TY - JOUR
AU1 - MD, Kevin Foster,
AU2 - MD, David Greenhalgh,
AU3 - MD, Richard L. Gamelli,
AU4 - MD, David Mozingo,
AU5 - MD, Nicole Gibran,
AU6 - MD, Michael Neumeister,
AU7 - MD, Steven Zvi Abrams,
AU8 - DVM, Edith Hantak,
AU9 - BS, Lisa Grubbs,
AU1 - MS, Bettina Ploder,
AU1 - PhD, Neil Schofield,
AU1 - MD, Louis H. Riina,
AB - Abstract The objective of this phase 3, multicentered, prospective, randomized, evaluator-blinded, clinical study was to compare skin graft adherence utilizing a fibrin sealant containing 4 IU/ml thrombin (FS 4IU VH S/D [FS 4IU VH S/D will be marketed under the trade name ARTISS upon licensure in the United States]) to graft adherence utilizing staples in burn patients requiring wound excision and skin grafting. FS 4IU VH S/D was compared with staples in 138 patients. Patients had burn wounds measuring ≤40% of total body surface area with two comparable test sites measuring between 1 and 4% total body surface area each. Wound closure at day 28 was assessed using test site planimetry and review of day 28 photographs by three independent blinded evaluators (primary endpoint analysis). Secondary efficacy measures included hematoma/seroma on day 1, engraftment on day 5, and wound closure on day 14. Investigator and patient-reported outcomes were also assessed. The proportion of test sites with complete wound closure at day 28 was 70.3% in FS 4IU VH S/D treated sites and 65.8% in stapled sites, as assessed by planimetry. Blinded review of day 28 photographs confirmed that the rate of complete wound closure was similar between the two treatments, although the overall assessed rates of closure were lower than those determined by planimetry: FS 4IU VH S/D (43.3%) and staples (37.0%). The lower limit of the 97.5% confidence interval of the difference between FS 4IU VH S/D and staples was −0.029, which is above the predefined noninferiority margin of −0.1. Therefore, FS 4IU VH S/D is at least as efficacious as staples at the 97.5% one-sided level for complete wound closure by day 28. Hematoma/seroma on day 1 occurred at significantly (P < .0001) fewer FS 4IU VH S/D-treated sites (29.7% [95% CI 22.2–38.1%]) compared with stapled sites (62.3% [95% CI 53.7–70.4%]). Engraftment on day 5 was deemed to be 100% in 62.3% (95% CI 53.7–70.4%) of the FS 4IU VH S/D-treated sites and 55.1% (95% CI 46.4–63.5%) of the stapled sites (P = .0890). Complete wound closure by day 14 occurred in 48.8% (95% CI 39.9–57.8%) of the FS 4IU VH S/D treated sites and 42.6% (95% CI 34.0–51.6%) of the stapled sites (P = .2299). FS 4IU VH S/D scored significantly better than staples for all investigator-assessed outcomes, namely quality of graft adherence (P < .0001), preference for method of fixation (P < .0001), satisfaction with graft fixation (P < .0001), and overall quality of healing (P < .0001). Likewise, FS 4IU VH S/D scored significantly better than staples for all patient-assessed outcomes, namely anxiety about pain (P < .0001) and treatment preference (P <.0001). The safety profile of FS 4IU VH S/D was excellent as indicated by the lack of any related serious adverse experiences. These findings demonstrate that FS 4IU VH S/D is safe and effective for attachment of skin grafts, with outcomes at least as good as or better than staple fixation. Fibrin sealants have been investigated as alternatives to staples or sutures in a number of exploratory studies involving skin grafting procedures.1,–7 Plasma-derived fibrin sealants mimic the final stage of the blood clotting cascade where cleavage of fibrinogen by thrombin culminates in the production of a fibrin clot matrix.8 The physical attributes of fibrin sealants, such as their tissue adhesive and hemostatic properties, are particularly suited to the task of affixing skin grafts to recipient wound beds.9 The fact that fibrin sealants are eventually broken down via the same mechanisms used in blood clot dissolution makes them an attractive alternative to staples or sutures, which require subsequent removal procedures. Staple removal can cause pain and anxiety in the patient and frequently requires intravenous analgesia and/or sedation, and in some instances conscious sedation or general anesthesia.10,11 Staples can be difficult to remove in certain situations, such as areas of granulation tissue,12,13 and retained staples have been reported to cause severe complications for the patient, if left in situ for extended periods of time.14,–16 A previous randomized controlled study compared a fibrin sealant with an extended clotting time (fibrin sealant with 4 IU/ml thrombin) to staples in autologous split-thickness skin grafting in 40 burn patients.7 The extended clotting time relative to a currently U.S. licensed fibrin sealant containing 500 IU/ml thrombin provides the surgeon with more time to apply and position the graft before the fibrin adhesive polymerizes.17,18 The results of this preliminary study supported further testing in a statistically powered clinical