VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial

Abstract

Despite the promise of proangiogenic gene therapy most clinical trials have failed to show benefit for the primary end point analysis. The NOGA angiogenesis Revascularization Therapy: assessment by RadioNuclide imaging (NORTHERN) trial was a double-blind, placebo-controlled study of intramyocardial vascular endothelial growth factor (VEGF165) gene therapy versus placebo, involving seven sites across Canada, designed to overcome major limitations of previous proangiogenic gene therapy trials. A total of 93 patients with refractory Canadian Cardiovascular Society (CCS) class 3 or 4 anginal symptoms were randomized to receive 2,000 microg of VEGF plasmid DNA or placebo (buffered saline) delivered via the endocardial route using an electroanatomical NOGA guidance catheter. There was no difference between the VEGF-treated and the placebo groups in the primary end point of change in myocardial perfusion from baseline to 3 or 6 months, assessed by single photon emission tomography (SPECT) imaging, although a significant reduction in the ischemic area was seen in both groups. Also, similar improvements in exercise treadmill time and anginal symptoms were seen in the VEGF and the placebo groups at 3 and 6 months, although again there were no differences between these groups. Despite the intramyocardial administration of a high "dose" of plasmid DNA using a percutaneous guidance catheter system, there was no benefit of VEGF gene therapy at 3 or 6 months for any of the end points studied.

Figure 1

Flow diagram of the NORTHERN trial. Patients were assigned to group 1—i.e., “no option” patients with advance coronary artery disease (CAD) or group 2—i.e., single vessel occlusion/in stent restenosis based on the coronary anatomy and suitability for standard revascularization procedures. Upon successful NOGA electromechanical mapping, patients were randomized to receive of VEGF plasmid DNA (active treatment) or saline (Sham) divided into 10 intramyocardial injections targeted to the ischemic region under NOGA guidance. Patients were seen at 7 and 30 days for routine follow-up and SPECT sestamibi myocardial perfusion was performed at 3 and 6 months along with exercise treadmill testing and other efficacy and safety assessments. AEs, adverse events; CCS, Canadian Cardiovascular Society; ECG, electrocardiogram; NORTHERN, NOGA angiogenesis Revascularization Therapy: assessment by RadioNuclide imaging; SPECT, single photon emission tomography; VEGF, vascular endothelial growth factor.

Figure 2

SPECT sestamibi myocardial perfusion imaging. Summary data for (a) summed stress score (SSS), (b) summed defect score (SDS), and (c) summed reversibility score (SRS) is presented at baseline (Base), 3 and 6 months (M) for patients receiving saline placebo (open bars) or VEGF plasmid DNA (closed bars). Of the 91 patients receiving injections of VEGF or placebo, scans were available in 83 patients at baseline, 89 at 3 months, and 82 at 6 months. The primary analysis, change (Δ) from Base to 3 and 6M is presented in panels d–f. A total of 81 patients (66 in group 1 and 15 in group 2) had complete baseline and 3-month follow-up nuclear perfusion study scores and 76 patients had complete data for the 6-month analysis (61 in group 1 and 15 in group 2). There were no significant differences between the active treatment group (VEGF, closed bars) and the placebo controls (Sham, open bars) in SSS (primary end point analysis), SDS and SRS at either 3 or 6 months. However, there was significant improvement in resting myocardial perfusion within the ischemic zone (SDS) at 6 months in the VEGF group and a trend in placebo group. The placebo group also showed lower SDS at 3 months which was however associated with a trend toward increased SRS. ^¶P < 0.1 versus baseline; *P < 0.05 versus baseline. SPECT, single photon emission tomography; VEGF, vascular endothelial growth factor.

Figure 3

Myocardial perfusion in patients with normal versus elevated levels of troponin I (TpI). Changes in (a) SSS, (b) SDS, and (c) SRS from baseline to 3 and 6 months (M) were not different between VEGF treated patients that exhibited elevated TpI levels (positive, open bars) compared to those that did not (negative, closed bars). SDS, summed defect score; SRS, summed reversibility score; SSS, summed stress score.

Figure 4

Exercise treadmill time (ETT). Summary data for ETT is presented in total time in minutes (a) and change from baseline (Base) to 3 and 6 months (M) (b). There were no significant differences between the active treatment group (VEGF, closed bars) and the placebo (open bars) controls; however, both groups showed significant improvements in exercise tolerance at 3 and 6 months (b). *P < 0.05 versus baseline; **P < 0.01 versus baseline. VEGF, vascular endothelial growth factor.

Figure 5

Proportion of patients in each CCS angina class (I white, II light shading, III dark shading, and IV black) is presented for (a) placebo and (b) VEGF-treated groups at baseline and at 3 and 6 months of follow-up. All patients exhibited class 3 or 4 symptoms at baseline (Base) by protocol, and there was a progressive increase in the proportion of patients within both groups showing improvement ≥1 CCS class which was highly significant; however, there were no significant differences in change in CCS class from baseline to 3 or 6 months between the VEGF and placebo groups. **P < 0.01 versus baseline. CCS, Canadian Cardiovascular Society; VEGF, vascular endothelial growth factor.

Figure 6

Plasma VEGF levels measured at baseline (Base), 7 days and 1 month in the VEGF (closed bars) and placebo (open bars) groups in a subset of patient at one clinical center. No significant increases in circulating VEGF levels were seen in either group and there were no differences between groups. VEGF, vascular endothelial growth factor.