NORTHERN: Intramyocardial VEGF Fails Proof of Concept

　　与安慰剂相比，心肌细胞灌注、运动耐量或心绞痛症状并未得到改善。
     

　　对于拟行血运重建术以及不能行血运重建术的患者，心肌注射VEGF165基因治疗其顽固性心绞痛无效。
     

　　研究者应用SPECT图像评估心肌灌注改变的初步结果，发现实验组与安慰剂组3个月和6个月总应激积分（summed stress scores）与总差值分(summed difference scores)没有差异。
     

　　同样的，两组之间运动平板时间的差异和改变以及功能分级没有统计学意义。

　　试验中有两位患者死亡，其中安慰剂组一例，试验组一例。试验组骨骼肌副作用的发生率为44%，安慰剂组24%（P=0.04），除此之外，两组之间其它不良反应事件相似。
     

　　University of Ottawa医学教授Duncan Stewart（MD）说：“在以往VEGF试验中，癌症是一个大家普遍关注的问题，但试验组与安慰剂组仅各发生了一例基底细胞癌。”
     

　　研究者进行了一个亚组分析，他们将拟行血运重建术的患者和由于严重的CAD“别无选择”的患者作为研究对象。发现亚组间总应激积分或总差别积分没有差异。Stewart说目前NORTHERN加入了研究组。
     

　　NORTHERN试验入组了来自加拿大7个中心的93名患者。患者或予2000um VEGF165DNA质粒，或予盐水作为安慰剂。7天、30天、3个月和6个月分别进行随访。
     

　　Stewart说：“对于慢性冠脉疾病而导致的顽固性心绞痛患者，血管基因代表了一种可能的新治疗方法。尽管临床预试验和早期临床试验作出了承诺，但大的循证研究并没有显示任何令人信服的结果。尽管单纯VEGF基因转化缺乏有效性，但试验组与安慰剂组心肌灌注的改善提高了自发侧支循环建立的可能性，而这支持了血管基因治疗策略的生物学论证。”
     

　　波士顿Harvard Medical School血管造影研究中心主任Roger J.Laham(MD)说：“例如运动平板时间等的测量方法对安慰剂的作用很敏感，这发生于很多患者。我们需要更好的结果测量方法。此外，NORTHERN试验中有很多糖尿病患者，占24%－38%。糖尿病患者的心脏内已有大量VEGF，所以这可能会影响结果。”

NORTHERN: Intramyocardial VEGF Fails Proof of Concept

No improvement in myocardial perfusion,exercise tolerance, or anginal symptom class compared with placebo.

Intramyocardial plasmid VEGF165 gene transfer was ineffective for the treatment of refractory angina in patients who were candidates for revascularization and in those with no option for revascularization procedures.

Researchers used SPECT imaging to assess the primary outcome of change in myocardial perfusion and found no difference between the treatment and placebo groups with regard to summed stress scores and summed difference scores at 3 and 6 months (Figure).

Likewise, differences in exercise treadmill time and change in exercise treadmill time were not
statistically signifi cant between groups.

No signifi cant differences in functional class were observed between groups, as well.

There were two deaths in the study, one in the placebo group and one in the treatment group. Other adverse events were similar between the two groups, with the exception of a higher rate of musculoskeletal adverse events, which were observed in 44% treated with VEGF165 and 24% in the placebo group (P = .04).

“Cancer has been a concern in previous VEGF trials, but there was only one incidence of basal-cell carcinoma in each group,” said Duncan Stewart, MD, professor of medicine at the University of Ottawa.

Researchers performed a subgroup analysis of patients who were either candidates for revascularization procedures or who were deemed “no option” due to severe CAD. No difference was observed between the placebo or treatment groups in summed stress score or summed difference score within the subgroups.

Appropriate outcomes

The NORTHERN trial enrolled 93 patients from seven centers in Canada. Patients were administered VEGF165 plasmid DNA at a 2,000-m dose or a saline placebo.

Follow-up was conducted at 7 days, 30 days, 3 months, and 6 months.“Angiogenesis represents a potential novel therapy for patients with refractory angina due to chronic coronary disease,” Stewart said.

“Despite the promise of the preclinical and early  linical trials, larger proof-of-concept studies have failed to show any convincing benefi t.”

Stewart said NORTHERN now joins that group of studies.

“However, the improvement in myocardial perfusion in both placebo and treatment groups raises the possibility of spontaneous development of collaterals, which supports the biological plausibility of proangiogenic therapeutic strategies despite the lack of effi cacy seen in simple VEGF gene transfer,” Stewart said.

“Measures like exercise treadmill time are susceptible to the placebo effect, which is very powerful in this patient population. We need better outcome measures,” said Roger J. Laham, MD, director of the Angiogenesis Research Center at Harvard Medical School in Boston.

Laham said the NORTHERN trial also had a high number of patients with diabetes, between 24% and 38%.

“Patients who are diabetic already have a lot of VEGF in their heart, so this may be affecting the results,”
Laham said.

Roger J. Laham, MD