Physicians' Academy for Cardiovascular Education

Oral K+-binding agent enables use of spironolactone in patients with resistant hypertension 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

Literature - Agarwal R, Rossignol P, Romero A et al., - The Lancet 2019.

Introduction and methods

The principle mechanism underlying resistant hypertension may be excessive sodium retention [1]. This may explain why chronic kidney disease (CKD) is commonly associated with resistant hypertension. Several studies have suggested that patients with CKD showed an about three times higher prevalence of resistant hypertension than the general population of those without CKD [2,3]. Treatment-resistant hypertension is associated with elevated risk of CV events and end-stage kidney disease [2], underscoring the urgent need to treat this condition.

The PATHWAY-2 study demonstrated that add-on therapy with spironolactone was more effective at lowering blood pressure in resistant hypertension than bisoprolol, doxazosin or placebo [4], consistent with resistant hypertension seeming to be a sodium retaining state. Studies that evaluated spironolactone excluded patients with advanced CKD because of the risk of hyperkalemia.

Oral K+-binding agents are now available, such as patiromer. This is a sodium-free, non-absorbed, K+-binding polymer that can lower serum K+ in patients with hyperkalemia [5,6]. In heart failure patients, patiromer enabled spironolactone use and prevented hyperkalemia in those with eGFR <60 mL/min/1.73m² or a history of hyperkalemia that led to discontinuation of RAAS-blocking treatment. These data form the rationale for a randomized controlled trial to evaluate the use of patiromer as an adjunctive therapy to spironolactone in patients with resistant hypertension and CKD.

This phase 2 study, the AMBER trial [7], tested the safety and efficacy of patiromer administered once daily for 12 weeks to allow persistent use of spironolactone for the treatment of resistant hypertension in patients with CKD. 295 Patients from 62 outpatient centres were recruited, with eGFR between 25 and 45 mL/min/1.73m², serum K+ between 4.3 and 5.1 mmol/L and resistant hypertension. The study consisted of a run-in period of maximum 4 weeks, a 12 week double-blind treatment period (weekly visits in week 1-4 and then biweekly) and a follow-up visit two weeks after the week 12 visit or early termination. Adherence to spironolactone treatment was assessed in plasma at week 1, 4, 8 and 12.

Main results


These data of the phase 2 AMBER trial show that use of the K+ binder patiromer enabled more persistent use of spironolactone in patients with uncontrolled resistant hypertension and advanced CKD. This effect was accompanied by fewer people developing hyperkalemia and less discontinuation of spironolactone because of hyperkalemia. A delay in time to hyperkalemia was seen in those also receiving patiromer.


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Find this article online at The Lancet

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