Comparison of fibrin sealants in peripheral vascular surgery: A systematic review and network meta-analysis.

BACKGROUND: Evidence comparing fibrin sealants (FSs) in surgery are limited. This study evaluated the efficacy and safety of FSs, and manual compression in peripheral vascular surgery. METHODS: A systematic review of randomized trials was conducted in Medline, Embase, and Cochrane databases within the last 15 years. Data were available to conduct a network meta-analysis (NMA) in peripheral vascular surgery. Fibrin sealant treatment arms were further broken-down and assessed by clotting time (i.e., 2-min [2C] or 1-min [1C]). The primary efficacy outcome was the proportion of patients achieving hemostasis by 4 min (T4). Treatment-related serious and non-serious adverse events (AEs) were qualitatively assessed. RESULTS: Five studies (n = 693), were included in the NMA. Results predicted VISTASEAL 2C, followed by EVICEL 1C, had the highest probability of achieving T4. Compared with manual compression, significant improvements in T4 were found with VISTASEAL 2C (relative risk [RR] = 2.67, 95% CrI: 2.13-3.34), EVICEL 1C (RR = 2.58, 95% CrI: 2.04-3.23), VISTASEAL 1C (RR = 2.00, 95% CrI: 1.45-2.65), and TISSEEL 2C (RR = 1.99, 95% CrI: 1.48-2.60). TISSEEL 1C was not significantly different than manual compression (RR = 1.40, 95% CrI: 0.70-2.33). Among FSs, VISTASEAL 2C was associated with a significant improvements in T4 compared with VISTASEAL 1C (RR = 1.33, 95% CrI: 1.02-1.82), TISSEEL 2C (RR = 1.34, 95% CrI: 1.05-1.77), and TISSEEL 1C (RR = 1.90, 95% CrI: 1.18-3.74). Treatment-related serious and non-serious AE rates were typically lower than 2%. CONCLUSIONS: In peripheral vascular surgeries, VISTASEAL 2C and EVICEL 1C were shown to have the highest probabilities for achieving rapid hemostasis among the treatments compared. Future studies should expand networks across surgery types as data become available.

Bleeding-Related Complications and Readmission Rates Associated With Fibrin Sealant Use in Patients Undergoing Coronary Artery Bypass Graft Surgery in the United States.

OBJECTIVES: To compare the clinical and economic outcomes of EVICEL (Ethicon, Inc., Somerville, NJ) and TISSEEL (Baxter Healthcare Corporation, Westlake Village, CA) use in patients undergoing primary coronary artery bypass graft (CABG) surgery. DESIGN: Retrospective database analysis. SETTING: Premier prospective hospital database (June 2009 through March 2014) covering approximately 20% of hospital discharges in the United States. PARTICIPANTS: Adults undergoing primary CABG surgery who received either EVICEL or TISSEEL on the day of surgery (index date). INTERVENTIONS: Two intervention groups were formed, EVICEL and TISSEEL. Clinical outcomes compared included postoperative bleeding complications (International Classification of Diseases, Ninth Revision, Clinical Modification code: 998.1) and number of blood transfusions received on the index day. Economic outcomes compared included hospital length of stay, hospital costs, and 30-day readmission rates. Propensity-score matching was used to control for patient and hospital characteristics. MEASUREMENTS AND MAIN RESULTS: A total of 129,014 primary CABG surgery patients were identified; 986 patients (mean age: 64 years, 73% male) received EVICEL and 6,340 patients (mean age: 65 years, 75% male) received TISSEEL on the index day. After propensity-score matching, patients who received EVICEL compared with TISSEEL had significantly fewer postoperative bleeding complications (3.0% v 5.0%, p = 0.0197), index-day blood transfusion rates (19% v 34%, p<0.0001), readmission rates (18% v 32%, p<0.0001), and costs ($40,736 [standard deviation $19,465] v $46,005 [standard deviation $24,049], p<0.0001). Results from a sensitivity analysis using a generalized linear model to control for other hemostatic agent use also favored EVICEL over TISSEEL. CONCLUSION: Results from this real-world retrospective database analysis showed fewer bleeding complications and lower costs in patients undergoing primary CABG surgery who received EVICEL compared with TISSEEL.

A method to measure thrombin activity in a mixture of fibrinogen and thrombin powders.

Thrombin and fibrinogen powders are the active components of advanced surgical hemostasis products including the EVARREST Fibrin Sealant Patch. Measuring the enzymatic activity of thrombin in the presence of fibrinogen is challenging, as hydration of the powders in a neutral aqueous environment will cause the enzyme to rapidly react with the fibrinogen to form a fibrin clot, which in turn binds and entraps the enzyme thus preventing subsequent measurement of thrombin activity. A novel approach has been developed to overcome this challenge. After isolation of the mixture of powders, an alkaline carbonate solution is used to solubilize the proteins, while reversibly inhibiting the activity of thrombin and preventing clot formation. Once the powders have been fully solubilized, thrombin activity can be restored by neutralization in a buffered fibrinogen solution resulting in fibrin clot formulation. The rate of clot formation can be quantified in a coagulometer to determine the thrombin activity of the original powder. Samples coated with powders containing fibrinogen and varying amounts of thrombin were tested using the method described herein. The results demonstrated that the method could consistently measure the activity of (alpha) thrombin in the presence of fibrinogen over a broad range of thrombin activity levels. The test was successfully validated according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines and thus is suitable for use as part of a commercial manufacturing process. A method has been developed that enables thrombin activity to be measured in a mixture of fibrinogen and thrombin powders.

