Chicago IL - A bioengineered anticomplement antibody with a tongue-twister name has joined a long list of potentially cardioprotective agents, especially anti-inflammatories, that should have improved outcomes after acute-MI reperfusion therapy based on experimental and early clinical research but failed when tested in a randomized, placebo-controlled trial [1].

An infusion of pexelizumab given with PCI, predominantly with stents, didn't reduce mortality or the risk of reinfarction, shock, or other complications in patients with acute ST-segment-elevation MI (STEMI) compared with PCI alone, in a study reported here today at the American Heart Association 2006 Scientific Sessions. The rate of death was about 4% at 30 days and approached 5% at 90 days in both the pexelizumab and placebo groups.

Dr Paul W Armstrong

During his formal presentation of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial, Dr Paul W Armstrong (University of Alberta, Edmonton) said the comparable outcomes could have been the result of the exceptionally good background medical therapy in both patient groups that included other anti-inflammatory agents. Other possible reasons, he said, include failure of the drug to reach sites of inflammation within the myocardium or a persistence of non-complement-mediated inflammation.

Armstrong described pexelizumab as an antibody fragment that blocks activation of complement C5, which is involved in inflammation, vasoconstriction, leukocyte activation, and apoptosis.

At the time of enrollment, Armstrong reported, virtually all of the study's more than 5000 patients were on aspirin and 84% were on ACE inhibitors. The rates of statin, thienopyridine, and beta-blocker use were each about 94%. Almost 70% of the PCI procedures involved glycoprotein IIb/IIIa-receptor blockers.

Outcomes at 30 days in APEX-AMI (revised end points and time frame)

End point	Pexelizumab, n= 2860 (%)	Placebo, n=2885 (%)
All-cause mortality*	4.06	3.92
Death, shock, or HF	8.99	9.19

Dr Timothy J Gardner

"I think that this was a very important targeted agent, and the fact that it was not effective would suggest that this line of investigation [suppression of inflammation during MI reperfusion therapy] may not be fruitful," Dr Timothy J Gardner (Christiana Care Health Services, Wilmington, DE), chair of the AHA program committee, said to heartwire.

Dr Robert A Kloner (Good Samaritan Hospital, Los Angeles, CA), one of the field's premier experts, told heartwire, "It's an important negative study that suggests maybe pursuing this concept of preventing reperfusion injury by inhibiting the early healing phase of myocardial infarction is perhaps not the right way to go, in terms of seeing benefits in outcomes and reduction of infarct size. . . . If you inhibit early healing, you actually may worsen remodeling and you may cause infarct expansion. We showed that many years ago with steroids and nonsteroidal anti-inflammatory agents."

Dr Robert A Kloner

As the discussant after Armstrong's presentation of APEX AMI, Kloner went into more detail. "The concept that inflammation itself is causing a so-called reperfusion injury, or killing additional myocardial cells, is in my opinion, unproven. Yes, a large infarct is going to have more inflammation, neutrophils, and macrophages, and a smaller infarct will have a smaller zone of inflammation. But this should not be misinterpreted to mean that inflammation caused myocardial-cell death to begin with. The initial degree and duration of ischemia and the size of the ischemic area are the culprits. A bigger area of necrosis results in a bigger area of inflammation."

Other acute therapies intended to fight inflammation or otherwise limit infarct size that failed in clinical trials, according to Kloner's presentation, include oxygen free-radical scavengers, anti-white-blood-cell adhesion molecules, n-3 fatty acids, and various devices for trapping potentially embolic debris released at PCI.

Dr Judith S Hochman

Dr Judith S Hochman (New York University School of Medicine, NY), who is a member of the APEX-MI steering committee, had apparently not entirely written off the use of anti-inflammatory agents in acute MI when interviewed by heartwire. "I am getting very pessimistic about inhibiting reperfusion injury," she said. "I'm very disappointed that blocking the activation of the systemic inflammatory cascade did not improve outcomes. I really thought that it was going to be beneficial. It's clear to me that some of the genesis and persistence of cardiogenic shock is due to systemic inflammation. The problem is we haven't hit the nail on the head as to how to interrupt it."

During his presentation of APEX-AMI, Armstrong said that anti-inflammatory agents might still turn out to be helpful in MI patients with unsuccessful reperfusion therapy or who are treated late after infarction onset, who often don't fare as well as those who achieve early infarct-related artery patency.

"Mechanistically, I think we're all convinced that inflammation plays a role [in the evolution of acute MI], Armstrong told heartwire. "I think patients who have long occlusions with big infarcts who are reperfused likely have a lot more of this complement activation." The concept of anti-inflammatory therapy for acute MI "isn't dead," he said, but it may be unlikely that clinical trials will show additional benefit from giving yet another drug with anti-inflammatory properties to patients already on comprehensive contemporary medical therapy.

APEX-AMI randomized 5745 patients undergoing PCI as the primary reperfusion therapy of acute anterior or "high-risk inferior" (characterized by pronounced ST-segment shifts) STEMI to receive placebo or pexelizumab as a 2-mg/kg bolus followed by a 0.05-mg/kg-per-hour infusion for 24 hours. The patients had been enrolled at 296 centers in 17 countries, primarily in North America and Europe.

The two APEX AMI randomization groups were similar with respect to systolic blood pressure, Killip class distribution, prevalence of inferior-wall infarctions, time from symptom onset to treatment, and how often stents were used at PCI (about 89% for each group).

The prospectively planned enrollment target had been 8500 patients, but when an interim analysis showed a lower-than-expected overall mortality for patients already in the trial, the target was revised and the primary end point was changed from 90-day all-cause mortality to the same outcome at 30 days. According to an agreement reached by the investigators, regulators, and the sponsors, Proctor & Gamble Pharmaceuticals and Alexion Pharmaceuticals, patient enrollment stopped in May 2006 and follow-up continued for another 30 days [2]. As previously reported by heartwire, the sponsors had wanted to halt the trial in 2005 after pexelizumab failed to show a benefit in two trials of patients undergoing coronary bypass surgery but relented with encouragement from the investigators.

There was no significant difference between the two groups in all-cause mortality at 90 days or in the 90-day rates of cardiogenic shock, reinfarction, or stroke. Rates of renal failure and moderate to severe bleeding were about the same. Subgroup analyses disclosed no significant pexelizumab effect by age, sex, infarct location, or Killip class.

Outcomes at 90 days in APEX AMI

End point	Pexelizumab, n= 2860 (%)	Placebo, n=2885 (%)
All-cause mortality*	4.51	4.93
Incident heart failure	4.82	4.76
Cardiogenic shock	3.47	3.36
Reinfarction	2.39	3.04
Stroke	1.18	1.36

Although the rate of severe infection within two weeks of PCI was about the same in both groups, there was a statistical trend toward fewer cases of sepsis among patients who received pexelizumab, according to Armstrong's presentation. The hazard ratio for sepsis in actively treated patients relative to the control group was 0.62 (95% CI 0.33-1.16).

The sepsis findings, Kloner said, are "almost paradoxical" and suggest that "there might be other uses of this therapy outside of acute MI, possibly in infection, possibly in shock."

APEX-AMI was funded by Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals. Armstrong and other coauthors are recipients of research grants from both companies. Members of the trial's steering committee received honoraria for their participation. Coauthor Dr Peter X Adams is an Alexion employee. Coauthor Dr Thomas G Todaro is an employee of P&G.