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Ann Thorac Surg 2000;69:1376-1382
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Controlled clinical trial of a novel hemostatic agent in cardiac surgery

^a Columbia University, College of Physicians and Surgeons, New York, New York, USA
^b The Cleveland Clinic Foundation, Cleveland, Ohio, USA
^c Washington Hospital, Fremont, California, USA
^d California Pacific Medical Center, San Francisco, California, USA

Address reprint requests to Dr Oz, Columbia University, College of Physicians and Surgeons, Milstein Pavilion 7-435, 177 Fort Washington Ave, New York, NY 10032
e-mail: mco2{at}columbia.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Appendix References

 
Background:. We performed a prospective randomized trial to compare FloSeal Matrix (Fusion Medical Technologies, Inc, Mountain View, CA), a gelatin-based hemostatic sealant, with Gelfoam-Thrombin (Gelfoam, Pharmacia and Upjohn, Kalamazoo, MI; Thrombin, Gentrac Inc, Middeton, WI) (control group) to control perioperative bleeding.

Methods:. A total of 93 patients undergoing cardiac operations were randomized into the FloSeal or control group after standard surgical means to control bleeding had failed. The bleeding site was evaluated at 1, 2, 3, 6, and 10 minutes after applying the hemostatic agent. If bleeding stopped within 10 minutes, the application was considered to be successful. In the case of a failure, the surgeon could use any means preferred (except FloSeal) to achieve hemostasis. All bleeding sites in a patient were treated with the hemostatic agent to which the patient was randomized. Follow-up evaluation was performed at 12 to 36 hours and 6 to 8 weeks after operation.

Results:. FloSeal stopped bleeding in 94% of the patients (first bleeding site only) within 10 minutes, compared to 60% in the control group (p = 0.001). At 3 minutes, successful hemostasis was achieved in 72% of the FloSeal group compared with 23% in the control group (p = 0.0001). There was no difference in the adverse event profile between the two groups.

Conclusions:. FloSeal Matrix demonstrated efficacy superior to that of Gelfoam-Thrombin and had a safety profile similar to that of Gelfoam-Thrombin when used as a topical hemostatic agent during cardiac surgery procedures.

	Introduction

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Perioperative bleeding leads to increased operating room time, blood product transfusions, pulmonary hypertension, and potentially to mortality. The coagulopathy induced by cardiopulmonary bypass and the multiple high pressure anastomoses created during cardiac surgery often result in bleeding, which is more effectively controlled with topical hemostatic agents than with sutures or electrocoagulation. The resulting $200 M industry has generated numerous products including gelatin (Gelfoam; Pharmacia and Upjohn, Kalamazoo, MI), thrombin, oxidized regenerated cellulose (Surgicel; Ethicon, Somerville, NJ), microfibrillar collagen (Avitene; Davol Inc, Woburn, MA), and fibrin glue (Tisseel; Osterreichisches Institut für Haemoderivate GES. M.B.H., Vienna, Austria) to control perioperative bleeding [1]. These products have demonstrated variable efficacy and their use is often hindered by difficulty in application, especially over aggressive bleeding sites or difficult-to-reach locations, and by lack of efficacy when used in heparinized patients.

The shortcomings of these topical hemostatic agents could potentially be overcome by use of a product that activates the clotting cascade while maintaining a hemostatic plug that is not easily displaced. A candidate solution, FloSeal Matrix (Fusion Medical Technologies, Inc, Mountain View, CA) is a combination of a gelatin-based matrix and thrombin solution. On coming into contact with blood after application at a bleeding site, the gelatin particles swell and tamponade bleeding. The bulk of the gelatin matrix–thrombin composite has the effect of slowing blood flow and providing exposure to a high thrombin concentration, thus hastening clot formation. We conducted a multicenter, randomized trial to compare the efficacy and safety of a standard clinical regimen of thrombin-soaked Gelfoam (Thrombin-Gelfoam) to FloSeal Matrix.

	Material and methods

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Fo ur cardiac centers were included in a prospective, randomized, controlled trial involving 93 patients over a 7-month enrollment period. The clinical trial involving human subjects was conducted in accordance with the Helsinki Declaration, as amended by the 41st World Medical Assembly in Hong Kong in 1989, and US Code of Federal Regulations 21CRF Part 812. The Institutional Review Board at each site approved the study before patient enrollment.

