干细胞疗法或将成为吸引心衰患者的治疗选择

最近发表在柳叶刀Lancet上的文章公布了ixCELL-DM临床试验2B期的最新结果,试验结果表明,干细胞疗法能够改善心力衰竭的心血管结局。

干细胞疗法在心衰的治疗可谓是欣欣向荣,ixCELL-DM就是其中一项研究。这项临床试验使用的是经骨髓细胞提取并培养2周的干细胞,其中两类单核细胞的比例明显多于其他细胞:一是CD90阳性间充质干细胞,还有CD45与CD14双阳性巨噬细胞。

      上述ixmyelocel-T细胞产物和安慰剂对照被分别随机注射入126名NYHA分级3/4级,左室射血分数LVEF<35%,发生过缺血性心肌病的心衰患者体内。受试患者还需要具备以下3个特征之一:接受过6个月的住院观察;脑钠肽BNP或N端BNP前体水平升高或6分钟步行测试小于400米

      经过1年后,对照组的51例患者中有25例患者出现了总共50次心血管事件,ixmyelocel-T细胞治疗组的58名患者中有22例患者出现了总共38次心血管事件心血管事件发生率降低37%[RR] 0.63; P=0.034)并且两组之间的死亡率失代偿性心力衰竭的就诊率也有显著差距,分别是3.4%vs13.7%,38%vs47%。

       不过这种治疗方法对左心室射血分数LVEF和左心室容积LV的改善效果并不是那么明显。这项2期双盲对照临床试验证实了,在缺血性心力衰竭的患者心肌中注射一类ixmyelocel-T干细胞能够减少患者的心血管事件,改善临床结局。

      文章报道6个月的时候,射血分数在治疗组和对照组之间有1%改变,然而之间的死亡率、住院率已经拉开了惊人的差距。所以一些专家也质疑心肌注射干细胞改善心肌功能的机制究竟是怎样的。

      不过该试验的研究者解释,就临床效果比LVEF的差别更显著这个结果来说,其他细胞治疗临床试验得到是类似的结果。并且在该试验中,LVEF和LV的检查采用是超声心电图检查而非MRI,超声心电图检查能够同时反映心脏的功能和容积。

      同时,这项双盲试验分析次要终点采用的数据分析方法相对比较保守,例如对于15%的没有生存到最后一次随访期的对照组患者,研究者使用了末次观测值结转法,也导致了两组之间差距的降低。

      这项临床试验提示我们,干细胞治疗可以成为心衰患者的选择之一,并且或许能在患者新功能进一步恶化之前给予有效的干预。

 

原文

Ixmyelocel-T for patients with ischaemic heart failure:a prospective randomised double-blind trial

Background Ixmyelocel-T is an expanded, multicellular therapy produced from a patient’s own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions.

Methods In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated

cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of allcause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modifi ed intention to treat. This trial is registered with ClinicalTrials.gov,number NCT01670981.

Findings Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=60) or placebo (n=66). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary effi cacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary effi cacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42–0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group(p=0·0197).

Interpretation To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes.


出处

Patel AN, Henry TD, Quyyumi AA, et al. Ixmyelocel-T for patients with ischemic heart failure: A prospective, randomized double-blind trial. Lancet 2016; DOI:10.1016/S0140-6736(16)30137-4.

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