Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

Abstract

Background: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies ­evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of ­135–160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker ­(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m². Screening serum potassium must be 4.3–5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. Results: Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m². Conclusion: AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.

Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial

“…The AMBER trial design (ClinicalTrials.gov identifier NCT03071263) has previously been published. 14 Patients with untreated secondary causes of hypertension were excluded; full details of the inclusion and exclusion criteria were previously published. 14 The study consisted of a run-in period (up to 4 weeks), double-blind treatment period (12 weeks) and follow-up visit 2 weeks after the week 12 visit or early termination.…”

“…The spironolactone dosing algorithm was previously published. 14 Patients with systolic AOBP ≤120 mmHg and serum K + > 5.1 mmol/L at week 3 continued on the 25 mg spironolactone dose until the first subsequent visit at which serum K + was ≤5.1 mmol/L (and systolic AOBP was ≥120 mmHg), at which time the spironolactone dose was increased to 50 mg. Patients with systolic AOBP <120 mmHg at week 3 continued on the 25-mg dose.…”

Management of hyperkalemia in patients with kidney disease: a position paper endorsed by the Italian Society of Nephrology

“…Recently, the rationale and design of a RCT have been published that will evaluate if the potassium-binding patiromer used concomitantly with spironolactone could prevent HK and allow spironolactone use for the management of hypertension in CKD patients (eGFR 25 to 45 mL/min/1.73 m 2 ) with RH. The endpoints are the differences in the proportion of patients remaining on spironolactone and in SBP values between the two groups (spironolactone and placebo) after 12 weeks of treatment [ 81 ].…”

Potassium Binders for Hyperkalemia in Chronic Kidney Disease—Diet, Renin-Angiotensin-Aldosterone System Inhibitor Therapy, and Hemodialysis

“…The AMBER trial (Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease; ClinicalTrials.gov Identifier: NCT03071263) is investigating the concomitant use of patiromer and spironolactone in patients with resistant hypertension and CKD to determine whether this strategy prevents hyperkalemia and allows for long-term use of spironolactone for the management of hypertension. 90 The primary end point of the AMBER study is the proportion of patients continuing to take spironolactone at week 12. Secondary end points include changes in blood pressure and albuminuria (a marker of CV and renal outcomes).…”