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Evaluation of the Efficacy and Safety of RLY5016, a Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients With Chronic Heart Failure (the PEARL-HF) Trial
Study Questions:
What is the efficacy and safety of RLY5016 (a non-absorbed, orally administered, potassium [K+]-binding polymer) on serum K+ levels in patients with chronic heart failure (HF) receiving standard therapy and spironolactone?
Methods:
One hundred and five patients with HF and a history of hyperkalemia resulting in discontinuation of a renin-angiotensin-aldosterone system (RAAS) inhibitor/blocker and/or beta-adrenergic blocking agent or chronic kidney disease (CKD) with an estimated glomerular filtration rate of <60 ml/min were randomized to double-blind treatment with 30 g/day RLY5016 or placebo for 4 weeks. Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if K+ was ≤5.1 mEq/L. Endpoints included the change from baseline in serum K+ at the end of treatment (primary), the proportion of patients with hyperkalemia (K+ >5.5 mEq/L), and the proportion titrated to spironolactone 50 mg/day. Safety assessments included adverse events (AEs) and clinical laboratory tests. RLY5016 (n = 55) and placebo (n = 49) patients had similar baseline characteristics.
Results:
At the end of treatment, compared with placebo, RLY5016 had significantly lowered serum K+ levels with a difference between groups of −0.45 mEq/L (p < 0.001); a lower incidence of hyperkalemia (7.3% RLY5016 vs. 24.5% placebo, p = 0.015); and a higher proportion of patients on spironolactone 50 mg/day (91% RLY5016 vs. 74% placebo, p = 0.019). In patients with CKD (n = 66), the difference in K+ between groups was −0.52 mEq/L (p = 0.031), and the incidence of hyperkalemia was 6.7% RLY5016 vs. 38.5% placebo (p = 0.041). AEs were mainly gastrointestinal, and mild or moderate in severity. AEs resulting in study withdrawal were similar (7% RLY5016, 6% placebo). There were no drug-related serious AEs. Hypokalemia (K+ <3.5 mEq/L) occurred in 6% of RLY5016 patients versus 0% of placebo patients (p = 0.094).
Conclusions:
The authors concluded that RLY5016 prevented hyperkalemia and was relatively well tolerated in patients with HF receiving standard therapy and spironolactone.
Perspective:
This prospective, double-blind trial of RLY5016 to prevent hyperkalemia in chronic HF patients receiving standard therapy, including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers and a beta-adrenergic blocking agent in addition to spironolactone 25-50 mg/day, demonstrated that RLY5016 significantly decreased serum K+, reduced the incidence of hyperkalemia, and increased the proportion of patients in whom the dose of spironolactone could be increased to 50 mg/day. These results were obtained in patients with HF and concomitant CKD, as well as in patients with HF and a history of hyperkalemia requiring prior discontinuation of a RAAS blocking agent. Longer-term studies with larger sample sizes are indicated to determine the long-term efficacy, safety, and tolerability of RLY5016 both for the prevention of hyperkalaemia as well as its treatment once it occurs.
Keywords: Incidence, Potassium, Polymers, Heart Failure, Renin-Angiotensin System, Hyperkalemia, Spironolactone
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