Safety of potassium-binding agents in HFrEF: a meta-analysis of randomized trials

Introduction Hyperkalemia is a common challenge in the management of heart failure with reduced ejection fraction (HFrEF) and often limits optimization of guideline-directed medical therapy (GDMT). In this setting, potassium-binding agents such as patiromer and sodium zirconium cyclosilicate (SZC) have gained increasing attention, as they lower serum potassium through gastrointestinal cation exchange and may enable continuation of GDMT. Nevertheless, their impact on hard cardiovascular outcomes in HFrEF remains uncertain. Purpose To evaluate the safety and clinical impact of potassium-binding agents on hard cardiovascular (CV) outcomes in patients with HFrEF. Methods We conducted this meta-analysis in accordance with PRISMA guidelines. We systematically searched PubMed/MEDLINE, EMBASE, CENTRAL, and Web of Science through January 15, 2026, for randomized controlled trials (RCTs). Eligible studies were RCTs enrolling HFrEF patients receiving GDMT, that compared patiromer or SZC with placebo or standard care. Four RCTs comprising a total of 1366 patients were included, with mean LVEF ranging from approximately 33% to 40% across trials. Outcomes included all-cause mortality, CV mortality, heart failure hospitalization, CV hospitalization, and composite endpoints. Safety outcomes comprised serious adverse events, treatment discontinuation, gastrointestinal events, hyperkalemia, and hypokalemia. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects models. Results Compared with placebo, potassium-binding agents were associated with increased total CV hospitalizations (OR 1.68; 95% CI 1.07–2.64; p=0.02) and a composite of total CV hospitalization and CV mortality (OR 2.02; 95% CI 1.37–2.97; p<0.01). Hyperkalemia was significantly reduced (OR 0.54; 95% CI 0.41–0.73; p<0.01), confirming pharmacological efficacy. However, treatment was associated with increased hypokalemia (OR 1.91; 95% CI 1.31–2.78; p<0.01) and more frequent gastrointestinal adverse events (OR 1.71; 95% CI 1.06–2.76; p=0.03), the latter primarily driven by patiromer. No significant differences were observed in atrial fibrillation, serious adverse events, or treatment discontinuation. Notably, ventricular arrhythmias, implantable cardioverter-defibrillator therapies, and sudden cardiac death were not reported in the included trials. Conclusion In HFrEF, potassium-binding agents may worsen CV outcomes. The increased risk of hypokalemia may promote ventricular arrhythmias in an already vulnerable myocardium, while sodium exchange (particularly with SZC) may contribute to fluid retention and congestion. These mechanisms may help explain the observed increase in CV outcomes in this meta-analysis.