The ACC/AHA/HFSA guideline considers either the xed-dose combination or the separate combination of isosorbide dinitrate and hydralazine as appropriate guideline-directed therapy for HF. ACC American College of Cardiology; ACEI angiotensin-converting enzyme inhibitor; AHA American Heart Association; ARB angiotensin receptor blocker; ARNI angiotensin receptor-neprilysin inhibitor; GDMT guideline-directed medical therapy; HF heart failure; HFrEF heart failure with reduced ejection fraction; HFSA Heart Failure Society of America; SGLT2 sodium-glucose cotransporter-2. Maddox et al. J HF is a complex syndrome typically associated with multiple comorbidities; most patients are on multiple medications. No clinical trials have speci cally evaluated the potential for greater bene t or excessive risk of indi- cated therapies among patients with multimorbidity. To assess tolerability of medications and best assess the trajectory of HF, it is often necessary for patients to have more frequent follow-ups, especially after initiation or titration of therapy. 5.1.1. Initiating GDMT Recommendations for starting GDMT in a patient with a new diagnosis of symptomatic HFrEF are detailed in Figure 2. In a patient with new-onset stage C HFrEF, a common question is whether to initiate a beta-blocker or an in- hibitor of the renin-angiotensin system (ARNI/ACEI/ARB) rst. The writing committee recommends that either an ARNI/ACEI/ARB or beta-blocker should be started. In some cases, an ARNI/ACEI/ARB and a beta-blocker can be started at the same time. 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). 