Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis

• Published in: Gut 2001-01, Vol.48 (1), p.62-69
• Main Authors: Johnson, C D, Kingsnorth, A N, Imrie, C W, McMahon, M J, Neoptolemos, J P, McKay, C, Toh, S K C, Skaife, P, Leeder, P C, Wilson, P, Larvin, M, Curtis, L D
• Format: Article
• Language: English
• Subjects: Acute Disease; acute pancreatitis; Adult; Aged; Antibiotics; Aqueous solutions; Biological and medical sciences; Biomarkers - blood; Cysts; Cytokines; Digestive system; Double-Blind Method; E-Selectin - blood; Endoscopy; Female; Gangrene; Humans; Imidazoles - therapeutic use; Interleukin-8 - blood; Length of Stay; Leucine - analogs & derivatives; Leucine - therapeutic use; lexipafant; Logistic Models; Male; Medical sciences; Middle Aged; Mortality; Multiple organ dysfunction syndrome; Multiple organ failure; Multiple Organ Failure - drug therapy; Multiple Organ Failure - mortality; Multiple Organ Failure - prevention & control; organ failure; Pancreatitis; Pancreatitis - drug therapy; Pancreatitis - mortality; Pharmacology. Drug treatments; Physiological aspects; Placebos; Platelet activating factor; Platelet Activating Factor - antagonists & inhibitors; Prevention; Prospective Studies; Rodents; systemic inflammatory response syndrome
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.48.1.62

BACKGROUND Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change −1 (range −4 to +8) versus 0 (−4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p