目的:抑制microRNA(miR)-132有效预防和逆转不良心脏重塑,使其成为有吸引力的心力衰竭(HF)目标。CDR132L,一种选择性阻断病理升高的miR-132的合成反义寡核苷酸,在相关临床前模型中对左心室(LV)结构和功能表现出有益作用,在稳定的慢性HF患者的1b期研究中,安全性和耐受性良好。急性心肌梗死(MI)和随后的LV功能障碍和重塑患者的治疗选择有限。并可能从早期CDR132L治疗中获益。
方法:HF-REVERT(第2阶段,多中心,随机化,平行,三臂,评估CDR132L在心肌梗死后左心室射血分数降低患者中的疗效和安全性的安慰剂对照研究)评估了CDR132L在急性MI后HF患者中的疗效和安全性(n=280),比较5和10mg/kgCDR132L的效果,以间隔28天的三次单次静脉给药,除了标准的护理。关键的纳入标准是急性MI的诊断,收缩功能障碍(LV射血分数≤45%)和N末端B型利钠肽前体升高的发展。该研究包括为期6个月的双盲治疗期,主要终点左心室收缩末期容积指数和相关次要终点,随后是6个月的开放标签观察期。
结论:HF-REVERT试验可能支持miR-132抑制的概念,以预防或逆转MI后HF的心脏重塑。结果将为后续结果试验的设计提供信息,以测试HF中的CDR132L。
OBJECTIVE: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b
study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment.
METHODS: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled
Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The
study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period.
CONCLUSIONS: The HF-REVERT
trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.