The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure

Daniel Murphy,Irina Chis Ster,Juan-Carlos Kaski,Debasish Banerjee,Lisa Anderson

doi:10.1186/s12882-021-02439-2

Abstract

BackgroundCKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy.MethodsWe propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants’ RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George’s Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline.DiscussionThis trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded.Trial registrationEudraCT number 2020–002946-18. Registered on 08 June 2020. Online record pending.

Highlights

Chronic kidney disease (CKD) is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia
Ejection fraction < 40%); patients with atrial fibrillation will be included provided the EF can be determined (3) New York Heart Association class II to IV (4) Most recent serum potassium 5.0–5.5 mmol/L (5) Adequate blood pressure (BP) (> 90 mmHg systolic and without postural hypotension; drop of systolic blood pressure (SBP) > 20 mmHg or feeling dizzy with change in posture; exclude patients with symptomatic hypotension due to high doses of angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) or mineralocorticoid receptor antagonists (MRA) unless the clinical condition has improved) (6) Formal diagnosis of CKD with stable estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. eGFR to be calculated according to the CKD-Epi formula [18], measured at a single time-point
Results from the study will be communicated to trial participants and local and national patients’ associations. This trial will be the first to look at the use of Sodium zirconium cyclosilicate (SZC) for the maximisation of RAASi dosing in CKD patients

Summary

Introduction

CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Patients with combined CKD-HF are at 2.3 times greater risk of all-cause mortality than those with HF alone [1]. Life-saving medications for systolic HF are underused in combined CKD-HF due to risk of hyperkalaemia [2]. These medications include renin-angiotensin-aldosterone system inhibitors (RAASi): angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) [3, 4]. There is reluctance amongst general practitioners, general physicians, and cardiologists managing these patients to prescribe medications that may increase serum potassium levels [10]

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