Na+/H+ Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions - EXPEDITION

Description:

The goal of the trial was to evaluate the efficacy of treatment with cariporide compared with placebo in reducing death or myocardial infarction (MI) in high-risk patients undergoing coronary artery bypass graft (CABG).

Hypothesis:

Treatment with cariporide will be associated with a reduction in death or MI compared with placebo in high-risk patients undergoing CABG surgery.

Study Design

Study Design:

Patients Enrolled: 5,770
Mean Follow Up: Six months

Patient Populations:

Patients undergoing bypass surgery; considered at high risk of postsurgical MI due to emergency bypass surgery, repeat surgery, left main disease, or had another risk factor for complications including age >65 years, female, diabetic, or heart failure

Primary Endpoints:

Death or MI by five days

Secondary Endpoints:

Death or MI by 30 days and six months

Drug/Procedures Used:

Patients were randomized to intravenous treatment with either cariporide (n=2,870) or placebo (n=2,891) for two hours prior to surgery and continuing for 49 hours after surgery. Cariporide dosage was 180 mg for one hour prior to surgery, followed by 40 mg/h for 24 hours and 20 mg/h for 24 hours. The trial was designed to enroll 7,000 patients (3,500 patients per arm).

Principal Findings:

The trial was discontinued early at the recommendation of the Data Safety Monitoring Board to explore the risks and benefits seen with cariporide therapy. The primary composite endpoint of death or MI at day five was lower in the cariporide arm compared with placebo (16.6% vs. 20.3%, relative risk reduction [RRR] 18.3%, p=0.0002), with similar results at 30 days (18.3% vs. 21.8%, RRR 16.1%, p=0.0009) and six months (20.2% vs. 23.9%, RRR 15.7%, p=0.0006).

The composite endpoint was driven by a reduction in MI in the cariporide arm (14.4% vs. 18.9% at five days, p<0.0001; 13.8% vs. 18.5% at six months, p<0.0001), while mortality was low overall, but directionally favored the placebo arm (2.2% vs. 1.5% at day five, p=0.028; 6.4% vs. 5.4%, p=0.11 at six months).

Cerebrovascular events were higher in the cariporide arm at both five days (3.0% vs. 1.3%) and six months (4.5% vs. 2.4%, p<0.0001), and were primarily ischemic strokes. Other increases in adverse events were seen with the cariporide arm in the renal system (3.0% vs. 1.7%, p<0.01) and nervous system (4.5% vs. 1.9%, p<0.01).

Interpretation:

Among high-risk patients undergoing CABG surgery, treatment with cariporide was associated with a reduction in the primary endpoint of death or MI at day five compared with placebo, but was associated with an increase in cerebrovascular adverse events, prompting the trial to be discontinued early to weight the risk-benefit profile.

The goal of cariporide therapy is to prevent calcium overload and subsequently reduce cardiac stunning. Other therapies have shown success in reducing ischemia and reperfusion injury in post-CABG patients, including adenosine.

References:

Presented by Dr. Robert M. Mentzer, Jr., at the November 2003 American Heart Association Annual Scientific Sessions, Orlando, FL.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Cardiac Surgery and Heart Failure, Acute Heart Failure, Interventions and Vascular Medicine

Keywords: Myocardial Infarction, Stroke, Guanidines, Clinical Trials Data Monitoring Committees, Risk Factors, Sulfones, Calcium, Reperfusion Injury, Reoperation, Heart Failure, Risk Assessment, Coronary Artery Bypass, Diabetes Mellitus


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