Guideline-Directed Heart Failure Pharmacotherapy in Adults Aged ≥75 Years: Evidence Gaps, Tolerability, and Implications for Clinical Practice.

Heart failure predominantly affects older adults, yet the evidence supporting guideline-directed medical therapy is largely derived from randomized controlled trials predominantly enrolling younger and less frail populations. Adults aged ≥75 years remain underrepresented, raising important questions regarding the generalizability of trial evidence to contemporary geriatric practice. This review focuses on the applicability, tolerability, and clinical relevance of guideline-directed medical therapy in adults aged ≥75 years, with particular attention to objective outcomes and feasibility markers such as adverse events, treatment discontinuation, hospitalization, mortality, frailty-related vulnerability, and patient-centred functional implications. We conducted a structured narrative critical review of pivotal randomized controlled trials underpinning modern heart failure pharmacotherapy, without formal systematic selection or meta-analysis. Published data were extracted on age distribution, exclusion criteria relevant to older adults, efficacy outcomes (mortality and hospitalization when reported), safety outcomes (hypotension, renal dysfunction, hyperkalaemia, and treatment discontinuation), and geriatric domains or frailty-related measures when available. Trial findings were interpreted through established geriatric frameworks, including frailty and multimorbidity constructs. Across major heart failure trials, mean participant age ranged from 61 to 67 years, with very limited inclusion of patients aged ≥75 years and very limited representation of patients aged ≥80 years. While relative treatment efficacy appears preserved with ageing, older participants experienced higher rates of hypotension, renal dysfunction, and treatment discontinuation, whereas frailty, functional status, cognition, and other geriatric domains were rarely measured. Key geriatric domains-frailty, functional status, cognition, nutrition, and polypharmacy-were systematically absent from trial designs. This narrative review highlights a persistent gap between clinical trial populations and older patients with heart failure in routine care. In adults aged ≥75 years, application of guideline-directed medical therapy should remain evidence-aligned but clinically adapted, with slower titration, closer monitoring, and acceptance of tolerated submaximal doses when frailty, multimorbidity, or limited physiological reserve reduce treatment feasibility.