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

Background-Platelet activating factor (PAF) is believed to amplify the acti vity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We te sted 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, multic entre trial of lexipafant (100 mg/24 hours intravenously for seven days com menced within 72 hours of the onset of symptoms) involving 290 patients wit h an APACHE II score >6. Power calculations assumed that complications woul d be reduced from 40% to 24%. Secondary end points studied included severit y of organ failure, markers of the inflammatory response, and mortality rat e. 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 primar y hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new org an 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 pla cebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipaf ant group (13/138 v 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%) pati ents, respectively (p=0.025). Deaths attributable to acute pancreatitis wer e not significantly different. Interleukin 8, a marker of neutrophil activa tion, and E-selectin, a marker of endothelial damage, decreased more rapidl y in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. Interpretation-The high incidence of organ failure within 72 hours of the o nset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this . Lexipafant had no effect on new organ failure during treatment. This adeq uately powered study has shown that antagonism of PAF activity on its own i s not sufficient to ameliorate SIRS in severe acute pancreatitis.