PROJECT SUMMARY/ ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects more than 3 million people in the United States (U.S.) and contributes to substantial impairments in health-related quality of life (QOL). While there are proven benefits of ß-blockers in other phenotypes of HF (e.g., HF with reduced ejection fraction [HFrEF]), there is limited evidence of benefit and some evidence suggesting harm in the setting of HFpEF. Despite this, >80% of adults with HFpEF receive ß-blockers often without a clear guideline-based indication. While ß-blockers were originally postulated to improve cardiac output in HFpEF by slowing down the heart rate and improving left ventricular filling, there is emerging evidence that ß-blockers may cause more harm than good by exacerbating chronotropic incompetence, worsening cardiac output, and/or reducing exercise tolerance. Relatedly, ß- blockers may worsen several domains of health-related physical and mental QOL. Taken together, these findings suggest that ß-blockers are a compelling target for deprescribing. Yet, ß-blockers are not commonly deprescribed, even when physicians recognize there is no evident clinical indication. A critical barrier to deprescribing in HFpEF is a lack of rigorous evidence regarding safety and efficacy, supporting the urgent need for our proposal. Our central hypothesis is that deprescribing ß-blockers will lead to net benefit in older adults with HFpEF. This hypothesis is supported by our preliminary data showing that withdrawal of ß-blockers is safe and improves both physical and mental health. To establish evidence for the net benefit of deprescribing ß-blockers in HFpEF, we will conduct a double-blinded, placebo-controlled, pragmatic randomized clinical trial in 320 older adults with HFpEF. Our “Determining Evidence in a Placebo-Controlled, Randomized Experiment Studying Continuation vs. Removal of Inessential Beta-Blockers in Elders with Heart Failure with Preserved Ejection Fraction (DEPRESCRIBE-HFpEF) study” will be conducted at Kaiser Permanente Northern California with pragmatic design elements. We will use an innovative hierarchical endpoint (analyzed using the win-ratio) for net benefit that reflects clinical priorities, incorporating both safety and efficacy. Our team is led by two cardiologists with expertise in HFpEF—one has studied deprescribing ß- blockers for the last 5 years (supported by NIA K76), and one has significant experience designing and conducting pragmatic RCTs within a learning health system. Our team also includes senior scientific leaders with expertise in aging research, HFpEF, deprescribing, QOL, pragmatic RCTs, and biostatistics. The expected outcome of this proposal is foundational evidence that will impact clinical practice guidelines for the management of older adults with HFpEF. This research directly addresses NIA’s Strategic Directions Research Goal C-3 to “develop interventions for treating…or mitigating the impact of age-related disease and conditions.”

PROJECT NARRATIVE With this proposal, we will conduct a double-blinded, placebo-controlled randomized clinical trial in 320 older adults with heart failure with preserved ejection fraction (HFpEF) to assess the net benefit of deprescribing ß- blockers, utilizing an innovative hierarchical endpoint incorporating clinical priorities and integrating both clinical events and quality of life measures. The expected outcome is foundational evidence that will impact clinical practice guidelines for the management of older adults with HFpEF. This research directly addresses NIA’s Strategic Directions Research Goal C-3 to “develop interventions for treating…or mitigating the impact of age- related disease and conditions.”