Review
Fibrin sealants: surgical hemostat, sealant and adhesive
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Samuel P Mandell† & Nicole S Gibran †
Harborview Medical Center, Seattle, WA, USA
1.
Introduction
2.
Overview of the market
3.
Expert opinion
Introduction: Fibrin sealants (FS) have been approved for use in the United States since 1998. Since approval, they have been used in a wide variety of clinical settings and new products continue to be introduced. Areas covered: This review covers the literature supporting the USA FDAapproved indications for FS products produced by Baxter Corp. Literature review of PubMed, the Cochrane Library, FDA approval documents and product websites yielded information contained in this article. Mechanism of action, efficacy and safety of these products are covered. Expert opinion: FS are generally safe, popular and are used for a wide variety of off-label indications. Their use appears to be expanding rapidly. For many uses, including approved ones, large well-controlled trials are still needed. Additionally, cost-effectiveness data for these products would be a great benefit in guiding their future use. Keywords: adhesive, fibrin sealant, fibrinogen, hemostasis, sealant, skin graft, surgery, thrombin Expert Opin. Biol. Ther. (2014) 14(6):821-830
1.
Introduction
Fibrin sealant (FS) or fibrin ‘glue’ is a class of compounds that form fibrin clot by combining the two primary components, fibrinogen and thrombin. The ability of these products to provide both tissue adhesion and hemostasis has made them attractive in a variety of clinical settings [1]. They have been used in the United States as blood-bank--derived products since the 1980s and subsequently produced as pharmaceutical agents since TISSEEL (Baxter Healthcare Corp., Westlake Village, CA, USA) was FDA approved in 1998. Currently, TISSEEL is approved as an adjunct to hemostasis when conventional surgical measures are ineffective and as an adjunctive sealant for colon anastomoses after reversal of temporary colostomy [2]. Difficult surgical bleeding can occur in a variety of settings across multiple specialties leading to a broad market for the use of this product. While the indication for colon sealing is rather narrow, it has led to significant interest in TISSEEL more broadly as a tissue sealant. A second Baxter FS, ARTISS (Baxter Healthcare Corp., Westlake Village, CA, USA), is also available. It has been approved for use in adhering skin grafts to surgically prepare burn wounds in adult and pediatric patients. The following review will focus on the function, current use and future of these two products. 2.
Overview of the market
Hemorrhage control and tissue repair are essential elements of nearly all surgery performed worldwide. The potential market for products that can produce rapid hemostasis, adhere tissue together and prevent leakage from anastomoses is vast. Spotnitz and Burks have organized these products into three broad groups: hemostats, sealants and adhesives (Table 1) [3]. These groups are further divided into categories and classes of agent. FSs (Box 1) are the only products FDA (USA) approved 10.1517/14712598.2014.897323 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase Indications
Mechanism of action Route of administration Pivotal trial(s)
Drug name Phase Indications
Mechanism of action: Route of administration Pivotal trial(s)
TISSEEL (Fibrin sealants [human]) FDA approved Hemostasis: TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in patients undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature and cautery) is ineffective or impractical. Not approved for neurosurgery Sealing: TISSEEL is a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies Conversion of fibrinogen to fibrin clot Topical spray or drip Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study: 333 cardiac reoperations compared with historical controls. Increase in controlled hemorrhage at 5 min with fibrin sealant
ARTISS (fibrin sealant [human]) FDA approved Burns: ARTISS is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than or equal to 1 year of age Rhytidectomy: ARTISS is indicated to adhere tissue flaps during facial rhytidectomy surgery Conversion of fibrinogen to fibrin clot Topical spray or drip Efficacy and safety of a fibrin sealant for adherence of autologous skin grafts to burn wounds: results of a Phase III clinical study: 138 burn patients with prepared surgical site with either staples or fibrin sealant. Each patient served as their own control. Fibrin sealant was equivalent to staples for wound closure and reduced hematoma post-operative day 1 Randomized, controlled, Phase III study to evaluate the safety and efficacy of fibrin sealant VH S/D 4 sapr (Artiss) to improve tissue adherence in subjects undergoing rhytidectomy: 75 patients (150 sides) with side of face randomized to standard care or standard care plus fibrin sealant. Decreased mean drainage after 24 h with fibrin sealant use
for an indication in each of these groups. This versatility gives them some advantage over other agents. This also means that they must compete with a variety of other products that may be better at a specific task. In each group, FSs have shown themselves to be at the high end of effectiveness, but also among the more costly agents [3]. Currently, there are five FS products that are FDA approved (Table 1) [4]. All of these, with the exception of ARTISS, are approved for the control of hemorrhage. Two products, EVARREST (Omrix Biopharmaceuticals, Israel) and TachoSiL (Nycomed, Austria), come as patches that can be applied to tissue. Vitagel (Stryker, Malvern, PA, USA) is a topical product that has approval as an adjunct to hemostasis, but contains no human fibrinogen; instead, bovine thrombin within the product acts on autologous fibrinogen to form a fibrin clot while bovine collagen forms a scaffold for fibroblast ingrowth. Several factors are likely to drive the market for these products. Increased healthcare costs will no doubt influence the choice of one product over another. A product with 822
multiple roles will have added versatility due to the decreased need to stock multiple agents. Additionally, increase in laparoscopic, endoscopic and robotic procedures may push surgeons to look for agents to aid in hemostasis or tissue adherence when pressure or suturing may be difficult [5-7]. Increasing evidence of the negative effects of blood transfusion may also drive a market for agents that reduce bleeding or surgical wound breakdown [8-10]. These products also have the potential to decrease operative time and postoperative complications such as anastomotic leaks. New products within this field are being developed outside of the classes already in use [11]. Currently, no single agent in any group has proven to be safe, effective, usable in broad settings, cost effective and approvable [3]. Lack of an ideal agent and considerable desire for one will drive this market into the future. 2.1
Introduction to the compounds TISSEEL
2.1.1
In 1998, TISSEEL became the first FDA-approved FS in the United States, though these sealants had previously been
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Fibrin sealants
Table 1. FDA-approved surgical hemostats, sealants and adhesives. Group Hemostat
Category Mechanical
Class
Brand
Porcine gelatin Bovine collagen
Oxidized regenerated cellulose Polysaccharide spheres
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Active
Flowable
Fibrin sealant
Sealants
PEG polymer
Albumin and glutaraldehyde Cyanoacrylate
Adhesives
Fibrin sealant Albumin and glutaraldehyde Cyanoacrylate
Fibrin sealant
Manufacturer
Bovine thrombin Pooled human thrombin Recombinant thrombin Bovine gelatin and pooled human thrombin Porcine gelatin Pooled human plasma Individual human plasma with bovine thrombin and collagen Pooled human plasma and equine collagen Pooled human plasma, polygalactin 910 and oxidized regenerated cellulose Pooled human plasma and equine collagen Two PEGs PEG and trilysine amine PEG and human serum albumin Bovine serum albumin, glutaraldehyde Octyl and butyl lactoyl cyanoacrylate Pooled human plasma Bovine serum albumin, glutaraldehyde Octyl cyanoacrylate Butyl cyanoacrylate
Pooled human plasma
