Cardiovascular outcomes with potassium binders in patients with heart failure and hyperkalemia

Background Hyperkalaemia complicates heart failure (HF) and may limit guideline-directed therapy. Potassium binders differ in pharmacologic properties and sodium load, raising cardiovascular safety concerns. Real-world comparative evidence on cardiovascular outcomes associated with the different novel potassium binders in HF is limited. We aimed to compare cardiovascular outcomes associated with patiromer, sodium zirconium cyclosilicate (SZC), and sodium polystyrene sulfonate (SPS) using a target-trial emulation framework. Methods We conducted a retrospective comparative effectiveness study in the TriNetX network including adults with HF and hyperkalaemia initiating patiromer, SZC, or SPS (2019–2024). Three pairwise 1:1 propensity-matched comparisons were performed. Follow-up was up to 365 days (mean 0.7±0.4 years). Outcomes included death, HF hospitalisation, cardiovascular hospitalisation, myocardial infarction, incident atrial fibrillation (AF), pulmonary oedema/cardiogenic shock, end-stage kidney disease (ESKD), and ventricular tachyarrhythmia/cardiac arrest. Results After matching, 5,589 patients per group were included for patiromer vs SPS, 15,769 per group for SZC vs SPS, and 4,381 per group for SZC vs patiromer. Compared with SPS, patiromer was associated with lower risk of HF hospitalisation (HR 0.573, 95%CI 0.535–0.613) and cardiovascular-related hospitalisation (HR 0.737, 95%CI 0.697–0.779), but slightly higher mortality (HR 1.096, 95%CI 1.027–1.170). In contrast, SZC was associated with higher risks of death (HR 1.139, 95%CI 1.095–1.185), HF hospitalisation (HR 1.184, 95%CI 1.143–1.225), myocardial infarction (HR 1.132, 95%CI 1.018–1.260), ESKD (HR 1.137, 95%CI 1.082–1.196), and cardiovascular hospitalisation (HR 1.193, 95%CI 1.157–1.229) compared with SPS. Direct comparison showed SZC was associated with markedly higher HF hospitalisation (HR 2.735, 95%CI 2.519–2.969) and cardiovascular hospitalisation (HR 1.914, 95%CI 1.797–2.037) versus patiromer, with no significant difference in mortality. In stratified analyses according to HF phenotype, associations between SZC and patiromer were consistent across HFrEF and HFpEF. However, formal interaction testing demonstrated significant effect modification for cardiovascular hospitalization (p for interaction = 0.01) and pulmonary oedema or cardiogenic shock (p = 0.03), with stronger relative associations observed in HFpEF. Conclusions In patients with HF and hyperkalaemia, potassium binders demonstrated distinct cardiovascular outcome profiles. SZC was associated with higher risks of HF and cardiovascular hospitalisation compared with both patiromer and SPS, while patiromer was associated with lower HF hospitalisation compared with SPS. These findings highlight that potassium binders are not interchangeable from a cardiovascular perspective and underscore the need for randomised trials specifically powered for hard cardiovascular endpoints.