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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

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Background

Spironolactone is effective at reducing blood pressure in patients with uncontrolled
resistant hypertension. However, the use of spironolactone in patients with chronic
kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium
binder patiromer to allow more persistent use of spironolactone in patients with chronic
kidney disease and resistant hypertension.

Methods

In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we
enrolled participants aged 18 years and older with chronic kidney disease (estimated
glomerular filtration rate 25 to ≤45 mL/min per 1·73 m
2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries
(Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the
UK, and the USA). Patients meeting all eligibility criteria at the final screening
visit were stratified by local serum potassium measurement (4·3 to vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1)
with an interactive web response system to receive either placebo or patiromer (8·4
g once daily), in addition to open-label spironolactone (starting at 25 mg once daily)
and their baseline blood pressure medications. Participants, the study team that administered
treatments and measured blood pressure, and the investigators were masked to assigned
treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks
(spironolactone). The primary endpoint was the between-group difference at week 12
in the proportion of patients on spironolactone. Efficacy endpoints and safety were
assessed in all randomised patients (intention to treat). The study was registered
with
Clinicaltrials.gov,
NCT03071263.

Findings

Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574
patients met all inclusion criteria and were randomly assigned to spironolactone in
addition to double-blind treatment with either placebo (n=148) or patiromer (n=147).
At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients
in the patiromer group remained on spironolactone (between-group difference 19·5%,
95% CI 10·0–29·0; p<0·0001). Adverse events were mostly mild or moderate in severity
and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147
patients in the patiromer group.

Interpretation

In patients with resistant hypertension and chronic kidney disease, patiromer enabled
more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent
spironolactone enablement in this population of patients has clinical relevance for
the treatment of resistant hypertension.

Funding

Relypsa, a Vifor Pharma Group Company.

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