European Journal of Cardio-thoracic Surgery 36 (2009) 708—714 www.elsevier.com/locate/ejcts

TachoSil surgical patch versus conventional haemostatic fleece material for control of in cardiovascular surgery: a randomised controlled trial§

Francesco Maisano a,*, Henrik K. Kjærga˚rd b, Robert Bauernschmitt c, Alain Pavie d, Gregorio Ra´bago e, Marc Laskar f, Jens Pauli Marstein g, Volkmar Falk h

a Istituto Scientifico H San Raffaele, Via Olgettina, 60, Milan 20132, Italy b Rigshospitalet Heart and Lung Surgical Clinic, Copenhagen, Denmark c German Heart Center, Cardiovascular Surgery, Munich, Germany d Heart Institute Pitie Salpetriere, Paris, France e Clinica Universitaria de Navarra, Department of Cardiovascular Surgery, Navarra, Spain f University Hospital Dupuytren, Limoges, France g Nycomed, Roskilde, Denmark h Heart Center Leipzig, Department of Cardiac Surgery, Leipzig, Germany

Received 5 February 2009; received in revised form 29 April 2009; accepted 30 April 2009

Abstract

Objective: Prolonged bleeding during cardiovascular surgery presents a risk for the patient and increases the time and cost of surgery.TachoSilW is a ready-to-use haemostatic agent that consists of an equine collagen patch coated with human fibrinogen and . This trial evaluated the efficacy and safety (30 days post-surgery) of TachoSil surgical patch compared with standard haemostatic fleece for the control of bleeding in patients undergoing cardiovascular surgery. Methods: Patients scheduled for elective surgery on the heart, ascending aorta or aortic arch requiring cardiopulmonary bypass were eligible for this open-label multicentre trial. After primary haemostatic measures, patients were randomised to TachoSilorconventional haemostatic fleeceif an area of persisting haemorrhage was identified (target area). After the application of trial treatment, haemostasis was evaluated at 3 min (primary endpoint). If haemostasis was not achieved, trial treatment was re-applied and haemostasis assessed at 6 min (secondary endpoint). Results: A total of 120 patients were randomised and 119 received trial treatment (TachoSil, n = 59; standard treatment, n = 60). Twenty-six percent of patients were female and the mean age was 67 years (range: 23—86 years). Baseline characteristics were similar in both the groups. Bleeding occurred mainly from the aorta (56%), right ventricle (16%) or right atrium (13%), more often from a vessel (68%) than tissue (32%), and was assessed to be arterial in 74% of cases. TachoSil was significantly superior to standard haemostatic fleece in controlling bleeding after insufficient primary haemostasis, with 75% (95% confidence interval (CI): 0.64—0.86) of the TachoSil group achieving haemostasis at 3 min compared with only 33% (95% CI: 0.21—0.45) of the standard treatment group ( p < 0.0001). This difference persisted at 6 min, with 95% of patients achieving haemostasis in the TachoSil group compared with 72% in the standard treatment group ( p = 0.0006). Three (5%) TachoSil patients compared with 17 (28%) standard treatment patients failed to achieve haemostasis at 6 min and received rescue treatment. TachoSil was well tolerated with adverse events generally similar in the two treatment groups. Conclusions: TachoSil was significantly superior to standard haemostatic fleece material in obtaining effective and fast intra-operative haemostasis in cardiovascular surgical procedures. TachoSil was safe and well tolerated. # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Keywords: Cardiovascular surgical procedures; Haemostasis; TachoSil

1. Introduction inisation and high arterial pressures all predispose to bleeding and mean that cardiovascular surgery is a challen- Prolonged bleeding is a serious complication of cardio- ging environment in which to achieve haemostasis. Re- vascular surgery and is associated with significant morbidity operation due to bleeding is performed in 2—6% of patients and mortality, increased duration and costs of surgery and undergoing cardiac surgery and is generally associated with a prolonged postoperative hospital stay [1,2]. Haemostatic worse prognosis [3,4]. changes associated with extracorporeal circulation, hepar- Topical haemostatic agents are used for the control of bleeding during surgery when conventional surgical methods such as compression, ligation, clipping and electrocautery § Medical writing support was provided by Andy Bond of Spirit Medical are impractical or inadequate. Liquid fibrin sealants, Communications Ltd., supported by Nycomed. This study was sponsored by synthetic glues, oxidised cellulose fleece and cotton gauze Nycomed, Roskilde, Denmark. * Corresponding author. Tel.: +39 02 2643 7111; fax: +39 02 2643 7125. are all widely used to help achieve haemostasis [5—8]. E-mail address: [email protected] (F. Maisano). However,there have been very few controlled clinical studies

