Background Activated prothrombin complex concentrate (aPCC) is indicated for bleed treatment and prevention in patients with hemophilia with inhibitors. The safety and tolerability of intravenous aPCC at a reduced volume and faster infusion rates were evaluated. Methods This multicenter, open-label trial (NCT02764489) enrolled adults with hemophilia A with inhibitors. In part 1, patients were randomized to receive three infusions of aPCC (85 +/- 15 U/kg) at 2 U/kg/min (the approved standard rate at the time of the study), in a regular or 50% reduced volume, and were then crossed over to receive three infusions in the alternative volume. In part 2, patients received three sequential infusions of aPCC in a 50% reduced volume at 4 U/kg/min and then at 10 U/kg/min. Primary outcome measures included the incidence of adverse events (AEs), allergic-type hypersensitivity reactions (AHRs), infusion-site reactions (ISRs), and thromboembolic events. Results Of the 45 patients enrolled, 33 received aPCC in part 1 and 30 in part 2. In part 1, 24.2 and 23.3% of patients with regular and reduced volumes experienced AEs, respectively; 11 AEs in eight patients were treatment related. AHRs and ISRs occurred in four (12.1%) and two (6.1%) patients, respectively. In part 2, 3.3 and 14.3% of patients with infusion rates of 4 and 10 U/kg/min experienced AEs, respectively; only one AE in one patient was treatment related; no AHRs or ISRs were reported. Most AEs were mild/moderate in severity. Overall, no thromboembolic events were reported. Conclusions aPCC was well tolerated at a reduced volume and faster infusion rates, with safety profiles comparable to the approved regimen.

This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes.NCT01286779, EudraCT: 2010-022726-33.

Introduction: Recombinant von Willebrand factor (rVWF) has demonstrated hemostatic efficacy and safety when used for on-demand treatment and for control of bleeding episodes in the surgical setting in patients with severe von Willebrand disease (VWD). rVWF is administered without recombinant FVIII (rFVIII) if an immediate rise in FVIII coagulant activity (FVIII:C) is not necessary or if baseline FVIII:C is sufficient to ensure hemostasis (≥40-100 IU/dL). In the elective surgical setting, rVWF may be given alone prior to surgery to raise endogenous FVIII:C. We analyzed prospective clinical trial data to better inform dosing decisions related to treatment and the pharmacodynamic effect of administering rVWF on endogenous FVIII:C.

This randomized, controlled, single-blinded multicenter study evaluated the efficacy of latest-generation fibrin sealant containing synthetic aprotinin as fibrinolysis inhibitor as supportive treatment for hemostasis after elective partial hepatectomy.

OBJECTIVES The aim of this study was to evaluate the extent and quality of new bone 6 months after sinus lift with biphasic micro- and macroporous calcium phosphate combined with fibrin sealant (MBCP-FS) and the 1-year implant success rate in the augmented site. MATERIAL AND METHODS MBCP-FS was applied to one sinus in 96 subjects requiring augmentation for delayed dental implant placement. In subjects who required bilateral lifts (N = 33), the MBCP-FS sinus was randomly selected; the contralateral sinus was grafted with autologous bone (mixed with Bio-Oss when harvested bone volume was insufficient. Panoramic views were taken periodically prior to and up to 18 months post-lift. Histomorphometric analysis was conducted on biopsies taken during implant placement 6 months after augmentation. Implant functionality and prosthesis success were assessed clinically 1 year after implant placement. RESULTS In MBCP-FS sinuses, 20.6 ± 8.5% new, mainly lamellar bone was observed. Implants were placed as planned in 78/85 evaluable subjects (91.8%) 6 months after sinus lift. Graft heights remained stable 1 year after placement; 94.7% (142/150) of implants were functional. The amount and quality of new bone and implant success rates with MBCP-FS were similar to autologous bone graft (mixed with Bio-Oss in 30/31 evaluable subjects). MBCP-FS was safe and well-tolerated. CONCLUSIONS MBCP-FS is safe and effective in sinus floor elevation for dental implant placement, supporting bone regeneration and with high 1-year implant success rates similar to autologous bone mixed with Bio-Oss.

OBJECTIVE:The 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. METHODS:Over 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. RESULTS:There 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. CONCLUSIONS:The 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.