used throughout Europe. Current indications are as an adjunct to hemostasis in patients undergoing surgery when control of bleeding by conventional means is ineffective or impractical, and as sealant to prevent leakage from colonic anastomoses following the reversal of temporary colostomies using standard technique. TISSEEL uses a thrombin syringe and a Sealer Protein syringe and the two are combined and applied to tissue using a spray applicator or drip cannula, forming fibrin clot. TISSEEL comes in both prefilled frozen syringes (2, 4, 10 ml) as well as a freeze-dried form (2, 4, 10 ml). The freeze-dried version can be stored at room temperature, but
Gelfoam Surgifoam Avitene Helistat Instat Surgicel, Surgicel Fibrillar, Knu-Knit Arista AH Vitasure Thrombin-JMI Evithrom Recothrom Floseal
Pharmacia, Kalamazoo, MI Ferrosan Medical Devices, Denmark Davol/Bard, Warwick, RI Integra Lifesciences, Plainsboro, NJ Integra Lifesciences, Plainsboro, NJ Ethicon, San Lorenzo, PR
Surgiflo TISSEEL EVICEL Vitagel
Omrix Biopharmaceuticals, Israel Baxter, Westlake Village, CA Omrix Biopharmaceuticals, Israel Stryker, Malvern, PA
Tachosil
Baxter, Westlake Village, CA
EVARREST
Omrix Biopharmaceuticals, Israel
TachoSil
Nycomed, Austria
Coseal DuraSeal Progel
Baxter, Hayward, CA Covidien, Mansfield, MA Neomend, Irvine, CA
Bioglue
Cryolife, Kennesaw, GA
Omnex
Ethicon, Somerville, NJ
TISSEEL Bioglue
Baxter, Westlake Village, CA Cryolife, Kennesaw, GA
Dermabond Derma+flex QS Liquiband Flex Surgiseal Indermil Histoacryl ARTISS
Ethicon, San Lorenzo, PR Chemence, Alpharetta, GA Advance Medical Solutions, UK Adhezion Biomedical, Wyomissing, PA Henkel, Ireland B. Braun, Bethlehem, PA Baxter, Westlake Village, CA
Medafor, Minneapolis, MN Stryker, Malvern, PA GenTrac, Inc., Middleton, WI Omrix Biopharmaceuticals, Israel ZymoGenetics, Seattle, WA Baxter, Hayward, CA
requires reconstitution prior to use. The contents of the reconstituted Sealer Protein and prefilled syringe are equivalent (Table 2). Reconstitution takes approximately 20 min to complete, and the frozen product may take 5 -- 160 min to thaw depending on the technique and syringe size. Reconstituted or warmed, thawed Sealer Protein must be used within 48 h. Frozen product that has been thawed at room temperature may be stored at room temperature for 48 h. 2.1.2
ARTISS
ARTISS is a similar two-component FS with a thrombin syringe and a Sealer Protein (Figure 1). It is applied to the
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Table 2. Comparison of Baxter Corp. fibrin sealants.
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Sealer Protein Total protein (mg/ml) Fibrinogen (mg/ml) Aprotinin (synthetic) (KIU/ml) Other ingredients
Thrombin solution Thrombin (human) (units/ml) Calcium chloride (µmol/ml) Other ingredients
TISSEEL
ARTISS
96 -- 125 67 -- 106 2250 -- 3750 Human albumin, trisodium citrate, histidine, polysorbate 80, water
96 -- 125 67 -- 106 2250 -- 3750 Human albumin, trisodium citrate, histidine, polysorbate 80, water
400 -- 625
2.6 -- 6.5
36 -- 44 Human albumin, sodium chloride, water
36 -- 44 Human albumin, sodium chloride, water
Figure 1. ARTISS in its prefilled, frozen syringe after thawing.
wound bed most often with a pressurized spray applicator (Figure 2). It is FDA approved to adhere autologous skin grafts to surgically prepared wound beds from burn injury in patients > 1 year of age. It is also approved to adhere flaps during rhytidectomy. Unlike TISSEEL, ARTISS is not approved as an adjunct to hemostasis. It is supplied in the same forms as TISSEEL described above and has the same reconstitution and thawing characteristics. The Sealer Protein Solution is identical to that for TISSEEL; however, there is significantly less thrombin. Chemistry Both TISSEEL and ARTISS act by mimicking the final step in the clotting cascade with the conversion of fibrinogen to fibrin clot in the presence of calcium and thrombin. All necessary factors for this reaction are present in each agent and fibrin clot will form in patients on heparin or antiplatelet agents. Fibrinogen consists of three pairs of polypeptides Aa, Bb and g connected by disulfide bridges. Thrombin is a protease that cleaves fibrinopeptides A and B from the N terminus of Aa and Bb chains. Once cleavage occurs, the monomers are 2.2
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insoluble and the N-termini are able to bind with the C-termini of other fibrin molecules, resulting in polymerization [12]. Factor XIII is not contained in either product, but may be present endogenously. The presence of calcium ions contained within the product catalyzes the thrombin activity, which may enhance fibrin crosslinking and stabilization. Aprotinin is a separate protease that functions to prevent the breakdown of fibrin polymers. Pharmacodynamics TISSEEL forms clot rapidly in 5 -- 10 s given high thrombin concentration. The lower thrombin concentration in ARTISS means that initial polymerization may take up to 60 s and continue to strengthen over a period of 2 h. 2.3
Pharmacokinetics and metabolism Since both of these agents are topical, systemic absorption is expected to be small. Specific pharmacokinetic studies have not been performed. Aprotinin is eliminated by renal excretion after a half-life of 30 -- 60 min. Animal and preclinical studies have demonstrated that inclusion of aprotinin decreases clot breakdown and improves sealant function [13-15]. 2.4
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Fibrin sealants
A Phase II trial in patients undergoing placement of expanded polytetrafluoroethylene (ePTFE) vascular grafts with ongoing suture line bleeding looked at 73 patients divided into 3 groups, FS clamp off at 60 or 120 s, or control with manual compression. The primary endpoint was hemorrhage control at 4 min. In the 120-s group treated with FS, hemorrhage was controlled in 62.5 versus 34.8% of control. No significant adverse events were noted [18]. This was followed by a randomized control trial of vascular patients undergoing ePTFE prosthesis placement, and 140 patients with ongoing bleeding from the suture line were randomized to FS or control (manual compression). The primary endpoint was hemostasis at the suture line within 4 min. The FS group had significantly more hemostasis 62.9 versus 31.4% at 4 min (p < 0.001). This improvement also held true in a subgroup on antiplatelet therapy [19]. Despite its approval as a sealant for colostomy closure, there are no randomized trials evaluating TISSEEL for this purpose. There is a report of a single-center open-label study of 118 patients randomized to standard care (58 patients) or standard care plus FS (60 patients) for elective colostomy reversal following temporary stoma placement for trauma. The TISSEEL group was found to have a statistically significant reduction in complications (leak, abscess, reoperation, septic shock, mortality) when compared to standard of care (p = 0.046) [2]. Much of the available data on the use of TISSEEL in colorectal anastomoses come from rats, which seem to suggest favorable outcomes [20].
Figure 2. ARTISS spray application.
2.5.2 2.5
Clinical efficacy TISSEEL
2.5.1
This product has been studied in a variety of clinical settings for use as a hemostat and is approved as a sealant in colon surgery. A total of 333 reoperative cardiac or resternotomy patients from 11 different centers in the United States were randomized to treatment with TISSEEL or conventional topical agents. The end point was the number of bleeding episodes controlled within 5 min. The FS group was then compared with historical matched controls. With FS, 92.6% had complete cessation of bleeding at 5 min compared with 12.4% in the historical matched control group (p < 0.001) [16]. Following initial approval by the FDA, a solvent detergent step was added to production for improved virus inactivation. A Phase III randomized, double-blind trial compared the new formulation to the older formulation in 288 patients. Hemostasis within 5 min was the outcome and the new formulation was determined to be as effective at 88.2 versus 89.6% for the old formulation [17]. A single-center open-label trial compared patients undergoing laparotomy for trauma to the liver or spleen with historical controls. Use of TISSEEL resulted in fewer splenectomies (0/19 vs 14/22; p < 0.001), but did not reduce mortality [2].
