Barriers to mineralocorticoid receptor antagonists dose escalation in heart failure: Findings from the OPRA-HF Run-in period

Background Patients with heart failure with reduced ejection fraction (HFrEF) are highly morbid, with the key therapy mineralocorticoid receptor antagonists (MRA) often limited by hyperkalemia (HK). Many patients on suboptimal MRA doses are not titrated due to concerns for HK. Sodium Zirconium Cyclosilicate (SZC) may enable safe MRA optimization which is tested in the ongoing OPRA-HF trial. A crucial first part of the study (run-in) is the escalation of MRA treatment to confirm HK. Aim To characterize patients who can tolerate MRA optimization early and reasons for run-in failure. Methods This multicenter, randomized, placebo-controlled trial enrolled HFrEF patients on suboptimal MRA therapy due to previous HK (>5.0 mmol/L in plasma) or risk for HK due to advanced age, renal dysfunction, or diabetes. OPRA-HF consists of 2 phases: 1) open-label run-in and 2) randomized, double-blinded, and SZC/placebo-controlled treatment for 6 months. During the run-in phase, all normokalemic patients underwent MRA dose escalation in 1 - 2 weeks, without SZC, to confirm HK. Run-in failure is defined if the patient can tolerate the target dose (50 mg for both spironolactone and eplerenone) MRA without developing HK and without receiving SZC. Randomization in OPRA-HF will be finalized by June 30, 2025. Results So far, 116 patients have been enrolled in the study. Of those, 21 (18.1%) were screening failures, 5 (4.3%) were still in the run-in period, 3 (2.6%) discontinued during maintenance phase, 35 (30.2%) were run-in failures and 52 (44.8%) got randomized. Among the run-in failures 93.3% were successfully up-titrated to 50 mg daily despite initial suboptimal MRA dosing. Compared with those randomized (59.8%), patients who failed in run-in phase had similar age (72.7±9.3 vs. 75.0±6.9 years) and sex (male: 85.7% vs. 82.7%) but had lower prevalence of type 2 diabetes (17.2% vs. 42.3%), less ischemic heart disease (45.7% vs. 59.6%), higher systolic blood pressure (130.1±14.9 mmHg vs. 120.3±22.9 mmHg) at baseline, lower baseline potassium levels (4.5 ± 0.3 vs. 4.7 ± 0.4 mmol/L), and higher estimated glomerular filtration rate (eGFR) (59.9±14.3 vs. 55.7±15.6 mL/min/1.73m), suggesting better renal function.. In both groups patients were well treated with beta-blocker (91.4% vs. 96.2%), ARNI (57.1% vs. 61.5%) and SGLT2 inhibitors (62.9% vs. 80.8%) in run-in failure vs. randomized patients except diuretic use was lower in the run-in failure group (20.0% vs. 34.6%). Conclusion With contemporary HF medications, more patients have a lower risk of HK and therefore better tolerability for MRA therapy. This highlights the urgent need for a renewed effort to optimize MRA treatment in those who are suboptimally treated.