1010-7940/$ — see front matter # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejcts.2009.04.057 F. Maisano et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 708—714 709 to assess the efficacy and safety of topical haemostatic additional active -stimulating compounds. Cen- agents in cardiovascular surgery. tralised randomisation was by an Interactive Voice Response TachoSilW (Nycomed, Linz, Austria) is a sterile, ready-to- System (IVRS) and was stratified by the centre. The bleeding use haemostatic agent and tissue sealant that consists of an target area was identified (aorta, left or right ventricle, left or equine collagen patch coated with human fibrinogen and right atrium, or other), and the site (vessels or heart tissue), human thrombin. TachoSil is a further development of type (arterial or venous) and severity of bleeding (mild oozing, TachoCombW that does not contain or any other moderate or severe) were assessed. In patients with more than component of bovine origin. Unlike other prepare-to-use one area of bleeding after primary haemostatic treatment, the fibrin sealants, which require the coating of fibrin glue onto a most prominent haemorrhage was considered the target area. fleece or patch immediately before or during surgery, TachoSil was provided as 9.5 cm  4.8 cm  0.5 cm patches TachoSil is a ready-to-use fixed combination that is activated and was applied after the target area had been cleaned of by moisture on application, providing adherence to the surgical debris. Patches had to extend 1—2 cm beyond the resection surface. Haemostasis is generally achieved after 3— wound margins. If more than one patch was needed, an overlap 5 min of compression. of 1—2 cm was required. TachoSil could be applied before or The efficacy and safety of TachoSil has previously been after protamine infusion. shown in studies in patients undergoing lung surgery [9,10], The trial treatments were applied with pressure to the kidney resection [11] and liver resection [12]. However,there target area for 3 min. If haemostasis was achieved within this are no previous controlled trials of TachoSil in cardiovascular time, the time to haemostasis was recorded as 3 min. If surgery. The current study was conducted to assess the haemostasis was not achieved, new trial treatment was re- efficacy and safety (for up to 30 days after surgery) of applied for a further 3 min. If haemostasis was then achieved, TachoSil compared with standard haemostatic fleece for the time to haemostasis was recorded as 6 min. If haemostasis control of bleeding in patients undergoing cardiovascular was not achieved after 6 min, rescue treatment could be surgical procedures. applied. Rescue treatment could include any conventional surgical method, liquid fibrin sealant or other haemostatic material, except for TachoSil in patients randomised to 2. Materials and methods standard treatment. The primary efficacy endpoint was the proportion of This was a randomised, parallel-group trial conducted at patients achieving haemostasis after 3 min. The secondary 10 centres in Europe (Denmark, France, Germany, Italy and efficacy endpoint was the proportion of patients achieving Spain). The trial was open-label because the appearance of haemostasis after 6 min. The duration of surgery (incision to TachoSil makes blinding of treatments during surgery skin-to-skin closure), duration of extracorporeal circulation, impossible. Relevant Ethics Committees approved the time of protamine infusion, use of aprotinin or other protocol and the trial was conducted in accordance with inhibitors of fibrinolysis and the need for intra-operative the Declaration of Helsinki, ICH Good Clinical Practice and transfusions were all recorded. Transfusion was based on any applicable local regulations. All patients provided routine practice at each centre rather than a standardised written informed consent. The trial is reported in accordance study transfusion protocol. with the CONSORT Statement for reporting of randomised Postoperative assessments included duration of drainage controlled trials [13]. (from the end of surgery to removal of drains), postoperative Adult patients (aged 18 years) with planned elective drainage volume, incidence of re-operation due to bleeding surgery on the heart, ascending aorta or arch requiring a complications, postoperative transfusion (type and number cardiopulmonary bypass procedure were eligible if bleeding of units) and other postoperative complications. Safety was from the heart muscle, pericardium, a major vessel assessed by adverse events (AEs) from screening to follow-up (including the aorta) or a vascular bed was present after 30 days after surgery, vital signs and clinical laboratory primary haemostatic treatment. The area of most prominent measurements. Body temperature was measured in the ear in haemorrhage had to be identifiable, and it had to be possible the evening of the day of surgery and in the morning and to apply the trial treatment by compression for a minimum of evening on days 1—5 after surgery. Any patients with a body 3 min. Patients were excluded if they had known coagulo- temperature >38.5 8C were evaluated in order to identify pathy or experienced microvascular bleeding (disseminated the possible cause. intravascular coagulation syndrome) during surgery. Other exclusion criteria included a history of allergic reactions 2.1. Statistical analysis after application of human fibrinogen, human thrombin or collagen of any origin, emergency surgery or treatment with Based on the previous studies of haemostatic agents [6,7], any fibrin glue during surgery within 6 min after the trial it was estimated that 75% of patients treated with TachoSil and treatment was applied. 45% of patients receiving standard treatment would achieve After screening, patients underwent surgery according to haemostasis after 3 min. To show a difference between the the routine of the centre. Primary haemostatic treatment treatments at a power of 90% (two-sided continuity corrected could include compression, suturing, clipping, electrocoagu- chi-square test) with a significance level of 5%, 120 patients lation or no treatment based on the surgeon’s discretion. were required (60 per treatment group). The primary and Patients requiring further haemostatic treatment who met the secondary efficacy endpoints (proportion of patients with intra-operative eligibility criteria were randomised to TachoSil haemostasis at 3 and 6 min) were analysed using the Cochran— or a standard haemostatic fleece material that did not contain Mantel—Haenszel test controlling for the centre and by the 710 F. Maisano et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 708—714

