MINNEAPOLIS — A reduced risk for death may balance out concerns about hyperkalemia when treating heart failure with renin-angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), new evidence suggests.

“In our analysis of the CARE-HK registry that exclusively enrolled patients with heart failure at high risk for hyperkalemia, we saw that optimal dosing of RAS inhibitors and MRA therapy was associated with marginally higher risk for hyperkalemia — but also associated with reduced all-cause mortality,” co-investigator Stephen Greene, MD, a cardiologist and associate professor of medicine at Duke Clinical Research Institute, Duke University School of Medicine, in Durham, North Carolina, told Medscape Medical News.

The results are from an analysis of more than 2500 patients with heart failure over a median of 12 months.

The findings are important, Greene added, because “among heart failure patients at high risk for hyperkalemia, clinicians may be particularly hesitant to escalate doses of RAS inhibitors and MRAs, and there may be some uncertainty regarding the risk-benefit calculus.”

Greene presented the study results at Heart Failure Society of America (HFSA) 2025 Annual Scientific Meeting.

Less Than One Third of Patients on Optimal Therapy

Greene and colleagues performed a secondary analysis of the CARE-HK multinational prospective registry that enrolled patients with heart failure, irrespective of ejection fraction, from 2021 through 2023.They assessed data for 2558 patients from 111 sites across nine countries. All patients had a history of current hyperkalemia or an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m².

Therapy was optimal, defined as receiving at least 50% of target doses for RAS inhibitors and MRAs, in 29% of patients and suboptimal in 71% of them. Patients in the optimal therapy group were younger, with a median age of 70 years vs 74 years in the suboptimal therapy group, and predominantly men (73.9% vs 66.3%). They also had fewer comorbid conditions, better renal function (median eGFR, 48 vs 42 mL/min/1.73 m²), and lower left ventricular ejection fraction (median, 35% vs 39%) at baseline.

A greater proportion of the optimal therapy group also had a prior history of hyperkalemia (79.5% vs 72.2%).

A Strong Association

The primary endpoint was all-cause mortality at 2 years, and a secondary endpoint was the number of hyperkalemia events during the same period.

During a median follow-up of 12 months, hyperkalemia occurred more often in the optimal therapy group (31.6% vs 27.8%). However, these patients were less likely to have RAS inhibitor or MRA dose adjustments related to hyperkalemia (9.9% vs 16.2%).

A total of 223 patients died during follow-up. Researchers noted significantly lower all-cause mortality in the optimal therapy group than in the suboptimal therapy group (3.8% vs 10.7%), with an unadjusted hazard ratio (HR) of 0.43 (95% CI, 0.30-0.61; P < .0001). This link between optimal therapy and decreased all-cause mortality remained significant after adjustment for age and sex (HR, 0.49; 95% CI, 0.33-0.69; P < .001) but lost strength in the fully adjusted model (HR, 0.70; 95% CI, 0.46-1.06; P = .09).

The observed decrease in death rate was partly related to other prognostic factors and confounders, according to Greene.

“But even after full adjustment, the findings were still strongly and directionally consistent with the mortality benefit,” he said.

“These data support the importance of current guideline recommendations to shoot for high, maximally tolerated target doses of RAS inhibitors and MRAs, even among our patients with heart failure at high risk for hyperkalemia,” Greene said.

Clinical Applications

Session co-moderator Kathleen Faulkenberg, PharmD, clinical pharmacist coordinator for Cardiovascular Services at the University of Kentucky HealthCare in Lexington, Kentucky, called it “a wonderful presentation” and asked Greene about the severity of hyperkalemia in the patients in the registry.

Hyperkalemia events were mild overall, with potassium levels ≤ 5.5 mEq/L in about 70%, he answered, noting that all results should be interpreted in the context of the study population, which was at high risk for hyperkalemia already.

“These data support the notion that even in the subset of heart failure patients known to be at high risk for hyperkalemia, the risk-benefit tradeoff still seems favorable for escalating doses of RAS inhibitors and MRAs towards target, especially in the era of novel potassium binders for use if or when hyperkalemia develops,” Greene said.

Asked about next steps, he noted further quality improvement initiatives are needed to help providers overcome clinical inertia toward escalating doses of these agents in eligible patients with heart failure.

“This especially applies to the high-risk subset of heart failure patients at risk of hyperkalemia, where clinician hesitancy towards escalating RAS inhibitors and MRAs may be strongest,” he said.

This study was independently supported. Greene reported disclosures related to Amgen, Bayer AG, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Cytokinetics, Pfizer, Novartis, Vifor Pharma, Roche, Sanofi-Aventis, Merck, Tricog Health, Bristol-Myers Squibb, AstraZeneca, Merck, Boehringer Ingelheim, Boehringer Ingelheim, PharmaIN, Lexicon Pharmaceuticals, scPharmaceuticals, Otsuka, and Novo Nordisk. Faulkenberg reported no conflicts of interest.

Damian McNamara is a freelance writer for Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024, after which he did a brief stint as a Federal Contractor for the Biomedical Advanced Research and Development Authority, a part of US Department of Health and Human Services that helps develop innovative products to protect people during public health emergencies. He uses what he learned in school — He has a BA in chemistry and an MA in science, health, and environmental reporting/journalism. He works out of a home office in Miami, with a 100-pound chocolate lab known to snore under his desk during work hours.