Parallel Evaluation of RLY5016 in Heart Failure - PEARL HF

Jan 09, 2011
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Supported by Relypsa, Inc.
Date Presented:
01/01/2010
Date Published:
01/01/2011
Date Updated:
01/09/2011
Original Posted Date:
01/09/2011
References

Description:

The goal of the trial was to evaluate treatment with the potassium binder RLY5016 (Relypsa) compared with placebo in patients with heart failure and prior hyperkalemia that resulted in discontinuation of heart failure medications or chronic kidney disease. RLY5016 does not bind dietary potassium, but acts as a lumen sink to pull potassium from the colon.

Hypothesis:

RLY5016 will be effective at reducing serum potassium.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Patients with heart failure and history of hyperkalemia, which led to the discontinuation of RAAS or beta-blockade medications
  • Chronic kidney disease on a background of RAAS or beta-blockade medications 
  • Serum potassium 4.3-5.1 mEq/L

    Number of enrollees: 104
    Duration of follow-up: 4 weeks
    Age range: mean 68 years
    Percentage female: 47%
    Ejection fraction: 40%
    NYHA class II: 53%, and NYHA class III: 44%

Exclusions:

  • Severe GI disorder
  • Major GI surgery
  • Significant primary valvular disease
  • Obstructive or restrictive cardiomyopathy
  • Uncontrolled or unstable arrhythmia
  • Unstable angina within 3 months prior to baseline
  • Acute coronary syndrome
  • Transient ischemic attack
  • A QTc value of >500 ms
  • Recent or anticipated cardiac surgery or intervention
  • Kidney transplantation or need for transplantation
  • Receiving dialysis or anticipated need for dialysis during the study
  • Sustained systolic blood pressure >170 or <90 mm Hg
  • Elevated liver enzymes
  • Any condition that could interfere with study compliance or jeopardize patient safety

Primary Endpoints:

  • Change in serum potassium

Secondary Endpoints:

  • Incidence of hyperkalemia >5.5 mEq/L
  • Spironolactone tolerability and safety

Drug/Procedures Used:

Patients with heart failure and prior hyperkalemia that resulted in discontinuation of heart failure medications or chronic kidney disease on a background of renin-angiotensin-aldosterone system (RAAS) or beta-blockade were randomized to RLY5016 30 g daily (n = 55) versus placebo (n = 49). All patients received spironolactone 25 mg at enrollment, which was up-titrated to 50 mg at day 15 if serum potassium was ≤5.1 mEq/L.

Concomitant Medications:

At baseline, in the RLY5016 group, the use of angiotensin-converting enzyme (ACE) inhibitor, angiotensin-receptor blocker (ARB), or beta-blocker was 24%; the use of ACE inhibitor or ARB, and beta-blocker was 73%; and the use of the ACE inhibitor, ARB, and beta-blocker was 4%.

Principal Findings:

Overall, 104 patients were randomized. In the RLY5016 group, mean age was 68 years, 47% were women, body mass index was 28 kg/m2, mean ejection fraction was 40%, proportion of diabetics was 27%, mean estimated glomerular filtration rate (eGFR) was 84 ml/min, New York Heart Association (NYHA) class II was 53%, and NYHA class III was 44%. In the RLY5016 group, 91% of patients were able to up-titrate to spironolactone 50 mg compared with 74% in the placebo group (p = 0.019).

The primary outcome, change in serum potassium from baseline, was -0.22 mEq/L in the RLY5016 group versus 0.23 mEq/L in the placebo group (p < 0.001 between groups). Among patients with an eGFR ≥60 ml/min, the proportion with hyperkalemia >5.5 mEq/L was 7.5% versus 19% (p = 0.13) and among those with an eGFR <60 ml/min, hyperkalemia was 6.7% versus 39% (p =  0.041), respectively, for RLY5016 versus placebo.

The number of patients with at least one gastrointestinal (GI)-related adverse event (flatulence, diarrhea, constipation, or vomiting) was 21% versus 6% (p = 0.028), and hypokalemia <3.5 mEq/L was 6% versus 0% (p = 0.094), respectively.

Interpretation:

Among patients with mild/moderate heart failure and mild chronic kidney disease, the use of RLY5016 was effective at preventing hyperkalemia. RLY5016 was especially effective at preventing hyperkalemia among those with eGFR <60 ml/min. This agent was well tolerated, except for an increase in GI-related adverse events (flatulence, diarrhea, constipation, or vomiting). There was a nonsignificant increase in hypokalemia with RLY5016. Larger studies with longer-term follow-up are needed to determine the efficacy and safety of this agent.

References:

Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Hung IZ, on behalf of the PEARL-HF Investigators. 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. Eur Heart J 2011;Jan 5:[Epub ahead of print].

Presented by Dr. Bertram Pitt at the European Society of Cardiology Congress, Stockholm, Sweden, August 2010.

Keywords: Vomiting, Follow-Up Studies, Diarrhea, Renin-Angiotensin System, Hyperkalemia, Spironolactone, Body Mass Index, Constipation, Heart Failure, Hypokalemia, Glomerular Filtration Rate, Potassium, Dietary, Flatulence, Diabetes Mellitus, Renal Insufficiency, Chronic


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