Bien que bénéfique, la faible thrombogénicité, porosité et élasticité des prothèses en polytétrafluoroéthylène expansé (ePTFE) peut exacerber le problème des saignements sur ligne de suture au niveau des anastomoses vasculaires et conduire à augmenter la durée opératoire. L'objectif global de cette étude prospective, randomisée, contrôlée, avec sujets aveugles, multicentrique de phase 2 était d'évaluer l'efficacité et la sécurité d'une colle de fibrine (CF) contenant 500 IU/mL de thrombine et d'aprotinine de synthèse (vendue aux Etats-Unis sous le nom de TISSEEL) pour l'hémostase chez les sujets opérés en chirurgie vasculaire recevant des prothèses vasculaires en ePTFE. La CF était comparée à la compression manuelle par compresses chirurgicales qui constitue le standard en matière d'hémostase en chirurgie vasculaire. Deux délais de polymérisation de la CF (60 et 120 secondes) étaient examinés afin d'évaluer l'influence sur les résultats en termes d'efficacité. Les patients qui avaient la mise en place d'une prothèse en ePTFE (N = 73) et qui nécessitaient un traitement supplémentaire après hémostase chirurgicale étaient randomisés pour traitement par CF à clamps ouverts pendant 60 secondes (CF-60 ; N = 26), traitement par CF à clamps ouverts pendant 120 secondes (CF-120 ; N = 24) ou compression manuelle par compresses chirurgicales (contrôles ; N = 23). La proportion de sujets chez lesquels l'hémostase était obtenue à 4 minutes (critère primaire de jugement) ainsi qu'à 6 et 10 minutes (critères secondaires de jugement) au sein des trois groupes de traitement était analysée en régression logistique, en prenant en compte le sexe, l'âge, le type d'intervention, la sévérité du saignement, la pression artérielle systolique, la pression artérielle diastolique, l'héparinisation des prothèses ePTFE et les antiagrégants plaquettaires. Il existait des différences substantielles concernant la proportion de sujets chez qui l'hémostase était obtenue au niveau de la ligne de suture à 4 minutes entre le groupe CF-120 (62,5%) et le groupe contrôle (34,8% ; amélioration relative de 79,6%). L'analyse en régression logistique retrouvait un effet thérapeutique statistiquement significatif à un niveau de 10% sur l'odds ratio (OR) concernant l'obtention de l'hémostase à 4 minutes entre le groupe CF-120 et le groupe contrôle (OR = 3,98, p = 0,0991). De plus, il était montré que l'administration péri-opératoire d'antiagrégants plaquettaires influençait significativement (OR = 3,89, p = 0,0607) le niveau d'hémostase suivant le critère primaire de jugement. Aucun effet thérapeutique statistiquement significatif n'était retrouvé pour les autres facteurs. Les analyses par régression logistique concernant les critères secondaires de jugement démontraient un effet thérapeutique significatif sur l'hémostase à 6 minutes (OR = 9,92, p = 0,0225) et à 10 minutes (OR = 6,70, p = 0,0708) entre le groupe CF-120 et le groupe contrôle. Des effets statistiquement significatifs au cours des analyses en régression logistique étaient trouvés à un niveau de 10% concernant l'OR d'obtention de l'hémostase à 6 et 10 minutes, respectivement, pour les facteurs suivants: CF-120 versus groupe contrôle (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'héparinisation des prothèses en ePTFE (OR = 4,83 ; p = 0,0413 et OR = 3,65 ; p = 0,911, respectivement). La CF était sûre et bien tolérée, comme indiqué par l'absence d'évènement indésirable sérieux. Les résultats de cette étude de phase 2 soutiennent le fort profil de sécurité de la CF et suggèrent qu'il s'agit d'un agent hémostatique efficace lors de la mise en place d'une prothèse chirurgicale en ePTFE et d'un outil utile en chirurgie vasculaire périphérique 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.

The objective of this phase 3, multicentered, prospective, randomized, evaluator-blinded, clinical study was to compare skin graft adherence utilizing a fibrin sealant containing 4 IU/ml thrombin (FS 4IU VH S/D [FS 4IU VH S/D will be marketed under the trade name ARTISS upon licensure in the United States]) to graft adherence utilizing staples in burn patients requiring wound excision mid skin grafting. FS 41U VH S/D was compared with staples in 138 patients. Patients had burn wounds measuring <= 40% of total body surface area with two comparable test sites measuring between 1 and 4% total body surface area each. Wound closure at day 28 was assessed using test site planimetry and review of day 28 photographs by three independent blinded evaluators (primary endpoint analysis). Secondary efficacy measures included hematoma/seroma on day 1, engraftment on day 5, and wound closure on day 14. Investigator and patient-reported outcomes were also assessed. The proportion of test sites with complete wound closure at day 28 was 70.3% in FS 4IU VH S/D treated sites and 65.8% in stapled sites, as assessed by planimetry. Blinded review of day 28 photographs confirmed that the rate of complete wound closure was similar between the two treatments, although the overall assessed rates of closure were lower than those determined by planimetry: FS 4IU VH S/D (43.3%) and staples (37.0%). The lower limit of the 97.5% confidence interval of the difference between FS 41U VH S/D and staples was -0.029, which is above the predefined noninferiority margin of -0.1. Therefore, FS 4IU VH S/D is at least as efficacious as staples at the 97.5% one-sided level for complete wound closure by day 28. Hematoma/seroma on day I occurred at significantly (P < .0001) fewer FS 4IU VH S/D-treated sites (29.7% [95% CI 22.2-38.1%]) compared with stapled sites (62.3% [95% CI 53.7-70.4%]). Engraftment on day 5 was deemed to be 100% in 62.3% (95% CI 53.7-70.4%) of the FS 4IU VH S/D-treated sites and 55.1% (95% CI 46.4-63.5%) of the stapled sites (P = .0890). Complete wound closure by day 14 occurred in 48.8% (95% CI 39.9-57.8%) of the FS 4IU VH S/D treated sites and 42.6% (95% CI 34.0-51.6%) of the stapled sites (P = .2299). FS 4IU VH S/D scored significantly better than staples for all investigator-assessed outcomes, namely quality of graft adherence (P < .0001), preference for method of fixation (P < .0001), satisfaction with graft fixation (P < .0001), and overall quality of healing (P < .0001). Likewise, FS 4IU VH S/D scored significantly better than staples for all patient-assessed outcomes, namely anxiety about pain (P < .0001) and treatment preference (P < .0001). The safety profile of FS 4IU VH S/D was excellent as indicated by the lack of any related serious adverse experiences. These findings demonstrate that FS 4IU VH S/D is safe and effective for attachment of skin grafts, with outcomes at least as good as or better than staple fixation.