Four Pillar Therapy for Heart Failure with Reduced Ejection Fraction

Four pillar therapy for heart failure with reduced ejection fraction combines an ACE inhibitor, angiotensin receptor blocker or sacubitril valsartan, a beta blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. Together they cut death and heart failure admission by more than half compared with no treatment. The classes act through different mechanisms, so all four are started as soon as tolerated, often within 2 to 4 weeks, in any order directed by pressure, heart rate, potassium and kidney function.

Sequencing. A usual early pair is an SGLT2 inhibitor with a beta blocker, followed by a mineralocorticoid antagonist and an ACE inhibitor or sacubitril valsartan. Alter the order when pressure, heart rate or potassium limits one class.

Contraindications. Pregnancy, angioedema, symptomatic hypotension, potassium over 5.0 mmol/L (mineralocorticoid antagonist), heart block (beta blocker) and eGFR under 20 mL/min/1.73 m2 (SGLT2 inhibitor).

Neurohormonal base. Ramipril 1.25 to 2.5 mg orally once daily, target 10 mg daily; or sacubitril valsartan 24/26 mg orally twice daily, target 97/103 mg twice daily. Start the lower dose if systolic pressure is under 100 mmHg, eGFR is under 30 mL/min/1.73 m2, or the person is ACE inhibitor naive. Stop the ACE inhibitor 36 hours before sacubitril valsartan. Do not combine them.

Beta blocker. Bisoprolol 1.25 mg once daily, target 10 mg daily; or carvedilol 3.125 mg twice daily, target 25 mg twice daily.

Mineralocorticoid antagonist. Spironolactone 12.5 to 25 mg once daily, target 25 to 50 mg daily.

SGLT2 inhibitor. Dapagliflozin 10 mg or empagliflozin 10 mg once daily.

Add-ons when symptoms persist.

• Ivabradine 5 mg twice daily (2.5 mg twice daily at age 75 or over), target 7.5 mg twice daily, in sinus rhythm with heart rate of 70 beats a minute or over on the maximum tolerated beta blocker.
• Hydralazine 37.5 mg with isosorbide dinitrate 20 mg three times daily, target double, in people of African ancestry or those who cannot take renin blockade.
• Digoxin 62.5 to 125 micrograms once daily for symptoms or atrial fibrillation.
• Intravenous iron for iron deficiency (ferritin under 100 micrograms/L, or 100 to 299 with transferrin saturation under 20%).

Special groups. In pregnancy and breastfeeding avoid sacubitril valsartan, ACE inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists. In older adults start low and step slowly. In hepatic impairment avoid carvedilol and sacubitril valsartan in severe disease. In East Africa, cost often limits sacubitril valsartan, so an ACE inhibitor remains an effective base.

Monitoring. Pressure, heart rate, potassium, sodium and creatinine at 1 to 2 weeks after each step, then at 3 months and every 6 months. Weigh daily.

Stop rules. Stop the mineralocorticoid antagonist at potassium of 6.0 mmol/L or over. Stop the SGLT2 inhibitor during acute illness with poor intake or before major surgery (3 days). Stop the ACE inhibitor or sacubitril valsartan for angioedema.

Switching. Move from an ACE inhibitor to sacubitril valsartan in people who stay symptomatic. Move from an ACE inhibitor to an angiotensin receptor blocker for cough.

Common errors. Starting only one or two classes, leaving doses at the starting level, combining an ACE inhibitor with sacubitril valsartan, and potassium supplements with a mineralocorticoid antagonist.

Referral and escalation. Refer for ejection fraction of 35% or under despite 3 months on optimum drugs (device assessment), worsening symptoms, repeated admissions or advanced heart failure.