trial.7 Although this investigator-evaluated endpoint study provided supportive evidence for the efficacy of fibrin sealant with 4 IU/ml thrombin, a blinded evaluation of outcomes is required to provide the most objective test of efficacy. Here we report the findings of a larger, multicentered, randomized, controlled phase three clinical study, which examined the primary efficacy endpoint of complete wound closure 28 days postsurgery. Day 28 was selected as the time point most likely to show any differences between the two treatments, as suggested by earlier clinical study findings.7 Measurement of complete wound closure at day 28 provides a landmark endpoint that best represents overall graft take, and is a prerequisite for long-term survival of the grafted tissue. Blinding with respect to treatment assignment to staples or fibrin sealant was not possible because of the distinctive physical attributes of these two treatment modalities. Therefore, success or failure for the primary endpoint was assessed from photographs by a panel of three independent experts blinded with respect to treatment assignment. The method reported here provides the most objective and robust testing to date of the efficacy of fibrin sealant for the attachment of autologous sheet split-thickness skin grafts in burned patients. In addition to the primary endpoint of complete wound closure at day 28, additional measures of efficacy were investigated including hematoma/seroma formation and long-term scar appearance outcomes. METHODS Patients and Test Sites Male and female patients 65 years of age or younger (including pediatric patients) with burn wounds measuring less than or equal to 40% total body surface area (TBSA) were eligible for inclusion in this study. Patients were required to have deep partial-thickness or full-thickness burn wounds that required excision and skin grafting. Each patient was treated with both FS 4IU VH S/D and staples on separate test sites. The test sites had to be either a single wound measuring between 2 and 8% TBSA (which could be split into two halves) or two comparable wounds each measuring between 1 and 4% TBSA. Both test sites were required to receive autologous split-thickness sheet skin grafts with a thickness of 8/1000 of an inch to 16/1000 of an inch. Digits and genitalia were not eligible as test sites due to potential difficulties performing planimetry and identifying comparable test sites. Exclusion criteria included pregnancy; presence of a venous or arterial vascular disorder directly affecting a designated test area; known immune deficiency disorder; preexisting hemolytic anemia; chronic malnourishment (as determined by the investigator); significant pulmonary compromise; treatment with systemic corticosteroids within 30 days before skin grafting (not including inhaled steroids); diabetes mellitus; electrical or chemical burns; infected test sites; known or suspected hypersensitivity to bovine protein; and participation in another clinical trial or previous treatment in this trial. Written informed consent was obtained from the patient or the patient's legally acceptable representative before screening activities. The protocol was approved by the Institutional Review Board at each investigative site before initiation. The study was conducted according to ICH/GCP (Good Clinical Practice) guidelines. The study is registered with the National Institutes of Health clinical trial register (www.clinicaltrials.gov) with the identification number NCT00157131. Preparation of the Test Site Wound Beds and Graft Fixation The designated test area selected by the surgeon was tangentially excised to form a viable wound bed for both test sites. Hemostasis was achieved in the wound beds before grafting according to surgeon preference. Acceptable methods for achieving hemostasis were tourniquets, pressure, cautery, and epinephrine with lidocaine-soaked gauze placed over the wound bed; use of solutions containing epinephrine and lidocaine was acceptable for control of hemostasis, but solutions were to be prepared without thrombin. Use of topical thrombin spray or any other fibrin sealant to achieve hemostasis was prohibited during this study. Staples were placed parallel to the seam of any grafts abutting the designated test area, including the test site with staples. In addition, when placing staples along the midline of a test site for a single contiguous wound divided into two test sites, the staples ran parallel to the midline so that they did not enter the FS 4IU VH S/D-treated site. The number of staples applied was recorded. FS 4IU VH S/D was administered topically by spray application using a dedicated spray device. A thin layer of FS 4IU VH S/D was applied to the wound bed using a “painting motion ” from side to side to achieve coverage. The recommended dosage was 2 to 4 ml/100 cm2 (It is important to observe the recommended dose of FS 4IU VH S/D, as much larger doses (15 ml/100 cm2) have been shown to