Heart Failure with Reduced Ejection Fraction (HFrEF) Management

Core Quadruple Therapy

The American College of Cardiology recommends starting sacubitril/valsartan 49/51 mg twice daily if previously on high-dose ACE inhibitor, or 24/26 mg twice daily if on low/medium-dose ACE inhibitor, ARB, or treatment-naïve, with a target dose of 97/103 mg twice daily as tolerated 1, 2
The American College of Cardiology suggests using bisoprolol, carvedilol, or metoprolol succinate as beta-blockers, starting at low doses and titrating slowly over weeks to months to target doses 3, 1
The European Society of Cardiology recommends using spironolactone or eplerenone as mineralocorticoid receptor antagonists, with spironolactone starting at 12.5-25 mg daily and target 25-50 mg daily, and eplerenone starting at 25 mg daily and target 50 mg daily 3, 1
The American College of Cardiology recommends using dapagliflozin 10 mg daily or empagliflozin 10 mg daily as SGLT2 inhibitors, with proven mortality and hospitalization benefits regardless of diabetes status 3, 2

The American College of Cardiology suggests starting ARNI/ACE inhibitor and beta-blocker simultaneously or in rapid sequence, without waiting to achieve target doses before starting the next medication, and titrating all medications to target doses every 2 weeks as tolerated 2

The American College of Cardiology strongly recommends (Class 1A) hydralazine/isosorbide dinitrate for Black patients with HFrEF who remain symptomatic despite optimal therapy, with hydralazine 25 mg three times daily titrated to 75 mg three times daily and isosorbide dinitrate 20 mg three times daily titrated to 40 mg three times daily 1, 2
The European Society of Cardiology recommends adding ivabradine when resting heart rate ≥70 bpm despite maximally tolerated beta-blocker doses, starting at 2.5-5 mg twice daily and titrating to heart rate 50-60 bpm, maximum 7.5 mg twice daily 3, 2

The American College of Cardiology recommends starting sacubitril/valsartan at 24/26 mg twice daily for patients with severe renal impairment, moderate hepatic impairment (Child-Pugh B), or age ≥75 years 1

The American College of Cardiology advises against failing to titrate to target doses due to asymptomatic hypotension or mild laboratory changes, and against permanently reducing doses when temporary reduction with subsequent re-titration would be appropriate 4
The European Society of Cardiology recommends against using ACE inhibitors when ARNI is available and tolerated, as ARNI is superior 3

The American College of Cardiology recommends monitoring blood pressure, renal function, and electrolytes within 1-2 weeks after initiation and with each dose increase 4

The European Society of Cardiology recommends that only bisoprolol, carvedilol, or metoprolol succinate reduce mortality in patients with heart failure, as this is not a class effect, and metoprolol tartrate should not be used 5, 6
The European Society of Cardiology suggests using spironolactone or eplerenone in all patients with NYHA Class II-IV symptoms and EF ≤35% despite ACE inhibitor/ARNI and beta-blocker, with critical monitoring of potassium and creatinine levels 6
For Black patients with HFrEF who remain symptomatic despite optimal therapy, the American College of Cardiology recommends adding hydralazine/isosorbide dinitrate 7
Beta-blockers should not be stopped suddenly unless absolutely necessary, due to the risk of rebound myocardial ischemia, infarction, and arrhythmias, and specialist advice should be sought before discontinuation 6

If congestion worsens during beta-blocker titration, the European Society of Cardiology recommends doubling the diuretic dose first before reducing beta-blocker, and only halving the beta-blocker dose if increasing the diuretic does not work 6
The European Society of Cardiology advises against permanently reducing doses due to asymptomatic hypotension or mild laboratory changes, and temporary reduction with subsequent re-titration is appropriate 6
Monitoring of blood chemistry is recommended at 1 and 4 weeks after starting/increasing the dose of MRAs, then at 8 and 12 weeks, 6, 9, and 12 months, then 4-monthly thereafter 6

The European Society of Cardiology recommends that bisoprolol and lisinopril provide significant cardiac protection in patients with heart disease, even with normal blood pressure, due to their direct organ-protective mechanisms 8, 9
Lisinopril prevents cardiac remodeling, increases ischemic preconditioning, reverses vasokonstriction and inotropy induced by angiotensin II, increases nitric oxide release, and reduces blood coagulability 10

The European Society of Cardiology/European Society of Hypertension 2007 guidelines state that the benefits of antihypertensive therapy are still evident even when initial blood pressure is <140/90 mmHg, with a target achievement of around 130/80 mmHg or lower 8, 9
In patients with coronary heart disease, blood pressure reduction is associated with a sharp decrease in cardiovascular events, regardless of initial blood pressure value 8, 9

Asymptomatic hypotension does not require therapy changes, as these medications provide proven mortality benefits 11, 12
If symptomatic hypotension occurs, review the need for nitrates, calcium channel blockers, and other vasodilators, and consider reducing diuretic doses or ACE inhibitor doses 11

In heart failure with reduced ejection fraction (HFrEF), combination therapy with bisoprolol, lisinopril, and spironolactone is a first-line treatment that has been shown to reduce mortality 12
High-dose lisinopril (32.5-35 mg) has been shown to have clinical superiority over low-dose lisinopril (2.5-5 mg) with a 12% reduction in risk of death or hospitalization 12