Optimizing mineralocorticoid receptor antagonist therapy with sodium zirconium cyclosilicate in heart failure

Background

Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in HFrEF but remain underused, largely due to hyperkalemia concerns. Sodium Zirconium Cyclosilicate (SZC), novel potassium binder may enable MRA optimization.

Aim

OPRA-HF trial investigated whether SZC is superior to placebo while maintaining an optimized MRA dose in patients with HFrEF on optimal background therapy.

Method

This investigator-initiated multicentred, randomized, placebo-controlled, double-blinded trial includes patients with HFrEF on suboptimal MRA dose based on history of hyperkalemia due to MRA, or risk of hyperkalemia due to reduced kidney function (eGFR 30-45 ml/min/m2) and current potassium 4.5-5-0 mmol/L. Eligible participants enter a run-in phase with up-titration of MRA to target doses and SZC was added if hyperkalemia developed. Patients who achieve normokalemia on SZC while tolerating MRA ≥25 mg daily or a ≥25 mg dose increase were randomized to SZC (5 g or 10 g, as needed) or placebo for 6 months. The primary endpoint was maintenance of a daily MRA dose ≥25 mg or ≥25 mg dose increase while maintaining normokalemia at the end of treatment without need for rescue therapy. Key secondary endpoints include safety and tolerability (including hypo-/severe hyperkalemia, need for rescue therapy, edema/fluid retention and gastrointestinal events), durability of achieved MRA dose, and patient-reported outcomes.

Results

A total of 123 patients with optimal background therapy including ARNI and SGLT2 inhibitors were screened and 103 enrolled and entered the run-in phase (age 74,0± 7,8 years, male 81,6%, LVEF 31,2 ±6,9%), 45 patients achieved target MRA dose without need of SZC (Run-In failure) and 58 patients were randomized. Baseline characteristics were well-matched between groups.

The primary endpoint analysis showed a significantly higher proportion of patients in the SZC group (67,9%) maintained their optimized MRA dose and S-K at 3,5-5,0 mmol/L at 6 months compared to placebo (24,1%) RR 2,81 (1,18-6,69), OR: 6.63 (2.07-21.23), p=0.0014) . Sensitivity analysis of primary variables (adjustment for site) showed RR 2,81 (1,16-6,83), OR: 6.63 (2.01-21.85), p=00,0025. Use of SZC enabled maintaining of MRA dose in 78,6% of patients vs 41,4 % in placebo (RR: 1,90 (0,94-3,84), p=0,0067). SZC was well-tolerated, adverse event profile similar to placebo including worsening heart failure events (3,6% in SZC-treated vs 6,7% placbo, p=1.0).

Conclusion

In patients with HFrEF, the use of SZC effectively enabled optimization of guideline-directed MRA treatment compared to placebo despite contemporary background heart failure therapy and a persistently high risk of hyperkalemia. Moreover SZC was well tolerated without incresing risk of heart failure events. This strategy may help bridge the gap between guideline recommendations and real-world clinical practice by mitigating hyperkalemia-related barriers to MRA use.Maintainance of MRA Dose and normokalemia