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ObjectiveThe ideal hemostatic agent for treatment of suture-line bleeding at vascular anastomoses has not yet been established. This study evaluated whether the use of a fibrin sealant containing 500 IU/mL thrombin and synthetic aprotinin (FS; marketed in the United States under the name TISSEEL) is beneficial for treatment of challenging suture-line bleeding at vascular anastomoses of expanded polytetrafluoroethylene (ePTFE) grafts, including those further complicated by concomitant antiplatelet therapies.MethodsOver a 1-year period ending in 2010, ePTFE graft prostheses, including arterio-arterial bypasses and arteriovenous shunts, were placed in 140 patients who experienced suture-line bleeding that required treatment after completion of anastomotic suturing. Across 24 US study sites, 70 patients were randomized and treated with FS and 70 with manual compression (control). The primary end point was the proportion of patients who achieved hemostasis at the study suture line at 4 minutes after start of application of FS or positioning of surgical gauze pads onto the study suture line.ResultsThere was a statistically significant difference in the comparison of hemostasis rates at the study suture line at 4 minutes between FS (62.9%) and control (31.4%) patients (P < .0001), which was the primary end point. Similarly, hemostasis rates in the subgroup of patients on antiplatelet therapies were 64.7% (FS group) and 28.2% (control group). When analyzed by bleeding severity, the hemostatic advantage of FS over control at 4 minutes was similar (27.8% absolute improvement for moderate bleeding vs 32.8% for severe bleeding). Logistic regression analysis (accounting for gender, age, intervention type, bleeding severity, blood pressure, heparin coating of ePTFE graft, and antiplatelet therapies) found a statistically significant treatment effect in the odds ratio (OR) of meeting the primary end point between treatment groups (OR, 6.73; P < .0001), as well as statistically significant effects for intervention type (OR, 0.25; P = .0055) and bleeding severity (OR, 2.59; P = .0209). The safety profile of FS was excellent as indicated by the lack of any related serious adverse events.ConclusionsThe findings from this phase 3 study confirmed that FS is safe and its efficacy is superior to manual compression for hemostasis in patients with peripheral vascular ePTFE grafts. The data also suggest that FS promotes hemostasis independently of the patient's own coagulation system, as shown in a representative population of patients with vascular disease under single- or dual-antiplatelet therapies.

Introduction Bien que benefique, la faible thrombogenicite, porosite et elasticite des protheses en polytetrafluoroethylene expanse (ePTFE) peut exacerber le probleme des saignements sur ligne de suture au niveau des anastomoses vasculaires et conduire a augmenter la duree operatoire. L'objectif global de cette etude prospective, randomisee, controlee, avec sujets aveugles, multicentrique de phase 2 etait d'evaluer l'efficacite et la securite d'une colle de fibrine (CF) contenant 500 IU/mL de thrombine et d'aprotinine de synthese (vendue aux Etats-Unis sous le nom de TISSEEL) pour l'hemostase chez les sujets operes en chirurgie vasculaire recevant des protheses vasculaires en ePTFE. Methodes La CF etait comparee a la compression manuelle par compresses chirurgicales qui constitue le standard en matiere d'hemostase en chirurgie vasculaire. Deux delais de polymerisation de la CF (60 et 120 secondes) etaient examines afin d'evaluer l'influence sur les resultats en termes d'efficacite. Les patients qui avaient la mise en place d'une prothese en ePTFE (N = 73) et qui necessitaient un traitement supplementaire apres hemostase chirurgicale etaient randomises pour traitement par CF a clamps ouverts pendant 60 secondes (CF-60 ; N = 26), traitement par CF a clamps ouverts pendant 120 secondes (CF-120 ; N = 24) ou compression manuelle par compresses chirurgicales (controles ; N = 23). La proportion de sujets chez lesquels l'hemostase etait obtenue a 4 minutes (critere primaire de jugement) ainsi qu'a 6 et 10 minutes (criteres secondaires de jugement) au sein des trois groupes de traitement etait analysee en regression logistique, en prenant en compte le sexe, l'âge, le type d'intervention, la severite du saignement, la pression arterielle systolique, la pression arterielle diastolique, l'heparinisation des protheses ePTFE et les antiagregants plaquettaires. Resultats Il existait des differences substantielles concernant la proportion de sujets chez qui l'hemostase etait obtenue au niveau de la ligne de suture a 4 minutes entre le groupe CF-120 (62,5%) et le groupe controle (34,8% ; amelioration relative de 79,6%). L'analyse en regression logistique retrouvait un effet therapeutique statistiquement significatif a un niveau de 10% sur l'odds ratio (OR) concernant l'obtention de l'hemostase a 4 minutes entre le groupe CF-120 