ARTISS
An initial Phase I/II study was performed in 40 patients at multiple institutions. Included subjects had a total body surface area (TBSA) burn of £ 40% and had two comparable test sites of 1 -- 4% TBSA. Fixation with staples was compared to fixation with FS. There was reduced seroma/hematoma formation with FS and generally greater wound closure. The maximum difference in wound closure was at day 28. There were no serious adverse events [21]. The initial study was followed by a multicenter, randomized, evaluator-blinded, Phase III clinical trial comparing FS to staples in adherence of skin grafts following surgically prepared wound beds. Patient inclusion was the same as the initial trial. The primary outcome was wound closure at day 28 by planimetry and evaluation by three independent, blinded evaluators. Secondary outcomes included hematoma/seroma on day 1, graft take on day 5 and wound closure on day 14. Planimetry showed 70.3% wound closure in the ARTISS group at 28 days compared with 65.8% in the stapled group. ARTISS was also found to be at least as efficacious as staples at the 97.5% one-sided level. Hematoma formation was significantly lower with FS (29.7 vs 62.3%; p < 0.001). No significant differences occurred in other secondary outcomes. Humanistic outcomes were also evaluated including provider and patient preference. Both of these favored FS use [22].
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Efficacy and safety of ARTISS in rhytidectomy were evaluated in a Phase II trial of 45 patients. Patients were randomized by side of the face to standard care on one side and standard car plus FS on the other. Patients were evaluated by blinded examiners for ecchymosis, grading of edema and ecchymosis, drainage, hematoma, seroma, safety and patient-reported pain and preference. Drainage was significantly reduced 24 h after surgery in the ARTISS group (11.5 vs 26.8 ml; p < 0.001). Additionally, patients preferred the FS-treated side of the face [23]. The follow-up Phase III study was a controlled, randomized, patient-blinded study at seven US centers. Again, standard treatment on one side was compared with adjunctive ARTISS on the other. There were 75 patients who finished the trial. Again, mean drainage at 24 h was significantly lower in the ARTISS group (7.7 vs 20.0 ml; p < 0.0001). There was no difference in hematoma or seroma formation. While a majority of patients stated that they preferred the ARTISS-treated side, this was not statistically significant. Patients did report experiencing less pain on the FS side. There were two serious adverse events reported, dehydration postoperative day 2 and an MRSA abscess. The abscess was ultimately deemed unrelated to product application as it occurred on day 14. The remaining 35 adverse events were considered mild [24].
presence of intravascular air during cardiac procedures using spray FS [30].
Safety and tolerability One of the main safety issues surrounding both of these products is their manufacture from pooled human plasma. That means that there is risk of transmission for both viruses and, theoretically, prion disease. Donors are screened and vapor heating and detergent/solvent treatments are used to remove viruses. It is noted, however, that these methods may be less effective against parvovirus B19. Calculated risk of transmission in these products remains low at 10-15 for HIV, HCV, HBC and HAV for both thrombin and fibrinogen [25]. For parvovirus, the risk was 1 in 500,000 for fibrinogen and < 1 in 10 million for thrombin [25]. Due to the presence of aprotinin in these products, anaphylaxis is a risk and they should not be used in patients with a known sensitivity. Anaphylaxis has been reported in postmarketing experience with TISSEEL, though not yet with ARTISS [2,26]. Given that both contain the same dosage of aprotinin, caution should be exercised with both products. Within the clinical data used for the approval of TISSEEL, there were no adverse events occurring in > 1% of the populations studied. For ARTISS, however, graft failure, pruritis and hematoma were most common in burn patients, while hematoma/seroma was most common in rhytidectomy [22,24]. Both products used in the spray form carry a warning regarding air embolus due to the pressure from the spray applicator device. TISSEEL as well as competitor products have been found in case reports to have caused life-threatening air embolus [27-29]. Animal models have also demonstrated the
Conclusion Overall, the clinical evidence for the approval of these two products comes from relatively small clinical trials. In the case of TISSEEL, the largest effect in the largest trial was seen in historical controls [16]. The approval for use as a colon sealant is based on one single-center study without controls at all. Despite this, there are now 16 years of experience with commercial FSs in the United States and a much longer experience in Europe. In that time, few adverse events have been reported. The approval of ARTISS as an adhesive is relatively recent and long-term follow-up data are not yet available. Ideally, larger well-controlled trials would be conducted to evaluate both of these products, but given the wide clinical use and popularity of FSs, this is unlikely [1,3,20,33-35]. On balance, these products appear safe and effective.
2.6
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Regulatory affairs While FSs were first approved in Europe in 1972, it was not until 1998 that the first product was approved in the USA. In 1995, a conference regarding the use of FSs was held in Bethesda, Maryland. At that time, the FDA continued to hold that a direct clinical benefit needed to be demonstrated in well-controlled trials, though the process for approval was facilitated [31]. Ultimately, following the first product approvals, the FDA issued a guidance for manufacturers wishing to produce FSs. Within this document, the Center for Biologics Evaluation and Research observes that one of the challenges to large placebo-controlled trials is that many clinicians are reluctant to conduct them because they already view FSs as standard of care [32]. It clearly describes that while each component of these products may be demonstrated to have efficacy in nonclinical settings, the entire product should be evaluated in clinical trials. Hemostasis is mentioned specifically as an appropriate end point for trials of these products, but other clinical endpoints are not identified. Nonetheless, newer agents in this class were approved following guidance publication [3]. 2.7
2.8
3.
