Evaluation of the impact of egfr decline on clinical practice patterns of medication withdrawal in heart failure

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Tufts Medical Center Parent, Inc. (doing business as Tufts Medical Center) $133,875 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847). The project grant funds an evaluation of how estimated glomerular filtration rate (eGFR) decline influences clinical practice patterns of medication withdrawal in heart failure patients. The research addresses a significant clinical problem: guideline-directed medical therapies including renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors reduce mortality and cardiovascular risk in patients with heart failure with reduced ejection fraction, yet each class causes an acute, hemodynamic eGFR decline that clinicians often cannot distinguish from true kidney injury, leading to inappropriate discontinuation and increased cardiovascular risk. The award covers the period of performance from September 1, 2026, through June 30, 2028, with work performed at Tufts Medical Center in Boston, Massachusetts. The project examines whether early discontinuation of guideline-directed medical therapy following eGFR decline harms patients, addressing barriers to optimal heart failure treatment initiation and continuation that persist despite strong clinical trial evidence of therapeutic benefit.

Abstract

Heart failure (HF) is a condition that carries very high rates of mortality and morbidity. Guideline-directed medical therapy (gdmt) including renin-angiotensin-aldosterone system inhibitors (raasi), mineralocorticoid receptor antagonists (MRA), and sodium-glucose CO-transporter 2 inhibitors (SGLT2I) have each been shown to reduce mortality and risk of adverse cardiovascular events, particularly for patients with heart failure with reduced ejection fraction (hfref). However, each of these gdmt medication classes is also associated with an acute decline in estimated glomerular filtration rate (egfr) which is considered hemodynamic and benign in nature. For clinicians, however, the egfr decline following initiation of gdmt appears no different from egfr decline due to true kidney injury, creating a significant degree of clinical angst over whether to discontinue or reduce the dose of the gdmt, which would potentially place the patient at higher risk of worsening cardiovascular function. Despite several large clinical trials showing the significant mortality and cardiovascular benefits of gdmt, rates of gdmt prescribing remain low, and rates of early gdmt discontinuation are high, with many clinicians citing concerns for egfr decline as a large obstacle to initiation and continuation of gdmt. Designing a study to determine whether discontinuation of gdmt following egfr decline is harmful for patients is very challenging for several reasons. First, the egfr fluctuates frequently in hfref both due to gdmt medications but also due to other causes. Second, with three separate classes of gdmt agents to be used in combination, there quickly become many iterations of different combinations of continuation, discontinuation, or dose change of both newly introduced (new use) gdmt as well as of previously prescribed (prevalent use) gdmt agents. The overall goal of this proposal is to use the stockholm creatinine measurement (scream) cohort, a regional health utilization cohort with complete pharmacy dispensation records, to describe prescribing patterns of raasi, MRA, and SGLT2I among patients with HF. We plan to examine egfr changes after gdmt initiation, their association with risk of cardiovascular death and hospitalizations for HF within the context of which agent and how many combined gdmt class agents are initiated. Based on incidence of egfr decline or not, we will then assess all the combinations of gdmt continuation, discontinuation, dose reduction or dose increase. These results will serve as preliminary data to inform design of appropriate future larger trials, including a target trial designed to emulate randomization of patients to gdmt continuation VS discontinuation following egfr decline with the ultimate goal of increasing rates of gdmt prescribing in order to improve mortality and cardiovascular outcomes among patients with HF.