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CHICAGO -- Treatment with the potassium binder sodium zirconium cyclosilicate (SZC; Lokelma) stabilized potassium levels among patients with heart failure with reduced ejection fraction (HFrEF) during spironolactone optimization, a prospective, randomized-withdrawal trial showed.

Among 203 patients, 71% of those taking SZC achieved the primary endpoint of optimal response -- normokalemia while on at least a 25-mg dose of spironolactone daily without rescue therapy for hyperkalemia -- compared with 36% of patients on placebo (OR 4.45, 95% CI 2.89-6.86, P<0.001), reported Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City, at the American Heart Association annual meeting.

The study was also published in the .

SZC also improved the first four key secondary endpoints versus placebo (P<0.01 for all):

• Normokalemia on randomization dose of spironolactone and without rescue therapy: 58% vs 23%; OR 4.58, 95% CI 2.78-7.55
• Receiving spironolactone ≥25 mg/daily: 81% vs 50%; OR 4.33, 95% CI 2.50-7.52
• Time to hyperkalemia: HR 0.51, 95% CI 0.37-0.71
• Time to decrease/discontinuation of spironolactone due to hyperkalemia: HR 0.37, 95% CI 0.17-0.73

While the SZC and placebo groups had similar rates of adverse events (64% vs 63%) and serious adverse events (23% vs 22%), a composite of cardiovascular death or worsening heart failure occurred in 11% of participants in the SZC group (one and 10 events, respectively) versus 3% of those in the placebo group (one and two events, respectively; nominal P=0.034).

Mineralocorticoid receptor antagonists (MRAs) such as spironolactone are one of the pillars of treatment for patients with HFrEF, but are often underutilized because of concerns about development of hyperkalemia, Hima Vidula, MD, of the University of Pennsylvania in Philadelphia, told 番茄社区app.

The researchers noted that "both the real and perceived risk of hyperkalemia remains the leading reason for suboptimal use of MRA, and commonly results in down-titration and discontinuation of treatment -- a practice that has been associated with worse heart failure outcomes in ."

"Accordingly, there is a need for additional treatment approaches to enable optimization of MRA therapy in patients with HFrEF, an issue that has been the clinical community and professional societies," they added.

Vidula said that a potassium binder such as SZC would be welcomed by doctors treating these patients. "Further studies will be needed to pinpoint which patients with heart failure are most likely to benefit from SZC therapy, and which ones will have problems."

Kosiborod said the patients who appeared to experience heart failure events were those with higher N-terminal pro-B-type natriuretic peptide levels, and Vidula noted that these patients may be the ones most in need of drugs like spironolactone.

This study shows there is a group of patients who would benefit from SZC; the question is to figure out who they are, Vidula added.

For this double-blind study, Kosiborod and colleagues enrolled 203 patients with HFrEF (New York Heart Association class II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA-induced hyperkalemia.

In the SZC group, median age was 73 years, 75% were men, and 89% were white. Median estimated glomerular filtration rate (eGFR) was 48 mL/min/1.73 m², and 47% had a previous heart failure hospitalization. In the placebo group, median age was 69 years, 74% were men, and 93% were white. Median eGFR was 60 mL/min/1.73 m², and 51% had a previous heart failure hospitalization. Overall, 88 SZC patients and 83 placebo patients completed treatment. Median follow-up in the two arms was about 6 months.

During the open-label run-in period, patients underwent spironolactone titration, with a target to 50 mg/daily, and those with hyperkalemia started SZC. Patients with normokalemia (potassium 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for 6 months.

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