Study Design and Patient Population

The protocol of the AMETHYST-DN trial was approved by local or national independent ethics committees at each study site and performed in accordance with the International Conference on Harmonization E6 Guideline for Good Clinical Practice, the Declaration of Helsinki principles, and local or national independent ethics committee requirements. All patients provided written informed consent before any study-specific procedures were performed.

The design of the AMETHYST-DN trial has been described previously as a multicenter open-label dose-ranging trial of 306 randomly assigned patients aged 30 to 80 years with CKD (estimated glomerular filtration rate [eGFR], 15 to <60 mL/min/1.73 m²), type 2 diabetes mellitus, and hypertension.11 Patients with hyperkalemia (potassium > 5.0 to <6.0 mEq/L) at screening or after an up to 4-week run-in period were randomly assigned. All patients had been receiving a stable dose of RAAS inhibitor for 28 days or longer before screening.

The 52-week study included an 8-week treatment period and 44-week long-term maintenance period for up to 52 weeks of total treatment and posttreatment follow-up of 4 weeks (Fig 1). Patients who were normokalemic (potassium, 4.3-5.0 mEq/L) at screening entered a run-in period (up to 4 weeks) and either switched from their current angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) medication to a maximum labeled dose of ARB (100 mg/d of losartan) and/or up to 50 mg of spironolactone (cohort 1) or continued their current ACE inhibitor or ARB treatment and added up to 50 mg of spironolactone (cohort 2). Patients who developed hyperkalemia at any point during the 4-week run-in period could be randomly assigned into the treatment phase. Patients with preexisting hyperkalemia (potassium >5.0 to <6.0 mEq/L) at screening (cohort 3) continued use of their prescribed ACE inhibitor or ARB, skipped the run-in period, and were randomly assigned directly to the treatment phase.

AMETHYST-DN study design. ∗Estimated glomerular filtration rate (eGFR) of 15 to <60 mL/min/1.73 m². ^†Before screening. ^‡Primary end points. ^§Renin-angiotensin-aldosterone system inhibitor (RAASi) therapy was continued after patiromer treatment discontinuation only in patients who were normokalemic (mean serum potassium ≤ 5.0 mEq/L) at the end of the maintenance phase. Abbreviations: ACR, albumin-creatinine ratio; BP, blood pressure; CKD, chronic kidney disease; HK, hyperkalemia; spiro, spironolactone; T2DM, type 2 diabetes mellitus.

Patients entering the treatment period were stratified to 1 of 2 strata: mild (serum potassium >5.0 to 5.5 mEq/L) and moderate hyperkalemia (serum potassium >5.5 to <6.0 mEq/L). These patients were randomly assigned to 1 of 3 starting doses of patiromer per stratum: patients with mild hyperkalemia received 4.2, 8.4, or 12.6 g twice daily and patients with moderate hyperkalemia received 8.4, 12.6, or 16.8 g twice daily. Following the baseline visit, patients were assessed at day 3, weekly thereafter during the 8-week treatment period, and monthly during the 44-week long-term maintenance period. The starting dose could be titrated up or down to achieve and maintain serum potassium levels ≤5.0 mEq/L during the treatment and long-term maintenance periods. By protocol, the RAAS inhibitor dose could not be downtitrated or discontinued because of hyperkalemia, but patiromer could be uptitrated using a protocol-defined dosing algorithm.

At the end of the long-term maintenance period, all patients with serum potassium levels >5.0 mEq/L discontinued patiromer treatment and all RAAS inhibitor medications and were followed up for 2 visits within 7 days. Patients with serum potassium level ≤5.0 mEq/L (normokalemic) at the end of the long-term maintenance period discontinued patiromer treatment but remained receiving RAAS inhibitors for 28 days and returned for 5 follow-up visits (day 3 and weekly through week 4 posttreatment).11

In this post hoc subgroup analysis, all 3 starting dose groups within each stratum (mild or moderate) were combined to evaluate the effect of patiromer on serum potassium levels.