Table 3.

Proposed algorithms of guidelines-directed medical therapy initiation and up-titration in patients with heart failure with reduced ejection fraction.

Authors	Strategy of GDMT Up-Titration	Target
McMurray et al. [60]	Upfront initiation of BB and SGLT2i (step 1), followed by ARNI within two weeks (step 2) and MRAs two more weeks later (step 3)	Achievement of GDMT within 4 weeks
Miller et al. [61]	Cluster scheme: Cluster (A) SGLT2i and diuretics for volume overload; Cluster (B) ARNI/MRAs for hypertension and Cluster (C) BB and SNI for high heart rate. Initiation of BB, ACEi/ARNI, MRAs and SGLT2i before single drug up-titration.	Weekly up-titration and achievement of GDMT within 2/3 months
Tomasoni et al. [13]	Early upfront administration of SGLT2i due to safety and tolerability; low dose initiation of BB, ACEi/ARNI and MRAs and subsequent up-titration as tolerated. Sequence of optimization should be based on patient’s characteristics.	Achievement of GDMT within 42 days
Greene et al. [62]	Nearly simultaneous introduction of low doses of each of the four classes of drugs during the first week. Up-titration every two weeks for BB, first up-titration suggested after 4 weeks for ARNI and MRAs	Achievement of GDMT within 42 days. Subsequently consider further up-titration, if possible, or device therapy, if needed.

GDMT: guidelines-directed medical therapy; BB: beta blocker; SGLT2i: sodium-glucose cotransporter 2 inhibitor; ARNI: angiotensin receptor neprilysin inhibitors; MRAs: mineralocorticoid receptor antagonists; SNI: sinus node inhibitors; ACEi: angiotensin-converting enzyme inhibitor.