Hyperkalemia: management tips for a subtle, deadly condition

Hyperkalemia is an easily missed, life-threatening condition that can recur frequently in high-risk populations, including patients with chronic kidney disease (CKD), heart failure and diabetes.

“This is a condition that is commonly underappreciated,” said Jeff Dunn, PharmD, in a webinar on the condition hosted by the AMCP and sponsored by Relypsa, manufacturer of the potassiumbinding agent patiromer (Veltassa).

Hyperkalemia can be classified as mild (serum potassium concentrations in mEq/L of 5.0-5.5), moderate (5.5-6.0) or severe (6.0 and above). “Serum potassium can elevate quickly and unexpectedly, and arrhythmias and sudden death may occur, so it needs to be addressed quickly,” said Dr. Dunn, who was the vice president for clinical strategy and programs and industry relations at Magellan Rx Management at the time of the webinar but is not head of clinical pharmacy at Haven.

The condition can be deceptive, said Frank Peacock, MD, a professor of emergency medicine at the Baylor College of Medicine, in Houston, in an interview with Specialty Pharmacy Continuum. “A person with 6.8 serum potassium can look normal and be sitting there talking to you. They have no idea how severe their condition is, and just by looking at them, you don’t either. They can look fine one moment and drop dead from an arrhythmia the next.

“Once you hit 5-5.5 or 6, the risk for mortality significantly increases, and it’s exponential,” said Dr. Dunn, who is also an associate chair and the research director for the Department of Emergency Medicine at Baylor. “That can be stratified and worsened among patients who have other comorbidities. If someone has diabetes, CKD and elevated potassium, their risk for sudden death is higher. If they have heart failure and CKD and elevated potassium, it’s even higher. If somebody has all of those things—heart failure, CKD and diabetes—which is not actually uncommon— their risk is higher still.”

The two most common causes of hyperkalemia are CKD and certain medications, including renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), commonly used to treat heart failure, as well as medications that inhibit potassium excretion, such as potassiumsparing diuretics and nonsteroidal antiinflammatory drugs (NSAIDs). Other common risk factors include diabetes and heart failure.

“Patients with multiple risk factors are more likely to have high potassium, compounding the complexity of management of these patients,” Dr. Dunn said. “One study found that 13% to 32% of patients with CKD had been diagnosed with hyperkalemia. Another population-based study found that, among CKD patients diagnosed with hyperkalemia for the first time, 25.4% had diabetes, compared with only 14.6% of those with normal potassium levels, and 19.8% had heart failure, compared with 8.5% of those who had normal potassium levels” (Nephrol Dial Transplant 2018;33[9]:1610-1620; Clin J Am Soc Nephrol 2016;11[1]:90-100).

Risk for hyperkalemia increases significantly as renal function declines, with an estimated glomerular filtration rate (GFR) of 30 mL/min/1.73 m 2 or less considered a threshold for a substantial increase in risk, Dr. Dunn said. He pointed to a study in veterans which showed that 20.7% of patients with stage 3 CKD (GFR, 30-59) had hyperkalemia, compared with 42.1% of stage 4 CKD

Based on disease recurrences after discontinuation of patiromer, ‘the take home is that these patients, in a lot of cases, need to be chronically treated.’

—Jeff Dunn, PharmD patients (GFR, 15-29), and 56.7% of stage 5 patients (GFR <15) (Arch Intern Med 2009;169[12]:1156-1162).

Providers, case managers and payors should be particularly vigilant for hyperkalemia associated with medications, which in addition to RAAS inhibitors such as ACE inhibitors and ARBs can include mineralocorticoid receptor agonists (MRAs), NSAIDs, beta blockers, cyclosporin, heparin, digoxin, trimethoprim and pentamidine. “This is a really important intervention point—managing these potential drug interactions,” Dr. Dunn said. Prior to the introduction of new potassium-binding agents in the late 2010s, hyperkalemia associated with RAAS inhibitor medications often required dosing adjustments to those medications, which posed a serious challenge.

The first step in emergency treatment of hyperkalemia is to stabilize the membranes to protect the myocardium, typically by administering IV calcium gluconate. Within the next few minutes, the priority is to quickly and temporarily redistribute potassium back

Hyperkalemia

By the Numbers

compared with 14.6% of those with normal potassium levels potassium levels CKD, chronic kidney disease Clin J Am Soc Nephrol 2016;11(1):90-100. into the cells. “In minutes, I can jam that potassium back in your cells and life is grand again—for a while. Because that doesn’t remove the potassium, it’s just hidden it,” Dr. Peacock said.

Insulin paired with glucose, with or without a beta-2 adrenergic receptor agonist, is the treatment of choice at this stage. “Insulin opens the door and glucose pours into the cells and takes potassium with it,” he explained. “That works very quickly, too. But too much insulin can cause a fatal drop in blood sugar, which means that you have to pair insulin with glucose.”

