New Therapies for Hyperkalemia

Silvia J. Leon; Oksana Harasemiw; Navdeep Tangri

Disclosures

Curr Opin Nephrol Hypertens. 2019;28(3):238-244. 

In This Article

Patiromer

Patiromer (formerly called RLY5016), a powder for oral suspension, is a nonabsorbed cation exchange polymer. It exchanges calcium for potassium in the lumen of the gastrointestinal tract, especially in the colon.[17,18] Patiromer clinical trials have demonstrated the drug's utility in the treatment of hyperkalemia for short periods of time (up to 12 weeks),[17,18] and have also evaluated the efficacy and safety of patiromer in CKD and heart failure patients. The recommended dose is 8.4 g once daily, titrated to 25.2 g/day.[19] Clinical trials have used a twice-a-day dose regimen,[9,20,21] with patients also concomitantly receiving RAAS inhibitors during the trials (Table 1).

The AMETHYST-DN, a phase 2 study, evaluated the safety and efficacy of patiromer as well as the optimal dose in 306 patients with hyperkalemia (serum potassium >5.0 mEq/l) and diabetic kidney disease.[22] Starting from week 4 through week 52, there was a significant (P < 0.001) mean decrease from baseline in serum potassium levels observed in the monthly follow-ups in participants with mild and moderate hyperkalemia. The least square mean reduction from baseline in serum potassium levels at week 4 went from −0.35 to −0.92 mEql/L in the different dose groups. However, only 2% of patients had an estimated glomerular filtration rate (eGFR) less than 15 ml/min/1.73 m2. Moreover, an increase in the mean serum potassium was observed after participants discontinued usage, suggesting the need for chronic management of hyperkalemia in this population.

Further subgroup analysis of patients with heart failure[23] in the same study cohort showed a significant (P < 0.001) mean decrease from baseline in mean serum potassium levels from week 4 through week 52. In this population, at least 88% patients with mild hyperkalemia and at least 73% with moderate hyperkalemia had serum potassium levels within the target range (3.8–5.0 mmol/l) from week 12 to 52.[23] However, patients with New York Heart Association (NYHA) class III or IV were excluded, so results cannot be generalized to this population.

The OPAL-HK study[9] evaluated the safety and efficacy of patiromer in 243 patients with CKD stages 3–4 receiving RAAS inhibitors with hyperkalemia (serum potassium between 5.1 and 6.5 mmol/l). Associated comorbidities in this population included diabetes mellitus (57%) and heart failure (42%). At the end of the randomized withdrawal phase, hyperkalemia recurrence (potassium >5.1 mEq/l) was described in 91% [95% confidence interval (CI), 83–99] of the patients on placebo, compared with 43% (95% CI, 30–56) on patiromer (P < 0.001). Likewise, 44% in the placebo group, compared with 94% in the patiromer group were still receiving RAAS inhibitors. Moreover, the study time was only 12 weeks, making it difficult to evaluate the effect of patiromer on chronic hyperkalemia.

A subgroup analysis in patients with heart failure from the OPAL-HK trial showed similar results to this cohort.[21] In the randomized withdrawal phase, the median change in serum potassium in patients with heart failure from baseline to week 4 was 0.74 mEq/l for patients in the placebo arm and 0.10 mEq/l for those in the patiromer arm. The between group-difference was 0.64 mEq/l (95% CI 0.29–0.99, P < 0.001).[21] By the end of the randomized withdrawal phase, 55% of heart failure patients on placebo and 100% of heart failure patients on patiromer were still receiving RAAS inhibitors. Furthermore, by the end of the study period, among the heart failure patients, 55% of patients on placebo and 100% of patients on patiromer were still using RAAS inhibitors.

The PEARL-HF trial, a multicenter randomized double blind placebo-controlled trial, evaluated RLY5016 (now patiromer) in patients with chronic heart failure with either CKD or a history of hyperkalemia.[20] Patients in the two study arms initiated spironolactone at a dose of 25 mg/day. After 2 weeks the dose was increased to 50 mg/day in those without hyperkalemia. At the end of the treatment period (28 days), the mean change in serum potassium from baseline was −0.22 mEq/l for patients receiving RLY5016 compared with +0.23 mEq/l in the placebo group. Furthermore, the spironolactone dose was increased in 91% patients in the RLY5016 group compared with 74% in the placebo group (P = 0.019). In the subgroup of patients with CKD, patients receiving RLY5016 (patiromer) had a decrease from baseline to the end of the study in the mean serum potassium of −0.14 mEq/l compared with the placebo group with a mean change in serum potassium of +0.38 mEq/l.

In 2018, the TOURMALINE trial compared the efficacy of patiromer when administered with versus without food.[24] The mean reduction in serum potassium from baseline to week 4 were −0.62 mEq/l in the without-food group and −0.65 mEq/l in the with-food group (P < 0.0001 versus baseline, P = NS for between groups difference). Similar to previous trials, an increase in serum potassium levels was observed after patiromer discontinuation.

Overall, patiromer was generally well tolerated in clinical trials[9,21,22,24] (Table 2). The most common adverse events were gastrointestinal related (constipation, diarrhea and nausea) and hypomagnesemia (Table 2). Hypokalemia was uncommon (no trial reported potassium levels <3.0 mEq/l)[23] and hypomagnesemia was generally mild-to-moderate with no reports of severe hypomagnesemia (<1.0 mg/dl).[22] Other electrolytes, such as sodium, calcium and phosphate, remained within normal range during the trials. No observed declines in kidney function were considered to be related to the intervention.[22] The most common adverse event leading to discontinuation were related to the gastrointestinal system (2.6%).[25] There were no serious treatment-related adverse events in the reported clinical trials. Furthermore, in a subgroup analysis of patients with heart failure, patiromer safety was similar to that observed in all patients.

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