Before the operation, each patient signed an Institutional Review Board–approved consent form to participate in the study. To be eligible, a patient must be aged 21 years or older; undergoing cardiovascular, vascular, or orthopedic operation; be willing and able to complete all follow-up visits; and sign an informed consent form. Patients were excluded if they were pregnant or if they had a known sensitivity to any components of bovine thrombin preparations or to any material of bovine origin. Patients were enrolled in the study intraoperatively if they did not have an active infection at the operative site, if there was bleeding that required the use of a topical hemostat, and if the use of a topical hemostatic agent was not contraindicated.

A baseline blood sample was obtained within 24 hours before operation to measure complete blood count, blood cell differentials, activated partial thromboplastin time, prothrombin time, and metabolic, hepatic, and renal panels. In addition, serum was used to assay antibodies to bovine thrombin and bovine factor V_a by the enzyme-linked immunosorbent assay (ELISA) method described by Tarantino and colleagues [2]. Enrollment was limited to those patients in whom the surgeon was able to identify a bleeding site for which conventional means to stop bleeding (including direct pressure, suture, and electrocoagulation) were impractical or proved unsuccessful. After identification of a bleeding lesion requiring a topical hemostatic agent, the patients were randomized to either Gelfoam-thrombin as a control or FloSeal. All bleeding sites in any patient were treated with the hemostatic agent to which the patient was randomized. The bleeding severity at each site was characterized as "oozing" or "heavy bleeding" (flowing or spurting). After application of the hemostatic product, the occurrence of continued bleeding was recorded at 1, 2, 3, 6, and 10 minutes. Reapplication of the assigned product was allowed, and the primary endpoint was cessation of bleeding of the first treated site within 10 minutes. Secondary endpoints included the outcome of additional treated bleeding sites and time to cessation of bleeding.

FloSeal Matrix (Fusion Medical Technologies, Inc, Mountain View, CA) was prepared immediately before use after the patient had been randomized. FloSeal Matrix was prepared by dispersing bovine thrombin (Jones Medical Industries, Inc, St. Louis, MO) within the gelatin matrix granules to a final concentration of 1000 Units/mL. The FloSeal was delivered to the site of bleeding by means of a single-barrel syringe and held in place with a gauze sponge for 10 minutes or until the bleeding stopped. The control hemostatic agent, Gelfoam 12 or Gelfoam 100 (Upjohn and Pharmacia, Kalamazoo, MI), was opened at the time of randomization and soaked in bovine thrombin (Jones Medical Industries, Inc, St Louis, MO) reconstituted to 1000 U/mL according to the manufacturer’s instructions for use. The Gelfoam-thrombin was applied to the bleeding site and light pressure applied for 10 minutes or until bleeding had stopped. In all cases, if the bleeding persisted beyond 10 minutes, the surgeon was free to use any hemostatic agent preferred, except reapplication of FloSeal Matrix, to control the bleeding.

After use of either product, surgeons were queried about handling characteristics. The three questions asked addressed ease of application, ability of material to conform to tissue surfaces, and access to difficult-to-reach locations. The answers were graded on a scale of 1 (easy or well) to 5 (difficult or poor).

Safety and adverse effects were assessed at 12 to 36 hours and 6 to 8 weeks postoperatively. Adverse events were categorized as mild, moderate, or severe and were assessed by the surgeons as unrelated, possibly related, or probably related to the products used. Hematologic and blood chemistry assays were performed as before at the evaluations 12 to 36 hours and 6 to 8 weeks postoperatively. In addition, at the 6-to-8 week follow-up, patient sera were tested for antibodies to bovine thrombin and bovine factor V_a by enzyme-linked immunosorbent assay.

The patients in this report comprised the cardiac cohort of a multispecialty study, which also included patients undergoing vascular and spinal surgery. The total study sample size of 309 patients (153 patients in the control group and 156 in the FloSeal group) was based on a power calculation that assumed equivalent performance of the treatment and control groups at 80% to 90%, an alpha of 0.05, and a beta of 0.90.

Institutions were block randomized and the effectiveness results were statistically analyzed in an intent-to-treat fashion using the Cochran-Mantel-Haenszel test stratified by site. The product handling questionnaire results were compared in a similar fashion. The proportion of out-of-reference range laboratory results were compared using Fisher’s exact test, and comparison of the times to bleeding cessation was performed using the Gehan-Wilcoxon test. Comparison between the baseline and 6-to-8 week antibody titers between groups was performed by Fisher’s exact test.

