Elsevier

The Lancet

Volume 394, Issue 10208, 26 October–1 November 2019, Pages 1540-1550
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(19)32135-XGet rights and content

Summary

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 m2) 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 <4·7 mmol/L 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.

Introduction

Resistant hypertension is defined as uncontrolled blood pressure when taking three or more classes of antihypertensive medication or taking four or more classes of antihypertensive medication regardless of blood pressure level.1, 2 The prevalence of true resistant hypertension evaluated by 24-h ambulatory blood pressure monitoring in a meta-analysis of 12 studies was found to be 10·25% (95% CI 7·65–13·19%),3 suggesting that it affects more than 100 million people globally. A 2018 study suggested that excessive sodium retention is the principle mechanism underlying resistant hypertension,4 which might explain why chronic kidney disease is commonly associated with resistant hypertension. In an Italian cohort of patients with chronic kidney disease, the prevalence of resistant hypertension was 22·9%, nearly 3 times that in the general population.5

Chronic kidney disease affects around 8–16% of the adult population,6 and among those with disease, the worldwide prevalence of apparent treatment-resistant hypertension is 2–4 times higher than that seen in a population without chronic kidney disease.7 About a quarter of patients with chronic kidney disease have apparent treatment-resistant hypertension.7 Treatment-resistant hypertension is associated with an almost 2 times increased risk of cardiovascular events and 2·7 times increased risk for end-stage kidney disease compared to those with controlled hypertension.5 Given this high prevalence of resistant hypertension in people with chronic kidney disease, there is an urgent unmet need for new therapies to treat this condition.

Research in context

Evidence before this study

Resistant hypertension—ie, blood pressure remaining higher than a desired goal despite treatment with optimally tolerated doses of three antihypertensive agents from different classes, including a diuretic—is a substantial medical problem. Assessed by 24-h ambulatory blood pressure monitoring, the prevalence of resistant hypertension in a large cohort was found to be 8%, but in most cohorts of patients with chronic kidney disease the prevalence of resistant hypertension is several times higher than this figure. A previous study of patients with resistant hypertension showed that spironolactone was superior to other treatment options—ie, a β blocker or α blocker—in improving blood pressure control. Consequently, spironolactone (25–50 mg daily) is now recommended for the treatment of resistant hypertension by international guidelines. However, guidelines acknowledge a lack of data on the safety and efficacy of spironolactone in patients with advanced chronic kidney disease and resistant hypertension. We searched PubMed for randomised clinical trials published in English between Jan 1, 1965, and Jan 1, 2017, with the search terms “resistant hypertension”, “chronic kidney disease”, and “spironolactone”. At the time of initiation of our study, to our knowledge, only one small randomised clinical trial (41 patients) of spironolactone versus placebo for the treatment of resistant hypertension in patients with advanced chronic kidney disease had been reported but was underpowered.

Added value of this study

In this 12-week, randomised, double-blind, placebo-controlled trial of patients with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2), once daily oral administration of patiromer was generally well tolerated and significantly increased the proportion of patients who remained on spironolactone. Patiromer use was associated with a significantly reduced risk for hyperkalaemia during spironolactone therapy.

Implications of all the available evidence

Patients with advanced chronic kidney disease have high proportions of poor blood pressure control, premature cardiovascular disease, and end-stage kidney disease. There is a clear unmet medical need for safe and effective therapies to better control blood pressure, especially in patients with resistant hypertension. Results from the AMBER study suggest that patiromer enables the use of spironolactone, which effectively lowers systolic blood pressure in patients with resistant hypertension and chronic kidney disease. Further clinical studies of patiromer to enable spironolactone use to reduce cardiovascular events and end-stage kidney disease are warranted.

Consistent with the observation that resistant hypertension appears to be a sodium retaining state,4 in the PATHWAY-2 study,8 further diuretic therapy via add-on therapy with spironolactone was shown to be significantly more effective at lowering blood pressure in resistant hypertension than bisoprolol, doxazosin, or placebo. This result was consistent with findings from a meta-analysis of smaller studies, which suggested that spironolactone was an effective treatment for resistant hypertension.9

Despite the high frequency of resistant hypertension in patients with chronic kidney disease, the aforementioned studies that evaluated spironolactone excluded patients with advanced chronic kidney disease because of the risk of spironolactone-induced hyperkalaemia. In a meta-analysis, addition of spironolactone to an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker doubled the risk of hyperkalaemia in patients with mild to moderate chronic kidney disease, which was dependent on baseline estimated glomerular filtration rate, serum potassium (K+) level, drug dose, and concomitant medications.10 Thus, the risk of hyperkalaemia has restricted the use of the potentially most effective treatment for resistant hypertension in patients with chronic kidney disease.

Recently, oral K+ binding agents with improved efficacy and tolerability have been developed to lower serum K+. Patiromer is a sodium-free, non-absorbed, K+-binding polymer that is approved in the USA, Europe, and other locations for lowering serum K+ in patients with hyperkalaemia.11, 12 Previously, patiromer enabled spironolactone use and prevented hyperkalaemia in patients with heart failure with an estimated glomerular filtration rate less than 60 mL/min per 1·73 m2 or a history of hyperkalaemia that provoked discontinuation of drugs blocking the renin–angiotensin–aldosterone system (RAAS).13 These findings in a population with heart failure supported the development of a randomised controlled trial to evaluate the use of patiromer as an adjunctive therapy to spironolactone in patients with resistant hypertension and chronic kidney disease, to reduce the risk of developing hyperkalaemia and thereby facilitate the use of spironolactone in addition to triple blood pressure-lowering therapy, improving blood pressure control in these patients.14

In the AMBER study, we aimed to test 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 chronic kidney disease.

Section snippets

Study design and participants

The AMBER trial design has previously been published.15 In this phase 2, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of patiromer to enable spironolactone use for blood pressure control in patients with resistant hypertension and chronic kidney disease, we enrolled participants from 62 outpatient centres in ten countries (appendix p 2). Patients were typically recruited from within the investigators' practices. Patients eligible for inclusion were aged 18

Results

Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients (figure 1). 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). Overall, 141 (95%) of 148 patients in the placebo group and 144 (98%) of 147 patients in the patiromer group completed the study. The most common reasons for premature study discontinuation were adverse events (three patients in the

Discussion

Use of the K+ binder patiromer enabled more persistent use of spironolactone in patients with uncontrolled resistant hypertension and advanced chronic kidney disease. This enablement was accompanied by a lower proportion of hyperkalaemia and fewer discontinuations of spironolactone because of hyperkalaemia, as well as a delay in the time to hyperkalaemia in patients treated with patiromer. Two-thirds of patients in the placebo group developed hyperkalaemia, and this risk was reduced by half in

Data sharing

Individual patient data will be shared. A research proposal must be approved by an independent review panel and the study sponsor, and researchers must sign a data sharing agreement. Anonymised individual patient-level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement. Data can be requested 24 months after the primary publication. Data will be available for a period of 3 years for requests. Proposals for access should

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