AGI-1067 is a lipophilic vascular protectant with strong antioxidant properties equal to those of probucol. While clinical trial evidence shows probucol to prevent coronary restenosis after balloon angioplasty, its toxicity (increases in QT interval) and pharmacokinetic profiles are less than optimal. It was removed from the U.S. market.

The CART-1 primary objective was to determine whether AGI-1067 given for 2 weeks before and 4 weeks after percutaneous coronary intervention, with or without stent placement, reduces restenosis as assessed by intravascular ultrasound. In the multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo, probucol 500 mg twice daily, or one of 3 AGI-1067 doses (70, 140 or 280 mg). Patients underwent coronary interventions of one or more lesions not previously treated. The treated vessels were native and had 50% or greater narrowing.

Overall, 305 patients were randomized, with 81% receiving stents. Evaluation of QTc interval showed increases of >60 msec at any follow-up visit in significantly (p=0.02) more patients in the probucol arm than in any other arm of the trial.

At follow-up, minimal lumen area at the coronary intervention site detected by intravascular ultrasound was significantly higher for probucol (p=0.01) and for AGI-1067 280 mg (p=0.046) than placebo. There was no significant difference between AGI-1067 and probucol. Lumen volume assessment showed the same pattern versus placebo, AGI-1067 280 mg (p=0.035, probucol p=0.02). The primary endpoint of restenosis occurred in 37.5% of placebo patients, 25.5% of probucol patients and in 26.0% of AGI-1067 patients.

Ultrasound assessment of lumen volume change in reference segments (non-intervention sites) showed -0.2 mm³ for probucol, +3.5 mm³ and +1.8 mm³ for the AGI-1067 140 mg and 280 mg doses, respectively.

The investigator concluded that both AGI-1067 and probucol reduce restenosis after percutaneous coronary intervention, but that only AGI-1067 improved lumen dimensions of the reference segments. Also, AGI-1067 did not cause prolongation of the QTc interval. Prolonged therapy with AGI-1067 may result in the prevention of both restenosis and atherosclerosis.

The discussant, David O. Williams, Providence, Rhode Island, said that a larger trial will be needed to determine if the magnitude of effect with AGI-1067 is enough to be clinically important.