Expert opinion
There are well over 3000 published articles on FSs in the medical literature and this number is growing [1]. Surgeons in all fields of expertise are likely to continue to use these products. One need only look at the vast number of off-label uses being studied and employed in practice. This widespread belief in effectiveness is a significant barrier to larger, controlled trials of these agents being conducted. FSs are being explored for anal fistula closure, adhesion prevention, seroma reduction, as well as urologic, vascular, intestinal and nerve anastomoses [20,36-43]. The adhesive
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Fibrin sealants
properties are being exploited as an alternative fixation technique in various hernia repairs, as a means of pain reduction from reduced suture or tack placement, or for pain reduction after plastic surgical procedures [44-50]. Even in its use as a hemostat, FSs are being used in a variety of new ways including postpartum hemorrhage, other gynecologic procedures and in neurosurgery [27,51-54]. The use of these products for hemostasis is the most widespread and they appear to be effective. The nature of the small studies and lack of large trials make publication bias likely [55]. Larger, randomized trials are still needed. One of the newer areas that is being explored with FSs is as a drug delivery device. Antibiotics and topical anesthetics have already been delivered to patients using FSs [56-58]. Additionally, there is interest in these products as scaffolds for tissue engineering outside of clinical use. Fibrin sealants appear to be relatively nontoxic, are derived from human tissue and have the ability to function in hemostasis, tissue adhesion and tissue sealing. This is a recipe for broad appeal. Not only is it likely that the number of off-label uses for these products will expand, but we are likely to see more products approved. Just as ARTISS is a version of TISSEEL designed to work best as an adhesive, allowing a surgeon to shift a graft into place, more products will be individually tailored to ideal use. One thing that must be kept in mind as use continues to expand, however, is cost. While institutional prices may vary, FSs are among the most expensive hemostats, sealers or adhesives available [3]. At a time in medicine where costs are skyrocketing, clinicians as well as industry should undertake careful evaluation of the cost benefit of using these agents. Despite their high price, the three separate functions of FSs make them an attractive choice as a single agent allowing facilities to reduce inventory. There are several other potential methods through which FSs could save costs including decreased operative time, decreased complication rates, fewer hospital days and fewer hardware infections. However, many of these have not been proven and cost benefit data should be obtained. Within the field of burn care, the use of glue in practice appears to be reducing the need for large numbers of staples in graft fixation. This in turn reduces the need for removal that occasionally requires moderate sedation or even general anesthesia. Not only could avoidance of these procedures decrease cost, but they have the potential to increase patient
satisfaction. The patient experience may also be improved without the need for drainage of hematomas and seromas following skin graft placement. Such procedures can produce pain, but more importantly result in anxiety for patients. As the patient experience becomes an essential part of how hospitals and providers are reimbursed, there is a significant potential for cost savings. That is to say nothing of the potential improvements in outcome and cosmetics that have not been evaluated. Particularly in areas like the face with multiple contours, future formulations could replace suture or staple fixation altogether. The overall safety record of FSs is quite good with few adverse events being reported in post-marketing follow-up. However, as clinicians push into new frontiers, care should be taken. Use of high-pressure spraying systems in confined spaces within the cranial vault, on large vessels such as hepatic veins, or near heparinized systems like extra-corporeal membrane oxygenation could result in rising complications [27,29,30]. Air embolus and intravascular thrombus even with heparinization are real concerns with these products. Finally, not all small studies using these products have been positive. Results in liver surgery to prevent bile leak, for example, have shown no difference [59]. The general safety of these products and relative ease of use may lead them to be used in settings where benefit has not been proven simply because a sealant or adhesive is desirable. This potential cost increase may offset any benefit gleaned from their use in approved settings. Without the introduction of an ideal hemostat, sealant and adhesive, FSs are here to stay into the foreseeable future. It is not feasible or probable that large randomized trials will be conducted for all the potential uses of these products. Clinicians should, therefore, carefully consider how far from approved use they are straying and consider if a new study should be performed. Regarding costs, clinicians and researchers should gather and examine data going forward. Costeffectiveness will likely be a critical criterion for the use of expensive agents in the near future.
Declaration of interest N Gibran is a co-author on two of the Phase II studies of the Baxter Fibrin sealant ARTISS. None of the other authors have any competing interests to declare and no funding was received in support of the manuscript.
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Foster K, Greenhalgh D, Gamelli RL, et al. Efficacy and safety of a fibrin sealant for adherence of autologous skin grafts to burn wounds: results of a phase 3 clinical study. J Burn Care Res 2008;29(2):293-303 Major study for establishing efficacy of fibrin glue in burn surgery.
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Hester TR Jr, Gerut ZE, Shire JR, et al. Exploratory, randomized, controlled, phase 2 study to evaluate the safety and efficacy of adjuvant fibrin sealant VH S/ D 4 S-Apr (ARTISS) in patients undergoing rhytidectomy. Aesthet Surg J 2013;33(3):323-33
24.
Hester TR Jr, Shire JR, Nguyen DB, et al. Randomized, controlled, phase 3 study to evaluate the safety and efficacy of fibrin sealant VH S/D 4 s-apr (Artiss) to improve tissue adherence in subjects undergoing rhytidectomy. Aesthet Surg J 2013;33(4):487-96 Major study establishing fibrin sealant efficacy in rhytidectomy.
Lowe J, Luber J, Levitsky S, et al. Evaluation of the topical hemostatic efficacy and safety of TISSEEL VH S/D fibrin sealant compared with currently licensed TISSEEL VH in patients undergoing cardiac surgery: a phase 3, randomized, double-blind clinical study. J Cardiovasc Surg (Torino) 2007;48(3):323-31
25.
Saha SP, Muluk S, Schenk W III, et al. Use of fibrin sealant as a hemostatic agent in expanded polytetrafluoroethylene graft placement surgery. Ann Vasc Surg 2011;25(6):813-22
Horowitz B, Busch M. Estimating the pathogen safety of manufactured human plasma products: application to fibrin sealants and to thrombin. Transfusion 2008;48(8):1739-53
26.
Baxter Corp. Package Insert: ARTISS [Fibrin Sealant (Human)]. 2011. Available from: http://www.baxter. com/downloads/healthcare_professionals/ products/ARTISS_PI.pdf [Cited 5 January 2013]
27.
Felema GG, Bryskin RB, Heger IM, Saswata R. Venous air embolism from Tisseel use during endoscopic cranial
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Saha SP, Muluk S, Schenk W III, et al. A prospective randomized study comparing fibrin sealant to manual compression for the treatment of anastomotic suture-hole bleeding in
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vault remodeling for craniosynostosis repair: a case report. Paediatr Anaesth 2013;23(8):754-6 28.
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Ebner FM, Paul A, Peters J, Hartmann M. Venous air embolism and intracardiac thrombus after pressurized fibrin glue during liver surgery. Br J Anaesth 2011;106(2):180-2 Umegaki T, Nishi K, Murao K, et al. [Lethal air embolism after spray of tissue adhesive-fibrinogen and factor XIII aerosol during laparoscopic partial nephrectomy]. Masui 2007;56(10):1203-5
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Olsen PS, Hjelms E. Intravascular air after fibrin sealing by spray gun in cardiovascular surgery. Eur J Cardiothorac Surg 1989;3(4):376-7
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Alving BM, Weinstein MJ, Finlayson JS, et al. Fibrin sealant: summary of a conference on characteristics and clinical uses. Transfusion 1995;35(9):783-90
