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

Initial Treatment for Heart Failure with Reduced Ejection Fraction

Patients with heart failure and reduced ejection fraction should be started on four foundational medication classes simultaneously: (1) ACE inhibitor or sacubitril/valsartan, (2) evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) mineralocorticoid receptor antagonist, and (4) SGLT2 inhibitor, with rapid uptitration to target doses over 6-12 weeks. 1, 2

Core Medication Classes

Renin-Angiotensin System Inhibition

• Start with sacubitril/valsartan 49/51 mg twice daily rather than an ACE inhibitor when possible, as it provides superior reduction in cardiovascular death and heart failure hospitalization 3
• If using sacubitril/valsartan, ensure a 36-hour washout period if switching from an ACE inhibitor 3
• If sacubitril/valsartan is not available or contraindicated, initiate an ACE inhibitor at low doses and uptitrate to target doses proven effective in clinical trials 1
• ACE inhibitors provide a modest 5-16% mortality reduction but do not reduce sudden death risk, making them less optimal than sacubitril/valsartan 1

Beta-Blockers

• Initiate carvedilol, metoprolol succinate, or bisoprolol as these specific agents have proven mortality benefit of at least 20% reduction 1
• These beta-blockers reduce sudden death risk, making early initiation critical even in clinically stable patients 1
• Start at low doses and uptitrate every 2-4 weeks to target doses used in landmark trials 1, 2

Mineralocorticoid Receptor Antagonists

• Start spironolactone or eplerenone as soon as possible as they provide meaningful mortality reduction (≥20%) and reduce sudden death 1
• MRAs have minimal blood pressure effects, making them ideal for early initiation even in patients with borderline low blood pressure 2
• Monitor potassium and renal function 1-2 weeks after initiation and with each dose change 1, 2

SGLT2 Inhibitors

• Add dapagliflozin or empagliflozin early in treatment as they reduce cardiovascular death and heart failure hospitalization 1, 2
• SGLT2 inhibitors have minimal blood pressure-lowering effects, making them suitable for patients with low blood pressure 2
• These agents are well-tolerated and provide benefits even in patients already on other guideline-directed therapies 4

Implementation Strategy

Simultaneous Initiation Approach

• Start multiple medication classes at low doses simultaneously rather than sequentially reaching target doses of one class before starting another 2
• This approach accelerates time to optimal therapy and improves outcomes compared to traditional sequential uptitration 2

Sequencing for Low Blood Pressure Patients

• Begin with SGLT2 inhibitor and MRA first as these have minimal blood pressure effects 2
• Add beta-blocker next if heart rate >70 bpm, then ACE inhibitor/ARB or sacubitril/valsartan at low doses 2
• This sequential approach allows treatment of hypotensive patients who might otherwise be undertreated 2

Dose Titration Protocol

• Uptitrate every 2-4 weeks to target doses used in landmark clinical trials, not just to symptomatic improvement 1, 2
• Target doses: sacubitril/valsartan 97/103 mg twice daily, not lower maintenance doses 3
• Asymptomatic changes in vital signs or laboratory values should not prevent uptitration to target doses 1
• Only maintain subtarget doses if higher doses threaten clinical stability with persistent or recurrent adverse events 1

Monitoring Requirements

Laboratory and Clinical Parameters

• Check renal function and electrolytes before initiation, 1-2 weeks after each dose increment, at 3 months, then every 6 months 1, 2
• Monitor blood pressure, heart rate, symptoms, and functional capacity at each visit 2
• More frequent monitoring is required in patients with baseline renal dysfunction or electrolyte disturbances 1

Reinitiation After Discontinuation

• Temporary discontinuation should not be permanent—investigators in landmark trials were encouraged to reinstitute treatment and achieve target doses 1
• Most adverse events in clinical trials were managed by adjusting other medications rather than permanently stopping guideline-directed therapy 1

Critical Pitfalls to Avoid

Underdosing and Underutilization

• The most common error is maintaining patients on starting doses indefinitely rather than uptitrating to target doses 1, 5
• In community practice, only 17% of patients receive target doses of ACE inhibitors/ARBs, 28% receive target beta-blocker doses, and 1% receive target doses of all medication classes simultaneously 5
• Subtarget dosing regimens have not been proven to prolong life 1

Contraindicated Medications

• Avoid NSAIDs and COX-2 inhibitors as they worsen renal function and counteract benefits of heart failure medications 1, 2
• Avoid class I antiarrhythmics, verapamil, diltiazem, and short-acting dihydropyridines 1
• Avoid tricyclic antidepressants, corticosteroids, and lithium 1

Delayed Referral

• Patients seen in heart failure clinics have significantly higher rates of guideline-directed therapy initiation across all medication classes (HR 1.54-2.49 for different drug classes) 6
• Early referral to heart failure specialists improves medication optimization and should not be delayed 6

Special Populations

Asymptomatic Left Ventricular Dysfunction

• Treat asymptomatic patients with reduced ejection fraction (<40-45%) with ACE inhibitors to delay or prevent development of symptomatic heart failure 1
• These patients also benefit from beta-blockers and MRAs to reduce sudden death risk 1

Patients with Fluid Retention

• Add diuretics to ACE inhibitors in patients with volume overload, but do not delay initiation of other guideline-directed therapies 1
• Diuretics address symptoms but do not reduce mortality, making the four foundational classes the priority 1