SEATTLE – An investigational agent that eliminates excess fluid through the gastrointestinal tract appears promising for treatment in patients with heart failure–related fluid overload who also have chronic kidney disease, new data suggest.
In a phase II trial among 111 such patients who were starting spironolactone, the new agent – known as cross-linked polyelectrolyte (CLP) – did not improve serum potassium levels when compared with placebo, the trial’s primary end point, investigators reported at the annual meeting of the Heart Failure Society of America. However, it did improve body weight and New York Heart Association (NYHA) functional class.
Dr. Barry M. Massie
The CLP group had a higher rate of gastrointestinal adverse effects. Additionally, the mortality rate was about 7% with the medication, compared with 0% with placebo. None of the deaths appeared to be related to treatment, according to the study’s lead investigator, Dr. Barry M. Massie, chief of the cardiology division at the San Francisco Veterans Affairs Medical Center.
"Use of CLP in the gastrointestinal tract may be an effective means for removal of sodium and water in heart failure patients already treated with guideline therapy including diuretics," said Dr. Massie. "Such extrarenal removal of fluid appears to result in meaningful improvements in function and symptoms in these patients, and warrants further investigation."
"An adequately powered trial is needed both to confirm the efficacy and further evaluate safety of the compound," he added.
Dr. Stephen S. Gottlieb of the University of Maryland, Baltimore, who was invited to discuss the trial, said that it addressed two critical issues in this population: hyperkalemia (a major barrier to using and adequately titrating cardiovascular medications) and fluid status (an ongoing problem as existing diuretics have known limitations).
"Unfortunately, CLP did not prevent hyperkalemia, and we clearly need ways to safely control potassium," he said. "We know that CLP caused sustained fluid loss. What we don’t know is how that compares with other ways of removing fluid: Would patients have done as well if they were given loop diuretics? Clearly, if we are going to address this issue, we have to decide whether, as compared to loop diuretics, is it really more efficacious, is it really safer, and does it lead to better outcomes."
The trial was conducted at 24 sites in Armenia, Georgia, and Moldova. Patients were eligible if they had heart failure with New York Heart Association class III or IV plus chronic kidney disease, and had recently been hospitalized for decompensation associated with fluid overload.
They were randomized to double-blind treatment with CLP (manufactured by Sorbent Therapeutics) or placebo for 8 weeks. Patients in both groups were also started on spironolactone.
CLP is an orally administered superabsorbent polymer that is neither metabolized nor absorbed, explained Dr. Massie, who also is professor of medicine at the University of California, San Francisco. It binds cations and water, and is excreted in stool.
Trial results showed that changes in serum potassium levels from baseline did not differ significantly between treatment groups. Also, the rate of trial discontinuation due to hyperkalemia was about 10% in each group.
However, patients in the CLP group had a significant reduction in body weight relative to their counterparts in the placebo group at weeks 1 and 2, and there was a trend toward a greater reduction over the entire 8 weeks (P = .065).
The CLP group was more likely to rate their dyspnea as moderately or markedly better (37% vs. 22%). According to physician ratings, the proportion having marked or disabling dyspnea on exertion fell in both groups over time, but to a greater extent among those in the CLP group.
Patients in the CLP group were also more likely to have an improvement of at least one NYHA class from baseline (49% vs. 17%, P = .0018).
Both groups had better 6-minute walk test results at 8 weeks, but the magnitude of improvement was 24% with CLP vs. 14% with placebo, corresponding to an absolute difference of 20 meters (P = .07). CLP also was associated with better scores on the Kansas City Cardiomyopathy Questionnaire.
In terms of safety, there were no clinically important changes in various ions or in serum aldosterone levels, according to Dr. Massie.
The overall rate of adverse events was 36% in the CLP group and 31% in the placebo group, a difference largely caused by a higher rate of gastrointestinal events (mainly abdominal discomfort) in the former (24% vs. 14%).
There were four deaths, all in the CLP group. However, there did not appear to be any common pattern, and investigators did not judge any deaths to be related to the study medication, according to Dr. Massie.