A Multicenter, Double blind, Randomized, Placebo Controlled Study to Measure the Effect of FX06 on Ischemia Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention (The F.I.R.E Trial). 

Presenter report: Atar, Dan (Norway

Background: FX06, a naturally occurring peptide derived from human fibrin, has been shown to reduce myocardial infarct size in animal models by mitigating reperfusion injury. In this exploratory trial we investigated whether FX06 would limit infarct size when given as adjunct to percutaneous coronary intervention.  slides

Methods: 234 patients presenting with acute ST-segment elevation myocardial infarction (STEMI) were randomized in 26 centres. FX06 or matching placebo was given as intravenous bolus at reperfusion. Infarct size was assessed 5 days post-MI by late gadolinium enhanced (LGE) cardiac magnetic resonance imaging. Secondary outcomes included size of necrotic core zone and microvascular obstruction at 5 days, infarct size at 4 months, left ventricular function, troponin I levels, and safety.

Results: There were no baseline differences between groups. On day 5, there was no significant difference in total LGE zone in the FX06 group compared to placebo (reduction by 21%; p=0.207). Necrotic core zone, however, was significantly reduced by 58% (median 1.77g (IQR 0, 9.09) vs. 4.20g (IQR 0.3, 9.93), p<0.025). There were no significant differences in troponin I levels (at 48hrs: -17% in the FX06 group). After 4 months, there were no significant differences in scar size. There were numerically fewer serious cardiac events in the FX06 treated group, and no differences in adverse events.

Conclusions: In this proof-of-concept trial, FX06 did not reach the primary endpoint of LGE-zone infarct reduction, but reduced one measure of infarct size: the necrotic core zone. The drug appeared safe and well-tolerated.
 

Discussant report: Marber, Michael (United Kingdom)

This is an interesting and well-performed study of a novel anti-inflammatory peptide, FX06, during primary PCI for STEMI. A number of previous trials targetting different aspects of inflammation have failed to limit infarction. Unfortunately the F.I.R.E. trial can probably be added to this list.    slides

The main positive secondary endpoint is a suggestion that the necrotic core of the infarct, imaged as a bright area of Gd late enhancement on MRI , is reduced in volume at Day 5 post-MI. However, the necrotic core forms only 10% of the total volume of Gd late enhancement. More importantly, this early signal in favour of FX06 is not reflected in scar or LV function measurements with MRI at 4 months post-MI or in a significant decrease in early biomarkers of MI. Thus, it is possible that the early reduction in necrotic core is the result of FX06 reducing oedema perhaps without influencing true necrosis.

Despite failing to influence the primary endpoint, FX06 does appear to be safe. However, the numerically low number of events means that patient follow up must be nearly complete for the conclusions regarding safety to be certain.

The investigators are to be congratulated on a high quality study in which patients with STEMI were treated extremely well, based on short pain to balloon time, preserved ejection fraction and the prevalence with which secondary prevention medication was prescribed. It may prove difficult to improve on this level of care. The multiple trends in favour of FX06 may signify a biological effect on reperfusion injury but unfortunately, this can only be determined in a much larger trial.