What is the recommended initial treatment regimen for patients with heart failure, particularly those with reduced ejection fraction?

Initial Treatment Regimen for Heart Failure with Reduced Ejection Fraction

All patients with symptomatic HFrEF should be started on four foundational medication classes simultaneously at low doses—SGLT2 inhibitor, mineralocorticoid receptor antagonist (MRA), ACE inhibitor (or sacubitril/valsartan), and beta-blocker—then uptitrated every 2-4 weeks to target doses, rather than optimizing one drug sequentially before starting another. 1

Immediate Initiation Strategy

Start All Four Classes Together

• Begin with SGLT2 inhibitor and MRA first as they provide mortality benefit (≥20% reduction) while having minimal blood pressure-lowering effects, making them ideal anchor medications 2, 1
• Add ACE inhibitor (or ARB if ACE inhibitor contraindicated) immediately, as it reduces cardiovascular death and hospitalization in all symptomatic patients with LVEF <40-45% 1
• Initiate beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) simultaneously with ACE inhibitor, which reduces mortality by at least 20% and prevents sudden death 1

Critical Pre-Initiation Protocol for ACE Inhibitors

Before starting an ACE inhibitor, you must: 1

• Review and potentially reduce diuretic dose 24 hours prior
• Avoid excessive diuresis (volume depletion increases hypotension and acute kidney injury risk)
• Check baseline blood pressure, renal function, and electrolytes
• Avoid NSAIDs and potassium-sparing diuretics during initiation

Dosing Strategy

Starting Doses

• ACE inhibitor: Start low dose and uptitrate 3
• Beta-blocker: Start low dose of evidence-based agents (carvedilol, metoprolol succinate, or bisoprolol) 1, 3
• MRA (spironolactone or eplerenone): Start as soon as possible 2, 1
• SGLT2 inhibitor: Start early in treatment course 2

Uptitration Protocol

• Increase doses every 2-4 weeks to target maintenance doses proven effective in clinical trials 3
• Uptitrate one drug at a time using small increments until the highest tolerated or target dose of each is achieved 4
• Monitor blood pressure, renal function, and electrolytes at baseline, 1-2 weeks after each dose increment, at 3 months, then every 6 months 1, 3

The evidence demonstrates early benefits with even low doses of foundational therapies, and the proven benefits in trials were achieved with average doses less than target, with many patients on sub-target doses. 5

Special Consideration: Low Blood Pressure Patients

If the patient presents with low blood pressure (SBP <90-100 mmHg): 4, 2

1. Start SGLT2 inhibitor and MRA first (no BP-lowering effect)
2. Then add beta-blocker if heart rate >70 bpm, using selective β₁ receptor blockers (lesser BP-lowering effect than non-selective agents) 4
3. Finally add low-dose sacubitril/valsartan (50 mg or 25 mg twice daily) or low-dose ACE inhibitor, then gradually uptitrate 4
4. If beta-blockers not tolerated hemodynamically, ivabradine may be a viable alternative (either alone or with low-dose beta-blockers) to facilitate their titration, particularly if heart rate remains >70 bpm 4, 2, 6

Upgrading to Sacubitril/Valsartan

Replace ACE inhibitor with sacubitril/valsartan in ambulatory patients who remain symptomatic despite optimal triple therapy, as it provides superior reduction in heart failure hospitalization and cardiovascular death compared to ACE inhibitors alone 2, 3

Alternatively, consider starting with low-dose sacubitril/valsartan instead of an ACE inhibitor in appropriate patients from the outset 2

Symptomatic Management with Diuretics

• Use loop diuretics for all patients with signs or symptoms of fluid overload to improve symptoms and exercise capacity, though they do not prolong survival 1, 3
• Adjust diuretics according to volume status; overdiuresis may result in lower BP and compromise uptitration of other medications 4
• Thiazides can be used if eGFR >30 mL/min, but switch to loop diuretics below this threshold 3

Critical Contraindications and Dangerous Combinations

Absolute Contraindications to Avoid

• Never combine ACE inhibitor with ARB and MRA simultaneously, which causes life-threatening hyperkalemia and renal dysfunction 1, 3
• Avoid diltiazem and verapamil in HFrEF, as they worsen heart failure and increase hospitalization risk 3
• Avoid NSAIDs due to potential worsening of renal function and counteraction of beneficial effects of heart failure medications 2

Ivabradine Contraindications

Ivabradine is contraindicated in patients with: 6

• Acute decompensated heart failure
• Clinically significant hypotension or bradycardia
• Sick sinus syndrome, sinoatrial block, or 3rd degree AV block (unless functioning pacemaker present)
• Pacemaker dependence
• Concomitant use of strong CYP3A4 inhibitors

Device Therapy Timing

• Implant ICD for primary prevention when LVEF ≤35% despite ≥3 months of optimal medical therapy, NYHA Class II-III, and expected survival >1 year 1, 3
• Do not implant ICD within 40 days of myocardial infarction, as it does not improve prognosis during this period 3
• Consider cardiac resynchronization therapy (CRT) for patients in sinus rhythm with QRS ≥150 msec, LBBB morphology, and LVEF ≤35% despite optimal medical therapy 3

Common Pitfalls to Avoid

• Underutilization of guideline-directed medical therapy and inadequate dose titration are the most common issues in heart failure management 2
• Do not wait to reach target doses of one medication before starting another—simultaneous initiation is superior 1
• Symptomatic hypotension (mild dizziness upon standing) does not always indicate poor tolerance and can usually be managed through patient education without reducing HF pharmacotherapy, as patients remain compliant when they understand transient dizziness is a side effect of life-prolonging drugs 4
• Excessive diuresis before initiating ACE inhibitors increases hypotension and acute kidney injury risk 3

Monitoring for Atrial Fibrillation

Regularly monitor cardiac rhythm, as ivabradine increases the risk of atrial fibrillation (5.0% per patient-year vs 3.9% with placebo); discontinue ivabradine if atrial fibrillation develops 6