Regardless of the initiation sequence, both classes of agent should be up-titrated to the maximum tolerated or target doses in a timely fashion (e.g., every 2 weeks). Initiation of an ARNI/ACEI/ARB (Table 1, Figures 2 and 3) is often better tolerated when the patient is still congested ( wet ), whereas beta-blockers are better tolerated when the patient is less congested ( dry ) with an adequate resting heart rate; FIGURE 2 Treatment Algorithm for Guideline-Directed Medical Therapy Including Novel Therapies Green color identi es a Class I therapy from clinical practice guidelines, whereas yellow color indicates a Class II therapy. J Maddox et al. beta-blockers should not be initiated in patients with decompensated signs or symptoms. Only evidence-based beta-blockers should be used in patients with HFrEF (Table 1, Figures 2 and 3). Titration of ARNIs/ACEIs/ARBs and beta-blockers is discussed in Section 5.2. With recent clinical trial data supporting the use of SGLT2 inhibitors in a reasonably broad spectrum of HFrEF severity, the addition of this class of therapy to the regimens of pa- tients with HFrEF provides improvements in clinical outcomes and in patient-reported outcome measures. FIGURE 3 Guideline-Directed Medical Therapy Including Novel Therapies in the Expert Consensus Decision Pathway for Chronic Heart Failure ARNIs are the preferred agents, but for patients in whom ARNI administration is not possible, an ACEI/ARB is recommended. Maddox et al. J 5.1.2. Angiotensin Receptor-Neprilysin Inhibitor Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, including the natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF (14). Because angiotensin II is also a substrate for neprilysin, neprilysin inhibitors raise angiotensin levels, which explains the rationale for coadministration of an ARB. 