Dr. Granger set up discussion of the 2 trials of the Complement and Reduction of Infarct Size After Angioplasty or Lytics (CARDINAL) program by noting that mortality and development of heart failure remain common after myocardial infarction, even after optimal reperfusion was achieved. No trial in the last 10 years has shown a reduction in mortality with an adjunct treatment for reperfusion, according to Granger, and researchers have remained focused on possible ways in which the cellular damage and inflammation associated with reperfusion techniques can be reduced or eliminated.

The CARDINAL program is a phase II study designed to test whether adjunct use of a complement inhibitor (pexelizumab) could reduce infarct size or improve clinical outcome after reperfusion. The program consisted of 2 trials: the COMPLY trial, in which reperfusion was achieved with thrombolysis, and the COMMA trial, in which reperfusion was achieved with angioplasty.

Characteristics of CARDINAL patients and their clinical presentation are shown in the table below.

Because pexelizumab's point of action in the complement cascade is at generation of C5a and C5b-9 fragments (which have strong inflammatory activity), there is hypothetical preservation of anti-bacterial activity through C3b, which is produced earlier in the cascade. However, both trials excluded patients with deficiencies of white blood cells or evidence of infection.

Each trial had 3 treatment arms from which data were generated: placebo, pexelizumab 2.0 mg/kg bolus over 10 minutes, and pexelizumab bolus followed by 1.0 mg/kg infusion over 20 hours.

The primary endpoint was infarct size determined by the area under the curve for CK-MB level with use of a log rank test. Secondary endpoints were clinical composite at 90 days (death, development of heart failure, cardiogenic shock, or stroke), as well as incidence of each clinical component.

Data from the trial with thrombolysis as primary therapy (COMPLY trial) show no difference in infarct size or clinical composite with use of bolus or bolus/infusion use of pexelizumab.

Data from the trial with angioplasty as primary therapy (COMMA trial) show that there was no drug effect on infarct size or clinical composite endpoint at 90 days. However, the investigators were pleasantly surprised to see a statistical difference in all-cause 90-day mortality (1.8% for bolus/infusion, 4.1% for bolus, and 5.9% for placebo).

Data from both trials showed that pexelizumab is effective as a complement inhibitor (complete inhibition of hemolysis for 4 hours with bolus, 24 hours with bolus followed by infusion). Safety data indicate it is well tolerated at the dosages used in the trial.

Dr. Granger said that the findings of safety and efficacy in reducing mortality (both trials and COMMA trial respectively) suggest that complement inhibition may have a clinical benefit through a mechanism other than reduction in volume of infracted myocardium. Additional research is indicated.