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US Food and Drug Administration. Guidance for Industry: efficacy Studies to Support Marketing of Fibrin Sealant Products Manufactured for Commercial Use. 1999. Available from: http://www.fda.gov/cber/guidelines.htm [Cited 5 January 2014] Jackson MR. Fibrin sealants in surgical practice: an overview. Am J Surg 2001;182(2 Suppl):1S-7S Lowenfels AB. ACS 2006 Latest Advances in Surgical Adhesives. Medscape General Surgery. 2006. Available from: http://www. medscape.org/viewarticle/548909 [Cited 4 Januray 2014]
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Yu L, Gu T, Song L, et al. Fibrin sealant provides superior hemostasis for sternotomy compared with bone wax. Ann Thorac Surg 2012;93(2):641-4 Carter TI, Fong ZV, Hyslop T, et al. A dual-institution randomized controlled trial of remnant closure after distal pancreatectomy: does the addition of a falciform patch and fibrin glue improve
Ding H, Yuan JQ, Zhou JH, et al. Systematic review and meta-analysis of application of fibrin sealant after liver resection. Curr Med Res Opin 2013;29(4):387-94
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Knox CJ, Hohman MH, Kleiss IJ, et al. Facial nerve repair: fibrin adhesive coaptation versus epineurial suture repair in a rodent model. Laryngoscope 2013;123(7):1618-21
Healy C, Greig AV, Murphy AD, et al. Prospective randomized controlled trial: fibrin sealant reduces split skin graft donor-site pain. Plast Reconstr Surg 2013;132(1):139e-46e
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Dhulkotia JS, Alazzam M, Galimberti A. Tisseel for management of traumatic postpartum haemorrhage. Arch Gynecol Obstet 2009;279(3):437-9
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List RJ, Thomas SP, Shenouda E, et al. Fibrin Sealant Injection: an Aid to Reduce Venous Bleeding during Jugular Bulb and Sigmoid Sinus Dissection in Glomus Jugulare (Jugulotympanic Paraganglioma) Surgery. Skull Base 2011;21(5):309-12
Randelli F, Banci L, Ragone V, et al. Effectiveness of fibrin sealant after cementless total hip replacement: a double-blind randomized controlled trial. Int J Immunopathol Pharmacol 2013;26(1):189-97
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Rousou JA. Use of fibrin sealants in cardiovascular surgery: a systematic review. J Card Surg 2013;28(3):238-47
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Sanjay P, Watt DG, Wigmore SJ. Systematic review and meta-analysis of haemostatic and biliostatic efficacy of fibrin sealants in elective liver surgery. J Gastrointest Surg 2013;17(4):829-36
Angioli R, Plotti F, Ricciardi R, et al. The use of novel hemostatic sealant (Tisseel) in laparoscopic myomectomy: a case-control study. Surg Endosc 2012;26(7):2046-53
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Eriksen JR, Bisgaard T, Assaadzadeh S, et al. Randomized clinical trial of fibrin sealant versus titanium tacks for mesh fixation in laparoscopic umbilical hernia repair. Br J Surg 2011;98(11):1537-45
Kim K, Park SI, Kim BJ, et al. Efficacy of fibrin sealant in reducing hemorrhage after a loop electrosurgical excision procedure. Gynecol Obstet Invest 2012;74(1):1-5
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Wong JU, Leung TH, Huang CC, Huang CS. Comparing chronic pain between fibrin sealant and suture fixation for bilayer polypropylene mesh inguinal hernioplasty: a randomized clinical trial. Am J Surg 2011;202(1):34-8
Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2003;(2):CD004171
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Mitra S, Khandelwal P, Roberts K, et al. Pain relief in laparoscopic cholecystectomy--a review of the current options. Pain Pract 2012;12(6):485-96
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Tofuku K, Koga H, Yanase M, Komiya S. The use of antibioticimpregnated fibrin sealant for the prevention of surgical site infection associated with spinal instrumentation. Eur Spine J 2012;21(10):2027-33
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Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: components of the surgical toolbox. Transfusion 2008;48(7):1502-16 Llewellyn-Bennett R, Greenwood R, Benson JR, et al. Randomized clinical trial on the effect of fibrin sealant on latissimus dorsi donor-site seroma formation after breast reconstruction. Br J Surg 2012;99(10):1381-8
hernia repair: effect on postoperative pain: a double-blind, randomized trial versus standard heavyweight mesh. Surgery 2013;153(1):126-30
outcomes? J Gastrointest Surg 2013;17(1):102-9
Campanelli G, Pascual MH, Hoeferlin A, et al. Randomized, controlled, blinded trial of Tisseel/ Tissucol for mesh fixation in patients undergoing Lichtenstein technique for primary inguinal hernia repair: results of the TIMELI trial. Ann Surg 2012;255(4):650-7
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Campanelli G, Sfeclan C, Cavalli M, Biondi A. Reducing postoperative pain: the use of Tisseel for mesh fixation in inguinal hernia repair. Surg Technol Int 2012;22:134-9
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Cashman JD, Jackson JK, Mugabe C, et al. The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant. J Orthop Sci 2013;18(1):165-74
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Vaid S, Nicholson T. A novel approach to closure of perineal wounds during abdominoperineal resection: use of fibrin sealant. Arch Surg 2012;147(8):778-80
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Canonico S, Benevento R, Perna G, et al. Sutureless fixation with fibrin glue of lightweight mesh in open inguinal
Figueras J, Llado L, Miro M, et al. Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients. Ann Surg 2007;245(4):536-42
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Affiliation
Samuel P Mandell†1 MD MPH & Nicole S Gibran2,3 MD FACS † Author for correspondence 1 Trauma/Critical Care Fellow, Harborview Medical Center, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA Tel: +1 206 744 3140; Fax: +1 206 744 2896; E-mail: [email protected] 2 Director, University of Washington Regional Burn Center, Harborview Medical Center, David & Nancy Auth - Washington Research Foundation, Chair in Restorative Burn Surgery, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA 3 Professor, University of Washington, Harborview Medical Center, Department of Surgery, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA
830
Expert Opin. Biol. Ther. (2014) 14(6)
Fibrin sealants: surgical hemostat, sealant and adhesive
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Samuel P Mandell† & Nicole S Gibran †
Harborview Medical Center, Seattle, WA, USA
1.
Introduction
2.
Overview of the market
3.
Expert opinion
Introduction: Fibrin sealants (FS) have been approved for use in the United States since 1998. Since approval, they have been used in a wide variety of clinical settings and new products continue to be introduced. Areas covered: This review covers the literature supporting the USA FDAapproved indications for FS products produced by Baxter Corp. Literature review of PubMed, the Cochrane Library, FDA approval documents and product websites yielded information contained in this article. Mechanism of action, efficacy and safety of these products are covered. Expert opinion: FS are generally safe, popular and are used for a wide variety of off-label indications. Their use appears to be expanding rapidly. For many uses, including approved ones, large well-controlled trials are still needed. Additionally, cost-effectiveness data for these products would be a great benefit in guiding their future use. Keywords: adhesive, fibrin sealant, fibrinogen, hemostasis, sealant, skin graft, surgery, thrombin Expert Opin. Biol. Ther. (2014) 14(6):821-830
1.
Introduction
Fibrin sealant (FS) or fibrin ‘glue’ is a class of compounds that form fibrin clot by combining the two primary components, fibrinogen and thrombin. The ability of these products to provide both tissue adhesion and hemostasis has made them attractive in a variety of clinical settings [1]. They have been used in the United States as blood-bank--derived products since the 1980s and subsequently produced as pharmaceutical agents since TISSEEL (Baxter Healthcare Corp., Westlake Village, CA, USA) was FDA approved in 1998. Currently, TISSEEL is approved as an adjunct to hemostasis when conventional surgical measures are ineffective and as an adjunctive sealant for colon anastomoses after reversal of temporary colostomy [2]. Difficult surgical bleeding can occur in a variety of settings across multiple specialties leading to a broad market for the use of this product. While the indication for colon sealing is rather narrow, it has led to significant interest in TISSEEL more broadly as a tissue sealant. A second Baxter FS, ARTISS (Baxter Healthcare Corp., Westlake Village, CA, USA), is also available. It has been approved for use in adhering skin grafts to surgically prepare burn wounds in adult and pediatric patients. The following review will focus on the function, current use and future of these two products. 2.