be detrimental to graft take in animal studies.19). Study Design and Procedures The study was a phase 3, multicentered, prospective, evaluator-blinded, randomized study comparing fibrin sealant with 4 IU/ml thrombin, vapor heated, and solvent/detergent treated (FS 4IU VH S/D) to staples. Randomization was conducted using sealed envelopes containing treatment assignments, which were opened after test site selection. FS 4IU VH S/D was used to affix sheet skin grafts at one test site (treatment) and staples used to affix sheet skin grafts at the other test site (control) in accordance with the predetermined randomization scheme. The day of the skin grafting procedure, when FS 4IU VH S/D and staples were used, was designated as day 0. The postoperative follow-up period was 1 year. Subjects were required to undergo evaluations and study procedures at screening/baseline and on days 0, 1, 5, 14, and 28, and months 3, 6, 9, and 12 visits. Efficacy assessments included the following: Complete wound closure by day 28, as assessed by blinded evaluators (primary endpoint) Wound closure by days 14 and 28, as assessed by planimetry Hematoma/seroma on day 1 Engraftment by day 5 Scar maturation assessed by blinded Vancouver Scar Scale evaluations on months 3, 6, 9, and 12 Planimetry was used to measure the total surface area of each test site, in addition to areas of graft loss, questionable viability, and/or hematoma or seroma that may have been present. Planimetry is a technique that involves the tracing of the wound perimeter and areas of interest, and this allowed quantification of percent wound closure, engraftment, and hematoma/seroma. All tracings were sent to Canfield Scientific, Inc. (Fairfield, NJ) for measurement using computer analysis. Where no areas of loss were observed, wound closure was deemed to be 100%. Vancouver Scar Scale assessments of graft pigmentation, vascularity, pliability, and height were performed by blinded evaluators at months 3, 6, 9, and 12 visits.20 If hematomas/seromas occurred, they were evacuated at the discretion of the surgeon on day 1, after tracing and photography of the site. Overall safety was assessed by monitoring all serious adverse events occurring at any time during the 12-month study period, and all nonserious adverse events up to and including day 28, regardless of causality. Blinded Review of Photographs The three reviewers on the blinded review panel were burn surgeons who were not involved with the study other than to assess wound closure. Reviewers were unaware of the treatments used in the study, treatment assignment to test sites, time point of assessment, and identity of the patient or operating surgeon. Each blinded reviewer independently determined whether a test site was completely depicted, and closed or not from the photographs taken on day 28. The majority decision of the three reviewers was used to determine the overall outcome. A test site was to be considered completely closed only if it met the strict definition of complete wound closure. Complete wound closure was stringently defined as total coverage of the wound with a contiguous layer of viable epithelium. Areas closing by secondary intention were also required to be completely closed. Factors to be considered during this assessment included color, presence of granulation tissue, and whether or not the entire wound was covered with a contiguous layer of viable epithelium. The following criteria were evaluated to determine the outcome of complete wound closure: The test site must not have any areas of graft necrosis. The color of the grafts should be consistent with that of viable skin. Areas that have closed by secondary intention must not have any granulation tissue present. Areas that have scabbed over must have a contiguous layer of epithelial cells present. Alternatively, a test site was to be regarded as not completely closed if it met any of the following criteria: The test site has areas of graft necrosis. The color of the grafts is consistent with that of necrotic skin. The presence of granulation tissue. Areas that have scabbed over that do not have a contiguous layer of epithelial cells present. The scab is still firmly attached. Preference and Health Resource Use Investigator and patient preferences were recorded based on systematic questions asked at each visit. Only patients 9 years or older were asked patient-reported outcome questions. Additionally, pain scores were assessed using a modified version of the visual analogue scale for pain. Health resource use was documented on day 5 (at time of staple removal) for each patient. During this time, parameters such as number of staples used, number of sessions and resources required to remove staples, time spent removing staples, and additional pain/sedation medication use were collected. Investigational Product FS 4IU VH S/D comprises two plasma-derived components: sealer protein solution and thrombin solution. The two components of FS 4IU