Impact of time to therapy and presence of collaterals on the efficacy of FX06 in acute ST elevation myocardial infarction: A substudy of the F.I.R.E., the Efficacy of FX06 in the prevention of myocardial reperfusion injury trial
To determine whether the efficacy of FX06 was dependent upon the timing of reperfusion therapy or the presence of collaterals in the Efficacy of FX06 in the prevention of myocardial reperfusion injury (F.I.R.E.) trial.
Two hundred and thirty-four (234) patients presenting with acute ST-segment elevation myocardial infarction were randomised to FX06 or matching placebo given as an intravenous bolus at reperfusion. Infarct size was assessed at 5-7 days and four months after myocardial infarction by cardiac magnetic resonance imaging determined total late enhancement and necrotic core zone. Patients were stratified according to presentation status (time-to-therapy <3 hours, n=108; time-to-therapy=3-6 hours, n=115) and presence of collaterals (yes, 46; no, 177). There were no statistically significant differences between groups at day 5-7. At four months, we observed statistically significant reductions of both measures of infarct size (0.3% vs. 2.4%, p=0.038; 8.0% vs. 16.0%, p=0.032) in the group given FX06 and presenting early. There was also a statistically significant reduction of total late enhancement zone among patients given FX06 with collaterals (7.3% vs. 15.2%, p=0.043). No differences were evident among late presenters or those without collaterals.
FX06 significantly reduced infarct size at four months in the early presenters and in those with collaterals.
[Show abstract][Hide abstract] ABSTRACT: Activation of the coagulation system during ischemia/reperfusion injury is an unavoidable event and even further augmented during cardiovascular surgery. Clotting not only leads to disturbance of blood rheology but also enhances the inflammatory response. We aim to highlight the inflammatory properties of the coagulation system and novel potential therapeutic approaches targeting both features.
Heparin, a thrombin inhibitor, is still the drug of choice for preventing coagulation following, for example, cardiovascular surgery. On the contrary, much effort is done to evaluate the utilization of direct thrombin inhibitors to prevent ischemia/reperfusion injury. Furthermore, targeting the inflammatory potential of the coagulation system seems to be very promising. Fibrin(ogen) and its degradation products modulate the inflammatory response, especially by inducing leukocyte migration. Inhibiting these pro-inflammatory effects, for example, by administration of Bβ15-42 was recently shown to be beneficial under various inflammatory conditions.
Ischemia and reperfusion are common activators of coagulation that is also accompanied by inflammation. Therefore, targeting this well orchestrated system might be of therapeutic benefit, as its mode of action is dual: clotting inhibition and anti-inflammation. This novel therapeutic approach might at least be of benefit in the treatment of systemic inflammatory syndromes following, that is, cardiovascular surgery.
Current opinion in anaesthesiology 06/2011; 24(4):375-80. DOI:10.1097/ACO.0b013e3283489ac0 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ(15-42) peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.
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