Table 1.

Current Clinical Consensus and Clinical Practice Guideline Recommendations on Sequencing

	Quadruple Therapy	Recommendation
2021 European Society of Cardiology (preview presented at European Society of Cardiology Heart Failure 2021 congress)	•Defined as ARNI (or ACE inhibitor/ARB), BB, MRA, and SGLT2i	Recommended for all eligible patients with HFrEF to reduce the risk of mortality
2021 American College of Cardiology Expert Consensus Pathway3	•For patients with newly diagnosed stage C HFrEF, a BB, ACE inhibitor/ARB/ARNI should be started in any order •After initiation of BB and angiotensin antagonist, addition of an MRA should be considered with close monitoring of electrolytes •SGLT2i should also be considered for HFrEF with NYHA functional class II-IV	Each agent should be uptitrated to maximally tolerated or target dose. Initiation of a BB is better tolerated when patients are “dry” and an ACE inhibitor/ARB/ARNI when patients are “wet”
2021 Canadian Cardiovascular Society4	•Standard (quadruple) therapies are applicable to most patients with HFrEF for reducing cardiovascular mortality and hospitalization for HF •Every attempt should be made to initiate and titrate therapies with the goal of medication optimization by 3-6 months after a diagnosis of HFrEF	It might be preferable to titrate doses of different classes of GDMT medications simultaneously (“in-parallel” approach), rather than fully titrate 1 medication class before initiating an additional agent (“strict sequential” approach)

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; BB = beta-blocker; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SGLT2i = sodium–glucose co-transporter 2 inhibitor.