VH S/D are provided frozen in two preloaded syringes presented in a single application device ready for topical application after thawing. The sealer protein solution contains 72 to 110 mg/ml fibrinogen (human) and 2250 to 3750 KIU/ml fibrinolysis inhibitor (synthetic aprotinin). The thrombin solution contains 2.5 to 6.5 IU/ml of thrombin (human) and 36 to 44 μM/mol calcium chloride. FS 4IU VH S/D undergoes two dedicated, independent virus inactivation/reduction steps during the manufacturing process: VH treatment and solvent/detergent (S/D) treatment. A strict plasma-screening program employed by the manufacturer also provides an additional layer of protection to the two virus inactivation steps employed during production. Statistical Methods The primary efficacy analysis was performed on the intent-to-treat (ITT) population. The ITT population consisted of all subjects with an available primary endpoint assessment. The primary statistical analysis was used to test noninferiority of FS 4IU VH S/D compared with staples with respect to complete wound closure at day 28 after surgery. To assess the noninferiority of success rate in wound closure with FS 4IU VH S/D as compared with staples, a one-sided 97.5% confidence interval for the difference of correlated proportions was calculated. The noninferiority margin was set to 10%. If the lower limit of the one-sided confidence interval of the difference in closure rate between FS 4IU VH S/D treated and staples sites is above the prespecified limit, it is considered proven that FS 4IU VH S/D treatment is noninferior to staples. Secondary endpoints (% areas of hematoma/seroma, % area of engraftment, % area of wound closure) were measured by planimetry (Gibran et al7 for details). These variables were analyzed using nonparametric signed rank statistics. The proportion of patients with presence of hematoma/seroma on day 1, 100% engraftment on day 5, and complete wound closure by day 14 were analyzed by McNemar's test. The Vancouver Scar Scale was evaluated with nonparametric signed rank test separately for each individual evaluation; scar maturation assessments were performed at months 3, 6, 9, and 12 visits. Patients who were regrafted or who received additional staples after day 0 (surgery) were excluded from the secondary efficacy evaluations because they were deemed to be treatment failures at day 28 by default. RESULTS Demographics and Burn Wound Characteristics A total of 138 patients were treated with both FS 4IU VH S/D and staples at two comparable tests sites during this study. The ITT analysis population contained 127 evaluable patients (ie available primary endpoint assessment). Of the 127 ITT patients, 66.1% were male and 33.9% were female. Distribution by racial group was as follows: white (69.3%), black (11.8%), Native American (3.1%), and Asian (2.4%); ethnicity was Hispanic in 17 (13.4%) subjects. The median age was 29 years (range: 1–62 years); 14.2% patients were 6 years or younger, 15.0% were 7 to 18 years, and 70.9% were greater than 18 years. The median TBSA for all burn wounds was 11.8% (range: 2.0–40.0%). The median TBSA of tests sites was identical for both FS 4IU VH S/D and staples, allowing a direct comparison of the treatments: 1.5% (range: 1.0–4.0%). Burn wound depth was full-thickness in 76.4% of the test areas and partial thickness in 23.6% of the test areas. Location of the test sites was as follows: 86.6% extremities and 13.4% torso/neck for FS 4IU VH S/D, and 87.4% extremities and 12.6% torso/neck for staples. Rates of Wound Closure on Day 28 The percent area of wound closure on day 28 (postsurgery) was greater than or equal to 90% in 93.4% of the FS 4IU VH S/D test sites and in 90.8% of the stapled test sites, as assessed by planimetry. The proportion of test sites with complete wound closure (100% wound closure) at day 28 was 70.3% in FS 4IU VH S/D treated sites and 65.8% in stapled sites (Figure 1). A blinded review of day 28 photographs was also performed to compare FS 4IU VH S/D with staples (primary endpoint analysis). In this blinded review of photographs, the rate of complete wound closure was found to be similar between the two treatments, although the overall assessed rates of closure for both treatments were lower than those determined by planimetry: FS 4IU VH S/D (43.3%) and staples (37.0%). The lower limit of the 97.5% confidence interval of the difference between FS 4IU VH S/D and staples was −0.029, which is above the predefined noninferiority margin of −0.1. Therefore, FS 4IU VH S/D is at least as efficacious as staples at the 97.5% one-sided level for complete wound closure by day 28 as tested by this prospectively defined primary efficacy analysis. Figure 1. View largeDownload slide Proportion of test sites achieving wound closure by day 28. The proportion of test sites and extent of wound closure at day 28 is shown for FS 4IU VH S/D and staples. Figure 1. View largeDownload slide Proportion of test sites achieving