What are the next steps in managing a patient with heart failure with reduced ejection fraction (EF 43%) and global hypokinesis after a negative left heart catheterization, given they are on empagliflozin (Jardiance), low‑dose losartan, spironolactone, and diuretic therapy with weight monitoring and a low‑sodium diet?

Next Steps: Add Beta-Blocker Therapy and Continue Optimization

The critical missing component in this patient's guideline-directed medical therapy (GDMT) is an evidence-based beta-blocker, which should be initiated immediately. After a negative left heart catheterization ruling out ischemic etiology, the focus shifts to completing and optimizing the four foundational pillars of HFrEF therapy.

Current Medication Status

Your patient is already on three of the four foundational GDMT pillars:

• SGLT2 inhibitor (Jardiance) - ✓
• Mineralocorticoid receptor antagonist (spironolactone) - ✓
• RAAS inhibition (losartan at low dose) - ✓
• Beta-blocker - MISSING

Immediate Action: Initiate Beta-Blocker Therapy

Start an evidence-based beta-blocker immediately 1, 2. The three beta-blockers with proven mortality benefit in HFrEF are:

• Carvedilol: Start 3.125 mg twice daily, target 25-50 mg twice daily
• Metoprolol succinate (CR/XL): Start 12.5-25 mg once daily, target 200 mg once daily
• Bisoprolol: Start 1.25 mg once daily, target 10 mg once daily

1

Titration Strategy

• Double the dose every 2 weeks (not less frequently) 1
• Aim for target dose or highest tolerated dose
• Monitor heart rate, blood pressure, clinical status, and body weight at each visit
• Check blood chemistry 1-2 weeks after initiation and after final dose titration 1
• Remember: some beta-blocker is better than no beta-blocker 1

Optimize Existing RAAS Inhibition

Consider transitioning from losartan to sacubitril/valsartan (Entresto) once beta-blocker is established 2, 3. This provides superior outcomes compared to ACE inhibitors or ARBs alone. However, given the patient is on "low-dose losartan," first ensure adequate RAAS inhibition:

Sequencing for RAAS Optimization:

1. If blood pressure tolerates: Up-titrate losartan toward target dose (50-100 mg daily for candesartan equivalent: 32 mg daily) 4
2. Once stable on adequate ARB dose: Transition to sacubitril/valsartan starting at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 3, 4
3. Washout period: Stop ARB for 36 hours before starting sacubitril/valsartan to avoid angioedema risk

Medication Sequencing in This Patient

The 2025 HFA consensus statement provides clear guidance for patients with HFrEF who are undertreated 3:

Recommended Sequence:

1. SGLT2i and MRA first (already done - these have minimal BP effects) 3
2. Next: Beta-blocker OR low-dose ARNI/ACEI/ARB - choose based on heart rate and blood pressure 3
   • If heart rate >70 bpm: Prioritize beta-blocker
   • If heart rate <70 bpm: Consider ARNI/ACEI/ARB optimization first
3. Then add the remaining drug class
4. Up-titrate one drug at a time with small increments every 1-2 weeks 3

Monitoring During Optimization

Check at Each Titration Visit:

• Heart rate: Target >50 bpm; if <50 bpm with symptoms, halve beta-blocker dose 1
• Blood pressure: Asymptomatic low BP does not require dose adjustment 1
• Symptomatic hypotension: Review need for other vasodilators, consider reducing diuretics if no congestion 1, 5
• Renal function and potassium: Particularly important with spironolactone on board 6
• Volume status: Adjust diuretics based on daily weights and clinical assessment 1

Common Pitfalls to Avoid

Worsening Symptoms During Beta-Blocker Initiation:

• 20-30% of patients experience temporary deterioration during initiation/up-titration 1
• If increasing congestion: Double diuretic dose first; only halve beta-blocker if diuretics don't work 1
• If marked fatigue/bradycardia: Halve beta-blocker dose (rarely necessary) 1
• Never stop beta-blocker suddenly - risk of rebound ischemia/arrhythmias 1

Managing Low Blood Pressure:

Since this patient is on low-dose losartan, blood pressure may be a concern. The 2025 HFA guidelines specifically address this 3:

• Asymptomatic low BP: Continue therapy, no adjustment needed 1, 3
• Symptomatic hypotension:
  • First, ensure adequate volume status (not over-diuresed)
  • Consider selective β₁-blockers (metoprolol, bisoprolol) over non-selective agents (carvedilol) for less BP effect 3
  • If beta-blocker not tolerated and sinus rhythm: Consider ivabradine as alternative or adjunct 3

Additional Considerations

Device Therapy Evaluation:

• Reassess EF after 3-6 months of optimal GDMT before considering ICD or CRT 5
• If EF remains ≤35% on optimal therapy with QRS ≥150 ms and LBBB: Consider CRT-D 2
• If EF remains ≤35% on optimal therapy: Consider ICD for primary prevention 2

Patient Education:

• Explain expected benefits: Beta-blockers prevent worsening and increase survival 1
• Symptomatic improvement may take 3-6 months 1
• Daily weight monitoring: Increase diuretic if weight increases by 1.5-2.0 kg over 2 days 1
• Low-sodium diet: Continue 2 g sodium daily restriction

Follow-Up Timeline:

• Week 2: Check tolerance to beta-blocker, consider first dose increase
• Week 4: Second beta-blocker titration if tolerated
• Week 6-8: Continue beta-blocker titration toward target
• Week 8-12: Consider ARNI transition if on adequate ARB dose
• 3-6 months: Reassess EF, symptoms, functional capacity, consider device therapy if indicated 5

Summary Algorithm

For this patient with HFrEF (EF 43%), negative cath, on SGLT2i/MRA/low-dose ARB:

1. ✓ Immediately start evidence-based beta-blocker (carvedilol 3.125 mg BID, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily)
2. ✓ Up-titrate beta-blocker every 2 weeks to target or maximum tolerated dose
3. ✓ Simultaneously optimize losartan toward target ARB dosing
4. ✓ Transition to sacubitril/valsartan once on adequate ARB dose and stable
5. ✓ Continue SGLT2i and spironolactone (already optimized)
6. ✓ Adjust diuretics based on daily weights and volume status
7. ✓ Reassess in 3-6 months for device therapy consideration

The evidence strongly supports that completing all four GDMT pillars rapidly provides additive mortality benefit, with SGLT2 inhibitors showing benefit within weeks and beta-blockers providing long-term survival advantage 2, 4, 7, 8, 9.