Breslow—Day test to assess homogeneity of odds ratios (i.e., Table 2 treatment effect) across the centres. Wilcoxon rank-sum tests Type of surgery (ITT population). were performed for duration and volume of postoperative TachoSil Standard drainage. The primary analysis was performed on the intent- (n=59) treatment a to-treat (ITT) population, which included all patients who (n = 61) were randomised and received trial treatment. AVR bio 11 12 AVR bio + otherb 14 9 AVR bio/mec + ascending valve 12 replacement 3. Results AVR bio/mec + CABG 3 2 AVR mec 0 1 3.1. Patients AVR mec + TVP + RFA 1 0 AVR mec + Bentall 1 2 A total of 326 patients were screened, 120 were AVR mec + decalcification of 01 heart valve randomised and 119 received trial treatment (ITT popula- MVR bio + otherb 16 tion: TachoSil, n = 59; standard treatment, n = 60) between MVR mec + TVR mec 0 1 March 2007 and September 2007. Two of the 10 participating Bentall 4 5 centres screened but did not randomise any patients. Three Bentall + CABG 1 0 Bentall + implant of valve conduit 0 1 patients randomised to standard treatment were mistakenly Bentall + implant of valve conduit 01 treated with TachoSil and were included in the TachoSil group + coronary ostial reconstruction for safety analyses (safety population: TachoSil, n = 62; Bentall + stent 0 1 standard treatment, n = 57). Five patients in the standard CABG 13 10 treatment group were treated with sutures (n = 4) or liquid CABG + MVP 1 0 CABG + MVP + TVP 0 1 fibrin glue (n = 1) for further haemostasis rather than MVP 3 0 haemostatic fleece but were included in the ITT analysis. MVP + CABG 0 1 Of the 119 patients who received trial treatment, 31 (26%) MVP + TVP 0 2 were female, the mean age was 67 years (range: 23—86 MVP + TVP + RFA 0 2 2 RFA 2 0 years) and the mean body mass index was 27.1 kg m (range: Heart transplant 1 0 2 16.5—50.2 kg m ). The baseline characteristics were similar Other procedure b 21 in the two groups (Table 1). AVR: aortic valve replacement; bio: bioprosthesis; CABG: coronary artery bypass graft; mec: mechanical prosthesis; MVP: mitral valve plasty; MVR: 3.2. Surgical procedures mitral valve replacement; RFA: radiofrequency ablation; TVP: tricuspid valve plasty; TVR: tricuspid valve replacement. a Surgical procedures were combined or complex (involving Includes one patient randomised to standard treatment who was not treated. two or more cardiovascular procedures) in 44% of patients in b AVR bio:+ other includes: MVR bio (TachoSil, n=1/standard treatment, the TachoSil group and 59% of patients in the standard n=1), TVP (0/1), Bentall (2/3), Bentall + CABG (2/0), CABG (5/2), CABG + RFA treatment group (Table 2). The mean duration of surgery (0/1), CABG + coronary ostial reconstruction (1/0), pacemaker insertion (1/0), (incision to skin-to-skin closure) was 249 Æ 77 min in the CABG + pacemaker insertion (1/0), CABG + RFA + coronary ostial reconstruc- TachoSil group (range: 120—453 min) and 235 Æ 59 min in the tion (0/1) and MVP (1/0). MVR bio:+ other includes: Bentall (0/1), CABG (0/2), TRV bio (1/0), RFA (0/1), TRV bio + RFA (0/1) and implant of valve conduit (0/ standard treatment group (range: 127—415 min), while the 1). Other procedures were aorta ascending tubegraft (0/1), resection of duration of extracorporeal circulation was 98 Æ 35 min subvalvular aortic stenosis (1/0) and resection of aortic aneurysm (1/0). (range: 40—195 min) compared with 109 Æ 46 min (range: 48—309 min). The aorta was the target area in a high proportion of patients (59% in the TachoSil group and 53% in in the two treatment groups. However, more were the standard treatment group). Bleeding was mainly vascular arterial (81% vs 67%) and more were classified as severe (9% vs rather than from tissue, arterial and mild to moderate in 3%) in the TachoSil group compared with the standard severity. There were no major differences between bleedings treatment group. Suturing was the primary haemostatic treatment in both Table 1 treatment groups (73% in the TachoSil group and 72% in the Baseline characteristics (ITT population). standard treatment group). The use of systemic aprotinin was less frequent in the TachoSil group than the standard TachoSil Standard treatment (n = 59) (n = 60) treatment group (46% vs 58% of patients), while use of other fibrinolysis inhibitors (primarily ) was similar Male/female (n) 45/14 43/17 (31% vs 33%). The characteristics of bleeding and haemostatic Age (years) 65 Æ 12 (23—82) 68 Æ 10 (36—86) Age >65 years (%) 59 65 variables are summarised in Table 3. Body mass index (kg/m2) 26.8 Æ 5.4 27.4 Æ 4.4 (18.3—50.2) (16.5—37.2) 3.3. Trial treatments pressure (mmHg) Systolic 128 Æ 17 (100—170) 128 Æ 22 (90—183) In the TachoSil group, 53 patients were treated with a Diastolic 74 Æ 13 (40—102) 73 Æ 11 (50—93) single patch, seven patients received two patches, one Data are mean Æ standard deviation (range). Blood pressure is presented for patient received three patches and another received four the safety population. patches. In the standard treatment group, 52 patients were F. Maisano et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 708—714 711

