EXPEDITION: Sodium-Proton Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions Trial

Luis Gruberg, MD, FACC

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Robert M. Mentzer Jr, MD, University of Kentucky (Lexington)

Myocardial infarction (MI) and reperfusion injury occur frequently following coronary artery bypass graft (CABG) surgery. One mechanism that has been implicated in this process is the excess accumulation of intracellular calcium, which leads to myocyte injury, necrosis, and cardiac enzyme release. The inhibition of the sodium-hydrogen inhibitor (NHE-1) is one proposed method to prevent the accumulation of intracellular calcium.

Aim

The Sodium-Proton Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions (EXPEDITION) trial was designed to investigate whether treatment with the NHE-1 inhibitor, cariporide, could reduce the incidence of death or MI in patients undergoing CABG surgery.

Endpoints

The primary endpoint of the EXPEDITION trial was the reduction in the combined incidence of all-cause mortality and nonfatal MI at day 5.

The secondary endpoint of the study was the reduction in the composite endpoint at 30 days and at 6 months.

Tertiary endpoints included reductions in the incidence of low cardiac output syndrome and other events related to left ventricular dysfunction.

Study Design

EXPEDITION was a multicenter, double-blind, randomized, placebo-controlled, parallel-group trial comparing cariporide with placebo in CABG patients at high risk for perioperative myocardial ischemia. High-risk features and inclusion criteria included:

  • Urgent or emergent CABG

  • Repeat CABG

  • Double/triple vessel disease and history of unstable angina with at least 1 high-risk factor:

    • Age > 65

    • Diabetes

    • Female gender

    • Ejection fraction < 35%

Patients were randomized to either intravenous (IV) cariporide (180 mg for 1 hour followed by a 24-hour infusion of 40 mg/hour followed by 20 mg/hour for 24 hours) or matching placebo.

After the second interim analysis and enrollment of 5761 patients, the trial's Data Safety and Monitoring Board advised investigators to close enrollment and initiate analysis "to better understand the risks and benefits associated with treatment."

Results

Intention-to-treat analysis revealed a significant reduction in the combined endpoint of death/MI at day 5, day 30, and at 6 months in patients randomized to cariporide (Figure 1). Use of the drug was also associated with a significant reduction in nonfatal MI (Figure 2).

Figure 1. EXPEDITION: death/MI.
Figure 2. EXPEDITION: nonfatal MI.

Despite the observed benefits of cariporide with regard to the combined endpoint and the incidence of nonfatal MI, use of the drug was associated with a significantly higher rate of mortality at days 5 and 30 and at 6 months compared with placebo (Figure 3).One potential explanation for this increase in mortality was the noted significant increase in the rate of cerebrovascular events in the cariporide group (P < .001) (Table).

Figure 3. EXPEDITION: mortality.
Table. Adverse Events
Adverse Event Placebo
(n = 2839)
Cariporide
(n = 2805)
Cardiac (%) 4.2 3.4
Gastrointestinal (%) 0.7 1.1
Hepatobiliary 9%) 0.5 0.7
Nervous system (%)* 1.9 4.5
Focal cerebrovascular events (%) 2.4 4.5
Renal (%)* 1.7 3.0
Respiratory (%) 2.9 4.0
*P < .01
Conclusions

On the basis of the results of EXPEDITION, investigators concluded that:

  • There is a significant incidence of nonfatal MI after CABG surgery

  • EXPEDITION demonstrated a marked and statistically significant reduction in the composite primary endpoint of death or nonfatal MI in patients treated with cariporide

  • For the first time, the feasibility of pharmacologic protection during CABG surgery was demonstrated

  • Whether it is possible to dissociate the adverse effects from the beneficial effects of cariporide remains to be determined

Discussant

Richard D. Weisel, MD, University of Toronto (Ontario, Canada), commented that mortality following CABG surgery is currently very low (1% to 2%), whereas the incidence of electrocardiographic changes, enzyme elevation, and periprocedural myocardial injury is approximately 10%. Therefore, according to Dr. Weisel, every effort should be made to try to reduce clinical perioperative events with myocardial protection during cardiac surgery to increase event-free survival.

Cardioplegia is the most common method of myocardial protection currently used during cardiac surgery, but cardioplegic additives are the future that may help resuscitate ischemic cardiomyocytes and restore endothelial function. For this purpose, several agents have been tried, such as acadesine, adenosine, insulin, arginine, and now cariporide.

Cariporide has demonstrated its ability to protect the heart during cardiac surgery, but unfortunately, according to the results of EXPEDITION, increases the risk of stroke. Dr. Weisel proposed that a potential solution to avoid this problem may be to reduce the dose, deliver a low dose directly to the heart, or perhaps to combine the drug with other pharmacotherapy. He concluded that the cardiac surgeon has a unique opportunity to modify ischemic injury, resuscitate myocytes, restore normal endothelial function, and reduce perioperative events to improve long-term survival.

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