Complement and Reduction of Infarct Size After Angioplasty or Lytics - CARDINAL

Description:

CARDINAL was a randomized, multi-dose study of the humanized anti-C5 complement monoclonal antibody fragment pexelizumab added to either thrombolytic therapy or percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (MI).

Hypothesis:

The addition of pexelizumab to either thrombolytic therapy or PCI will result in a reduction of infarct size at 72 hours.

Study Design

Study Design:

Patients Enrolled: 1,903
Mean Follow Up: 90 days for composite endpoint; 6-month mortality.
Female: 24

Patient Populations:

Symptom onset <6 hrs; >=2 mm ST elevation in >=2 leads or new left bundle branch block.

Exclusions:

Known anemia or thrombocytopenia, complement deficiency, active infections, renal insufficiency.

Primary Endpoints:

Creatine kinase-MB area under the curve

Secondary Endpoints:

Composite of death, heart failure, shock, or disabling stroke at 90 days; death at 6 months.

Drug/Procedures Used:

There were 2 distinct stratified groups in the CARDINAL trial: 1) the thrombolytic arm, named the COMPLY strategy and 2) the PCI arm, named the COMMA strategy. After stratification, patients were randomized to either placebo (PCI or thrombolytic, depending on the arm); 2.0 mg/kg/10 min bolus of pexelizumab; or 2.0 mg/kg/10 min bolus of pexelizumab plus infusion of 0.05 mg/kg/hr pexelizumab for 20 hours.

Principal Findings:

COMPLY thrombolytic strategy: Complement was effectively inhibited to 4 hours in the bolus arm and at 24 hours in the bolus plus infusion arm. There was no difference in infarct size as measured by the CKMB area under the curves at 72 hours between the 3 arms (p=0.85 for the placebo vs bolus comparison; p=0.81 for the placebo vs bolus+infusion comparison). There was no difference in the 90-day composite event rate between the 3 arms (18.6% placebo vs 18.4% bolus vs 19.7% bolus+infusion, p=0.84). COMMA PCI strategy: Complement was effectively inhibited to 4 hours in the bolus arm and at to 24 hours in the bolus plus infusion arm. There was no difference in infarct size as measured by the CKMB area under the curves at 72 hours between the 3 arms (p=0.89 for the placebo vs bolus comparison; p=0.76 for the placebo vs bolus+infusion comparison). There was no difference in the 90-day composite event rate between the 3 arms (11.1% placebo vs 10.7% bolus vs 8.4% bolus+infusion, p=0.39). Mortality at 6-months was lower in pexelizumab treated patients (7.4% placebo vs 4.2% bolus vs 3.2% bolus+infusion, p=0.018).

Interpretation:

Infarct size, the primary endpoint of the trial, showed no difference between placebo and pexelizumab in either the COMPLY thrombolytic strategy or the COMMA PCI strategy, nor was there a difference in the secondary composite clinical endpoint at 90-days. The only clinical benefit shown was 6-month mortality in the COMMA PCI strategy; however, the number of deaths was very small (n=16 for placebo, n=11 for pexelizumab bolus, n=5 for pexelizumab bolus+infusion). Due to the small number of events, the secondary endpoint nature of the analysis, and the lack of consistent benefit in other clinical endpoints, conclusions regarding a mortality benefit must be drawn cautiously.

References:

1. Mahaffey KW, Granger CB, Nicolau JC, Ruzyllo W, Weaver WD, Theroux P, Hochman JS, Filloon TG, Mojcik CF, Todaro TG, Armstrong PW. Effect of Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Fibrinolysis in Acute Myocardial Infarction. The COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) Trial. Circulation. 2003;108:1176-1183. 2. Granger CB, Mahaffey KW, Weaver WD, Theroux P, Hochman JS, Filloon TG, Rollins S, Todaro TG, Nicolau JC, Ruzyllo W, Armstrong PW. Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction. The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) Trial. Circulation. 2003;108:1184-1190. 3. Presented at AHA 2002, late breaking clinical trials.

Clinical Topics: Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Novel Agents

Keywords: Antibodies, Monoclonal, Humanized, Thrombolytic Therapy, Myocardial Infarction, Bundle-Branch Block, Fibrinolytic Agents, Complement C5, Single-Chain Antibodies, Percutaneous Coronary Intervention


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