wound closure by day 28. The proportion of test sites and extent of wound closure at day 28 is shown for FS 4IU VH S/D and staples. A number of prognostic factors were examined to investigate potential effects on the primary efficacy endpoint. Age, gender, wound depth (full vs partial thickness), wound size (TBSA of wound), wound location (extremities vs neck/torso), and number of dressing changes were examined using logistic regression. Gender, wound depth, and number of dressings did not have a significant effect on wound closure by day 28 in FS 4IU VH S/D-treated or stapled test sites (data not shown). However, wound location appeared to have an effect on wound closure in FS 4IU VH S/D sites (but not stapled sites) when extremities (hands, feet, arms, legs, shoulders. and thighs) were compared with neck/torso (neck, chest, abdomen, back). Wounds located on neck/torso were more likely to achieve complete wound closure by day 28 than wounds located on the extremities in FS 4IU VH S/D sites (odds ratio = 0.07; 95% CI for odds ratio = 0.01–0.37, P = .0016). The reason for this apparent effect of wound location on wound closure at FS 4IU VH S/D sites is not clear; however, it should be noted that the overall distribution of test site locations was uneven, with the majority of FS 4IU VH S/D test sites located on extremities (N = 114), rather than on the neck/torso (N = 21). In addition, the rate of wound closure on extremities was in the same range in FS 4IU VH S/D and stapled sites (37.3% vs 35.1%, respectively in ITT subjects). Wound size may also have had a marginal effect on complete wound closure by day 28 in FS 4IU VH S/D-treated sites (odds ratio = 0.49; 95% CI for odds ratio = 0.25–0.93, P = .0291). However, no effect of wound size on complete wound closure by day 28 was observed in the stapled sites. Logistic regression indicated that age might have had a marginal effect on complete wound closure by day 28 in stapled sites. Complete wound closure by day 28 occurred more often in younger subjects (odds ratio = 0.97; 95% CI for the odds ratio = 0.95–1.00, P = .0305). This effect was observed for both staples and FS 4IU VH S/D when different age groups were examined; the rate of complete wound closure by day 28 was higher in the ≤6 years group for both FS 4IU VH S/D and staples when compared with the 7 to 18 years group or the >18 years group. Assessment of Hematoma/Seroma, Engraftment, and Wound Closure on Day 14 The secondary efficacy endpoints analyzed included hematoma/seroma occurrence on day 1, engraftment on day 5, and wound closure as measured by planimetry on day 14 (Table 1). Hematoma/seroma on day 1 occurred at significantly (P < .0001) fewer FS 4IU VH S/D-treated sites (29.7%) compared with stapled sites (62.3%). The median percent area of the test site with hematoma/seroma on day 1 was 0% (range: 0–15.8%) for FS 4IU VH S/D and 1.2% (range: 0–48.9%) for staples (data not shown). Table 1. Secondary efficacy endpoints View Large Table 1. Secondary efficacy endpoints View Large Engraftment on day 5 was deemed to be 100% in 62.3% of the FS 4IU VH S/D-treated sites and 55.1% of the stapled sites (P = .0890). The median percent area of engraftment on day 5 was 100% (range: 34.4–100%) for FS 4IU VH S/D and 100% (range: 56.3–100%) for staples (data not shown). Complete wound closure on day 14 occurred at 48.8% of the FS 4IU VH S/D treated sites and 42.6% of the stapled sites (P = 0.2299). The median percent area of complete wound closure on day 14 was 100% (range: 68.5–100%) for FS 4IU VH S/D and 99.8% (range: 62.7–100%) for staples (data not shown). Humanistic Outcomes A number of patient- and investigator-reported outcomes were measured during the study. These measures included staple use/removal statistics, patient anxiety regarding staple removal, and pain scores measured immediately before and after staple removal using a 1 to 10 scale (10 being the most painful). Patient preference was also recorded throughout the study. Investigator outcomes included satisfaction with graft fixation, quality/rate of healing, and overall preference. The median number of staples used was 30 (range: 7–88). The median cumulative time spent by the team removing staples was 10 minutes (range: 1–365 minutes). Significantly, 58.7% of patients required additional pain medication/sedation during the staple removal process (Figure 2). The mean pain score reported by subjects was significantly higher immediately after staple removal (6.2 ± 2.9) than that assessed immediately before staple removal (3.3 ± 2.8; P < .0001). In addition, subjects reported less anxiety about pain with FS 4IU VH S/D than with staples on day 14 (P < .0001). Overall, subjects had a significant preference for FS 4IU VH S/D over staples as assessed on day 5, day 14, day 28, and month 12 (P < .0001; Figure 2). Figure 2. View largeDownload slide Humanistic outcome measures. A. Health resource parameters. B. Investigator satisfaction with graft