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

Heart Failure with Reduced Ejection Fraction: Initial Treatment Guidelines

All patients with heart failure and reduced ejection fraction (HFrEF, typically LVEF <40%) should be started on four foundational drug classes simultaneously at low doses and rapidly titrated: an ACE inhibitor (or preferably sacubitril/valsartan), a beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and an SGLT2 inhibitor (dapagliflozin), plus diuretics if fluid retention is present. 1, 2, 3

Core Medication Regimen

First-Line Therapy - Start All Four Classes Early

Renin-Angiotensin System Inhibition:

• ACE inhibitors are the traditional first-line agents for all patients with HFrEF, whether symptomatic or asymptomatic, as they reduce mortality, hospitalization, and delay disease progression 1, 4
• Sacubitril/valsartan (ARNI) is superior to ACE inhibitors and should replace them in patients who remain symptomatic, providing greater reduction in heart failure hospitalization and cardiovascular death 3, 5
• Start sacubitril/valsartan at 49/51 mg twice daily and titrate to target dose of 97/103 mg twice daily over 2-4 weeks 5
• Critical: Allow 36-hour washout period when switching from ACE inhibitor to sacubitril/valsartan to avoid angioedema 5
• If ACE inhibitors cause cough or angioedema, use angiotensin receptor blockers (ARBs) as alternative 1, 6

Beta-Blockers:

• Initiate beta-blockers in all stable HFrEF patients (NYHA class II-IV) using only evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol 1, 3
• These agents reduce mortality by at least 20%, reduce sudden death, and decrease hospitalizations 1
• Start at low doses and titrate gradually to target doses proven effective in trials 1
• Contraindicated in severe bradycardia or high-degree heart block 3

Mineralocorticoid Receptor Antagonists (MRAs):

• Spironolactone or eplerenone should be started early in all HFrEF patients, particularly those with NYHA class III-IV symptoms 1, 7
• MRAs reduce mortality by at least 20% and have minimal blood pressure effects, making them ideal for early initiation 1, 2
• Spironolactone is indicated for NYHA Class III-IV heart failure with reduced ejection fraction to increase survival, manage edema, and reduce hospitalization 7
• Monitor potassium and renal function closely: serum creatinine should be ≤2.5 mg/dL in men and ≤2.0 mg/dL in women; serum potassium should be <5.0 mEq/L 6

SGLT2 Inhibitors:

• Dapagliflozin should be initiated early as it reduces heart failure hospitalization and cardiovascular mortality with minimal blood pressure effects 1, 2, 3
• Benefits are independent of diabetes status 3
• Particularly useful in patients with borderline low blood pressure as it has minimal hemodynamic effects 2

Diuretics for Congestion

• Loop diuretics (or thiazides if GFR >30 mL/min) are essential for fluid retention and should always be administered in addition to neurohormonal antagonists 1
• If GFR <30 mL/min, avoid thiazides except when used synergistically with loop diuretics 1
• For insufficient response: increase diuretic dose, combine loop diuretics with thiazides, or administer loop diuretics twice daily 1
• In severe chronic heart failure with persistent fluid retention, add metolazone with frequent monitoring of creatinine and electrolytes 1

Implementation Strategy

Sequencing and Titration Approach

Modern Paradigm - Simultaneous Initiation:

• Start multiple medications at low doses simultaneously rather than sequentially - do not wait to reach target dose of one drug before starting another 2, 3
• This approach gets patients on life-saving therapy faster and is now the preferred strategy 1, 2

For Patients with Normal Blood Pressure:

• Initiate all four foundational classes (ACE inhibitor/ARNI, beta-blocker, MRA, SGLT2 inhibitor) together at low doses 2, 3
• Titrate gradually to target doses over 6-12 weeks as tolerated 2

For Patients with Low Blood Pressure (systolic <100 mmHg):

• Prioritize medications with minimal BP effects first: Start SGLT2 inhibitor and MRA 2
• Then add beta-blocker if heart rate >70 bpm 2
• Finally add ACE inhibitor/ARNI at low dose 2
• If symptomatic hypotension develops during titration, prioritize beta-blockers over vasodilators 8

