Potassium binder helps optimize spironolactone use in patients with HF, hyperkalemia risk
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Key takeaways:
- A potassium binder enabled more patients with heart failure to stay on spironolactone.
- There was a signal of increased risk for HF hospitalization with the potassium binder.
CHICAGO — A potassium binder helped patients with HF who have or are at high risk for hyperkalemia stay on spironolactone at an optimal dose, but showed a signal of HF hospitalization risk, researchers reported.
For the REALIZE-K trial, presented at the American Heart Association Scientific Sessions and simultaneously published in the Journal of the American College of Cardiology, Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, and colleagues randomly assigned 203 patients with HF with reduced ejection fraction and hyperkalemia or elevated risk for it (mean age, 71 years; 75% men; mean serum potassium, 5 mEq/L) to spironolactone plus the potassium binder sodium zirconium cyclosilicate (SZC; Lokelma, AstraZeneca) or to spironolactone plus placebo.
“Despite recognized benefits and widespread availability, spironolactone remains woefully underused in heart failure,” Anu Lala, MD, associate professor of medicine (cardiology) and population health and director of heart failure research at Icahn School of Medicine at Mount Sinai, who was an investigator on the trial, told Healio. “Patiromer (Veltassa, Vifor Pharma) and SZC are two currently used potassium binders. SZC allowed for greater spironolactone use, less discontinuation of the drug, and less hyperkalemia. What sets this trial apart is the inclusion criteria of patients requiring hyperkalemia or history of hyperkalemia, where more than 70% had hyperkalemia in response to spironolactone in the run-in phase mimicking what is encountered in clinical practice.”
Spironolactone use optimized
The primary endpoint of optimal treatment response at 6 months, defined as normokalemia (serum potassium 3.5 mEq/L to 5 mEq/L), taking spironolactone 25 mg per day or more and no rescue therapy since prior visit, occurred more often in the SZC group compared with the placebo group (71.2% vs. 35.7%; OR = 4.45; 95% CI, 2.89-6.86; P < .001), Kosiborod said during the presentation.
Two sensitivity analyses did not change the results, he said. The first excluded patients taking the 15 g dose of SZC or placebo at randomization, as that dose is not available in the European Union (OR = 4.82; 95% CI, 3.03-7.68; P < .001) and the second used a different definition of hyperkalemia (5.5 mEq/L or more instead of more than 5 mEq/L; OR = 5.37; 95% CI, 2.97-9.7; P < .001).
Kosiborod said the first four of the five hierarchically tested secondary endpoints favored SZC:
- normokalemia on the randomization dose of spironolactone and without rescue therapy for hyperkalemia (OR = 4.58; 95% CI, 2.78-7.55; P < .001);
- taking a spironolactone dose of at least 25 mg per day (OR = 4.33; 95% CI, 2.5-7.52; P < .001);
- time to first hyperkalemia episode (HR = 0.51; 95% CI, 0.37-0.71; P < .001); and
- time to first decreased dose or discontinuation of spironolactone due to hyperkalemia (HR = 0.37; 95% CI, 0.17-0.73; P = .006).
The fifth secondary endpoint of difference in Kansas City Cardiomyopathy Questionnaire overall summary score was neutral (mean treatment difference, –1.01 points; 95% CI, –6.64 to 4.63; P = .72), Kosiborod said.
The rates of any adverse events and serious adverse events were similar between the groups, and while the rate of serious cardiac adverse events was higher in the SZC group, all of those events were resolved or resolving by the end of the study, he said.
In exploratory and post hoc analyses, the rate of CV death or HF hospitalization was higher in the SZC group than in the placebo group (11% vs. 3%; nominal log-rank P = .034), driven by HF hospitalization (10% vs. 2%), which was mostly germane to patients with N-terminal pro-B-type natriuretic peptide levels of more than 4,000 pg/mL at baseline; NT-proBNP levels at 6 months were higher in the SZC group (estimated treatment ratio = 1.26; 95% CI, 0.99-1.61; nominal P = .061); and there were no differences between the groups in loop diuretic dose, body weight or systolic BP at 6 months, Kosiborod said.
“SZC effectively enables more optimal use of MRAs in patients with HFrEF, and although not powered for clinical outcomes, more patients had heart failure events with SZC than placebo despite the use of spironolactone, which should be factored into clinical decision-making,” Kosiborod said during the presentation.
“I feel reassured by these data that SZC is safe and effective in decreasing hyperkalemia rates, and allowing optimization of spironolactone in a patient population representative of clinical practice wherein they had demonstrated hyperkalemia prior to study entry,” Lala told Healio. “As a note of caution, I will be careful about its use in those I consider living with more advanced heart failure, though whether there is a real cause for prudence in this population is unclear.”
The good, the bad and the ugly
In a discussant presentation, Larry A. Allen, MD, associate head of clinical affairs for cardiology, medical director of advanced heart failure and chief of the division of cardiology at the University of Colorado Anschutz Medical Campus, said the situation with SZC is “mostly good, some bad and a little ugly.
“Here we have the good: Sodium zirconium cyclosilicate works,” he said. “There was ... a halving of the number of patients who had to come off of their high-dose spironolactone. Sodium zirconium cyclosilicate leads to more MRA use and less urgent potassium issues. The bad is that there are burdens and side effects, and perhaps concerns. There are 400 mg of sodium in each 5 g packet of this drug. I think that there is some concern that you see a higher NT-proBNP as well as a trend toward higher heart failure hospitalizations. A very important issue is that these patients have a major issue with polypharmacy. This drug requires that other medications are taken 2 hours before or 2 hours after. We need to ask whether a low-potassium diet can obviate issues in many of these patients. The ugly is the cost. With insurance, coverage is variable, preauthorization is typically required and a copay can be significant. Without insurance, this drug in the U.S. costs $10,000 per year.”
Reference:
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Kosiborod MN, et al. LBS.06. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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