	Results

Top Abstract Introduction Material and methods Results Comment Appendix References

 
A total of 146 cardiac surgery patients were screened for this study. Of these, 93 patients were enrolled, with 48 patients in the FloSeal group and 45 in the control (Gelfoam-thrombin) group. The 48 patients in the FloSeal Matrix group had a total of 104 bleeding sites and the 45 patients in the control group had a total of 61 bleeding sites that were treated. Patient demographics and types of procedures performed for each group within the cardiac cohort are presented in Table 1.

View larger version (17K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time to hemostasis for first bleeding site treated. Comparison of differences between treatment groups performed using the Gehan-Wilcoxon test. FloSeal group versus control, p less than 0.001.

View larger version (18K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of time to hemostasis for all bleeding sites treated. Comparison of differences between treatment groups performed using the Gehan-Wilcoxon test. FloSeal group versus control, p less than 0.001.

View larger version (24K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot of time to hemostasis for bleeding sites stratified by bleeding severity (first treated bleeding sites only). Comparison of differences between groups performed using the Gehan-Wilcoxon test. (A) For "oozing" category, FloSeal group versus control, p = 0.0001 . (B) For "heavy bleeding" category, FloSeal group versus control, p = 0.0011.

The safety of each hemostatic agent used to control perioperative bleeding was assessed by comparing the incidence and types of adverse events that were reported for patients in each group. There were 5 deaths in each group. However, none of the deaths in either group was associated with use of either product. A total of 88 adverse events were reported in 36 patients in the FloSeal group and 71 adverse events in 32 patients in the control group. None of the adverse events was atypical of the type of complications normally experienced by patients who have undergone cardiac surgery. Of the reported adverse events, two adverse events in the FloSeal group (mediastinal bleeding, cough) and two adverse events in the control group (leukocytosis, postoperative bleeding) were reported to have either an "unknown" or a "possible" relationship to the hemostatic agent used. All four adverse events in the category of "unknown" or "possible" relationship to the hemostatic agent used were successfully resolved. All other adverse events in both groups were determined to be "not related" to the use of either hemostatic agent.

Comparison of blood assays between baseline, 12 to 36 hours, and 6 to 8 weeks postoperatively, demonstrated no statistically significant differences that were judged to be clinically significant.

One patient in the FloSeal group and no patients in the control group assayed positively for antibodies to bovine thrombin before surgery. The corresponding numbers for antibodies to bovine factor V_a were 3 and 1, respectively. At the evaluation 6 to 8 weeks postoperatively, 9 patients in the FloSeal group had developed antibodies to bovine thrombin, and 11 patients had developed antibodies to bovine factor V_a. In the control group, 12 patients tested positive for bovine thrombin antibodies and 15 tested positive for bovine factor V_a antibodies. There was no statistical significance in the differences by Fisher’s exact test (p = 0.757 and 0.428, respectively).

There was no evidence of antibody-related coagulopathy in either treatment group. Six patients in the FloSeal group and 5 patients in the control group who had positive antibody tests (either bovine thrombin antibodies or bovine factor V_a antibodies, or both) had elevated prothrombin time at the evaluation 6 to 8 weeks postoperatively. All of these patients were taking anticoagulant medication at the time.

	Comment

Top Abstract Introduction Material and methods Results Comment Appendix References

 
One important complication of cardiac surgical procedures, especially after cardiopulmonary bypass, is bleeding resulting from an alteration in the hemostatic mechanism [3, 4]. The morbidity, mortality, and increased costs associated with perioperative bleeding have been documented [5, 6]. Studies with antifibrinolytic agents have demonstrated reduced operating room times, usually at an hourly cost of approximately $1500, by mitigating the impact of minor bleeding sites that are not amenable to suture or electrocautery. Likewise, costs and morbidity associated with blood transfusion (in particular, platelets) after open-heart surgery impose a significant burden on the health care system [7]. Finally, the physiologic changes associated with bleeding, including pulmonary hypertension, have been documented in cases involving left ventricular assist devices [8], Fontan procedures [9], and animal models of hemorrhage [10–12]. In the case of left ventricular assist devices, a correlation between bleeding and mortality has also been made [6]. As surgeons become more aggressive in pursuing high risk cases, attempting minimally invasive incisions, and performing beating heart operations, the desirability of placing additional sutures for small bleeding sites is diminished. The availability of reliable products in this setting will facilitate these procedures

