Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial.
BACKGROUND
Inflammatory responses induced by reperfusion of previously ischemic myocardial tissue may lead to further damage of the microvascular structures. A group of cell adhesion molecules, named selectins, initiate those inflammatory changes at the endothelial wall surface. Recombinant P-selectin glycoprotein ligand-immunoglobulin (rPSGL-Ig), a P-selectin antagonist, was shown to have beneficial effects in several animal models of acute myocardial ischemia. We performed a mechanistic study with positron emission tomography to test the potential benefits of rPSGL-Ig in patients with ST-segment elevation acute myocardial infarction.


METHODS
Patients with ST-elevation acute myocardial infarction presenting within the first 6 hours of onset of chest pain were enrolled. All patients received alteplase. Patients were randomly assigned in a 1:1:1 ratio to 3 treatment groups: placebo; 75 mg rPSGL-Ig; 150 mg rPSGL-Ig, given intravenously. Coronary angiography was performed 90 minutes after the start of thrombolytic therapy for TIMI flow grading. Myocardial blood flow (MBF) was measured with 13NH3 at rest and after adenosine administration on day 5. Myocardial blood flow at rest was measured again at day 30, followed by measurement of 18FDG uptake. In addition, a multigated acquisition, gated equilibrium blood pool study was performed at day 30. Continuous 12-lead electrocardiogram recording was performed during the first 24 hours.


RESULTS
The trial was prematurely stopped by the sponsor for lack of efficacy in an accompanying larger trial after enrolling 88 patients in the current study. Median MBF in the infarct-related territory (expressed as percentage of the normalized blood flow) at day 5 was similar in the 3 treatment groups (9.1% in the placebo group vs 3.8% in the 75-mg dose and 4.3% in the 150-mg rPSGL-Ig treatment group; P = not significant). No significant differences in MBF reserve, myocardial metabolism, ST-segment resolution, left ventricular ejection fraction, or TIMI flow grade were found among the 3 groups.


CONCLUSIONS
In this prematurely stopped mechanistic study, there was no evidence of a benefit of rPSGL-Ig given as an adjunct to thrombolysis on epicardial vessel patency, myocardial tissue reperfusion, or recovery of function.
Mertens
Paul
P
Department of Cardiology, University of Leuven, Leuven, Belgium.
Maes
Alex
A
Nuyts
Johan
J
Belmans
Ann
A
Desmet
Walter
W
Esplugas
Enric
E
Charlier
Filip
F
Figueras
Jaime
J
Sambuceti
Gianmario
G
Schwaiger
Markus
M
Mortelmans
Luc
L
Van de Werf
Frans
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012039:Regional Blood Flow; D013318:Stroke Volume; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon
D005343:Fibrinolytic Agents; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator