Which medications should be prescribed at discharge for a patient hospitalized with a heart‑failure exacerbation (reduced ejection fraction) to reduce all‑cause mortality?

Discharge Medications for Heart Failure with Reduced Ejection Fraction

Patients hospitalized with heart failure exacerbation (HFrEF) should be discharged on four foundational medication classes to reduce all-cause mortality: an ACE inhibitor (or preferably sacubitril/valsartan), an evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, plus diuretics as needed for congestion. 1, 2

The Four Pillars of Guideline-Directed Medical Therapy

1. Renin-Angiotensin System Inhibition (Class I, Level A)

• ACE inhibitors are recommended in addition to a beta-blocker for all symptomatic HFrEF patients to reduce hospitalization and death 1
• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors when patients remain symptomatic, as it further reduces HF hospitalization and death (Class I, Level B) 1
• ACE inhibitors reduce all-cause mortality by 5-16%, though they do not reduce sudden death risk 3
• Real-world data confirms ACE inhibitor/ARB use at discharge reduces all-cause mortality by 45% (HR 0.55) across all ejection fraction categories 4

2. Evidence-Based Beta-Blockers (Class I, Level A)

Only three beta-blockers have proven mortality benefit:

• Carvedilol
• Metoprolol succinate (extended-release)
• Bisoprolol

These agents reduce all-cause mortality by at least 20% and specifically reduce sudden cardiac death 3. Beta-blocker use at discharge is associated with 35% lower risk of all-cause death and 21% lower HF readmission risk in Medicare beneficiaries 5. The mortality benefit persists even when all-cause readmissions are not reduced 5.

3. Mineralocorticoid Receptor Antagonists (Class I, Level A)

• Spironolactone or eplerenone are recommended for patients who remain symptomatic despite ACE inhibitor and beta-blocker therapy 1
• MRAs reduce mortality by at least 20% and decrease sudden death risk 3
• Meta-analysis shows MRA use at discharge reduces all-cause death by 5% in HFrEF 6

Critical caveat: Avoid triple renin-angiotensin system blockade (ACE inhibitor + ARB + MRA) due to increased risk of renal dysfunction and hyperkalemia (Class III, Level C) 1

4. SGLT2 Inhibitors (Class 2a, Level B-R)

• Dapagliflozin or empagliflozin can be beneficial in decreasing HF hospitalizations and cardiovascular mortality 2
• Benefits emerge within weeks of initiation, making early discharge prescription essential 7
• While not included in the 2016 ESC guidelines, the 2022 AHA/ACC/HFSA guidelines and 2025 Canadian guidelines strongly support their use 8, 2

5. Diuretics (Class I, Level B)

• Loop diuretics are recommended to improve symptoms and exercise capacity in patients with signs/symptoms of congestion 1
• These address quality of life but do not independently reduce mortality

Implementation Strategy: "Four Drugs in 4 Weeks"

The evidence strongly supports rapid, early initiation rather than sequential addition:

• Starting at least 3 pillars of GDMT at hospital discharge reduces all-cause mortality (HR 0.22), cardiovascular death (HR 0.21), and HF hospitalization (HR 0.28) compared to fewer medications 9
• GDMT initiation at discharge (beta-blocker + RASI ± MRA) reduces the composite endpoint of death or HF rehospitalization by 37% (HR 0.63) 10
• Triple therapy (ACE inhibitor/ARB + beta-blocker + MRA) in HFrEF patients shows the lowest mortality risk (HR 0.21) compared to no therapy 4

Practical sequencing approach:

1. Start ACE inhibitor (or sacubitril/valsartan if already on stable ACE inhibitor) + beta-blocker simultaneously at low doses
2. Add MRA within days if potassium and renal function permit
3. Add SGLT2 inhibitor immediately (can be started in hospital during acute phase)
4. Uptitrate all medications to target doses over 4-6 weeks using forced-titration strategy 3

Common Pitfalls and How to Avoid Them

Renal Impairment Concerns

• Renal impairment is the major factor associated with GDMT underprescription (78.4% of patients receiving <3 pillars had CKD stage 3-5) 9
• However, GDMT prescription is NOT associated with observable adverse renal outcomes 9
• Do not withhold life-saving therapy based solely on elevated creatinine

Suboptimal Dosing

• Most patients in clinical practice remain on starting doses indefinitely, but only target doses used in trials have proven mortality benefit 3
• Use forced-titration strategy: increase doses at planned intervals unless persistent adverse events occur
• Temporary dose reductions should prompt re-escalation attempts

Medications to AVOID (Class III)

• Diltiazem or verapamil increase HF worsening and hospitalization risk 1
• Triple RAAS blockade (ACE inhibitor + ARB + MRA) increases renal dysfunction and hyperkalemia 1

Target Doses for Mortality Reduction

While specific target doses vary by agent, the principle is clear: uptitrate to the doses used in landmark mortality trials, not just to symptom control. Each 20% increase toward target dose provides incremental mortality benefit 3.

The evidence unequivocally demonstrates that comprehensive, early GDMT initiation at hospital discharge—not delayed sequential addition—provides the greatest mortality reduction in HFrEF patients.