Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis - VIVA

Description:

The goal of the Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis (VIVA) trial was to evaluate the safety and efficacy of intracoronary (IC) and intravenous (IV) infusions of recombinant human vascular endothelial growth factor protein (rhVEGF) in patients with chronic myocardial ischemia unsuitable for standard revascularization.

Hypothesis:

To assess the safety and efficacy of rhVEGF in patients with chronic myocardial ischemia unsuitable for standard revascularization.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 178
Mean Follow Up: 120 days
Mean Patient Age: Mean age 60
Female: 11

Patient Populations:

Age 40 to 75 years, stable exertional angina and areas of viable but underperfused myocardium according to perfusion imaging, judged unsuitable for revascularization on the basis of coronary angiography within the previous six months, and ability to exercise between 3 and 11 minutes on an ETT

Exclusions:

Unstable angina, MI, or CABG within the previous six months; percutaneous coronary intervention within the previous three months; previous myocardial laser revascularization or angiogenic growth factor treatment; ejection fraction <25%, pregnancy, history of cancer within the previous five years; proliferative retinopathy or macular degeneration; renal insufficiency; or other severe concurrent illness

Primary Endpoints:

Change in exercise treadmill time from baseline to 60 days

Secondary Endpoints:

Change in ETT time from baseline to day 120, rest and exercise myocardial perfusion imaging on day 60, and angina class and QOL measurements at days 60 and 120

Drug/Procedures Used:

Patients were randomized to placebo (n=63), low-dose (17 ng/kg/min, n=56), or high-dose (50 ng/kg/min, n=59) IC and IV recombinant VEGF. IC infusions were given over 20 minutes, and IV infusions were administered on days 3, 6, and 9 over a four-hour period.

Principal Findings:

At 60 days, there were no significant differences in the treadmill exercise times between patient groups. The exercise times at 60 days increased by 48 seconds for the placebo group, 30 seconds for low-dose rhVEGF (p=0.52), and 30 seconds for high-dose rhVEGF (p=0.45). At 120 days, the exercise treadmill test (ETT) trended higher in the high-dose group versus placebo (48 seconds vs. 24 seconds, p=0.15).

There was no significant change in angina class at 60 days. The mean angina class at baseline was 2.8 in the placebo group, and 2.6 in both the low- and high-dose rhVEGF groups. Mean angina class at 60 days was 2.0, 1.9, and 1.8 for the placebo, low-dose, and high-dose arms (p=NS for between group comparisons), and at 120 days was 2.1, 1.8, and 1.6, respectively (p<0.05 for high-dose vs. placebo comparison). Quality-of-life (QOL) assessments using the Seattle Angina Questionnaire showed no differences at baseline. At 60 days of follow-up, there was an improvement in QOL compared with baseline, but no significant differences between patients treated with placebo or rhVEGF.

Therapy with rhVEGF appeared to be safe, with no excess adverse effects in the treatment arms. Two patients in the placebo group died. No patients in the rhVEGF arms died. There were no myocardial infarctions (MIs) during follow-up. Three placebo patients developed cancer, whereas no VEGF patients were diagnosed with malignancy. Hospital admission was required for angina in four placebo patients, six low-dose rhVEGF patients, and four high-dose rhVEGF patients.

Laboratory data showed no thrombocytopenia, proteinuria, or other changes in electrolyte or hematologic parameters.

Interpretation:

Among patients with chronic myocardial ischemia unsuitable for standard revascularization, treatment with IC and IV rhVEGF was safe and well-tolerated, but showed no difference in the primary end point of change in exercise treadmill time at 60 days compared with placebo.

VIVA was the first randomized, double-blind, placebo-controlled trial using rhVEGF for therapeutic angiogenesis. The trial was powered to detect a two-minute improvement in ETT in rhVEGF-treated patients compared with placebo, given the findings of earlier Phase I trials. A notable placebo effect was evident at 60 days, with a mean improvement in ETT of 48 seconds in the placebo arm.

The trend toward longer ETT and improvement in angina class by 120 days in the high-dose arm suggests longer follow-up may be required to see a treatment effect.

References:

Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation. 2003;107:1359-65.

Presented at the ACC 48th Annual Scientific Session, New Orleans, LA, 1999.

Keywords: Electrolytes, Myocardial Ischemia, Neoplasms, Myocardial Infarction, Follow-Up Studies, Proteinuria, Vascular Endothelial Growth Factor A, Quality of Life, Placebo Effect, Questionnaires, Thrombocytopenia, Exercise Test


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