Temporal therapeutic mismatch in frail older adults with heart Failure: A framework for Frailty-Informed prescribing

Heart failure in older adults increasingly occurs in the context of frailty, multimorbidity, and declining physiological reserve. In this population, therapeutic efficacy demonstrated in selected clinical trial populations does not automatically translate into meaningful clinical benefit. This discrepancy may create tension between guideline-driven care and goal-concordant prescribing. This narrative review proposes a conceptual framework to distinguish therapeutic efficacy from clinical relevance in ageing heart failure populations. Using tafamidis for transthyretin cardiac amyloidosis and apixaban for atrial fibrillation as illustrative paradigms, we examine how frailty severity, competing risks, life expectancy, and therapy-specific time-to-benefit influence the likelihood that a treatment will provide meaningful benefit for an individual patient. Disease-modifying therapies with delayed benefit may lose proportionality when lag-time-to-benefit exceeds the patient's anticipated window of preserved survival or functional autonomy. In contrast, preventive strategies that rapidly reduce autonomy-threatening events may retain broader clinical relevance across vulnerability strata, although individualized reassessment remains essential. We introduce the concept of temporal therapeutic mismatch, defined as a situation in which expected therapeutic benefit occurs beyond the patient's remaining functional trajectory or life expectancy. A pragmatic framework integrating frailty severity, estimated life expectancy, competing risks, therapy-specific time-to-benefit, and patient-defined goals is proposed to support proportional prescribing. In ageing cardiovascular populations, high-quality care requires moving beyond efficacy alone toward frailty-informed clinical relevance. Structured reassessment-including consideration of non-initiation or deprescribing when appropriate-represents a key component of patient-centered cardiovascular care.