OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure

Target subject population

Stable and symptomatic patients with chronic heart failure and LVEF ≤ 40% despite Guideline-Directed Medical Treatment (ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, MRA) at the discretion of physician´s judgement AND remaining suboptimal treatment of MRA

Duration of treatment

This study consists of 2 treatment phases: 1) Open-label Run-in, and 2) Randomized, pla-cebo-controlled, double-blinded treatment during 6 months. The Open-label phase, in turn, consists of three periods: up-titration (normally 1 - 2 weeks, or longer in some cases), Cor-rection (maximum up to 72 hours) and Maintenance (4-7 weeks)

Investigational product, dosage and mode of administration Sodium Zirconium Cyclosilicate (SZC) (Lokelma)®, 5 g, 10 g, orally, is an approved drug in Sweden. For correction of hyperkalemia, the recommended starting dose is 10 g, three times daily. Once normokalemia has been achieved, the maintenance regimen should be started with 5 g once daily. The dose can be adjusted up to 10 g once daily or lowered to 5 g once every other day as needed, to maintain a normal level of potassium.

Inclusion criteria

Recruiting will take place mainly from specialist care at University hospitals or Province hospitals in Sweden. But some of patients might have simultaneous follow-up at primary care as well.

Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this study. Under no circumstances can there be exceptions to this rule.

Inclusion criteria

For inclusion in the study subjects should fulfil the following criteria:

• Obtain signed informed consent prior to any study specific procedures
• >18 yrs.
• LVEF ≤ 40% within past 2 years (including recovered EF later on).
• NYHA II-IV.
• On optimal treatment including ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, as per physician´s judgement.
• Suboptimal treatment with MRA (defined as: no use or ≤ 25 mg daily)
• And one of following:

• Prior hyperkalemia (S-K> 5.0 mmol/L or P-K> 4.8 mmol/L*) during MRA treat-ment within last 24 months, and current S-K ≤ 5.0 or P-K ≤ 4.8 mmol/L
• Current S-K 4.5-5.0 mmol/L or P-K 4.3-4.8 mmol/L, and potential risk of hyper-kalemia as indicated by eGFR 30-45 ml/min/1,73 m2 (modified MDRD formula)
• Current S-K 5.1-5.9 mmol/L or P-K 4.9-5.7 mmol/L

• Corresponding plasma K (P-K) level is 0.2 mmol lower than serum K(S-K) (The Nordic Reference Interval Project).

Depending on the S-K status during screening, patients are divided into two groups before treatment initiation /run-in:

• Group 1: Patients who are hyperkalemic (S-K 5.1 - 5.5 mmol/L measured within last 2 weeks)
• Group 2: Patients who are normokalemic (S-K 3.5 - 5.0 mmol/L) during screening but are at a high risk of developing hyperkalemia associated with MRA initiation / increase. Namely, one (or both) of the following:

• Prescription of MRA within last 12 months and documented hyperkalemia after MRA prescription
• S-K 4.5-5.0 mmol/L and GFR < 45 mL/min/1,73 m2

Note: All S-K related limits in this protocol concern serum measurements. In Sweden it is plasma that is analyzed, which makes 4.8 mmol/l (plasma) equivalent to 5.0 mmol/L(serum)

Exclusion criteria

Subjects should not enter the study if any of the following exclusion criteria are ful-filled:

• Symptomatic hypotension (< 90/60 mmHg)
• eGFR < 30 ml/min/1,73 m2 (modified MDRD formula)
• HF due to restrictive cardiomyopathy, hypertrophic (obstructive) cardio-myopathy or primary valvular disease
• Current/recent (within 3 months) hospitalization due to myocardial infarc-tion, unstable angina pectoris, coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or other interven-tions (valvular repair/replacement, cardiac transplantation or implantation of a ventricular assistance device)
• Ongoing or planned dialysis
• Prior history of hypersensitivity (other than hyperkalemia) to a MRA, or SZC
• Advanced malignancy requiring treatment
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• Congenital long QT syndrome.
• Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymp-tomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
• QTc(f) > 550 msec
• Currently pregnant (confirmed with positive pregnancy test) or planned pregnancy or breast-feeding
• Can not sign informed consent.