Effect of Ad5FGF-4 in patients with angina - An analysis of pooled data from the AGENT-3 and AGENT-4 trials
Effect of Ad5FGF-4 in patients with angina - An analysis of pooled data from the AGENT-3 and AGENT-4 trials
复制标题
DOI：
10.1016/j.jacc.2007.06.010
复制
发表时间：
2007-09-11
影响因子：
24
通讯作者：
Engler, Robert L.
中科院分区：
文献类型：
--
作者：
Henry, Timothy D.;Grines, Cindy L.;Engler, Robert L.
目的探讨血管生成基因治疗慢性心绞痛的临床前研究结果表明，Ad 5 FGF-4（alferminogene tadenovec，Generx，Berlex Biosciences，里士满，加州）可诱导血管生成，为临床治疗慢性心绞痛提供了新的途径。两项初步临床试验提供了证据，表明它可以改善运动平板试验（ETT）时间和心肌灌注。在美国和其他国家启动了低剂量和高剂量Ad 5 FGF-4治疗慢性心绞痛的AGENT（Anglogenic GENe Therapy）-3和-4试验，并以随机、双盲、地方对照的方式招募了532名患者。两项研究都在对药物进行中期分析时停止，3项临床试验表明，主要终点12周总ETT时间较基线的变化不会达到显著性。方法我们对2项几乎相同的临床试验进行汇总数据分析，以研究预先指定的亚组中可能的主要和次要终点影响。结果安慰剂的影响较大，与活性药物无差异。在男性中，安慰剂的效果可以忽略不计，治疗效果显著大于安慰剂。我们发现Ad 5 FGF-4对女性的总ETT时间、至1 mm ST段压低的时间、至心绞痛的时间和加拿大心血管学会分级有显著的、性别特异性的有益作用。这是第一个临床报告的性别差异，在回应心脏血管生成therapy.Conclusions观察到的性别特异性血管生成反应的临床治疗难治性心绞痛的潜在重要性是实质性的，值得进一步调查。
Objectives The goal of this study was to explore the effects of angiogenic gene therapy.Background Preclinical studies with intracoronary administration of Ad5FGF-4 (alferminogene tadenovec, Generx, Berlex Biosciences, Richmond, California) suggested it could induce angiogenesis and provide a new clinical approach to the treatment of chronic angina pectoris. Two preliminary clinical trials provided evidence that it could improve exercise treadmill test (ETT) time and myocardial perfusion. The AGENT (Anglogenic GENe Therapy)-3 and -4 trials of a low and high dose of Ad5FGF-4 for chronic angina were initiated in the U.S. and other countries and enrolled 532 patients in a randomized, double-blind, place bo-controlled fashion. Both studies were halted when an interim analysis of the AGENT-3 trial indicated that the primary end point change from baseline in total ETT time at 12 weeks would not reach significance.Methods We performed a pooled data analysis from the 2 nearly identical trials to investigate possible treatment effects on primary and secondary end points in prespecified subgroups.Results The effect of placebo was large and not different than active treatment in men, but the placebo effect in women was negligible and the treatment effect was significantly greater than placebo. We found a significant, gender-specific beneficial effect of Ad5FGF-4 on total ETT time, time to I mm ST-segment depression, time to angina, and Canadian Cardiovascular Society class in women. This is the first clinical report of a gender difference in response to cardiac angiogenic therapy.Conclusions The potential importance of the observed gender-specific angiogenic response on the clinical treatment of refractory angina is substantial and deserves further investigation.