Clinical Challenge: Managing Hyperkalemia With RAAS Inhibitors

The management of severe or chronic hyperkalemia, especially in patients with hypertension, diabetes, stage 3/4 chronic kidney disease (CKD), and congestive heart failure remains a significant clinical challenge, according to experts.

Clinicians must balance the risks of hyperkalemia against the benefits of recommended treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

While these drugs offer cardiovascular and renal benefits, they can also provoke hyperkalemia, putting patients directly in the path of potential cardiac arrhythmia and sudden death. Guidelines recommend that in the setting of hyperkalemia, RAAS inhibitors should be eliminated, down-titrated, or discontinued.

"This represents a true dilemma in daily practice since [RAAS inhibitors] are the cornerstones of nephroprotective and cardioprotective strategies in CKD patients, as well as in hypertensive patients with or without CKD," said Patrick Rossignol, MD, PhD, of Centre Hospitalier Universitaire de Nancy and the Université de Lorraine in France, in a recent review.

In the meantime, the long-term consequences of eliminating optimal disease-specific pharmacotherapy can be devastating. Studies show that in patients with CKD, submaximal dosing and discontinuation of RAAS inhibitors is associated with earlier onset of end-stage renal disease, and increased rates of cardiovascular mortality.

Analysis of a large U.S. database that included 43,388 patients with stage 3/4 CKD revealed that the discontinuation of RAAS inhibitor therapy after a hyperkalemic event resulted in an adverse outcome or death in more than 50%. In 20,000 patients with congestive heart failure, the analysis showed that nearly 60% who discontinued RAAS inhibitors after an hyperkalemic episode had an adverse outcome or died compared with 52% of patients on suboptimal RAAS inhibitor dosing and 44% of patients who received optimal dosing.

In the U.S. and the European Union (EU), the approval of two novel potassium-binding agents for the treatment of hyperkalemia in adults has opened up new possibilities for at-risk patients on RAAS inhibitor maintenance therapy. Patiromer (Veltassa), which was approved by the FDA in 2015 and in the EU in 2017, exchanges potassium for calcium. Sodium zirconium cyclosilicate (SZC; Lokelma), which was approved in both the U.S. and the EU in 2018, exchanges potassium for sodium.

"It is unclear if these treatments have a long-term benefit by lowering the risk of heart rhythm disturbances or cardiovascular mortality," Csaba Kovesdy, MD, of the University of Tennessee Health Science Center in Memphis, told MedPage Today. "This results in uncertainty about whether or not to treat all patients with hyperkalemia, such as those with mild abnormality, and for how long to treat patients. It is important to perform more research involving these newer meds to fully understand their benefits and potential risks," he said.

Nevertheless, results from the recent phase II randomized controlled AMBER trial demonstrate a paradigm shift, said Rossignol, who is one of the investigators in the ongoing trial. In 105 patients with advanced CKD and resistant hypertension, the trial showed that patiromer can be safely used to prevent hyperkalemia. Notably, all patients were being treated with concomitant spironolactone therapy, which has been associated with an increased risk of hyperkalemia.

"This population is prone to experience dismal cardiovascular and renal outcomes," Rossignol told MedPage Today. "Whether this strategy, along with potassium normalization, may translate into improved CV [cardiovascular] and renal outcomes needs to be tested prospectively."

The AMBER trial followed results from the PEARL-HF trial showing that the use of patiromer prevented hyperkalemia in spironolactone-treated heart failure patients with a history of hyperkalemia.

In addition, results from an open label, phase III study in patients with hyperkalemia treated with SZC show promise for longer-term management of hyperkalemia alongside concomitant RAAS inhibitor therapy. The findings demonstrated that the use of SZC was associated with rapid correction of hyperkalemia, and that normokalemia was successfully maintained for up to 12 months.

Most participants had multiple comorbidities, required concomitant RAAS inhibitor therapy, and had a history of hyperkalemia, said Bruce Spinowitz, MD, of NewYork-Presbyterian Queens in New York City, and colleagues.

Three-times-daily SZC dosing restored serum potassium concentrations to normal values in more than 99% of 751 outpatients within 24 to 72 hours. Following this, once-daily dosing with SZC was started at 5 g, and then individualized. Normokalemia was maintained in 87% of the 746 patients who achieved serum potassium levels of 5.1 mmol/L or less at day 365. All of this was accomplished without dietary or restriction of RAAS inhibitor medication, the researchers stated.

They said that notably, serum potassium levels increased after SZC treatment ended, highlighting the need for chronic treatment in this population. "Our findings also suggest that SZC is associated with good tolerability during 12 months of treatment, supporting the utility of SZC in the long-term management of individuals with hyperkalemia, including those who would benefit from continuation and optimization of concomitant [RAAS inhibitor] therapy," Spinowitz and co-authors said.

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