SAN DIEGO, CA — The investigational oral potassium-binding agent patiromer (Relypsa) was safe and effective in a 1-year, phase 2 study of patients with chronic kidney disease (CKD), type 2 diabetes, and hypertension, with or without heart failure (HF), and with mild or moderate hyperkalemia due to treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. In the two study subgroups—patients with and without HF—mean serum potassium levels were normal within 3 days and stayed normal for a year, and the agent was well tolerated.
Dr Bertram Pitt (University of Michigan, Ann Arbor, MI) presented these findings from the AMETHYST-DN study in a poster here at the American College of Cardiology 2015 Scientific Sessions.
"For people with heart failure, we know that RAAS inhibitors—ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs)—are lifesaving, but as soon as they get hyperkalemia, people are dropping the doses or stopping them entirely, which puts them at risk" of sudden death from cardiac arrhythmia, he told heartwire from Medscape.
"We [still] have to show that in the long run [this agent] really can provide that [lifesaving] benefit, but this is the clue that we can do that," he said. Moreover, if and when patiromer and another investigational potassium-binding agent, ZS-9 (ZS Pharma), are approved, "it looks like there is a new era . . . for renal disease and HF that really will change the game," according to Pitt.
Asked to comment, Dr Mark H Drazner (University of Texas Southwestern, Dallas) was more cautious. "There are notable examples [in cardiology] where the use of surrogate end points (such as suppression of premature ventricular contractions after MI) has led us astray when assessing whether a pharmacological therapy improves hard clinical outcomes," he pointed out. "Whether patiromer's impact on the surrogate end point of treating hyperkalemia and/or allowing more RAAS inhibition in heart-failure patients will have a similar fate or instead will result in improved survival or favorably impact other heart-failure outcomes such as hospitalization needs to be tested, in my opinion," he said.
Game Changer for Patients With CKD and HF?
Amethyst-DN randomized, stratified, and treated 304 patients with CKD, type 2 diabetes, and hypertension who were taking RAAS inhibitors. Patients with mild hyperkalemia (serum K >5.0 to <5.5 mEq/L) received starting patiromer doses of 4.2, 8.4, or 12.6 g twice daily, and patients with moderate hyperkalemia (serum K >5.5 to <6.0 mEq/L) received starting patiromer doses of 8.4, 12.6, or 16.8 g twice daily, which were titrated to achieve and maintain serum potassium of 5.0 mEq/L or less.
Of these patients, 105 had HF (77 with mild hyperkalemia and 28 with moderate hyperkalemia) and 199 did not have HF (143 with mild hyperkalemia and 56 with moderate hyperkalemia).
The patients were white, with a mean age of 58.9 to 69.1, and most (59% to 71%) were male. In the HF group, 79.2% of patients with mild hyperkalemia and 60.7% of patients with moderate hyperkalemia completed the study, and 66% of the patients in both subgroups without HF completed the study.
On study day 3 (about 48 hours after receiving the first dose of patiromer), mean serum potassium decreased by 0.33 mEq/L from 5.13 mEq/L in the HF patients with mild hyperkalemia and by 0.55 mEq/L from 5.62 mEq/L in the HF patients with moderate hyperkalemia (P<0.001 for both)
In the HF patients, mean serum potassium was below 5.0 mEq/L on day 3 for patients with mild hyperkalemia and at week 1 for patients with moderate hyperkalemia. Most patients with HF (74% to 96%) had serum K in the 3.8–5.0-meQ/L (normal) range from 12 weeks to 52 weeks. Stopping the drug led to a rise in serum potassium. Results were similar in the patients without heart failure.
The most common adverse events in the HF patients were hypomagnesemia assessed by the principal investigator (10 patients; 9.5%), diarrhea (4.8%), and hypokalemia (serum potassium <3.5 mEq/L; 3.8%).
Eight patients with HF (7.9%) stopped taking patiromer due to adverse effects. There were 9 deaths in HF patients and 6 in patients with no HF, but none were considered to be related to serum potassium levels.
But Will Patiromer or ZS9 Improve Hard Outcomes?
Patiromer and ZS9 are different molecules with slightly different mechanisms of action but are more similar than dissimilar, according to Pitt. ZS9 exchanges potassium for sodium, whereas patiromer exchanges potassium for calcium; ZS9 may be a little quicker and patients have some edema in some studies, whereas some patients taking patiromer have hypomagnesemia. "There are pluses and minuses, and until we do comparative studies, I don't know which is better," he continued. "But bottom line, both are good and [would] provide new opportunities to patients."
These drugs "will make a real difference in [HF] mortality [and] cost," Pitt said. "This will be expensive, but if you get hospitalized for heart failure, that's $10 000 right there, so I'm sure it's going to be cost-effective."
Drazner is not yet convinced. He was impressed that hyperkalemia rapidly reoccurred when the drug was stopped at 1 year, highlighting its ongoing efficacy until then. However, a major unanswered question remains: "Will patiromer improve hard clinical outcomes in heart-failure patients?"
Studies are needed to answer this question, "not only because there will be financial costs, but also because there can be side effects (gastrointestinal, some hypokalemia and hypomagnesemia) from this agent, [and] there is always the potential for [as-yet-unknown] drug-drug or off-target effects . . . especially because the total number of patients with heart failure treated with this agent remains relatively small," he said.
Relypsa submitted a new drug application for patiromer to the Food and Drug Administration (FDA) in December 2014 , and the FDA review is scheduled for completion on October 21, 2015. ZS Pharma has not yet submitted data to the FDA for ZS9.
Pitt received fees from AstraZeneca, Bayer, Juventis, Novartis, Pfizer, Relypsa, Stealth Peptides, Takeda, and Tricida and has equity interest in Relypsa, DaVinci Therapeutics, and scPharmaceuticals. Disclosures for the coauthors are linked to the abstract. Drazner has no relevant financial relationships.
Heartwire from Medscape © 2015 Medscape, LLC
Cite this: Patiromer May Control Hyperkalemia, Potentially Let HF Patients Stay on RAAS Inhibitors - Medscape - Mar 26, 2015.