Examples of populations that have been relatively understudied in HFrEF trials include African Americans, older adults ($75 years), and frail patients. African Americans. ARNIs, SGLT2 inhibitors, and ivabradine were tested in clinical trial populations with few or no African Americans. In fact, the landmark ivab- radine study SHIFT included almost no African Americans (12,28,135). Nonetheless, no signi cant differences in the ef cacy of ARNIs or SGLT2 inhibitors have been observed by race. Ivabradine is now actively being studied in Afri- can Americans with HF. Given the established bene ts in the general public, we recommend that African Americans receive these newer medications as part of their HF GDMT. TABLE 11 Speci c Patient Cohorts in HF Care Patient Cohorts Description Evidence-based recommendations Risks Uncertainties African-American patients Self-identi ed GDMT n ARNIs, ACEIs, and ARBs: possibly higher risk of angioedema compared with Caucasian patients n Uncertain risk of hypotension when combining new drugs with HYD/ISDN Expected outcomes of ARNI, SGLT2 inhibitors, and/or ivabradine in those treated with HYD/ISDN Older adults $75 years of age n GDMT, but recognize that this pop- ulation is excluded from many trials supporting GDMT n Consider starting with lower doses of GDMT n Potential falls n Worsening of renal function n Polypharmacy n Comorbidity Ef cacy of lower-dose GDMT on outcomes Frail patients Meets established frailty GDMT as tolerated n Uncertain response to GDMT n Possibly increased risk for adverse drug reactions Ability to have an impact on natural history in the frail with HF ACEI angiotensin converting enzyme inhibitors; ARB angiotensin receptor blockers; ARNI angiotensin receptor-neprilysin inhibitor; GDMT guideline-directed medical therapy; HF heart failure; HYD/ISDN hydralazine/isosorbide dinitrate. Maddox et al. J A key therapy among African Americans with HFrEF is HYD/ISDN. 