fixation. C. Investigator satisfaction with overall quality of healing. D. Patient preference: staples vs glue. Figure 2. View largeDownload slide Humanistic outcome measures. A. Health resource parameters. B. Investigator satisfaction with graft fixation. C. Investigator satisfaction with overall quality of healing. D. Patient preference: staples vs glue. Overall, investigators also expressed a significant preference of FS 4IU VH S/D over staples (P < .0001). Quality of graft adherence was assessed by the investigator on a scale of 1 to 10 (10 being the highest quality of adherence) on day 0 and day 5. The mean score on day 0 was 9.4 ± 0.8 for FS 4IU VH S/D sites and 8.3 ± 1.7 for stapled sites (P < .0001). On day 5, the mean score was 9.2 ± 1.5 for FS 4IU VH S/D sites and 8.6 ± 1.5 for stapled sites (P < .0001). Investigator satisfaction with graft fixation was monitored at day 14, day 28, and month 12. The overall level of satisfaction with graft fixation was significantly higher for FS 4IU VH S/D over staples at all time points (P < .0001; Figure 2). Likewise, investigators were significantly more satisfied with quality of healing with FS 4IU VH S/D than staples (P < .0001; Figure 2). Long-Term Scar Appearance Outcomes To assess any differences in long-term scar appearance between FS 4IU VH S/D and staples, Vancouver Scar Scale assessments were performed at months 3, 6, 9, and 12 follow-up visits. No significant differences were observed for any of the Vancouver Scar Scale parameters (pigmentation, vascularity, pliability, height) at all time points observed (data not shown). These results are consistent with the similar progression of healing observed for FS 4IU VH S/D and staples in photographs taken at various visits (Figure 3). Figure 3. View largeDownload slide Healing of FS 4IU VH S/D and staples sites from day of grafting to month 12. Both the FS 4IU VH S/D and stapled test sites are shown on day 0 (day of grafting procedure), day 1, day 5, day 14 day 28, and month 12 (postoperatively). Figure 3. View largeDownload slide Healing of FS 4IU VH S/D and staples sites from day of grafting to month 12. Both the FS 4IU VH S/D and stapled test sites are shown on day 0 (day of grafting procedure), day 1, day 5, day 14 day 28, and month 12 (postoperatively). Safety Evaluation The safety population comprised all 138 treated subjects. The mean calculated dosing volume ± SD was 1.8 ± 1.1 ml/100cm2. There were no related serious adverse events reported during the 12-month period of follow-up. The profile of adverse events occurring in ≥5% of the patients at either the FS 4IU VH S/D test site or the stapled test site was similar, except for a higher incidence of graft complications in the stapled sites (Table 2). Of the 15 graft complications at stapled sites, 12 were because of retained staples. The most common adverse event at both FS 4IU VH S/D (25.4%) and stapled sites (23.2%) was graft loss (partial or complete). Five incidences of graft loss at the FS 4IU VH S/D site and four incidences at the stapled site were considered serious. In all cases, the graft loss was secondary to infection or mechanical shearing of the graft, and was not considered related to the treatment received (FS 4IU VH S/D or staples). Table 2. Comparison of adverse events at FS 4IU VH S/D and stapled test sites. Adverse events occurring on test sites in ≥5% of patients are shown View Large Table 2. Comparison of adverse events at FS 4IU VH S/D and stapled test sites. Adverse events occurring on test sites in ≥5% of patients are shown View Large DISCUSSION A previous exploratory study indicated that fibrin sealant with 4 IU/ml thrombin might be a promising candidate for a pivotal clinical study comparing it's efficacy and safety with that of staples, the current standard of care.7 Here we report the results of such a study employing a panel of three independent burn surgeons (blinded with respect to treatment assignment) to evaluate whether or not complete wound closure (100% closure) was achieved, using photographs of the test sites taken 28 days after surgery. This blinded evaluation of the primary endpoint provides the most objective method of assessment of complete wound closure for these two physically different treatments. In addition to the use of a blinded review panel, planimetry was also performed as a confirmatory analysis to calculate the actual percent area of wound closure by tracing the entire wound perimeter and any open areas at the time point measured. Interestingly, the proportion of test sites deemed completely closed (100% wound closure) by the blinded review panel was lower than would be expected in normal clinical practice; however, both FS 4IU VH S/D and staples were found to be similarly efficacious using this method. A strict definition of complete wound closure was employed during the blinded review to investigate any slight differences in efficacy that might exist between the two treatments, which would most