The REVEAL study

背景：急性ST段抬高型心肌梗死（STEMI）是 发病率和死亡率。在心肌梗死的实验模型中，促红细胞生成素减少了梗死 尺寸和改善左心室（LV）功能。 目的：评价单次静脉推注依泊苷的安全性和有效性 Alfa治疗STEMI患者。 设计、设置和患者：一项前瞻性、随机、双盲、安慰剂对照研究 一项具有剂量递增安全性阶段和单次给药（60 000 U依泊苷）的试验 alfa）疗效期;收缩期扩张和心室重构减少 在大心肌梗死后使用促红细胞生成素（REVEAL）试验 2006年10月至2010年2月，在28家美国研究中心，纳入222例患者 成功接受经皮冠状动脉介入治疗（PCI）的STEMI患者， 主要或补救再灌注策略。 干预：参与者被随机分配到静脉注射依泊苷治疗组， 在再灌注4小时内给予α或匹配的生理盐水安慰剂。 主要观察指标：左室大小，表示为左室质量的百分比， 研究后2 - 6天进行心脏磁共振（CMR）成像 药物给药（第一次CMR）和122周后再次给药（第二次CMR）。 结果：在疗效队列中，两组之间的梗死面积无差异， 第一次CMR扫描（n=136; 15.8% LV质量95%置信区间CI，13.3- 依泊苷α组的LV质量为18.2% vs 15.0%，95% CI，12.6-17.3% 安慰剂组的LV质量; P= 0.67）或第二次CMR扫描时（n=124; 10.6%） LV质量95% CI，8.4-12.8% LV质量vs 10.4% LV质量95% CI，8.5-12.3% LV 质量; P= 0.89）。在对70岁或70岁以上患者进行的预先规定的分析中 （n=21），第一周内的平均梗死面积（首次CMR）在EpoA组大于EpoB组， α组（19.9% LV质量; 95% CI，14.0-25.7% LV质量）高于安慰剂组 组（11.7% LV质量; 95% CI，7.2-16.1% LV质量）（P=.03）。在安全性队列中， 在125例接受依泊苷α治疗的患者中，死亡，MI， 5例患者发生卒中或支架内血栓形成（4.0%; 95%CI，1.31%-9.09%），但无一例发生 97名接受安慰剂治疗的患者中， 结论：在STEMI患者中， PCI，PCI后4小时内单次静脉推注依泊苷α并不能减少梗死 并且与更高的不良心血管事件发生率相关。亚组 分析提出了对老年患者梗死面积增加的担忧。 在后续研究中，我们旨在确定集中分析EPC水平的可行性，以评估EPC水平与EPO给药和梗死面积之间的关系。 研究方法：在抢救或直接经皮冠状动脉介入治疗前以及介入治疗后24 h和48 h-72 h采集的样本中，将单核细胞（MNCs）局部冷冻保存，用于中央处理，并分析表达CD 133、CD 34和醛脱氢酶活性的细胞。 结果：在222例入组患者中，163例尝试了EPCs取样。在125例患者中获得了至少一个可分析的样本，在83例患者中获得了所有三个时间点。EPO治疗组和安慰剂治疗组患者的EPC数量随时间变化或绝对EPC水平无统计学显著差异。在接受30 000 U EPO的患者中，从干预后24 h到干预后48 C 72 h，EPC水平有更大的增加趋势（= 0.11（安慰剂）vs 0.092（EPO），p=0.05）。基线时的EPC数量与梗死面积呈负相关（p=0.006，r=-0.39）。 结论：局部全细胞冷冻保存和中央EPC分析是可能的。 大剂量EPO（30 000 U）可在48 C 72 h动员EPCs。 基线EPC水平与梗死面积呈负相关，表明急性EPC动员可能是一种可行的策略，以尽量减少急性损伤。

Context: Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function. Objective: To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI. Design, Setting, and Patients: A prospective, randomized, double-blind, placebocontrolled trial with a dose-escalation safety phase and a single dose (60 000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy. Intervention: Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion. Main Outcome Measure: Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 122 weeks later (second CMR). Results In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n=136; 15.8% LV mass 95% confidence interval CI, 13.3- 18.2% LV mass for the epoetin alfa group vs 15.0% LV mass 95% CI, 12.6-17.3% LV mass for the placebo group; P=.67) or on the second CMR scan (n=124; 10.6% LV mass 95% CI, 8.4-12.8% LV mass vs 10.4% LV mass 95% CI, 8.5-12.3% LV mass, respectively; P=.89). In a prespecified analysis of patients aged 70 years or older (n=21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P=.03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P=.04). Conclusions: In patients withSTEMIwhohad successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients. In a follow-up study, we aimed to determine the feasibility of centrally analyzing EPCs levels to assess the relationship between EPC levels, and EPO administration and infarct size. Methods: Mononuclear cells (MNCs) were locally cryopreserved for central processing from samples obtained prior to rescue or primary percutaneous coronary intervention, as well as at 24 h and 48C72 h postintervention, and analyzed for cells expressing CD133, CD34, and aldehyde dehydrogenase activity. Results: Sampling of EPCs was attempted in 163 of 222 enrolled patients. At least one analyzable sample was obtained in 125 patients, and all three time points were available in 83 patients. There were no statistically significant differences in EPC numbers over time or in the absolute EPC levels between EPO- and placebo-treated patients. There was a trend toward a greater increase in EPC levels from 24 h postintervention to 48C72 h postintervention in patients receiving 30 000 U of EPO ( = 0.11 (placebo) vs 0.092 (EPO), p=0.05). EPC numbers at baseline were inversely related to infarct size (p=0.006, r=-0.39). Conclusions: Local whole cell cryopreservation and central EPC analysis is possible. High-dose (30 000 U) EPO may mobilize EPCs at 48C72 h. Baseline EPC levels are inversely associated with infarct size, suggesting that acute EPC mobilization may be a viable strategy to minimize acute injury.