Preparation, characterization, and preliminary application of fibrinogen-coated olive oil droplets for the targeted delivery of docetaxel to solid malignancies.

Micronized droplets of olive oil loaded with docetaxel (1.0 mg.ml(-1)) and coated with fibrinogen were prepared and then characterized for physicochemical and cytotoxic properties in vitro and anticancer activity in vivo. The droplets remain readily dispersible and relatively stable in size for at least 24 h when stored at 4 degrees C. During storage, the fibrinogen remains bound to the droplets and thrombin coagulable. Nucleoside incorporation assays, growth inhibition assays, and clonogenic assays involving several different tumor cell lines all indicate that the cytotoxicity in vitro of docetaxel applied in olive oil droplets is at least as great as that of docetaxel applied in DMSO. When compared with Taxotere, an equivalent dose of docetaxel administered in fibrinogen-coated oil droplets improved the median survival time of B16F10 melanoma-bearing mice from 21 days to 69 days. Furthermore, whereas none of the Taxotere-treated mice survived longer than 34 days, 33% (three of nine) of the mice treated with docetaxel-loaded, fibrinogen-coated oil droplets were apparently free of disease after 139 days. Preliminary studies indicate fibrinogen adsorbed to docetaxel-loaded oil droplets facilitates the retention of the droplets within the fibrin-rich tumor microenvironment. We propose this new formulation may prove generally useful for the treatment of taxane-sensitive, fibrin-rich tumors.

Fibrinogen in rat gastrointestinal lymph before, during and after intraduodenal administration of emulsified triglyceride: fibrinogen bound to chylomicrons in gastrointestinal lymph is functional.

Samples of gastrointestinal lymph were collected from fasted, male, Sprague-Dawley rats before, during and after intraduodenal administration of either a phospholipid-stabilized, triglyceride-rich emulsion or the dextrose-saline diluent of the emulsion. In lipid-treated rats, the triglyceride, total protein, and functional fibrinogen contents of lymph increased significantly during the 4 h of continuous lipid infusion, with all analytes returning to near baseline values by 20 h later. Levels of the same analytes changed little, if at all, in control animals. As assessed using immunoblotting, chylomicrons in gastrointestinal lymph are coated with fibrinogen. Fibrinogen-coated chylomicrons readily incorporate into solution phase clots and, in the presence of thrombin, adhere in heparin-preventable fashion to each other and to other fibrinogen-coated surfaces. Taken together, these data indicate that lipid feeding creates in gastrointestinal lymph a condition that is conducive temporally to the physical association of fibrinogen with newly ingested lipids before they reach the circulatory system.

Distribution of silicon/e in tissues of mice of different fibrinogen genotypes following intraperitoneal administration of emulsified poly(dimethylsiloxane) [correction of poly(dimethysiloxane)].

Following injection into the abdominal cavity of a C57BL/6 mouse, droplets of emulsified PDMS visible by light microscopy (diameter > or = 1 microm) disseminate to multiple organs of the animal. Because fibrinogen may facilitate dissemination, we compared histologically the accumulation of PDMS droplets in lymph nodes, lungs, spleen, liver, and left kidney of Fib +/+, Fib +/-, and Fib -/- mice of C57BL/6 background 35 and 75 days after intraperitoneal injection of an emulsion of the polymer. We also used ICP-AES to assess the accumulation of silicon in the lymph nodes, livers, and spleens of the animals. The emulsion droplets ranged in diameter from approximately 0.04 to approximately 80 microm. PDMS droplets visible by light microscopy were in all organs of both Fib +/+ mice and Fib +/- mice. In those animals, droplets were invariably either within or adjacent to inflammatory cells, predominantly macrophages. In contrast, PDMS droplets were visible in none of the organs of Fib -/- mice. Despite the absence of visible droplets in them, the lymph nodes, livers, and spleens of Fib -/- mice, like the corresponding organs of Fib +/+ and Fib +/- mice, contained measurable silicon after 35 and 75 days. The amount of silicon, however, was always greater in the organs of Fib +/+ and Fib +/- mice than in the organs of Fib -/- mice. We attribute the presence of silicon in organs that had no histologic evidence of droplets to diffusion of the very smallest droplets/soluble species of PDMS from the abdominal cavity. Taken together, our data and observations implicate a role for fibrinogen in the dissemination of larger PDMS droplets in vivo. We propose this role involves recognition of droplet-bound fibrinogen by macrophages and, perhaps, other inflammatory cells, and the subsequent fibrinogen-facilitated ingestion and/or extracellular movement of the droplets by those cells.