likely be manifested as small open (nonepithelialized) areas at day 28. The strict definition of complete wound closure, coupled with the challenge of determining closure without the benefit of physical examination may have contributed to the lower than expected success rates for both treatments. In fact, a conservative assessment of complete wound closure by the blinded review of photographs was revealed when the planimetry data was analyzed. The proportion of test sites with complete wound closure (100% wound closure) at day 28 was 70.3% in FS 4IU VH S/D treated sites and 65.8% in stapled sites as assessed by planimetry, compared with 43.3 and 37.0%, respectively in the blinded review assessment. Therefore, the planimetry results confirm the conclusion of the primary endpoint analysis that FS 4IU VH S/D is at least as efficacious as staples for the attachment of sheet skin grafts in burn patients. These results also confirm the conclusions of the previous phase 1/2 study.7 Taken together these findings demonstrate that FS 4IU VH S/D is efficacious for the attachment of skin grafts in burn patients. Logistic regression analysis was performed to investigate any influencing factors on the primary endpoint outcome. No major confounding factors were revealed by the analysis, although age seemed to have an influence on complete wound closure rates in both treatments. Specifically, the rate of closure was higher in the ≤6 years group, than the older age groups. The reason for this observation in the ≤6 years group is unclear, but it may be explained by the smaller absolute wound sizes of the 1 to 4% TBSA wounds in this age group compared with older patients who generally have a larger absolute surface area. Regardless, the results presented here indicate that FS 4IU VH S/D is at least as efficacious in pediatric patients as the older populations studied. This finding is significant because increasing the treatment options available for pediatric burn patients is paramount in this clinically important group.21 The autologous sheet grafting procedures selected for this study represent a more challenging situation in terms of graft adhesion than mesh grafting, where drainage of serous fluids through the mesh reduces the risk of complications or graft loss. Therefore, demonstration of efficacy in the more challenging indication of sheet grafting suggests that an equivalent level of success in mesh grafting might be expected, although this remains to be confirmed. One limitation imposed on the current study design was the exclusion of digits and genitalia as test sites because of the difficulty in selecting comparable test sites, and potential difficulties performing planimetry. However, these anatomical areas are frequently grafted in burn patients and so further investigation is warranted. Intriguingly, reports in the literature suggest that fibrin sealant may prove to be beneficial when used in these difficult-to-graft areas.2,3,22 A number of secondary efficacy endpoints were analyzed during this study including hematoma/seroma on day 1, engraftment on day 5, and wound closure on day 14. Both the incidence and the extent of hematoma/seroma were significantly lower for FS 4IU VH S/D-treated sites than for stapled sites; a result that confirms an earlier finding in the phase 1/2 exploratory study.7 The decrease in the incidence and extent of hematoma is not surprising when the hemostatic properties of fibrin sealants are considered23,–25; TISSEEL VH S/D, an identical fibrin sealant with 500 IU/ml thrombin, is currently licensed in the United States as an adjunct to conventional methods of hemostasis during cardiac and spleen surgery.26 Likewise, the adhesive properties of FS 4IU VH S/D may reduce seroma formation via continuous full surface adhesion of the graft to the wound bed, closing the space that exists when grafts are attached using point fixation techniques such as staples. The reduction in hematoma and seroma is clinically significant because of the additional procedures that are required to deal with these complications in certain cases. Indeed, the data here suggest that the practice of early monitoring of sheet grafts for hematoma/seroma on day 1 may become less critical with the use of FS 4IU VH S/D. The outcomes of the other secondary efficacy measures of engraftment on day 5 and wound closure on day 14 were similar between the two treatments, which is consistent with the primary efficacy outcome on day 28. The long-term scar appearance outcomes of FS 4IU VH S/D and staples were also similar as measured by Vancouver Scar Scale assessments at months 3, 6, 9, and 12 visits. These results indicate that FS 4IU VH S/D provides a similar and satisfactory long-term outcome to that of staples during the period studied. Staple removal measures were assessed to examine any impact that this procedure has in terms of additional patient treatment and resource use. During the removal of staples, time spent on removal