The REVEAL study

REVEAL 研究

• 批准号: 8552344
• 负责人: Edward Lakatta
• 金额: $ 4.99万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552344
• 关键词: Acute; Acute myocardial infarction; Animal Model; Apoptosis; CD34 gene; Cardiac; Cardiovascular system; Cause of Death; Cell Count; Cells; Cessation of life; Confidence Intervals; Cryopreservation; Dose; Double-Blind Method; Enrollment; Epoetin Alfa; Erythropoietin; Event; Experimental Models; Hour; Infarction; Injury; Intervention; Intravenous; Intravenous Bolus; Ischemia; Left Ventricular Function; Left Ventricular Mass; Left Ventricular Remodeling; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Methods; Mononuclear; Morbidity - disease rate; Multicenter Trials; Myocardial Infarction; Outcome; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Process; Randomized; Reperfusion Therapy; Safety; Saline; Sampling; Scanning; Site; Stem cells; Stents; Stroke; Subgroup; Thrombosis; Time; Ventricular Remodeling; aged; aldehyde dehydrogenases; cohort; design; follow-up; improved; indexing; mortality; neovascularization; older patient; percutaneous coronary intervention; prospective; trend

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.

背景：急性ST段抬高心肌梗死(STEMI)是主要原因 发病率和死亡率。在实验性心肌梗死模型中，促红细胞生成素减少心肌梗死 大小和改善左心室(LV)功能。 目的：评价单次静脉推注依曲替丁的安全性和有效性。 阿尔法在STEMI患者中的应用。 设计、设置和患者：一项前瞻性、随机、双盲、安慰剂对照研究 剂量递增安全期试验和单次剂量(60000 U)Epoetin 阿尔法)有效期；减少心肌梗死扩大和心室重构 大心肌梗死后应用促红细胞生成素(REVIEW)试验 在2006年10月至2010年2月期间在美国28个地点进行了调查，包括222名患者 接受经皮冠状动脉介入治疗(PCI)成功的STEMI患者 主要或抢救性再灌注策略。 干预：参与者被随机分配到静脉注射依维汀治疗 在再灌流后4小时内给予阿尔法或相应的生理盐水安慰剂。 主要观察指标：心肌梗死面积，以左室心肌质量百分比表示，评估 通过心脏磁共振(CMR)成像在研究后2至6天进行 给药(第一次CMR)，122周后再次给药(第二次CMR)。 结果在有效队列中，脑梗塞面积在两组间均无差异。 第一次CMR扫描(n=136；15.8%左心室质量，95%可信区间CI，13.3- Epoetin Alfa组18.2%LV质量与15.0%LV质量95%可信区间12.6-17.3% 安慰剂组的左心室重量；P=.67)或第二次CMR扫描(n=124；10.6%) 左心室质量95%可信区间，8.4~12.8%左心室质量VS 10.4%左质量区间95%可信区间，8.5~12.3%左心室 质量分别为；P=.89)。在对70岁或70岁以上患者的预先指定分析中 (n=21)，第一周内(首次CMR)的平均梗塞范围在Epoetin中较大 ALFA组(19.9%的LV质量；95%的CI，14.0-25.7%的LV质量)比安慰剂组 组(11.7%LV质量；95%CI，7.2-16.1%LV质量)(P=0.03)。在安全队列中， 在接受促红细胞生成素α治疗的125名患者中，死亡、心肌梗死、 5例发生卒中或支架血栓形成(4.0%；95%可信区间为1.31%-9.09%)，无一例发生 在接受安慰剂治疗的97名患者中(P=0.04)。 结论：在STEMI患者中，直接再通或抢救成功的患者 经皮冠状动脉介入治疗后4小时内单次静脉注射促红细胞生成素α不能减少心肌梗死 大小与不良心血管事件的发生率较高有关。子群 分析提出了对老年患者心肌梗死面积增加的担忧。 在一项后续研究中，我们旨在确定集中分析EPC水平以评估EPC水平与EPO给药和脑梗塞范围之间关系的可行性。 方法：对急救或直接经皮冠状动脉介入治疗前、介入治疗后2 4h和48C72h的单个核细胞(MNC)进行局部深低温保存，检测CD133、CD34的表达及乙醛脱氢酶活性。 结果：222名登记的患者中有163人尝试了内皮祖细胞的抽样。125名患者中至少获得了一个可分析样本，83名患者中所有三个时间点都可用。在EPO和安慰剂治疗的患者中，随着时间的推移，EPC数量和EPC绝对值之间没有统计学上的显著差异。在接受30000U EPO治疗的患者中，从干预后24小时到干预后48C72小时，EPC水平有更大的上升趋势(=0.11(安慰剂)对0.092(EPO)，P=0.05)。基线时内皮祖细胞数量与梗塞面积呈负相关(p=0.006，r=-0.39)。 结论：局部全细胞冷冻保存和中心EPC分析是可行的。大剂量(3万U)EPO可在48C72小时动员EPC。基础EPC水平与梗塞面积呈负相关，提示急性EPC动员可能是减少急性损伤的可行策略。