassium (≤5.0 mmol/L). 1
MRAs require serum creatinine ≤2.5 mg/dL in men and ≤2.0 mg/dL in women (or eGFR >30 mL/min/1.73 m²). 2
With normal renal function, this patient has no contraindications to any of the four foundational medication classes. 1
Common Pitfalls
Underutilization of MRAs remains a significant problem, with only 22-33% of eligible patients receiving this mortality-reducing therapy despite Class I recommendations. 2
Failure to uptitrate medications to target doses limits therapeutic benefit; only 29.9% of octogenarians with HFrEF receive triple therapy at adequate doses. 3
Concerns about hyperkalemia and acute kidney injury often lead to underuse of ACE inhibitors/ARBs in patients with any degree of renal impairment, even when renal function is adequate. 1
Additional Therapies
Diuretics should be used as needed to relieve signs and symptoms of congestion, though they have not been shown to reduce hospitalization or death. 1
Loop diuretics are the mainstay for volume management, with dosing adjusted based on clinical response. 1
Digoxin may be considered for symptom management in patients remaining symptomatic despite optimal GDMT. 1