Background

Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA.

Objectives

We evaluated the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia.

Methods

REALIZE-K (NCT04676646) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA II–IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA- induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/daily); those with hyperkalemia started SZC. Participants with normokalemia (potassium 3.5–5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia [months 1–6]). The five key secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening HF events (hospitalizations and urgent visits).

Results

Overall, 203 participants were randomized (SZC 102, placebo 101). Higher percentage of SZC- versus placebo-treated participants had optimal response (71% vs 36%; OR 4.45 [95% CI 2.89–6.86]; p<0.001). SZC (versus placebo) improved the first four key secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR 4.58 [2.78–7.55]; p<0.001), receiving spironolactone ≥25 mg/daily (81% vs 50%; OR 4.33 [2.50–7.52]; p<0.001), time to hyperkalemia (HR 0.51 [0.37–0.71]; p<0.001), time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37 [0.17–0.73]; p=0.006). There was no between-group difference in KCCQ-CSS at 6 months (-1.01 points [-6.64–4.63]; p=0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of CV death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal p=0.034).

Conclusions

In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalaemia and down-titration/discontinuation of spironolactone.Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making.

中文翻译：

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环硅酸锆钠在螺内酯优化期间治疗心力衰竭患者高钾血症

 背景

盐皮质激素受体拮抗剂 （MRA） 可改善心力衰竭和射血分数降低 （HFrEF） 患者的预后，但在临床实践中未得到充分利用。观察数据表明，高钾血症是 MRA 使用不理想的主要障碍。

 目标

我们评估了环硅酸锆钠 （SZC） 在 HFrEF 和高钾血症参与者中优化螺内酯使用的影响。

 方法

REALIZE-K （NCT04676646） 是一项前瞻性、双盲、随机退出试验，受试者为 HFrEF （NYHA II-IV;左心室射血分数 ≤40%）、最佳指南指导治疗 （MRA 除外） 以及普遍或事件 MRA 诱导的高钾血症。在开放标签磨合期间，参与者接受了螺内酯滴定（目标：50 毫克/天）;高钾血症患者开始 SZC。接受 SZC 和螺内酯 ≥25 mg/d） 治疗正常碱血症（钾 3.5-5.0 mEq/L）的参与者被随机分配到持续 SZC 或安慰剂组，为期 6 个月。主要终点是最佳治疗反应 （螺内酯 ≥25 mg/d，高钾血症未进行挽救治疗 [第 1-6 个月]）。对 5 个关键次要终点进行了分层测试。探索性终点包括经裁定的心血管死亡或 HF 恶化事件 （住院和紧急就诊） 的综合结果。

 结果

总体而言，203 名参与者被随机分配 （SZC 102 名，安慰剂 101 名）。与安慰剂治疗相比，SZC 受试者获得最佳反应的百分比更高 （71% 对 36%;OR 4.45 [95% CI 2.89–6.86];p<0.001）。SZC（与安慰剂相比）改善了前四个关键次要终点：螺内酯随机剂量和无挽救治疗的正常血统（58% vs 23%;或 4.58 [2.78–7.55];p<0.001），接受螺内酯≥25 mg/天（81% 对 50%;或 4.33 [2.50–7.52];p<0.001）、高钾血症时间（HR 0.51 [0.37–0.71];p<0.001）、高钾血症导致螺内酯减少/停药的时间（HR 0.37 [0.17–0.73];p=0.006）。6 个月时 KCCQ-CSS 组间无差异 （-1.01 分 [-6.64–4.63];p=0.72）。SZC 和安慰剂之间的不良事件 （64% vs 63%） 和严重不良事件 （23% vs 22%） 分别处于平衡状态。SZC 组 11 名 （11%） 参与者 （1 名 CV 死亡，10 名 HF 事件） 和安慰剂组 3 名 （3%） 参与者 （1 名 CV 死亡，2 名 HF 事件;对数秩名义 p=0.034） 发生 CV 死亡或 HF 恶化的复合情况。

 结论

在患有 HFrEF 和高钾血症的参与者中，SZC 导致在最佳螺内酯剂量下正常参与者的百分比大幅提高，并降低了高钾血症和螺内酯下滴定/停药的风险。尽管临床结局的把握度不足，但与安慰剂相比，SZC 发生 HF 事件的参与者更多，这应该被纳入临床决策。