Negative FIRE Trial Retains Flicker of Hope

September 02, 2008

September 2, 2008 (Munich, Germany) — A new small peptide compound, FX06, for reperfusion injury, has failed to reduce the primary end point, infarct size, in an exploratory phase 2 study, FX06 in Ischemia and Reperfusion (FIRE), in patients with ST-elevation MI (STEMI) undergoing primary PCI. Dr Dan Atar (Aker University Hospital, Oslo, Norway) reported the findings at a hotline session here today.

Although the compound failed to reduce the primary end point, Atar said it did significantly reduce the size of the necrotic core zone, something he says is very important. "This was an exploratory study, so the choice of primary end point was an arbitrary measure," he told heartwire . "We chose the gray zone around the infarction, which is not as relevant for prognosis and for the infarction scarring process as the true necrotic core."

But discussant of the study, Dr Michael S Marber (Kings College, London, UK), said this was essentially another failed trial of the anti-inflammatory approach to reperfusion injury. "Every single anti-inflammatory intervention study for reperfusion injury has been negative, and for that reason I am going to be fairly critical of this study," he noted.

Almost 60% Reduction in Size of Necrotic Core With FX06

Atar explained that there is a risk of reperfusion injury with PCI and that there is currently no successful pharmacological strategy to reduce this. FX06 is an anti-inflammatory and vasoprotective compound that inhibits the binding of the fibrin E1 fragment to vascular endothelial cadherin, a target on the surface of endothelial cells. It is under development by a small start-up biotech company, Fibrex Medical, based in Vienna, Austria.

In this exploratory study, 234 STEMI patients due to undergo primary PCI for their first MI were randomized to receive either 400 mg of FX06 (n=114) or placebo (n=120) intravenously at the start of the PCI procedure--when the guidewire was passed through the lesion--and 10 minutes later, which was generally when reperfusion was established.

Infarct size as measured by MRI after five days was the primary outcome, and the same measure after four months was a secondary outcome. Other end points included biomarkers at four months and major adverse clinical events (MACE).

Atar noted that there was a high degree of large infarctions in this study population, which involved patients from 26 leading interventional cardiology sites in Europe.

After five days there was no difference in the primary end point between the groups (p=0.207), but when just the necrotic core of the infarct was considered, those who had received FX06 had a smaller area (1.77 g) compared with those who got placebo (4.2 g; p=0.019), a 58% reduction.

After four months, the resulting scar mass was decreased by 37% in those who received FX06. Although this was not a statistically significant reduction, it suggests that reducing reperfusion injury may lead to less scar-tissue formation, Atar said.

There were also no significant differences between the groups in terms of biochemical markers of cardiac necrosis or in left ventricular ejection fraction (LVEF), although these trended in favor of FX06.

But is Benefit Simply Due to Reduction in Edema?

Marber said there were several shortcomings with the study. First and foremost, he said, the relative contributions of ischemia and inflammation to reperfusion injury are not known, thereby making it difficult to understand how important an anti-inflammatory agent would be. But the fact that every other single trial that has tried this approach in reperfusion injury has failed to show a benefit must say something, he said.

He criticized the units chosen to express infarct size--grams--"usually infarct size is assessed as a percentage of LVmass," he noted. "And we don't know if the necrotic core was a prespecified analysis," he added. It's also possible that the early observation of the reduction in the size of the necrotic core at five days "could simply have been due to a reduction in edema with FX06, as there were no significant differences whatsoever" in any of the end points by MRI at four months.

In terms of safety, there was no difference in adverse events between those who received FX06 and those who got placebo. "There were no safety signals with FX06: no arrhythmogenic potential, no thrombogenic potential, and no hypotension," Atar noted, and Marber agreed that this was indeed the case. But "the positive trends seen in biomarkers and some MRI outcomes require verification in a larger trial," he added.

Atar told heartwire a much larger study is being discussed, in which it is hoped 4000 patients from centers in North America, Europe, and possibly elsewhere will be included: "We will have a meeting with the FDA in November," he said.

Fibrex Medical Research and Development sponsored the trial. Atar has received honoraria from the company. Marber reports no conflicts of interest.

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