Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial.
Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial.
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DOI：
10.1016/s1474-4422(14)70318-7
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Cripe LH
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作者：
Raman SV;Hor KN;Mazur W;Halnon NJ;Kissel JT;He X;Tran T;Smart S;McCarthy B;Taylor MD;Jefferies JL;Rafael-Fortney JA;Lowe J;Roble SL;Cripe LH
心肌病是Duchenne肌营养不良症患者的主要死亡原因，心肌损伤先于左室收缩功能下降。我们测试了依普利酮在Duchenne型肌营养不良症合并早期心肌病患者的背景治疗上的疗效。在这项随机、双盲、安慰剂对照的试验中，来自美国三个中心的男孩患有杜氏肌营养不良症、晚期Gd增强心脏核磁共振心肌损害并保留射血分数，除接受血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体阻滞剂(ARB)的背景临床指导治疗外，还接受依普利酮25 mg或安慰剂口服治疗，第一个月每隔一天服用一次，此后每天一次。计算机生成的随机化是使用4和6的区块大小集中完成的，只有研究统计员和研究药房有预设的随机化分配。主要结果是12个月后左室周向应变(ECC)的变化，这是一种衡量收缩功能障碍的指标。安全性是通过一系列血钾水平和胱抑素C的测定来确定的，胱抑素C是肾功能的一种非内生性指标。这项试验在ClinicalTrials.gov注册，编号NCT01521546。在2012年1月26日至2013年7月3日期间，188名男孩接受了筛查，42人入学。20人被随机分配接受依普利酮治疗，22人接受安慰剂治疗，其中20人接受依普利酮治疗，20人接受安慰剂治疗，分别完成基线、6个月和12个月的治疗。12个月后，接受依普利酮治疗的患者的左心室周向应变下降幅度小于接受安慰剂治疗的患者(中位数ΔECC1.0[IQR0.3-2.2]vs2.2[1.3-3.1]；p=0.020)。两组患者的半胱氨酸氨基转移酶C浓度均保持正常，所有非溶血性血样的血钾浓度均正常。安慰剂组中的一名23岁患者死于脂肪栓塞，安慰剂组中的另一名患者因解决长期存在的消化问题而退出试验。所有其他不良事件都是轻微的：一名服用依普利酮的患者出现了短暂的头痛和季节性过敏，一名服用安慰剂的患者出现了脸红，另一名服用安慰剂的患者出现了焦虑。在Duchenne肌营养不良和射血分数保留的男孩中，在背景ACEI或ARB治疗的基础上加用依普利酮可以减轻左心室收缩功能的进行性下降。在心脏死亡的高危人群中，早期使用可用的药物值得考虑，但需要进一步的研究来确定联合心脏保护治疗对Duchenne肌营养不良症无事件生存的影响。BallouSkies，肌肉营养不良家长项目，美国国家促进翻译科学中心，以及美国国家卫生研究院。
Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.