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 <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 , .

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.

中文翻译：

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Patiromer 与安慰剂相比，使螺内酯能够用于顽固性高血压和慢性肾病 (AMBER) 患者：一项 2 期、随机、双盲、安慰剂对照试验。

背景

螺内酯可有效降低无法控制的顽固性高血压患者的血压。然而，在慢性肾病患者中使用螺内酯可能会受到高钾血症的限制。我们评估了钾结合剂patiromer的使用，以便在慢性肾病和顽固性高血压患者中更持久地使用螺内酯。

方法

在这项 2 期多中心、随机、双盲、安慰剂对照研究中，我们招募了 18 岁及以上患有慢性肾病（估计肾小球滤过率 25 至 ≤45 mL/min/1·73 m ²）且不受控制的参与者来自 10 个国家（保加利亚、克罗地亚、格鲁吉亚、匈牙利、乌克兰、法国、德国、南非、英国和美国）的 62 个门诊中心的顽固性高血压。在最终筛选访问时满足所有资格标准的患者通过局部血清钾测量进行分层（4·3 至 <4·7 mmol/L vs4·7 至 5·1 mmol/L) 和糖尿病史。参与者被随机分配 (1:1) 使用交互式网络响应系统，以接受安慰剂或 Patiromer（8·4 g，每天一次），以及开放标签螺内酯（从 25 mg 开始，每天一次）和他们的基线血压药物。参与者、进行治疗和测量血压的研究团队以及研究人员被掩盖到分配的治疗组。1 周（patiromer）和 3 周（螺内酯）后允许进行剂量滴定。主要终点是第 12 周时使用螺内酯的患者比例的组间差异。在所有随机患者（意向治疗）中评估疗效终点​​和安全性。该研究在 , 注册。

发现

在 2017 年 2 月 13 日至 2018 年 8 月 20 日期间，我们筛查了 574 名患者。574 名患者中的 295 名 (51%) 符合所有纳入标准，并被随机分配至螺内酯组以及安慰剂（n=148）或patiromer（n=147）的双盲治疗组。第 12 周时，安慰剂组 148 名患者中的 98 名（66%）和 Patiromer 组 147 名患者中的 126 名（86%）继续使用螺内酯（组间差异 19·5%，95% CI 10·0-29 ·0；p<0·0001)。不良事件的严重程度大多为轻度或中度，安慰剂组 148 名患者中有 79 名（53%）发生，patiromer 组 147 名患者中有 82 名（56%）发生不良事件。

解释

在患有顽固性高血压和慢性肾病的患者中，patiromer 使更多的患者能够继续使用螺内酯治疗，并减少高钾血症。在这组患者中持续使用螺内酯与治疗顽固性高血压具有临床相关性。

资金

Relypsa，一家 Vifor 制药集团公司。