Oral Medications That Increase Ejection Fraction in Heart Failure
For patients with heart failure and reduced ejection fraction (HFrEF), the oral medications proven to improve ejection fraction are ACE inhibitors, ARBs, sacubitril/valsartan (ARNI), beta-blockers (specifically carvedilol, metoprolol succinate, and bisoprolol), mineralocorticoid receptor antagonists (spironolactone/eplerenone), and SGLT2 inhibitors. 1, 2, 3, 4
Core Medications with Proven EF Improvement
First-Line Therapy: Neurohormonal Blockade
ACE Inhibitors or ARBs form the foundation of therapy and modestly improve ejection fraction by reducing afterload and preventing adverse remodeling. 5, 1 Start with low doses (e.g., enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg once daily) and titrate to target doses shown in clinical trials (enalapril 10-20 mg twice daily, lisinopril 20-40 mg once daily). 1, 2
Sacubitril/Valsartan (ARNI) demonstrates superior efficacy compared to ACE inhibitors alone, with studies showing significant improvements in left ventricular ejection fraction. 6, 7 In the SAVE-ICD study, sacubitril/valsartan increased LVEF from 28.3% to 32.2% after 6 months, with nearly one in four patients no longer meeting criteria for primary prevention ICD. 6 A 2026 study demonstrated LVEF improvement of 42.1% with accompanying 18% reduction in LV end-diastolic volume and 31.8% reduction in LV end-systolic volume after one year. 7 Start at 24/26 mg or 49/51 mg twice daily and target 97/103 mg twice daily. 2, 4
Beta-Blockers (carvedilol, metoprolol succinate, bisoprolol) are essential and reduce mortality by at least 20% while improving ejection fraction through rate control and anti-remodeling effects. 1, 2, 8 Start with very low doses (carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, bisoprolol 1.25 mg once daily) and titrate slowly every 1-2 weeks to target doses (carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg once daily, bisoprolol 10 mg once daily). 1, 2, 9
Additional Proven Therapies
Mineralocorticoid Receptor Antagonists (spironolactone 12.5-25 mg once daily, eplerenone 25-50 mg once daily) reduce mortality and improve reverse remodeling in NYHA class II-IV patients with LVEF ≤35%. 1, 2, 3, 4 These agents have minimal blood pressure effects and should be prioritized, especially in patients with low blood pressure. 10
SGLT2 Inhibitors (empagliflozin, dapagliflozin) represent a major advance with rapid beneficial effects on outcomes and minimal blood pressure impact. 10, 4 The 2022 AHA/ACC/HFSA guidelines give these a Class 2a recommendation for HFmrEF (LVEF 41-49%) based on EMPEROR-Preserved data showing 21% reduction in cardiovascular death or HF hospitalization. 4 Recent 2026 data projects that combined SGLT2i with nsMRA therapy could provide 3.6 additional years free from cardiovascular death or HF events in 65-year-old patients. 11
Supportive Evidence for Other Agents
Digoxin improves ejection fraction in elderly patients with HF in sinus rhythm, with one study showing improvement from 0.36 to 0.45 (p<0.01), with maximal benefit at serum concentrations of 0.4-1.0 ng/ml. 12 However, digoxin primarily reduces hospitalizations rather than mortality and receives only Class II recommendations in guidelines. 9
Hydralazine-Isosorbide Dinitrate combination (target 75 mg hydralazine/40 mg isosorbide dinitrate three times daily) improves outcomes particularly in Black patients with NYHA class III-IV HF. 1, 2
Optimal Sequencing Strategy
For treatment-naïve patients with low blood pressure: Start SGLT2 inhibitors and MRAs first (least BP effect), then add low-dose beta-blocker if HR >70 bpm or very low-dose sacubitril/valsartan (25 mg twice daily), then gradually uptitrate. 10 Selective β₁ receptor blockers (bisoprolol, metoprolol) cause less BP lowering than non-selective agents like carvedilol. 10
For patients with normal blood pressure: Initiate all four foundational drug classes (ARNI or ACE inhibitor, beta-blocker, MRA, SGLT2 inhibitor) simultaneously at low doses, then uptitrate sequentially. 2, 3, 4
Critical Monitoring Parameters
Monitor renal function and potassium within 1-2 weeks of initiating ACE inhibitors, ARBs, or MRAs, especially with baseline creatinine >3 mg/dL or potassium >5.0 mEq/L. 1 Discontinue ACE inhibitors permanently if angioedema occurs (<1% incidence, higher in Black patients), as this is life-threatening. 5, 1 ARBs may be substituted but use extreme caution as cross-reactivity can occur. 5, 1
For patients with HFmrEF (LVEF 41-49%): Evidence-based therapies for HFrEF should be considered, particularly in those with LVEF on the lower end of this spectrum, as they respond similarly to HFrEF patients. 4 SGLT2 inhibitors receive the strongest recommendation (Class 2a) for this population. 4