BACKGROUND It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding. METHODS We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], −0.6 to 0.8; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P = 0.005 for superiority). CONCLUSIONS In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.)

Perioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended approaches aim to simplify patient management and minimize adverse clinical outcomes.

Toxin A from Clostridium diffcile mediates acute inflammatory enterocolitis in experimental animals, while cholera toxin causes noninammatory secretory diarrhea. The purpose of this study was to investigate whether an antagonist to the peptide substance P, a constituent of primary sensory neurons known to participate in inflammatory responses, would inhibit toxin A-mediated enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg per kg of body weight), a substance P antagonist, dramatically inhibited fluid secretion (P < 0.01) and mannitol permeability (P < 0.01) in ileal loops exposed to toxin A. The protective effects, which were dose dependent, caused a significant reduction of inflammation in the lamina propria, reduction of the necrosis of intestinal epithelial cells, and complete inhibition of toxin A-mediated release of rat mast cell protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the substance P antagonist, CP-96,344, had no effect. In contrast, pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of cholera toxin into the ileal loops. From these data, we conclude that the peptide substance P is involved in the secretory and inflammatory effects of toxin A but not of cholera toxin.Toxigenic strains of Clostridium difficile cause the diarrhea and colitis frequently associated with antibiotic use in children and adults (1). Many studies have shown that these effects appear to be mediated primarily by toxin A (2-4), a 308-kDa protein exotoxin (5) that possesses potent enterotoxic and cytotoxic properties (6). In vivo studies using ileal loops indicate that a major effect oftoxin A is to elicit an acute inflammatory response in the lamina propria. Exposure of rabbit and rat intestinal loops to highly purified toxin A resulted in disruption of the villous architecture, congestion and edema of the mucosa, and an intense infiltration with neutrophils (3,4,7,8). These were accompanied by increased secretion of fluid and increased permeability to mannitol and release of the inflammatory mediators leukotrienes B4 and C4, prostaglandin E2, platelet-activating factor (8, 9), histamine (10), and rat mast cell protease II (RMCPII) (8), a specific mucosa mast cell protease (11). The importance of mast cells and neutrophils is underscored by studies in which pretreatment of experimental animals with ketotifen, a drug that inhibits release of mediators from mast cells and neutrophils, or with an antibody directed against the neutrophil adhesion protein CD18 significantly reduced the inflammation and secretion caused by toxin A (8, 12).The mechanism by which toxin A causes its intestinal effects appears to result from direct effects on intestinal epithelial cells (13) Because of data suggesting possible involvement of SP in inflammatory responses, we postulated that SP might be involved in toxin A-mediated diarrhea. The recent development of potent, highly specific nonpeptide SP antagonists provides unique tool...

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