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PEARL HF: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, multiple-dose study to evaluate the effects of RLY5016 in heart failure patients

Heart Failure

Bertram Pitt
Presenter | see Discussant report Webcasts become available 12h after the end of the session
Pitt, Bertram
(United States of America)

List of Authors:
Bertram Pitt, MD, I-Zu Huang, MD, Stefan Anker, MD, PhD, David Bushinsky, MD, Dalane Kitzman, MD, Faiez Zannad, MD, PhD for the PEARL-HF Investigators


Despite the efficacy of aldosterone antagonists (AAs) in heart failure (HF), use of AAs has been limited by the occurrence or fear of hyperkalemia (HK). RLY5016 is a unique, nonabsorbed, oral, potassium binding polymer that is being developed as a serum potassium (K+) management tool.

The use of Relypsa’s K+ binding polymer (RLY5016) will prevent hyperkalemia in patients with HF and chronic kidney disease (CKD) receiving an AA.

A total of 105 chronic HF patients clinically indicated to receive spironolactone therapy were randomized, with 104 evaluable: 55 patients to RLY5016 and 49 to placebo. Patients with a serum K+ of 4.3-5.1 mEq/L, and CKD (eGFR< 60mL/min) on one or more HF therapies (ACEIs, ARBs, or β-blockers [BBs]) or documented history of hyperkalemia (HK) within last 6 months which led to the discontinuation of an AA, ACEI, ARB, or BB were given spironolactone 25-50 mg daily and randomized to 30 g/d RLY5016 or placebo for 4 weeks. The primary endpoint was change from baseline in serum K+ at the end of the double-blind treatment period and was based on the LOCF method. Efficacy was also assessed by proportion of patients with HK (K+>5.5 mEq/L) and proportion of patients whose spironolactone dose could be increased. Efficacy was assessed in the eGFR<60 mL/min subgroup. Safety was assessed by adverse events and clinical laboratory findings.

Baseline characteristics were similar between both treatment groups. At baseline, serum K+ averaged 4.69 ± 0.06 mEq/L on RLY5016 and 4.65 ± 0.07 mEq/L on placebo. The mean change from baseline in serum K+ was -0.22 mEq/L and +0.23 mEq/L in the RLY5016 and placebo patients, respectively (p<0.001). RLY5016 significantly reduced the incidence of HK compared to placebo (7% vs. 25%, p=0.015) and increased the proportion of patients whose spironolactone dose could be increased (91% vs. 74% p=0.019). Patients with eGFR < 60 mL/min appeared to have a more pronounced treatment effect than those with a documented history of HK. RLY5016 was well tolerated. Withdrawal from the study due to an adverse event was 7% on RLY5016 compared to 6% on placebo, and there were no drug-related SAEs.

RLY5016 may enable the use of RAAS blockers in patients with HF and CKD who are at high risk for HK. Further studies at multiple doses will however be required before clinical application.

Henry J Dargie, FESC
Discussant | see Presenter abstract Webcasts become available 12h after the end of the session
Dargie, Henry J
(United Kingdom)
Open presentation slides


Severe hyperkalaemia is a life threatening condition which can occur in several clinical situations including heart failure especially in patients with renal impairment with which it is commonly associated. Renal impairment in heart failure can be due to many factors including reduced renal blood flow from a low cardiac output, the adverse renal effects of its treatment or associated intrinsic renal disease especially from diabetes or renovascular disease. This study, performed by experienced investigators, examines the effects of a new medicine, RELYPSA (RYL 5016), a cation binding compound which removes potassium via the colon thereby lowering the total body potassium and the levels in the blood.
It is designed to prevent the hyperkalaemia that can occur during the treatment of heart failure with standard medications including ACE inhibitors and beta blockers when spironolactone, a potassium sparing diuretic which has been shown to improve outcome in severe heart failure (NYHA III/IV), is added.

This is a double blind randomized controlled parallel group trial in a total of 100 patients of whom 50 received active medication and 50 a placebo. Patients had largely mild to moderate HF (57/59% NYHA I/II) and LVEF 39.6/41.2 in the RELYPSA and placebo groups respectively suggesting a mixture of reduced and preserved LV systolic function. The end points were change in serum K (1y) and Incidence of hyperkalaemia (K > 5.5 mmol/L)/ spironolactone dose titration/tolerability and safety respectively.

The study met its 1y and first 2y end points but was less well tolerated than placebo partly due to GI adverse events. Interestingly 74% on placebo also uptitrated to 50 mg of spironolactone.

Strengths and Weaknesses
The good trial design lends credence to the conclusion that RYL 50 16 could be useful in ameliorating aldosterone receptor antagonist associated hyperkalaemia.
Advantages of RYL 5016 in patients with heart failure include the mechanism of action which does not involve exchange with and therefore loading of sodium.

Conclusions and future directions
The ‘K+ continuum’ in heart failure is a double edged sword with hazard from life threatening cardiotoxicity in the form of malignant arrhythmia and other adverse events at both ends of the spectrum of blood potassium levels which may fluctuate without significant shifts in the total body potassium content. Since iatrogenic hyperkalaemia is most common in older patients with more severe heart failure and renal dysfunction than were tested in this study, further studies are required to establish safety and efficacy in the likely target patient groups in whom hypokalaemia is the more frequent ‘peril’.
The PEARL investigators are to be congratulated on an interesting and thought provoking study which raises awareness of the continuing conundrum of the homeostasis of potassium in heart failure.


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Hot Line I - Heart failure and left ventricular dysfunction
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.