et le groupe controle (OR = 3,98, p = 0,0991). De plus, il etait montre que l'administration peri-operatoire d'antiagregants plaquettaires influencait significativement (OR = 3,89, p = 0,0607) le niveau d'hemostase suivant le critere primaire de jugement. Aucun effet therapeutique statistiquement significatif n'etait retrouve pour les autres facteurs. Les analyses par regression logistique concernant les criteres secondaires de jugement demontraient un effet therapeutique significatif sur l'hemostase a 6 minutes (OR = 9,92, p = 0,0225) et a 10 minutes (OR = 6,70, p = 0,0708) entre le groupe CF-120 et le groupe controle. Des effets statistiquement significatifs au cours des analyses en regression logistique etaient trouves a un niveau de 10% concernant l'OR d'obtention de l'hemostase a 6 et 10 minutes, respectivement, pour les facteurs suivants: CF-120 versus groupe controle (OR = 9,92 ; p = 0,0225 et OR = 6,70 ; p = 0,0708, respectivement), le type d'intervention (OR = 0,3 ; p = 0,0775 et OR = 0,25 ; p = 0,0402, respectivement), et l'heparinisation des protheses en ePTFE (OR = 4,83 ; p = 0,0413 et OR = 3,65 ; p = 0,911, respectivement). La CF etait sure et bien toleree, comme indique par l'absence d'evenement indesirable serieux. Conclusion Les resultats de cette etude de phase 2 soutiennent le fort profil de securite de la CF et suggerent qu'il s'agit d'un agent hemostatique efficace lors de la mise en place d'une prothese chirurgicale en ePTFE et d'un outil utile en chirurgie vasculaire peripherique avec de possibles applications.

Background The low thrombogenicity, porosity, and limited elasticity of expanded polytetrafluoroethylene (ePTFE) vascular grafts, although beneficial, may exacerbate the problem of suture-line bleeding at vascular anastomoses and consequently lead to increased operating times. The overall objective of this prospective, randomized, controlled, subject-blinded, multicenter phase 2 study was to evaluate the efficacy and safety of a fibrin sealant containing 500 IU/mL thrombin and synthetic aprotinin (FS; marketed in the United States under the name TISSEEL) for hemostasis in subjects undergoing vascular surgery and receiving prosthetic ePTFE vascular grafts. Methods FS was compared with manual compression with surgical gauze pads, a standard of care for hemostasis in vascular surgery. Two FS polymerization/setting times (60 and 120 seconds) were investigated to evaluate influence on the efficacy results. Patients undergoing ePTFE graft placement surgery ( N = 73) who experienced bleeding that required treatment after surgical hemostasis were randomized to be treated with FS with clamps opened at 60 seconds (FS-60; N = 26), with FS with clamps opened at 120 seconds (FS-120; N = 24), or with manual compression with surgical gauze pads (control; N = 23). The proportion of subjects achieving hemostasis at 4 minutes (primary endpoint) as well as at 6 and 10 minutes (secondary endpoints) in the three treatment groups was analyzed using logistic regression analysis, taking into account gender, age, type of intervention, severity of bleeding, systolic blood pressure, diastolic blood pressure, heparin coating of the ePTFE graft, and platelet inhibitors. Results There were substantial differences in the proportion of subjects who achieved hemostasis at the study suture line at 4 minutes from treatment application between FS-120 (62.5%) and control (34.8%) groups (a 79.6% relative improvement). Logistic regression analyses found a statistically significant treatment effect at the 10% level in the odds ratio (OR) of achieving hemostasis at 4 minutes between the FS-120 and control groups (OR = 3.98, p = 0.0991). Furthermore, it has been shown that the perioperative administration of platelet inhibitors significantly influences (OR = 3.89, p = 0.0607) hemostasis rates at the primary endpoint. No statistically significant treatment effects were found for the other factors. Logistic regression analyses performed on the secondary endpoints demonstrated a significant treatment effect of achieving hemostasis at 6 minutes (OR = 9.92, p = 0.0225) and at 10 minutes (OR = 6.70, p = 0.0708) between the FS-120 and control groups. Statistically significant effects in the logistic regression analyses were found at the 10% level in the OR of achieving hemostasis at 6 and 10 minutes, respectively, for the following factors: FS-120 versus control group (OR = 9.92; p = 0.0225 and OR = 6.70; p = 0.0708, respectively), type of intervention (OR = 0.3; p = 0.0775 and OR = 0.25; p = 0.0402, respectively), and heparin coating of the ePTFE prosthesis (OR = 4.83; p = 0.0413 and OR = 3.65; p = 0.0911, respectively). FS was safe and well-tolerated, as indicated by the lack of any related serious adverse events. Conclusion The findings from this phase 2 study support the strong safety profile of FS and suggest that it is an efficacious hemostatic agent in ePTFE graft placement surgery, as well as a useful tool in peripheral vascular surgery applications.