Overview of the market
Hemorrhage control and tissue repair are essential elements of nearly all surgery performed worldwide. The potential market for products that can produce rapid hemostasis, adhere tissue together and prevent leakage from anastomoses is vast. Spotnitz and Burks have organized these products into three broad groups: hemostats, sealants and adhesives (Table 1) [3]. These groups are further divided into categories and classes of agent. FSs (Box 1) are the only products FDA (USA) approved 10.1517/14712598.2014.897323 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase Indications
Mechanism of action Route of administration Pivotal trial(s)
Drug name Phase Indications
Mechanism of action: Route of administration Pivotal trial(s)
TISSEEL (Fibrin sealants [human]) FDA approved Hemostasis: TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in patients undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature and cautery) is ineffective or impractical. Not approved for neurosurgery Sealing: TISSEEL is a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies Conversion of fibrinogen to fibrin clot Topical spray or drip Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study: 333 cardiac reoperations compared with historical controls. Increase in controlled hemorrhage at 5 min with fibrin sealant
ARTISS (fibrin sealant [human]) FDA approved Burns: ARTISS is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than or equal to 1 year of age Rhytidectomy: ARTISS is indicated to adhere tissue flaps during facial rhytidectomy surgery Conversion of fibrinogen to fibrin clot Topical spray or drip Efficacy and safety of a fibrin sealant for adherence of autologous skin grafts to burn wounds: results of a Phase III clinical study: 138 burn patients with prepared surgical site with either staples or fibrin sealant. Each patient served as their own control. Fibrin sealant was equivalent to staples for wound closure and reduced hematoma post-operative day 1 Randomized, controlled, Phase III study to evaluate the safety and efficacy of fibrin sealant VH S/D 4 sapr (Artiss) to improve tissue adherence in subjects undergoing rhytidectomy: 75 patients (150 sides) with side of face randomized to standard care or standard care plus fibrin sealant. Decreased mean drainage after 24 h with fibrin sealant use
for an indication in each of these groups. This versatility gives them some advantage over other agents. This also means that they must compete with a variety of other products that may be better at a specific task. In each group, FSs have shown themselves to be at the high end of effectiveness, but also among the more costly agents [3]. Currently, there are five FS products that are FDA approved (Table 1) [4]. All of these, with the exception of ARTISS, are approved for the control of hemorrhage. Two products, EVARREST (Omrix Biopharmaceuticals, Israel) and TachoSiL (Nycomed, Austria), come as patches that can be applied to tissue. Vitagel (Stryker, Malvern, PA, USA) is a topical product that has approval as an adjunct to hemostasis, but contains no human fibrinogen; instead, bovine thrombin within the product acts on autologous fibrinogen to form a fibrin clot while bovine collagen forms a scaffold for fibroblast ingrowth. Several factors are likely to drive the market for these products. Increased healthcare costs will no doubt influence the choice of one product over another. A product with 822
multiple roles will have added versatility due to the decreased need to stock multiple agents. Additionally, increase in laparoscopic, endoscopic and robotic procedures may push surgeons to look for agents to aid in hemostasis or tissue adherence when pressure or suturing may be difficult [5-7]. Increasing evidence of the negative effects of blood transfusion may also drive a market for agents that reduce bleeding or surgical wound breakdown [8-10]. These products also have the potential to decrease operative time and postoperative complications such as anastomotic leaks. New products within this field are being developed outside of the classes already in use [11]. Currently, no single agent in any group has proven to be safe, effective, usable in broad settings, cost effective and approvable [3]. Lack of an ideal agent and considerable desire for one will drive this market into the future. 2.1
Introduction to the compounds TISSEEL
2.1.1
In 1998, TISSEEL became the first FDA-approved FS in the United States, though these sealants had previously been
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Fibrin sealants
Table 1. FDA-approved surgical hemostats, sealants and adhesives. Group Hemostat
Category Mechanical
Class
Brand
Porcine gelatin Bovine collagen
Oxidized regenerated cellulose Polysaccharide spheres
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Active
Flowable
Fibrin sealant
Sealants
PEG polymer
Albumin and glutaraldehyde Cyanoacrylate
Adhesives
Fibrin sealant Albumin and glutaraldehyde Cyanoacrylate
Fibrin sealant
Manufacturer
Bovine thrombin Pooled human thrombin Recombinant thrombin Bovine gelatin and pooled human thrombin Porcine gelatin Pooled human plasma Individual human plasma with bovine thrombin and collagen Pooled human plasma and equine collagen Pooled human plasma, polygalactin 910 and oxidized regenerated cellulose Pooled human plasma and equine collagen Two PEGs PEG and trilysine amine PEG and human serum albumin Bovine serum albumin, glutaraldehyde Octyl and butyl lactoyl cyanoacrylate Pooled human plasma Bovine serum albumin, glutaraldehyde Octyl cyanoacrylate Butyl cyanoacrylate
Pooled human plasma
used throughout Europe. Current indications are as an adjunct to hemostasis in patients undergoing surgery when control of bleeding by conventional means is ineffective or impractical, and as sealant to prevent leakage from colonic anastomoses following the reversal of temporary colostomies using standard technique. TISSEEL uses a thrombin syringe and a Sealer Protein syringe and the two are combined and applied to tissue using a spray applicator or drip cannula, forming fibrin clot. TISSEEL comes in both prefilled frozen syringes (2, 4, 10 ml) as well as a freeze-dried form (2, 4, 10 ml). The freeze-dried version can be stored at room temperature, but
Gelfoam Surgifoam Avitene Helistat Instat Surgicel, Surgicel Fibrillar, Knu-Knit Arista AH Vitasure Thrombin-JMI Evithrom Recothrom Floseal
Pharmacia, Kalamazoo, MI Ferrosan Medical Devices, Denmark Davol/Bard, Warwick, RI Integra Lifesciences, Plainsboro, NJ Integra Lifesciences, Plainsboro, NJ Ethicon, San Lorenzo, PR
Surgiflo TISSEEL EVICEL Vitagel
Omrix Biopharmaceuticals, Israel Baxter, Westlake Village, CA Omrix Biopharmaceuticals, Israel Stryker, Malvern, PA
Tachosil
Baxter, Westlake Village, CA
EVARREST
Omrix Biopharmaceuticals, Israel
TachoSil
Nycomed, Austria
Coseal DuraSeal Progel
Baxter, Hayward, CA Covidien, Mansfield, MA Neomend, Irvine, CA
Bioglue
Cryolife, Kennesaw, GA
Omnex
Ethicon, Somerville, NJ
TISSEEL Bioglue
Baxter, Westlake Village, CA Cryolife, Kennesaw, GA
Dermabond Derma+flex QS Liquiband Flex Surgiseal Indermil Histoacryl ARTISS
Ethicon, San Lorenzo, PR Chemence, Alpharetta, GA Advance Medical Solutions, UK Adhezion Biomedical, Wyomissing, PA Henkel, Ireland B. Braun, Bethlehem, PA Baxter, Westlake Village, CA
Medafor, Minneapolis, MN Stryker, Malvern, PA GenTrac, Inc., Middleton, WI Omrix Biopharmaceuticals, Israel ZymoGenetics, Seattle, WA Baxter, Hayward, CA
requires reconstitution prior to use. The contents of the reconstituted Sealer Protein and prefilled syringe are equivalent (Table 2). Reconstitution takes approximately 20 min to complete, and the frozen product may take 5 -- 160 min to thaw depending on the technique and syringe size. Reconstituted or warmed, thawed Sealer Protein must be used within 48 h. Frozen product that has been thawed at room temperature may be stored at room temperature for 48 h. 2.1.2
ARTISS
ARTISS is a similar two-component FS with a thrombin syringe and a Sealer Protein (Figure 1). It is applied to the
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Table 2. Comparison of Baxter Corp. fibrin sealants.