These two initial treatments work quickly and well, but they are temporary. “They don’t actually change your total body potassium amount at all,” Dr. Peacock said. “The next phases of treatment are focused on removing potassium from the body, [best done with] dialysis; you’re done in a couple of hours. But that can be a logistical nightmare in the emergent setting and is very expensive and invasive.”

The historical standard of care for hyperkalemia was a low-potassium diet and discontinuing/modifying RAAS inhibitors. “That’s not ideal, because a low-potassium diet is actually quite hard to do, and we want those patients on those RAAS inhibitors and achieving the outcome benefit of those drugs,” Dr. Dunn said.

Two newer potassium-binding agents have proven to be effective at lowering serum potassium with minimal side

19.8% of hyperkalemia patients had heart failure, compared with 8.5% of those with normal

Source: Nephrol Dial Transplant 2018;33(9):1610-1620;

effects: patiromer, first approved by the FDA for hyperkalemia in 2015, and sodium-zirconium cyclosilicate (Lokelma, AstraZeneca), first approved in 2018.

In the OPAL-HK trial, one of several trials that led to the approval of patiromer, the drug provided significant reductions in serum potassium in CKD patients receiving RAAS inhibitors and reduced the rapid recurrence of hyperkalemia during a placebocontrolled withdrawal phase (N Engl J Med 2015;372[3]:211–221). “Everybody got to below 5, and that was maintained over the four weeks of the study,” Dr. Dunn said. “In the second phase of the study, which assessed what would happen if patients were withdrawn from the drug, 60% of patients who switched to placebo experienced a recurrence of hyperkalemia, compared with 15% who were maintained on patiromer (P<0.001). So the take home [message] is that these patients, in a lot of cases, need to be chronically treated.”

The FDA’s approval for sodium-zirconium cyclosilicate was primarily based on data from the HARMONIZE trial, in

which 258 patients with hyperkalemia received 10 g of the drug three times daily during an initial 48-hour openlabel phase; 98% of participants achieved normal serum potassium levels within 48 hours. During the randomized phase, the 237 patients who achieved normokalemia were assigned to either 5, 10, or 15 g of the drug daily or placebo. Compared with placebo, all three doses of sodium-zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days (JAMA 2014;312[21]:2223-2233). More recent data from an open-label extension trial showed that all patients taking sodium-zirconium cyclosilicate maintained potassium levels at or below 5.5 for at least 11 months, and 88.3% maintained potassium levels at or below 5.0 (Am J Nephrol 2019;570:473-480). N

Both agents appear to be well tolerated, Dr. Peacock said, with sodium-zirconium cyclosilicate’s side effects including edema and hypokalemia, and patiromer’s including gastrointestinal symptoms such as constipation, diarrhea and nausea. “From everything we have seen to date, both of these drugs are effective and safe, and patients can be comfortable taking them daily on a long-term basis,” said Dr. Peacock, who noted that both have a preferable side effect profile compared with a previous potassium binder, sodium polystyrene sulfonate ( Kayexalate, Concordia Pharmaceuticals), which has been associated with debilitating diarrhea as well as intestinal bleeding and necrosis and upper GI tract injury (Surgery 1987;101[3]:267-272; Am J Surg Pathol 1997;21[1]:60-69; Am J Surg Pathol 2001;25[5]:637-644).

No head-to-head studies have been conducted between sodium-zirconium cyclosilicate and patiromer. “The biggest difference between the two drugs is that patiromer uses calcium as the exchange ion, while [sodium- zirconium cyclosilicate] exchanges sodium for potassium,” Dr. Dunn said. “So you have to be careful with [sodium- zirconium cyclosilicate] in patients who are at risk for issues with elevated sodium.”

Neither of these drugs is indicated for use in emergent control of hyperkalemia, but, given that they take some time to have an effect. Dr. Peacock is pursuing trials to assess higher doses of potassium binders as possible emergency treatments. “Rather than giving IV insulin plus glucose and then a binder, could we give four times the recommended dose of the binder and be able to send the patient home? That’s what we would like to investigate. I suspect that there’s a level of effect. If your patient is at 6.5-7, there’s no binder that can bring potassium down quickly enough, but if they are above normal but not scary, from 5.5-6, this approach might be effective. That’s what we want to figure out.” —Gina Shaw

Dr. Peacock reported fi nancial relationships with Abbott, AseptiScope, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Brainbox, Braincheck, CSL Behring, Comprehensive Research Associates, Daiichi-Sankyo, ImmunArray, Ischemia DX, Instrument Labs, Janssen, Johnson & Johnson, Nabriva, Ortho, Portola, Quidel, Relypsa, Roche, Salix and Siemens, Dr. Dunn reported no relevant fi nancial relationships other than his stated employment.

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