A wide variety of products have been developed and are available to assist surgeons in the management of bleeding in the setting of diffuse coagulopathy [1, 13, 14]. These include gelatin sponges/powder (Gelfoam), collagen sponges/powder (Hemopad, Hemoterie, Actifoam, Avitene, Instat, Helistat, Helitene, and Lypostat), oxidized cellulose (Surgicel, Oxycel), thrombin (Thrombin, Thrombogen, Thrombistat), and fibrin glues (Tisseel, Hemaseel, Beriplast, Viguard Fibrin Sealant, Quixil, Bioheal, and Tachocomb). Although surgeons often prefer a specific topical hemostatic agent depending upon the procedure or type of bleeding, the gelatin-based sponges/powder (Gelfoam) soaked with thrombin is frequently used. The shortcomings of this option include the inability to tamponade the bleeding, thus reducing the time for blood to interact with thrombin, and the lack of efficacy before reversal of heparin. In addition, the clot formed at the tissue surface–Gelfoam interface is often disrupted when the sponge is removed, and can result in recurrent bleeding. This is also true when only surgical gauze is used to apply compression, as demonstrated by Coln and colleagues [12] in a standardized rabbit splenic laceration model. Thrombin alone has been argued to be of benefit on diffusely bleeding surfaces, but the lack of a framework onto which the clot can adhere has limited this application.

Surgicel (oxidized cellulose) provides a lattice for natural clot formation but is unable to enhance this process in coagulopathic patients in whom platelet count and function are compromised, such as during cardiopulmonary bypass [4, 15]. Avitene (microfibrillar collagen) has been packaged in a powder form and stimulates the patient’s intrinsic hemostatic cascade. The product is used less commonly in open-heart surgery, as it has been reported to embolize and to induce a localized inflammatory response if used before discontinuation of the cardiopulmonary bypass machine suction devices [16].

Much research has focused on autologous and allogenic fibrin glue, which is the only product that can cause clot without a contribution from the patient [17]. However, currently available commercial fibrin glues are limited by the time required to prepare the product for use. Surgeons must order the product 15 to 45 minutes before use depending on the source to allow for preparation time. In addition, fibrin glues do not adhere strongly to wet tissue and have little impact on actively bleeding wounds. A small risk of viral transmission still exists if blood bank products are used to make fibrin glues [1].

All of these products have demonstrated variable efficacy, but their use can be hindered by difficulty in application, especially over aggressive bleeding sites or difficult to access locations, and lack of efficacy when used in heparinized patients, and patients with adhesions derived from earlier operations. These shortcomings could potentially be overcome by use of a product that is not easily diffusable and that activates the clotting cascade while maintaining a hemostatic plug. The gelatin-based matrix of FloSeal tested in the present study is a promising option.

The gelatin-matrix of FloSeal is derived from bovine collagen and consists of granules with a mean size of 500 to 600 µm that are cross-linked with glutaraldehyde and packaged in a syringe in a hydrated state that is below the equilibrium swell of the gelatin. Before use, the gelatin-matrix is combined with bovine thrombin solution to a final thrombin concentration of 1000 U/mL. This mixing process can be completed in less than 2 minutes. The granular nature of the thrombin-coated gel allows conformation to irregular wound geometries, resulting in intimate contact of the gelatin granules with the tissue surface at the site of bleeding. Upon contact with blood, the gelatin granules swell to produce a tamponade effect and restrict blood flow. Blood percolating through the spaces between the granules is exposed to high concentrations of thrombin, thereby accelerating formation of a clot that is reinforced by the incorporation of the gelatin granules within the fibrin mesh of the clot. Preclinical studies have shown the material to be fully resorbed within 6 to 8 weeks, consistent with the body’s normal healing process.

The efficacy of FloSeal has been clearly demonstrated in this multicenter, randomized trial. FloSeal stopped bleeding earlier in more patients and for more bleeding sites than the standard regimen of Gelfoam-Thrombin. Of particular importance to cardiac surgery, bleeding was stopped more effectively under heparinized conditions. In addition to the superior performance compared to Gelfoam-Thrombin in this study, the FloSeal success rate was much better than the reported rates of 75% to 77% for other collagen-based hemostatic agents tested in a similar prospective randomized study [13].