Dose Titration Protocol:

• Start ACE inhibitors at low doses (e.g., lisinopril 2.5-5 mg daily) and uptitrate to target doses proven in trials 1
• Target doses are goals based on tolerability, not absolute requirements - even low doses provide significant benefit 9
• Double doses every 2-4 weeks as tolerated 1, 2
• High doses provide incremental but modest additional benefit over intermediate doses - the difference between intermediate and high doses is small 10, 9

Critical Monitoring Parameters

Before and During Titration:

• Check blood pressure, renal function (creatinine, GFR), and electrolytes (particularly potassium) at baseline 1
• Recheck 1-2 weeks after each dose increment 1, 2
• Monitor at 3 months, then every 6 months once stable 1
• More frequent monitoring required in patients with baseline renal dysfunction or electrolyte disturbances 1

Ongoing Assessment:

• Daily weight monitoring for fluid status 8
• Assess symptoms (dyspnea, orthopnea, edema), functional capacity, and heart rate 8, 3
• Monitor for signs of worsening heart failure requiring immediate attention 8

Special Considerations and Common Pitfalls

Medications to Avoid

Absolutely contraindicated or use with extreme caution:

• NSAIDs and COX-2 inhibitors - worsen renal function and counteract benefits of heart failure medications 1, 3
• Class I antiarrhythmic agents 1
• Calcium channel blockers (verapamil, diltiazem, short-acting dihydropyridines) 1
• Tricyclic antidepressants, corticosteroids, lithium 1

Renal Function Management

When to adjust or stop ACE inhibitors:

• If renal function deteriorates substantially, stop ACE inhibitor temporarily 1
• Avoid potassium-sparing diuretics during ACE inhibitor initiation 1
• If hyperkalaemia persists after ACE inhibitor initiation, add potassium-sparing diuretics (triamterene, amiloride) only then, with frequent monitoring every 5-7 days until stable 1

Common Clinical Errors

Underutilization of guideline-directed medical therapy:

• Most patients in practice receive starting doses indefinitely rather than target doses - this represents suboptimal care 1
• Forced-titration strategies used in trials are rarely followed in clinical practice 1
• Do not maintain patients on very low doses unless higher doses are truly not tolerated 10

Inadequate dose titration:

• While target doses are ideal, benefits are seen even with low doses - do not delay starting therapy to achieve perfect dosing 9
• The proven benefits in trials were demonstrated with average doses below target, with many patients on sub-target doses 9

Asymptomatic Left Ventricular Dysfunction

• Asymptomatic patients with documented LVEF <40-45% should receive ACE inhibitors to delay or prevent development of symptomatic heart failure 1
• ACE inhibitors also reduce risk of myocardial infarction and sudden death in this population 1

Dietary and Lifestyle Modifications

Sodium and Fluid Management:

• Sodium restriction is more critical in advanced heart failure than mild disease 1
• Fluid restriction of 1.5-2 L/day is advised in advanced heart failure, with or without hyponatremia 1
• Moderate alcohol intake (one beer, 1-2 glasses wine/day) is permitted except in alcoholic cardiomyopathy where it is prohibited 1

Exercise:

• Exercise training programs are encouraged in stable NYHA class II-III patients to improve skeletal muscle function and functional capacity 1
• Physical rest or bed rest is recommended only during acute decompensation 1

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Indicated for patients with LVEF ≤30-35%, NYHA class II-III symptoms on optimal medical therapy, and life expectancy >1 year 3, 6
• Required for ischemic heart disease patients at least 40 days post-MI or nonischemic cardiomyopathy patients 6
• Also indicated for history of cardiac arrest, ventricular fibrillation, or hemodynamically unstable ventricular tachycardia 6

Cardiac Resynchronization Therapy (CRT):

• Recommended for symptomatic patients in sinus rhythm with QRS ≥150 msec, LBBB morphology, and LVEF ≤35% despite optimal medical therapy 3, 6