ARISE: Effects of Succinobucol, an Antioxidant and Anti-inflammatory, on Clinical Events in Patients With Acute Coronary Syndrome

Luis Gruberg, MD, FACC

Disclosures

April 26, 2007

Although the results of ARISE failed to achieve their primary endpoint, the use of succinobucol had a beneficial effect on other hard endpoints that warrant further study.

Presenter: Jean-Claude Tardif, MD (Montreal Heart Institute, Montreal, Quebec, Canada), on Behalf of the ARISE Investigators

The morbidity and mortality of patients with atherosclerotic disease remain elevated regardless of advances in contemporary therapy. Oxidative stress and inflammation have been shown to be involved in the pathogenesis of atherosclerosis.

The first in the class of drugs known as vascular protectants, succinobucol (AGI-1067; Atherogenics Inc., Atlanta, Georgia) is a monosuccinic acid ester of the lipid-lowering agent probucol. The agent has antioxidant and lipid-lowering effects, as well as anti-inflammatory properties.[1] In preclinical studies, it has been shown to reduce atherosclerosis.

Study Design

The Aggressive Reduction of Inflammation Stops Events (ARISE) trial was designed to assess whether adding succinobucol to standard medical therapy would reduce the incidence of cardiovascular events in patients with recent acute coronary syndrome (ACS).

The phase 3, double-blind, placebo-controlled trial was conducted at 261 centers in 4 countries and enrolled patients with ACS occurring 14-365 days before recruitment and either age ≥ 60 years, diabetes, or age ≥ 55 years with ≥ 1 risk factor. Patients were randomized to succinobucol (300 mg/day) or placebo; mean follow-up was 24 months.

Primary endpoints: Composite of cardiovascular death, resuscitated cardiac arrest, myocardial infarction (MI), stroke, unstable angina, or coronary revascularization.

Secondary endpoints:

  • Primary composite endpoint with all-cause death;

  • Primary composite endpoint without coronary revascularization; and

  • Primary composite endpoint without coronary revascularization or unstable angina.

Results

A total of 6144 patients were randomized to succinobucol 300 mg/day (n = 3078) or to placebo (n = 3066). Baseline clinical characteristics were well balanced between the 2 groups; all patients were treated with standard medical therapy ( Table 1 ).

At a mean follow-up of 24 months, the primary endpoint of the study (composite of cardiovascular death, cardiac arrest, MI, stroke, unstable angina, or coronary revascularization) was identical in both the succinobucol and placebo groups (17.2% vs 17.3%, respectively; P = .99). However, the secondary endpoint of cardiovascular death, cardiac arrest, MI, or stroke was significantly lower in patients randomized to succinobucol (6.7% vs 8.2%, P = .028; Table 2 ), accounting for a 19% risk reduction. Of interest, in the succinobucol group, new-onset diabetes was significantly lower but heart failure occurred more frequently than in the placebo group. Overall serious adverse events were not significantly different between the 2 groups ( Table 2 ). The most common side effect, diarrhea, was seen in 3.3% of patients.

Conclusions

  1. The addition of succinobucol to standard medical therapy in patients with recent ACS did not reduce the primary endpoint.

  2. Succinobucol reduced the risk for the hard atherosclerotic composite endpoint of cardiovascular death, cardiac arrest, MI, or stroke by 19%.

  3. Succinobucol was associated with a 64% reduction in new-onset diabetes.

  4. Heart failure hospitalizations tended to be increased by succinobucol.

  5. Although the primary endpoint was not reduced, ARISE indicates that succinobucol may lead to meaningful reductions in the composite of cardiovascular death, MI, and new-onset diabetes.

Viewpoint

Although the results of ARISE failed to achieve their primary endpoint, the use of succinobucol had a beneficial effect on other hard endpoints. In particular, the beneficial effect in the reduction of new-onset diabetes is certainly a promising area that warrants further study.

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