CHICAGO — The investigational C5 complement inhibitor pexelizumab had no effect on mortality or morbidity in a massive clinical trial involving primary percutaneous coronary intervention for ST-elevation MI, Dr. Paul W. Armstrong said at the annual scientific sessions of the American Heart Association.
Based on the negative results of the 5,745-patient Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial, pexelizumab now joins the lengthy list of once-promising anti-inflammatory therapies that ultimately failed to prevent myocardial cell damage due to reperfusion therapy, added Dr. Armstrong, professor of medicine at the University of Alberta, Edmonton, and chairman of APEX AMI.
The repeated failed trials have caused some observers to question the whole strategy of trying to improve MI outcomes by impeding the early inflammatory process involved in reperfusion injury.
APEX AMI was a double-blind, placebo-controlled study involving close to 6,000 patients with an anterior or high-risk inferior MI who presented within 6 hours of symptom onset to nearly 300 participating centers in 17 countries. All underwent primary PCI; 36% required transfer to do so, further boosting the overall risk status. Patients got placebo or a bolus of pexelizumab followed by a 24-hour infusion.
The primary end point was 30-day all-cause mortality: 4.06% with pexelizumab, 3.92% with placebo. Based upon the favorable results of smaller phase II studies, investigators had expected pexelizumab would cut mortality by one-quarter.
The unexpectedly low mortality in the placebo arm highlights the efficacy of contemporary MI therapy. “We had projected that the placebo group would have a mortality of 6.5%, so this was a striking and important surprise for us,” Dr. Armstrong noted.
The secondary end point was 30-day death, cardiogenic shock, or heart failure: 8.99% with pexelizumab, 9.19% with placebo.
In addition to the possibility that phase II studies painted an overly rosy picture due to the play of chance, Dr. Armstrong said, another possible explanation for the negative results in APEX AMI is that pexelizumab failed to penetrate into heart tissue, where the inflammatory process involved in reperfusion injury takes place.
But discussant Dr. Robert A. Kloner proposed a more sweeping alternative explanation: “Perhaps interfering with the early inflammatory process of the MI—which really is the first step of healing—is not the correct approach.”
It could even have long-term deleterious consequences, including infarct zone expansion, worsened left ventricular dilation, and aneurysm formation. Such effects have been seen with the use of corticosteroids and NSAIDs in acute MI, according to Dr. Kloner, professor of medicine at the University of Southern California, Los Angeles.
Among the other therapies that have failed to work in clinical trials are oxygen radical scavengers, anti-WBC adhesion molecules, magnesium, and antibiotics.
Pexelizumab is a humanized monoclonal antibody that binds specifically to the C5 fraction of complement, blocking its cleavage into injurious components such as the membrane attack complex.
APEX AMI was jointly funded by Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals.
'We had projected that the placebo group would have a mortality of 6.5%, so this was a striking … surprise for us.' DR. ARMSTRONG