of staples varied widely as did the level of resources involved in staple removal (ie nurses, and MDs), as might be expected with the differing resources available to the various study centers involved. There was a significant increase in patient-reported pain scores on day 5 immediately after staple removal relative to baseline pain scores immediately before staple removal. It has been documented in the literature that a clinically significant difference between consecutive acute ratings of pain translates to approximately 1.3 points when measured on a 10-point scale.27,28 Therefore, the statistically significant increase in pain scores from 3.3 to 6.2 is also clinically significant in this setting, and directly translates to increased trauma perceived by the patient during staple removal. Notably, 58.7% of all patients required additional pain medication/sedation during the staple removal process. This result is consistent with a previous study showing that burn patients report higher levels of pain during procedures, despite the concurrent use of analgesics or sedatives.29 This finding is significant because the use of conscious sedation during staple removal involves risks that could be completely eliminated by the use of FS 4IU VH S/D as the standard of care. In addition, staple fixation of skin grafts is associated with postoperative costs because of the time and labor required for their removal.10 These factors should not be overlooked when conducting a benefit/risk evaluation of available treatments for standard of care. This study also included a number of patient- and investigator-reported outcomes. There were significant differences in favor of FS 4IU VH S/D for all measures including investigator satisfaction for method of fixation and overall quality of healing. Patient preference was significantly in favor of FS 4IU VH S/D over staples, something that should be considered along with a patient's anxiety level during the staple removal process. The safety of FS 4IU VH S/D was assessed by measuring the incidence of adverse events at the test sites during study participation. The safety profile was excellent for FS 4IU VH S/D as demonstrated by the lack of any related serious adverse events during the 12-month follow-up period. The incidence of all adverse experiences, regardless of causality, was similar between FS 4IU VH S/D and staples, except for an increased rate of graft complications in stapled sites that were mainly the result of retained staples. Overall, the results presented here strongly support the use of FS 4IU VH S/D as an integral part of the surgical armamentarium for skin grafting procedures. ACKNOWLEDGMENTS We acknowledge Dr. Sangeeta Narayan for assistance with humanistic outcome assessments and Bill Canfield at Canfield Scientific Inc. for technical assistance with photography and blinded review administration. In addition to Drs. Foster, Greenhalgh, Gamelli, Mozingo, Gibran, and Neumeister, the following clinical investigators were contributing members of the FS 4IU VH S/D Clinical Study Group: John Griswold, MD, Texas Tech University Health Sciences Center, Lubbock, TX; James Cross, MD, University of Alabama Burn Center, Birmingham, AL; Arnold Luterman, MD, University of South Alabama Medical Center, Mobile, AL; Daniel Lozano, MD, Lehigh Valley Hospital, Allentown, PA; Richard J. Kagan, MD, Shriner's Hospitals for Children, Cincinnati, OH and University of Cincinnati, Cincinnati, OH; Michael Schurr, MD, University of Wisconsin Hospital, Madison, WI; and Chester Paul, MD, St. Elizabeth Regional Medical Center, Lincoln, NE. 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K.F., D.G., R.G., D.M., N.G., and M.N. are burn surgeons who were clinical investigators on this study and contributed to the writing of this manuscript. All investigators completed financial disclosures per US 21 Code of Federal Regulations Part 54. No conflicts of interest were reported for any of the investigators named on this manuscript. Baxter Healthcare Corporation (Westlake Village, California) was the sponsor and paid all costs associated with the administration of this clinical study. S.Z.A., E.H., L.G., B.P., and N.S. are all paid employees of Baxter Healthcare Corporation who were involved in the conduct of this study and were participants in the writing of this manuscript. L.H.R. is a practicing burn surgeon and a paid consultant of Baxter; he was integrally involved in the study design, but was not a data-collecting investigator in this study. Copyright © 2008 by the American Burn Association
TI - Efficacy and Safety of a Fibrin Sealant for Adherence of Autologous Skin Grafts to Burn Wounds: Results of a Phase 3 Clinical Study
JF - Journal of Burn Care & Research
DO - 10.1097/BCR.0b013e31816673f8
DA - 2008-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/efficacy-and-safety-of-a-fibrin-sealant-for-adherence-of-autologous-09RBa7K1I0
SP - 293
EP - 303
VL - 29
IS - 2
DP - DeepDyve
ER -