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Sealer Protein Total protein (mg/ml) Fibrinogen (mg/ml) Aprotinin (synthetic) (KIU/ml) Other ingredients
Thrombin solution Thrombin (human) (units/ml) Calcium chloride (µmol/ml) Other ingredients
TISSEEL
ARTISS
96 -- 125 67 -- 106 2250 -- 3750 Human albumin, trisodium citrate, histidine, polysorbate 80, water
96 -- 125 67 -- 106 2250 -- 3750 Human albumin, trisodium citrate, histidine, polysorbate 80, water
400 -- 625
2.6 -- 6.5
36 -- 44 Human albumin, sodium chloride, water
36 -- 44 Human albumin, sodium chloride, water
Figure 1. ARTISS in its prefilled, frozen syringe after thawing.
wound bed most often with a pressurized spray applicator (Figure 2). It is FDA approved to adhere autologous skin grafts to surgically prepared wound beds from burn injury in patients > 1 year of age. It is also approved to adhere flaps during rhytidectomy. Unlike TISSEEL, ARTISS is not approved as an adjunct to hemostasis. It is supplied in the same forms as TISSEEL described above and has the same reconstitution and thawing characteristics. The Sealer Protein Solution is identical to that for TISSEEL; however, there is significantly less thrombin. Chemistry Both TISSEEL and ARTISS act by mimicking the final step in the clotting cascade with the conversion of fibrinogen to fibrin clot in the presence of calcium and thrombin. All necessary factors for this reaction are present in each agent and fibrin clot will form in patients on heparin or antiplatelet agents. Fibrinogen consists of three pairs of polypeptides Aa, Bb and g connected by disulfide bridges. Thrombin is a protease that cleaves fibrinopeptides A and B from the N terminus of Aa and Bb chains. Once cleavage occurs, the monomers are 2.2
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insoluble and the N-termini are able to bind with the C-termini of other fibrin molecules, resulting in polymerization [12]. Factor XIII is not contained in either product, but may be present endogenously. The presence of calcium ions contained within the product catalyzes the thrombin activity, which may enhance fibrin crosslinking and stabilization. Aprotinin is a separate protease that functions to prevent the breakdown of fibrin polymers. Pharmacodynamics TISSEEL forms clot rapidly in 5 -- 10 s given high thrombin concentration. The lower thrombin concentration in ARTISS means that initial polymerization may take up to 60 s and continue to strengthen over a period of 2 h. 2.3
Pharmacokinetics and metabolism Since both of these agents are topical, systemic absorption is expected to be small. Specific pharmacokinetic studies have not been performed. Aprotinin is eliminated by renal excretion after a half-life of 30 -- 60 min. Animal and preclinical studies have demonstrated that inclusion of aprotinin decreases clot breakdown and improves sealant function [13-15]. 2.4
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Fibrin sealants
A Phase II trial in patients undergoing placement of expanded polytetrafluoroethylene (ePTFE) vascular grafts with ongoing suture line bleeding looked at 73 patients divided into 3 groups, FS clamp off at 60 or 120 s, or control with manual compression. The primary endpoint was hemorrhage control at 4 min. In the 120-s group treated with FS, hemorrhage was controlled in 62.5 versus 34.8% of control. No significant adverse events were noted [18]. This was followed by a randomized control trial of vascular patients undergoing ePTFE prosthesis placement, and 140 patients with ongoing bleeding from the suture line were randomized to FS or control (manual compression). The primary endpoint was hemostasis at the suture line within 4 min. The FS group had significantly more hemostasis 62.9 versus 31.4% at 4 min (p < 0.001). This improvement also held true in a subgroup on antiplatelet therapy [19]. Despite its approval as a sealant for colostomy closure, there are no randomized trials evaluating TISSEEL for this purpose. There is a report of a single-center open-label study of 118 patients randomized to standard care (58 patients) or standard care plus FS (60 patients) for elective colostomy reversal following temporary stoma placement for trauma. The TISSEEL group was found to have a statistically significant reduction in complications (leak, abscess, reoperation, septic shock, mortality) when compared to standard of care (p = 0.046) [2]. Much of the available data on the use of TISSEEL in colorectal anastomoses come from rats, which seem to suggest favorable outcomes [20].
Figure 2. ARTISS spray application.
2.5.2 2.5
Clinical efficacy TISSEEL
2.5.1
This product has been studied in a variety of clinical settings for use as a hemostat and is approved as a sealant in colon surgery. A total of 333 reoperative cardiac or resternotomy patients from 11 different centers in the United States were randomized to treatment with TISSEEL or conventional topical agents. The end point was the number of bleeding episodes controlled within 5 min. The FS group was then compared with historical matched controls. With FS, 92.6% had complete cessation of bleeding at 5 min compared with 12.4% in the historical matched control group (p < 0.001) [16]. Following initial approval by the FDA, a solvent detergent step was added to production for improved virus inactivation. A Phase III randomized, double-blind trial compared the new formulation to the older formulation in 288 patients. Hemostasis within 5 min was the outcome and the new formulation was determined to be as effective at 88.2 versus 89.6% for the old formulation [17]. A single-center open-label trial compared patients undergoing laparotomy for trauma to the liver or spleen with historical controls. Use of TISSEEL resulted in fewer splenectomies (0/19 vs 14/22; p < 0.001), but did not reduce mortality [2].
ARTISS
An initial Phase I/II study was performed in 40 patients at multiple institutions. Included subjects had a total body surface area (TBSA) burn of £ 40% and had two comparable test sites of 1 -- 4% TBSA. Fixation with staples was compared to fixation with FS. There was reduced seroma/hematoma formation with FS and generally greater wound closure. The maximum difference in wound closure was at day 28. There were no serious adverse events [21]. The initial study was followed by a multicenter, randomized, evaluator-blinded, Phase III clinical trial comparing FS to staples in adherence of skin grafts following surgically prepared wound beds. Patient inclusion was the same as the initial trial. The primary outcome was wound closure at day 28 by planimetry and evaluation by three independent, blinded evaluators. Secondary outcomes included hematoma/seroma on day 1, graft take on day 5 and wound closure on day 14. Planimetry showed 70.3% wound closure in the ARTISS group at 28 days compared with 65.8% in the stapled group. ARTISS was also found to be at least as efficacious as staples at the 97.5% one-sided level. Hematoma formation was significantly lower with FS (29.7 vs 62.3%; p < 0.001). No significant differences occurred in other secondary outcomes. Humanistic outcomes were also evaluated including provider and patient preference. Both of these favored FS use [22].
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Efficacy and safety of ARTISS in rhytidectomy were evaluated in a Phase II trial of 45 patients. Patients were randomized by side of the face to standard care on one side and standard car plus FS on the other. Patients were evaluated by blinded examiners for ecchymosis, grading of edema and ecchymosis, drainage, hematoma, seroma, safety and patient-reported pain and preference. Drainage was significantly reduced 24 h after surgery in the ARTISS group (11.5 vs 26.8 ml; p < 0.001). Additionally, patients preferred the FS-treated side of the face [23]. The follow-up Phase III study was a controlled, randomized, patient-blinded study at seven US centers. Again, standard treatment on one side was compared with adjunctive ARTISS on the other. There were 75 patients who finished the trial. Again, mean drainage at 24 h was significantly lower in the ARTISS group (7.7 vs 20.0 ml; p < 0.0001). There was no difference in hematoma or seroma formation. While a majority of patients stated that they preferred the ARTISS-treated side, this was not statistically significant. Patients did report experiencing less pain on the FS side. There were two serious adverse events reported, dehydration postoperative day 2 and an MRSA abscess. The abscess was ultimately deemed unrelated to product application as it occurred on day 14. The remaining 35 adverse events were considered mild [24].
presence of intravascular air during cardiac procedures using spray FS [30].
