What new medications can be added for a patient with heart failure with reduced ejection fraction who is already receiving guideline‑standard therapy (ACE inhibitor or ARB, beta‑blocker, and mineralocorticoid receptor antagonist)?

New Medications for Heart Failure with Reduced Ejection Fraction

For patients with HFrEF already on ACE inhibitor/ARB, beta-blocker, and MRA, you should add an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) immediately, and strongly consider replacing the ACE inhibitor/ARB with sacubitril-valsartan (ARNI) to achieve the now-standard quadruple therapy regimen. 1

The Four-Pillar GDMT Framework

The 2022 AHA/ACC/HFSA guidelines explicitly state that guideline-directed medical therapy for HFrEF now includes four medication classes as foundational therapy 1:

1. ARNI (preferred) or ACE inhibitor/ARB
2. Evidence-based beta-blocker
3. Mineralocorticoid receptor antagonist (MRA)
4. SGLT2 inhibitor (the newest pillar)

Since your patient already has three pillars established, here's what to add:

Primary Addition: SGLT2 Inhibitor

Add an SGLT2 inhibitor immediately - this is now a Class 2a recommendation with Level B evidence 1. The two evidence-based options are:

• Dapagliflozin 10 mg once daily (no titration needed)
• Empagliflozin 10 mg once daily (can increase to 25 mg daily) 2

SGLT2 inhibitors reduce HF hospitalization and cardiovascular death regardless of diabetes status 1, 2. Benefits emerge within weeks of initiation 3, 4, making early deployment critical. These agents work through multiple mechanisms beyond glucose lowering: they reduce preload and afterload, have anti-inflammatory and antifibrotic effects, reduce oxidative stress, and improve endothelial function 2.

Secondary Optimization: Switch to ARNI

Replace the ACE inhibitor or ARB with sacubitril-valsartan (ARNI) - this is a Class I, Level B recommendation 5. The 2016 ESC guidelines specifically state that sacubitril/valsartan is recommended "as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA" 5.

Dosing strategy for sacubitril-valsartan:

• Start: 24/26 mg or 49/51 mg twice daily
• Target: 97/103 mg twice daily 2

Critical safety consideration: Allow a 36-hour washout period when switching from an ACE inhibitor to avoid angioedema risk. No washout is needed when switching from an ARB.

Evidence Supporting This Approach

The most recent network meta-analysis (2025) demonstrates that quadruple therapy (ARNI + beta-blocker + MRA + SGLT2i) provides 5.3 additional life-years compared to no treatment for a representative 70-year-old patient 3. This combination showed an HR of 0.39 (95% CI: 0.32-0.49) for all-cause mortality compared to placebo 3.

The 2022 guidelines elevated SGLT2 inhibitors to foundational status based on trials like DAPA-HF and EMPEROR-Reduced, which showed significant reductions in HF hospitalization and cardiovascular death 1, 2.

Emerging Fifth Pillar: Vericiguat

Consider adding vericiguat if the patient remains symptomatic despite quadruple therapy, particularly if they've had recent decompensation. This represents an exploratory fifth pillar:

• Vericiguat (soluble guanylate cyclase stimulator) may provide an additional 0.7 life-years beyond quadruple therapy 3
• Most beneficial in patients with recent HF hospitalization 6
• The VICTOR trial showed mortality reduction in stable HF, though the primary composite endpoint was not met 3

However, prioritize achieving optimal doses of the four foundational pillars before adding a fifth agent.

Implementation Strategy

Rapid initiation approach ("four drugs in 4 weeks") 4:

1. Week 1: Add SGLT2 inhibitor at full dose (no titration needed)
2. Week 2-4: Transition ACE inhibitor/ARB to ARNI, starting low and up-titrating
3. Continue optimizing doses of beta-blocker and MRA concurrently

Real-world data shows that delayed initiation is common but harmful - SGLT2 inhibitors have the longest mean time-to-initiation (88 days) in practice, yet their benefits emerge within weeks 7, 4.

Common Pitfalls to Avoid

• Don't wait for "stability" - initiate SGLT2 inhibitors early, even during or shortly after hospitalization
• Don't add triple neurohormonal blockade (ACE inhibitor + ARB + MRA together) - this increases risk of renal dysfunction and hyperkalemia without benefit 5
• Don't use verapamil or diltiazem - these are Class III (harm) recommendations in HFrEF 5
• Monitor potassium and renal function closely when optimizing MRA and RAAS inhibition, checking 1-2 weeks after each dose change

Monitoring Parameters

After adding SGLT2 inhibitor and switching to ARNI:

• Blood pressure (watch for hypotension with ARNI)
• Renal function and electrolytes at 1-2 weeks, then 3 months, then every 6 months
• Volume status (SGLT2 inhibitors have mild diuretic effect)
• Symptoms and functional capacity

The real-world challenge is not identifying effective therapies but ensuring their timely implementation - structured follow-up and protocol-driven titration significantly improve adherence and outcomes 8, 4.