REALIZE-K: A New Potassium Binder to Help Keep Spiro on Board

This transcript has been edited for clarity. 
Hello. I’m Ileana Piña, professor of medicine at Thomas Jefferson University in Philadelphia, and this is my blog. We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias. 
Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.
Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them.The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium.Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid. 
Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.
Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.
They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min/1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study. 
The second group had some history of or were at risk for hyperkalemia.Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.
They started with about 366 patients.These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic. 
Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to checkwhether the patient had to come off the drug or had to reduce or remove the spironolactone. 
These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America.There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see. 
The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min/1.73 m2.The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors. 
This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.
At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone.They even did a sensitivity analysis, which really showed that it was consistent across the board. 
Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.
There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled. 
What does that tell you?Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small. 
According to the investigators, these were issues that could be resolvedthrough an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid. 
My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.
The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy. 
This is Ileana Piña. Thank you for joining me today. Signing off.
Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA’s Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.