Safety and tolerability One of the main safety issues surrounding both of these products is their manufacture from pooled human plasma. That means that there is risk of transmission for both viruses and, theoretically, prion disease. Donors are screened and vapor heating and detergent/solvent treatments are used to remove viruses. It is noted, however, that these methods may be less effective against parvovirus B19. Calculated risk of transmission in these products remains low at 10-15 for HIV, HCV, HBC and HAV for both thrombin and fibrinogen [25]. For parvovirus, the risk was 1 in 500,000 for fibrinogen and < 1 in 10 million for thrombin [25]. Due to the presence of aprotinin in these products, anaphylaxis is a risk and they should not be used in patients with a known sensitivity. Anaphylaxis has been reported in postmarketing experience with TISSEEL, though not yet with ARTISS [2,26]. Given that both contain the same dosage of aprotinin, caution should be exercised with both products. Within the clinical data used for the approval of TISSEEL, there were no adverse events occurring in > 1% of the populations studied. For ARTISS, however, graft failure, pruritis and hematoma were most common in burn patients, while hematoma/seroma was most common in rhytidectomy [22,24]. Both products used in the spray form carry a warning regarding air embolus due to the pressure from the spray applicator device. TISSEEL as well as competitor products have been found in case reports to have caused life-threatening air embolus [27-29]. Animal models have also demonstrated the
Conclusion Overall, the clinical evidence for the approval of these two products comes from relatively small clinical trials. In the case of TISSEEL, the largest effect in the largest trial was seen in historical controls [16]. The approval for use as a colon sealant is based on one single-center study without controls at all. Despite this, there are now 16 years of experience with commercial FSs in the United States and a much longer experience in Europe. In that time, few adverse events have been reported. The approval of ARTISS as an adhesive is relatively recent and long-term follow-up data are not yet available. Ideally, larger well-controlled trials would be conducted to evaluate both of these products, but given the wide clinical use and popularity of FSs, this is unlikely [1,3,20,33-35]. On balance, these products appear safe and effective.
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Regulatory affairs While FSs were first approved in Europe in 1972, it was not until 1998 that the first product was approved in the USA. In 1995, a conference regarding the use of FSs was held in Bethesda, Maryland. At that time, the FDA continued to hold that a direct clinical benefit needed to be demonstrated in well-controlled trials, though the process for approval was facilitated [31]. Ultimately, following the first product approvals, the FDA issued a guidance for manufacturers wishing to produce FSs. Within this document, the Center for Biologics Evaluation and Research observes that one of the challenges to large placebo-controlled trials is that many clinicians are reluctant to conduct them because they already view FSs as standard of care [32]. It clearly describes that while each component of these products may be demonstrated to have efficacy in nonclinical settings, the entire product should be evaluated in clinical trials. Hemostasis is mentioned specifically as an appropriate end point for trials of these products, but other clinical endpoints are not identified. Nonetheless, newer agents in this class were approved following guidance publication [3]. 2.7
2.8
3.
Expert opinion
There are well over 3000 published articles on FSs in the medical literature and this number is growing [1]. Surgeons in all fields of expertise are likely to continue to use these products. One need only look at the vast number of off-label uses being studied and employed in practice. This widespread belief in effectiveness is a significant barrier to larger, controlled trials of these agents being conducted. FSs are being explored for anal fistula closure, adhesion prevention, seroma reduction, as well as urologic, vascular, intestinal and nerve anastomoses [20,36-43]. The adhesive
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properties are being exploited as an alternative fixation technique in various hernia repairs, as a means of pain reduction from reduced suture or tack placement, or for pain reduction after plastic surgical procedures [44-50]. Even in its use as a hemostat, FSs are being used in a variety of new ways including postpartum hemorrhage, other gynecologic procedures and in neurosurgery [27,51-54]. The use of these products for hemostasis is the most widespread and they appear to be effective. The nature of the small studies and lack of large trials make publication bias likely [55]. Larger, randomized trials are still needed. One of the newer areas that is being explored with FSs is as a drug delivery device. Antibiotics and topical anesthetics have already been delivered to patients using FSs [56-58]. Additionally, there is interest in these products as scaffolds for tissue engineering outside of clinical use. Fibrin sealants appear to be relatively nontoxic, are derived from human tissue and have the ability to function in hemostasis, tissue adhesion and tissue sealing. This is a recipe for broad appeal. Not only is it likely that the number of off-label uses for these products will expand, but we are likely to see more products approved. Just as ARTISS is a version of TISSEEL designed to work best as an adhesive, allowing a surgeon to shift a graft into place, more products will be individually tailored to ideal use. One thing that must be kept in mind as use continues to expand, however, is cost. While institutional prices may vary, FSs are among the most expensive hemostats, sealers or adhesives available [3]. At a time in medicine where costs are skyrocketing, clinicians as well as industry should undertake careful evaluation of the cost benefit of using these agents. Despite their high price, the three separate functions of FSs make them an attractive choice as a single agent allowing facilities to reduce inventory. There are several other potential methods through which FSs could save costs including decreased operative time, decreased complication rates, fewer hospital days and fewer hardware infections. However, many of these have not been proven and cost benefit data should be obtained. Within the field of burn care, the use of glue in practice appears to be reducing the need for large numbers of staples in graft fixation. This in turn reduces the need for removal that occasionally requires moderate sedation or even general anesthesia. Not only could avoidance of these procedures decrease cost, but they have the potential to increase patient
satisfaction. The patient experience may also be improved without the need for drainage of hematomas and seromas following skin graft placement. Such procedures can produce pain, but more importantly result in anxiety for patients. As the patient experience becomes an essential part of how hospitals and providers are reimbursed, there is a significant potential for cost savings. That is to say nothing of the potential improvements in outcome and cosmetics that have not been evaluated. Particularly in areas like the face with multiple contours, future formulations could replace suture or staple fixation altogether. The overall safety record of FSs is quite good with few adverse events being reported in post-marketing follow-up. However, as clinicians push into new frontiers, care should be taken. Use of high-pressure spraying systems in confined spaces within the cranial vault, on large vessels such as hepatic veins, or near heparinized systems like extra-corporeal membrane oxygenation could result in rising complications [27,29,30]. Air embolus and intravascular thrombus even with heparinization are real concerns with these products. Finally, not all small studies using these products have been positive. Results in liver surgery to prevent bile leak, for example, have shown no difference [59]. The general safety of these products and relative ease of use may lead them to be used in settings where benefit has not been proven simply because a sealant or adhesive is desirable. This potential cost increase may offset any benefit gleaned from their use in approved settings. Without the introduction of an ideal hemostat, sealant and adhesive, FSs are here to stay into the foreseeable future. It is not feasible or probable that large randomized trials will be conducted for all the potential uses of these products. Clinicians should, therefore, carefully consider how far from approved use they are straying and consider if a new study should be performed. Regarding costs, clinicians and researchers should gather and examine data going forward. Costeffectiveness will likely be a critical criterion for the use of expensive agents in the near future.
Declaration of interest N Gibran is a co-author on two of the Phase II studies of the Baxter Fibrin sealant ARTISS. None of the other authors have any competing interests to declare and no funding was received in support of the manuscript.
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Affiliation
Samuel P Mandell†1 MD MPH & Nicole S Gibran2,3 MD FACS † Author for correspondence 1 Trauma/Critical Care Fellow, Harborview Medical Center, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA Tel: +1 206 744 3140; Fax: +1 206 744 2896; E-mail: [email protected] 2 Director, University of Washington Regional Burn Center, Harborview Medical Center, David & Nancy Auth - Washington Research Foundation, Chair in Restorative Burn Surgery, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA 3 Professor, University of Washington, Harborview Medical Center, Department of Surgery, 325 9th Avenue, Box 359796, Seattle, WA 98104-2499, USA
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