Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Department of Emergency Medicine, Indiana University, Indianapolis, IN, USA.
Clin Res Cardiol. 2023 Jul;112(7):901-910. doi: 10.1007/s00392-022-02144-6. Epub 2023 Jan 19.
We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes.
We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure.
Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)].
Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.
我们旨在研究在因急性心力衰竭（HF）住院的患者中，松弛素改善肾功能是否可以解释对临床结局的任何潜在影响。
我们纳入了 RELAXin 在急性心力衰竭-2 研究（RELAX-AHF2）中的 6318 名患者。肾功能改善定义为血清肌酐下降≥0.3mg/dL 和≥25%，或肾小球滤过率估计值增加≥25%，与基线相比第 2 天。肾功能恶化（WRF）定义为相反。我们针对 180 天全因死亡率（ACM）、心血管死亡（CVD）和心力衰竭/肾衰竭住院进行了因果中介分析。
与安慰剂相比，松弛素更常观察到肾功能改善[比值比 1.88（95%置信区间 1.64-2.15，p<0.0001）]，但与随后的临床结局无关。松弛素发生 WRF 的频率较低[比值比 0.70（95%置信区间 0.60-0.83，p<0.0001）]，与 ACM、HF 恶化和 CVD 以及 HF 或肾衰竭住院的复合风险增加相关。肾功能改善并未介导松弛素的治疗效果[CVD 风险比 1.01（0.99-1.04），ACM 风险比 1.01（0.99-1.03），HF/肾衰竭住院风险比 0.99（0.97-1.00）]。
尽管松弛素在急性 HF 患者中显著改善了肾功能，但潜在的有益治疗效果并未通过改善肾功能来介导。这些数据表明，在未来使用新型松弛素药物治疗急性 HF 的研究中，肾功能改善可能不是潜在治疗效果的合适替代标志物。
中心图示：解释中介分析的概念模型；心力衰竭治疗的疗效通过肾功能介导。
