Aggressive Reduction of Inflammation Stops Events - ARISE

Jun 04, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
AtheroGenics Inc.
Date Presented:
01/01/2007
Date Published:
01/01/2008
Date Updated:
06/04/2008
Original Posted Date:
06/04/2008
References

Description:

The goal of the trial was to evaluate treatment with the novel antioxidant agent succinobucol compared with placebo among high-risk patients with recent acute coronary syndrome (ACS).

Hypothesis:

Succinobucol will be more effective among high-risk patients with recent ACS.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded

Patients Screened: 6,635
Patients Enrolled: 6,144
Mean Follow Up: 24 months
Mean Patient Age: 65 years
Female: 28

Patient Populations:

Hospitalized for acute MI or unstable angina in the prior 14-365 days and either: 1) age ≥60 years, 2) diabetes, or 3) age ≥55 years with ≥1 risk factor

Exclusions:

Bypass surgery in the prior 90 days or percutaneous coronary intervention in the prior 28 days, moderate or severe symptomatic heart failure, uncontrolled hypertension, serum creatinine ≥2.5 mg/dl, elevated liver enzymes, use of medications prolonging the QT interval >15 ms, or expected survival <2 years

Primary Endpoints:

Composite of CV death, cardiac arrest, MI, stroke, unstable angina, or coronary revascularization

Secondary Endpoints:

Primary endpoint plus all-cause death; primary endpoint without coronary revascularization; or primary endpoint without unstable angina or coronary revascularization (CV death, cardiac arrest, MI, or stroke)

Drug/Procedures Used:

Following a 14-day placebo run-in phase, patients were randomized in a double-blind manner to treatment with succinobucol (300 mg/day, n = 3,078) or placebo (n = 3,066).

Concomitant Medications:

At baseline, the use of aspirin was 92%, clopidogrel was 56%, statin was 91%, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was 74%, beta-blocker was 80%, and antidiabetic medication was 31%.

Principal Findings:

At baseline, 72% of patients had experienced a prior myocardial infarction (MI) and 83% had undergone prior revascularization. Diabetes was present in 37% of patients. Mean baseline low-density lipoprotein (LDL) was 87 mg/dl and high-density lipoprotein (HDL) was 45 mg/dl. LDL was increased in the succinobucol group, but did not change in the placebo group, whereas HDL was reduced in the succinobucol group, but did not change in the placebo group.

There was no difference in the primary composite endpoint between treatment groups (17.2% for succinobucol vs. 17.3% for placebo, hazard ratio [HR] 1.00, p = 0.96). The secondary endpoint of cardiovascular (CV) death, cardiac arrest, MI, or stroke was lower with succinobucol than placebo (6.7% vs. 8.2%, HR 0.81, p = 0.028). New-onset diabetes was lower in the succinobucol group (1.6% vs. 4.2%, p < 0.0001). New-onset atrial fibrillation was more common in the succinobucol group (3.8% vs. 2.0%, p = 0.0002).

Heart failure was marginally increased with succinobucol (3.5% vs. 2.7%, p = 0.09). Bleeding was marginally increased with succinobucol (1% vs. 0.6%, p = 0.07).

Interpretation:

Among high-risk patients with recent ACS, treatment with the novel antioxidant agent succinobucol was not associated with a difference in the primary endpoint of CV death, cardiac arrest, MI, stroke, unstable angina, or coronary revascularization compared with placebo at 2-year follow-up.

While some endpoints such as the new-onset diabetes and the composite of CV death, cardiac arrest, MI, and stroke were in favor of succinobucol, others such as heart failure and bleeding showed higher event rates with succinobucol. Additionally, the increase in LDL and decrease in HDL over time with succinobucol despite high rates of background statin therapy (~90%) was puzzling. Further data are required to more precisely delineate the efficacy and safety of this agent.

References:

Tardif JC, McMurray JJ, Klug E, et al., on behalf of the Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008;317:1761-8.

Presented by Dr. Jean-Claude Tardif at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.

Keywords: Lipoproteins, LDL, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Heart Failure, Coronary Disease, Heart Arrest, Lipoproteins, HDL, Diabetes Mellitus, Probucol


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