Prevention and management of hyperkalemia in patients treated with renin–angiotensin–aldosterone system inhibitors

Reducing dietary potassium

Although guidelines recommend that patients at risk of hyperkalemia, in particular those with advanced CKD, decrease the amount of potassium in their diet, few trials have directly studied the impact of dietary potassium restriction in patients with CKD.9^,19^,22 Nonetheless, given the increased risk of chronic hyperkalemia for patients with CKD and heart failure, clinicians should consider referring these patients to a dietitian for guidance. The potential benefit of consuming a low-potassium, predominantly plant-based diet is an important area for future study.

Judicious use of diuretics

Diuretics, especially loop diuretics, are commonly used to control volume overload and prevent increases in serum potassium. The efficacy of diuretics to reduce serum potassium depends on a patient’s kidney function; guidelines recommend this intervention when diuresis or an additional antihypertensive agent is desired.19 Use of diuretics can precipitate acute kidney injury and electrolyte abnormalities, however, and the hypokalemic response to diuretics is diminished with low estimated GFR.3^,8 Diuretics may not be ideal for the long-term maintenance of serum potassium levels, especially for patients with no other compelling reason for their use (i.e., extracellular volume overload).

Use of sodium bicarbonate

Treatment with oral sodium bicarbonate promotes potassium elimination through increased urinary potassium excretion. It can be used effectively to reduce the risk of hyperkalemia in patients with CKD and metabolic acidosis. However, in patients who develop volume overload, sodium bicarbonate may need to be stopped.8^,19

Careful dosing of RAAS inhibitors

Reducing and stopping medications that induce hyperkalemia — such as RAAS inhibitors — are commonly used strategies for preventing recurrent episodes of hyperkalemia.3^,19^,22 However, given evidence that the benefits of RAAS inhibitors outweigh their potential harms, including hyperkalemia, recent guidelines now recommend that clinicians maintain an evidence-based dose of RAAS inhibitors. Lowering the dose to reduce the likelihood of recurrent hyperkalemia should be undertaken as a last resort after attempting measures to maintain the evidence-based dose of RAAS inhibitors, including using potassium binders.

Use of potassium binders

Sodium polystyrene sulfonate, sodium zirconium cyclosilicate and patiromer are potassium binders approved for use in Canada.8^,9^,23^–25 For many years, sodium polystyrene sulfonate was the only medication specifically indicated for the treatment of hyperkalemia, but it was approved before the introduction of modern regulatory standards, and evidence from randomized trials to support its use is sparse.3 A small, single-centre study of 33 outpatients with CKD and mild hyperkalemia (5.0–5.9 mmol/L) found that sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels at 1 week (mean difference between groups −1.04 mmol/L, 95% CI, −1.37 to −0.71 mmol/L).26 However, the effects of the drug are not predictable and it has been associated with risk of acute bowel necrosis, hypernatremia, diarrhea and gastrointestinal toxicity, particularly with older formulations that contain sorbitol.27 One retrospective, matched cohort study found that, over 30 days, use of sodium polystyrene sulfonate was associated with nearly double the incidence of adverse gastrointestinal events than nonuse (37 events [0.2%] v. 18 events [0.1%], HR 1.94, 95% CI 1.10–3.41).28 Moreover, systemic alkalosis has been reported after administration of sodium polystyrene sulfonate in combination with nonabsorbable cation-donating antacids and laxatives such as magnesium hydroxide and aluminum carbonate; magnesium-containing laxatives should not be used with sodium polystyrene sulfonate.23 Thus, clinicians must be cognizant of the potential for serious adverse events when managing hyperkalemia with sodium polystyrene sulfonate. Newer potassium binders should be considered instead, if available.

Sodium zirconium cyclosilicate and patiromer, are newer potassium binders that are generally safer, more predictable and better tolerated by the patient (Table 1). Sodium zirconium cyclosilicate is an orally administered, insoluble, inorganic cation exchanger that selectively captures potassium ions in exchange for hydrogen and sodium ions in the gastrointestinal lumen, thereby increasing potassium fecal excretion and reducing serum potassium. Its efficacy and safety have been shown in phase 2 and 3 clinical trials in both patients receiving dialysis and those not on dialysis. Reported adverse events are generally mild to moderate in severity and are manageable without interruption of treatment. Edema has been reported, possibly a consequence of the drug containing sodium, and patients should be monitored for fluid overload.30^–36 In clinical trials, 4.1% of patients treated with sodium zirconium cyclosilicate also developed hypokalemia with a serum potassium value less than 3.5 mmol/L, which was resolved by adjusting the dose or stopping the drug.25

Volume overload was not identified as an adverse outcome in trials of patiromer. This drug contains calcium as its gastrointestinal exchange ion and acts in the colon, which means its onset of action is relatively prolonged. The utility of patiromer in treating hyperkalemia has been shown in phase 2 and 3 trials of patients with hyperkalemia, including those with CKD and heart failure on RAAS inhibitors. No serious adverse events have been associated with patiromer, although reported adverse events include non-serious constipation, diarrhea, nausea or vomiting, abdominal discomfort, flatulence and electrolyte disturbances (e.g., hypokalemia and hypomagnesemia).37^–40

A growing body of evidence supports using the newer potassium binders to facilitate the continuation and optimization of RAAS inhibitors in patients with hypertension, heart failure and CKD.35^,37^,38^,40 In a phase 2, double-blind, placebo-controlled trial of patients with heart failure (PEARL-HF), patients randomized to patiromer showed a significantly lower incidence of hyperkalemia (7.3% v. 24.5% on placebo), which enabled greater use of spironolactone at 50 mg/d (91% v. 74%).37 Similarly, in the AMBER trial of patients with resistant hypertension and CKD, more patients in the treatment arm were able to continue spironolactone with less incidence of hyperkalemia than those on placebo.40 Although no study has been specifically designed to assess the RAAS inhibitor–enabling potential of sodium zirconium cyclosilicate, most patients with hyperkalemia enrolled in the ZS-005 study achieved normal potassium levels without substantial changes in their RAAS inhibitor regimen.35

Cost and drug plan reimbursement may limit adoption of the new potassium binders. Although the new potassium binders are funded through certain private plans, and the Canadian Agency for Drugs and Technologies in Health has recommended reimbursement of patiromer by public drug plans, it costs about $3500 to $7000 per patient annually, depending on dose.29 Further price negotiations are believed to be underway through the pan-Canadian Pharmaceutical Alliance. Manufacturers and drug plans are urged to find a price that allows access to these drugs for all patients who would benefit from them.