Until recently, international guidelines for the management of HFrEF advocated a stepwise sequencing strategy when establishing patients on foundational HFrEF treatments. The recommended order of therapy initiation (renin-angiotensin system [RAS] inhibitor and beta-blocker, followed by an MRA, a neprilysin inhibitor, and an SGLT2 inhibitor) was based not on clinical trial evidence supporting that order, but simply on the historical sequence in which the landmark evidence-generating trials were conducted. However, based on several clinical trials and evidence, it is quite clear that the benefits of each foundational drug class are independent and additive to the others. Each drug class has a distinct mechanism of action; RAS inhibitors, beta-blockers, and MRA independently antagonize the maladaptive neurohumoral activation that occurs in HF; neprilysin inhibitors augment endogenous levels of vasoactive peptides, including the natriuretic peptides; and SGLT2 inhibitors have a wide range of proposed mechanisms of action.

Therefore, an alternative, evidence-based, rapid three-step sequencing strategy was proposed to establish HFrEF patients on low doses of all four foundational treatments within four weeks. This new strategy was designed to ensure that all the benefits of every single therapy are independent and additive to the others. Step one of the therapy suggested beta-blockers and SGLT 2 inhibitors (dapagliflozin or empagliflozin) as one of the two first-line medications due to the early and large magnitude of benefit in reducing the risk of sudden death. The rationale behind the combination is that the increased risk of non-fatal HF hospitalization seen after initiation in several clinical studies of a beta-blocker can be offset by the substantial effect that SGLT2 inhibitors have in reducing the risk of worsening HF, as well as the SGLT2 inhibitors potential short-term diuretic effect.

The second step of the sequence is the initiation of a combined ARB/neprilysin inhibitor in the form of sacubitril/valsartan, one to two weeks following Step 1. Sacubitril/valsartan has a comparable impact similar to beta-blockers in terms of lowering the risk of mortality and a substantial effect on both primary mechanisms of death in HFrEF. Tolerance can be achieved in a subset of individuals with low systolic blood pressure by starting with a low dosage of an ARB and then adding a neprilysin inhibitor after tolerance is established.

Further, one to two weeks following Step 2, the 3rd step of the new sequence, i.e., an MRA can be introduced, provided the renal function and serum potassium measurements are within the acceptable limits for commencing an MRA (potassium ≤5.0 mmol/L and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m²). It is believed that starting an MRA after patients have been on a neprilysin inhibitor and an SGLT2 inhibitor will improve tolerance. Also, it can reduce the risk of deteriorating renal function and hyperkalemia. In the new sequence, it was also suggested that steps 2 and 3 can be reversed in patients who have difficulty with clinical hypotension. However, the four basic medications should be titrated to the clinical trial target dosage or the maximally tolerated dose.

Reference: Docherty and McMurray, Br J Cardiol. 2022 Jan 12;29(1):2.

Doi: 10.5837/bjc.2022.002.