Hyperkalaemia: novel treatment strategies to manage potassium levels in heart failure
Several therapeutic options exist for hyperkalaemia. Insulin, beta-adrenergic agonists and sodium bicarbonate are used in acute situations. In case of very high potassium levels, dialysis can be done. This is, however, invasive and expensive and therefore not a preferable option. For chronic treatment, kayexalate and resonium calcium are indicated. These drugs exchange potassium for calcium. These medications have, however, severe side effects, for instance affecting the gastrointestinal tract. Therefore, there is a need for new treatment options for hyperkalaemia that are effective, safe and well-tolerated. Patiromer and ZS-9 (sodium zirconium cyclosilicate) are two novel potassium binders that are currently under investigation. By binding to potassium, potassium levels in the circulation are lowered.
One of few trials evaluating patiromer is the AMETHYST-DN trial, which included 306 diabetic patients that had low eGFR (15-60 mL/min), who were on RAAS inhibition (RAASi) and had potassium levels >5mmol/L (10). The efficacy and safety of low- and high dose patiromer treatment were evaluated. For both conditions a significant decrease in potassium levels was seen, which remained stable and increased again upon withdrawal of the treatment. Adverse events were modest and included worsening of CKD, hypomagnesaemia, worsening of hypertension, constipation, diarrhoea and hypoglycaemia. However, it was difficult to determine whether these adverse events were truly related to treatment, as this trial did not include a placebo group for comparison.
Another study with patiromer is the PEARL-HF trial, which investigated the efficacy and safety of patiromer in 104 spironolactone-treated (25 mg/day) HF patients with high risk for hyperkalaemia (history of hyperkalaemia or eGFR <60 mL/min), in order to evaluate whether the dose of spironolactone could be enhanced when patiromer was used (11). This showed that potassium levels clearly decreased when patients were treated with patiromer, in contrast to potassium levels of placebo-treated patients, which increased upon spironolactone treatment. After 2 weeks, spironolactone dose was uptitrated to 50 mg/day, and resulted a slight potassium level increase in both groups. This translated into an efficacy (number of patients with hyperkalaemia) that was significantly higher in de patiromer versus the placebo group. However, 6% of the patients treated with patiromer were hypokalaemic (3.5 mmol/L), versus none in the placebo group. But most importantly, 91% of the patiromer-treated patients could tolerate 50 mg/day spironolactone instead of 74% of the placebo-treated patients, which was a significant difference. Adverse events were also slightly more common in patiromer-treated patients, however there was no difference in the frequency of serious side effects or events leading to discontinuation.
*“The novel potassium binders patiromer and ZS-9 are highly effective in lowering serum potassium levels”*
ZS-9 is the other new potassium binder, which is more selective. Several large trials have been performed with ZS-9, the most important being a multicentre phase 3 trial (12) that included all kinds of patients with hyperkalaemia (n=753) receiving different doses of ZS-9 or placebo. This revealed a significant dose-dependent decrease in potassium levels within hours. Upon withdrawal of the drug, potassium levels increased again. The safety profile of ZS-9 seems very promising with no differences between ZS-9 and placebo-treated patients in adverse events such as gastrointestinal events.
In addition, another ZS-9 study in 94 HF patients showed a significant decrease in potassium levels when patients were treated with ZS-9 for 48 hours, which quickly increased in patients who were randomised to placebo after these 48 hours. However, potassium levels reached around 4.5 mmol/L in patients that remained on ZS-9 (several doses). Also in this study, a favourable safety profile was observed, although there was a marginal increase in the frequency of peripheral oedema in patients treated with the highest ZS-9 dose. However, whether this is related to the doses and the underlying mechanism is as yet unclear.
In summary, the novel potassium binders patiromer and ZS-9 have a favourable safety profile when compared to that of the older potassium binders. They both resulted in a quick decrease of potassium levels, which enabled dose uptitration of spironolactone. It remains to be investigated whether this will also result in an improved long-term outcome.