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Novel potassium-lowering agents may benefit patients with HF
Two novel potassium-lowering agents that could be approved by the FDA in the near future for the treatment of hyperkalemia may be beneficial for patients with HF in several ways, experts told Cardiology Today.
The FDA has assigned Prescription Drug User Fee Act (PDUFA) action dates of Oct. 21 for the potassium-binding polymer patiromer (Relypsa) and May 26 for the selective cation exchanger sodium zirconium cyclosilicate (ZS-9, ZS Pharma).
Both agents treat hyperkalemia by lowering potassium levels. According to published data, patiromer starting doses of 4.2 g to 16.8 g twice daily resulted in significant reductions in serum potassium level starting at 4 weeks and continuing through 52 weeks in patients with hyperkalemia and moderate kidney disease. In a separate placebo-controlled trial, patients with chronic kidney disease taking renin-angiotensin-aldosterone system (RAAS) inhibitors assigned patiromer had a decrease in serum potassium levels and a reduction in the recurrence of hyperkalemia compared with those assigned placebo (P < .001 for both). Likewise, patients with hyperkalemia who received ZS-9 had a significant reduction in potassium levels at 48 hours compared with those assigned placebo, and normokalemia was maintained for 12 days of maintenance therapy (P < .001).
Potential use in patients with HF
Patients with HF eventually develop some degree of renal insufficiency, and with the renal insufficiency comes an increased risk for hyperkalemia, Javed Butler, MD, MPH, chief of cardiology and professor of medicine at Stony Brook Medicine and co-director of the Stony Brook University Heart Institute, Stony Brook, New York, told Cardiology Today.
“But more importantly, especially for patients with low ejection fraction, some of the staple drugs for patients with HF — ACE inhibitors, angiotensin receptor blockers and, in particular, mineralocorticoid receptor antagonists — cause hyperkalemia just by their mechanism of action. And that side effect is accentuated in patients with worsening renal function,” Butler said in an interview. “What happens is that a lot of patients are either not treated at all with these agents because of the risks for hyperkalemia or, if they are treated, receive smaller doses because the patients cannot tolerate higher doses. Clinical trials [of RAAS inhibitors] are not even done in the patients with the highest risk for hyperkalemia because of the high risk.”
Patients with HF and a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2, especially less than 45 mL/min/1.73 m2, have dramatically increased risk for hyperkalemia when using a RAAS inhibitor, particularly if they are also taking spironolactone, according to Cardiology Today Editorial Board member George L. Bakris, MD, FAHA, FASN, professor of medicine and director of the University of Chicago Medicine Comprehensive Hypertension Center.
The novel agents “will bind excess potassium in the gut and allow for use of RAAS blockers in this setting,” Bakris said. “It will also allow us to study whether, in fact, RAAS blockers are beneficial at these low levels of GFR, for example, less than 30 mL/min/1.73 m2.”
Potentially, the agents could “help initiation of [RAAS inhibitor] therapy for patients in whom the risk for hyperkalemia is felt to be too high currently to even try using RAAS modulators, or re-introduce a trial with these drugs in patients who had previously developed hyperkalemia,” Butler said. “Importantly, for patients who are on a therapy at small doses, we might be able to optimize doses. We might now be able to conduct research in avenues where we have not really used [RAAS inhibitors] because of the risk.”
More research on the way
The next priority is more research specifically in patients with HF.
“The trials done so far have been in hyperkalemic patients irrespective of etiology to treat hyperkalemia per se. The next step would be trials designed specifically for patients with HF to see if you can optimize therapy and how much clinical benefit you can get,” Butler said.
In addition, Bakris noted, “there are a number of studies being planned both in patients with advanced kidney disease and HF to assess whether, for example, spironolactone can be given to patients with advanced HF since hyperkalemia won’t be an issue. Will it change mortality?” – by Erik Swain
- References:
- Bakris GL, et al. JAMA. 2015;doi:10.1001/jama.2015.7446.
- Gumz ML, et al. N Engl J Med. 2015;doi:10.1056/NEJMra1313341.
- Lazich I, Bakris GL. Semin Nephrol. 2014;doi:10.1016/j.semnephrol.2014.04.008.
- Packham GK, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1411487.
- Weir MR, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410853.
- For more information:
- George L. Bakris, MD, FAHA, FASN, can be reached at University of Chicago-Pritzker School of Medicine, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637; email: gbakris@gmail.com.
- Javed Butler, MD, MPH, can be reached at 26 Research Way, East Setauket, NY 11733-3453; email: javed.butler@stonybrookmedicine.edu.
Disclosures: Bakris reports consulting for Relypsa and serving as principal investigator and steering committee member on trials of patiromer. Butler reports consulting for Relypsa and ZS Pharma.