The number and types of adverse events between the two study groups were similar, suggesting that FloSeal was as safe as the Thrombin-Gelfoam combination that has been used safely as a hemostatic agent for more than 50 years. The number of deaths in each group was similar, and none of the deaths were attributed to the use of either product. Use of bovine thrombin has been criticized as predisposing human patients to future anaphylaxis because of thrombin or factor V_a preformed antibodies [18–21]. This concern also exists with FloSeal, which uses bovine thrombin as the catalyst to initiate the coagulation cascade. In this study the rates of seroconversion are similar to previously reported rates [22], showing that the presence of gelatin in FloSeal did not have any adverse impact on the body’s exposure to bovine thrombin. Furthermore, none of these seroconversions were associated with any coagulopathy in the present study. Patients that tested positive for either one or both antibodies and whose measured prothrombin time was elevated at the evaluation 6 to 8 weeks postoperatively were all taking anticoagulant medication at the time. Although not observed in the present study, the development of anaphylactic reaction in patients with positive antibovine thrombin and antibovine factor V_a antibodies may be of concern to some surgeons.

Product handling characteristics were judged by evaluating surgeon responses to three questions relating to ease of use, ability of product to conform to tissue surfaces, and the ability of the surgeon to deliver the product to hard-to-reach surfaces. Both products were judged to be easy to apply. However, responses to the other two questions showed FloSeal to be superior to Gelfoam-thrombin. Because of its nature, FloSeal does not have the problem of adherence to gloves and instruments that is typical of some other hemostatic agents [13]. A potential limitation of FloSeal is the need to train surgeons on the application style, as it differs from other products on the market. Unlike other commonly available hemostatic agents, FloSeal is not a solid, powder, or liquid, but is instead a highly viscous gel that is delivered from a syringe. Care must be taken by the surgeon to deliver an adequate volume to the bleeding site and to ensure that the gel makes intimate contact with the bleeding tissue. An additional potential limitation of FloSeal is failure when used to control aggressive bleeding sites. FloSeal is not a primary closure device and the need for tissue glues, rather than just hemostatic agents, still exists.

In summary, the standard regimen of Thrombin-Gelfoam that is currently used to manage perioperative bleeding in cardiac surgery was effective in only 60% of cases in this prospective randomized trial. FloSeal Matrix was a safe and effective alternative, with a faster time of action and better efficacy overall (94%). The product should be added to surgeons’ treatment options when dealing with moderate bleeding where additional suture placement is nonoptimal, and where coagulation may be compromised by the mechanical and pharmacologic effects of cardiopulmonary bypass and heparinization. Appendix

	Acknowledgments

 
We are grateful to Joseph F. Rondinone, PhD, Narinder S. Shargill, PhD, and Kristen J. Trent, BA, at Fusion Medical Technologies, Inc, for the collection, organization, and analysis of the data and the preparation of this manuscript. We are also grateful to Neil Winterbottom, PhD, and Jacqueline Kuo, BS, at Fusion Medical Technologies, Inc, for performing immunoassays to measure antibodies to bovine thrombin and bovine factor V_a.

	Footnotes

 
Fusion Medical Technologies, Inc, Mountain View, CA, funded this multicenter clinical trial. Brian R. Badduke, MD, was a paid Consultant to Fusion Medical Technologies, Inc, at the time this study was conducted. Mehmet C. Oz, MD, became a paid consultant to Fusion Medical Technologies, Inc, after completion of this study.

	Appendix

Top Abstract Introduction Material and methods Results Comment Appendix References

 
"The Fusion Matrix Study Group" included the following coinvestigators: Columbia University, College of Physicians and Surgeons, New York: Eric A. Rose, MD, Niloo M. Edwards, MD; The Cleveland Clinic Foundation, Cleveland: Patrick M. McCarthy, MD, A. Marc Gillinov, MD, Bruce W. Lytle, MD, Nicholas G. Smedira, MD, Joseph F. Sabik, MD; California Pacific Medical Center, San Francisco: G. James Avery II, MD, Kevin Turley, MD

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mehmet C. Oz Delos M. Cosgrove, III Brian R. Badduke Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oz, M. C. Articles by Topic, N. Search for Related Content PubMed PubMed Citation Articles by Oz, M. C. Articles by Topic, N.