The 4 pillars of HFrEF therapy are:

1. ACE inhibitors (switch to an ARB in case of intolerance ) (always if LVEF < 40%, NYHA I to IV) / ARNI ( angiotensin II receptor neprilysin inhibitor, sacubitril-valsartan ) . Always titrate these medications to the target dose or maximum tolerated dose.
2. Beta-blockers (always if LVEF < 40%, NYHA I to IV). Always titrate these medications to the target dose or maximum tolerated dose up to a resting heart rate of approximately 60/min.
3. Mineralocorticoid receptor antagonists (MRA), aldosterone blockers ( spironolactone – so intolerance due to gynecomastia to switch to eplerenone ) (always if LVEF < 40%, NYHA II to IV) (at target dose or maximum tolerated dose).
4. SGLT-2 inhibitors (class IA recommendation since 2021).

The first 3 classes together are the neurohormonal blockers.

The ACE inhibitors, ARB, ARNI and MRA are together also called RAAS blockers, because they all inhibit a component in the RAAS (renin- angiotensin - aldosterone system).

Targets:

• Aim for the recommended target dose or maximum tolerated dose. Hypotension is accepted up to 90-95/60 mmHg as long as it is asymptomatic and as long as renal function and electrolytes remains stable or acceptable.
• Aim for a resting heart rate of approximately 60/min with:
  • Beta-blockers (at target dose or maximum tolerated dose).
  • and/or Ivabradine (on indication of the treating cardiologist).

• Devices (ICD, CRT, etc.) : on indication of the cardiologist.
• In iron deficiency intravenous administration of iron - as indicated by the cardiologist.
• In case of hyperkalemia : in case of low potassium diet and persistent hyperkalemia : consider potassium binders rather than reducing RAAS inhibitors.
• Options for treatment-resistant or advanced heart failure, as indicated by the treating cardiologist:
  • Nitrates and/or hydralazine
  • Digoxin
  • Ultrafiltration/dialysis.
  • Advanced HF therapies such as LV assist device (LVAD) / heart transplant : on indication of the treating cardiologist.
  • Palliative policy.

In patients with HFrEF, an ACE inhibitor (or ARB)/ARNI and a beta blocker should be started at a low dose and gradually increased in the short term ( uptitration ) to the recommended target dose or up to the maximum tolerated dose.

This up-titration should also be continued with normal or rather low blood pressure as long as there are no complaints of dizziness when standing up and renal function remains acceptable.

In the STRONG-HF study, this therapy was further increased as long as:

• The systolic blood pressure was > 95 mmHg .
• The heart rate was > 55/min (before beta blocker up-titration ).
• The potassium was ≤ 5.0 mmol /l (for ACE inhibitor, ARB or ARNI).
• The creatinine clearance was eGFR ≥ 30 ml/min (for ACE inhibitor, ARB or ARNI). With a creatinine clearance eGFR < 30 ml/min, an attempt was made to reduce diuretics and, if necessary, further increase the ACE inhibitor, ARB or ARNI shortly afterwards.

Rationale of this uptitration :

• The weakened left ventricle must contract and generate a pressure higher than blood pressure to allow blood circulation. By slightly lowering blood pressure, this weakened left ventricle will be able to work against lower resistance (afterload reduction) and pump blood more easily. The stroke volume and therefore also the cardiac output increase and the pressure in the left heart decreases.
• Aiming for a calmer heart rate with a beta blocker increases the duration of diastole. This increases the filling time of the ventricles and the time for blood flow to the myocardium. Due to better filling ( preload ) and better blood flow, the ventricle will often contract slightly better. This will also increase stroke volume and cardiac output.
  • Due to this increase in cardiac output, blood pressure will often remain stable or only decrease minimally, while the patient's hemodynamic condition improves. In addition, these therapies also have beneficial effects on the myocardium in the longer term (less fibrosis, less hypertrophy, less apoptosis, etc.).
  • After some time, the LV function can be partially or completely recovered. Up-titration of these therapies to the maximum tolerated dose increases the likelihood that a patient with HFrEF will progress to heart failure with improved LVEF ( HFimpHF ) .