Table 3 Characteristics of bleeding and haemostatic variables during surgery (ITT population).

TachoSil Standard (n = 59) treatment (n =60)

Primary haemostatic treatment (%) Suturing 73 72 Electrocoagulation 10 8 Clips 5 3 Gauze 0 2 None 17 20 Target area (%) Aorta 59 53 Right ventricle 19 13 Right atrium 9 17 Left ventricle 5 3 Left atrium 5 3 Coronary anostomosis 3 5 Internal mammary artery vascular bed 2 2 Intercostal muscle 0 2 Pulmonary artery 2 2 Sternum 2 0 Vena cava 2 0 Site of bleeding (vessel/tissue) (%) 73/27 63/37 Fig. 1. Proportions of patients with haemostasis at 3 and 6 min. Type of bleeding (arterial/venous) (%) 81/19 67/33

Severity of bleeding (%) In a post-hoc subgroup analysis, significantly more Mild 32 40 Moderate 59 57 patients in the TachoSil group than the standard treatment Severe 9 3 group achieved haemostasis at 3 min when the site of Intra-operative transfusions (%) 27 37 bleeding was either the vessels or heart tissue (Fig. 2a). TachoSil was also significantly more effective in patients who Use of fibrinolysis inhibitors (%) received trial treatment during or after protamine infusion, Aprotinin 46 58 Others a 31 33 with more patients in the TachoSil group compared with standard treatment achieving haemostasis at 3 and 6 min a Thirteen patients in each group received tranexamic acid; in the standard group one patient received vasopressin and one patient received antithrombin (Fig. 2b). III. Type of fibrinolysis inhibitor in other patients unknown. 3.5. Postoperative assessments treated with compression and haemostatic fleece. Four patients were treated with sutures and one with liquid fibrin The mean duration of drainage was 93 Æ 177 h (median: glue (TissucolW, Baxter AG, Vienna, Austria) rather than the 46 h, range: 18—1093 h) in the TachoSil group and 67 Æ 106 h intended haemostatic fleece. (median: 44 h, range: 15—687 h) in the standard treatment group ( p = 0.11). The mean total volume of postoperative 3.4. Haemostasis at 3 and 6 min drainage was 1005 Æ 1128 ml (median: 600 ml, range: 75— 5240 ml) in the TachoSil group and 932 Æ 1320 ml (median: Haemostasis at 3 min was achieved by 75% of patients in 498 ml, range: 100—9100 ml) in the standard treatment the TachoSil group (95% confidence interval (CI): 0.64—0.86) group ( p = 0.24). compared with 33% of patients in the standard treatment Re-operation was required in three patients (5%) in the group (95% CI: 0.21—0.45). This difference was statistically TachoSil group and eight patients (13%) in the standard significant ( p < 0.0001) (Fig. 1). The proportion of patients treatment group. The need for re-operation was not related achieving haemostasis at 6 min was also significantly higher in to the trial treatment or target area in any patient. Twenty- the TachoSil group ( p = 0.0006) with 95% of the TachoSil- six patients (42%) in the TachoSil group had 51 postoperative treated patients (95% CI: 0.89—1.0) achieving haemostasis blood transfusions while 22 patients (39%) in the standard compared with 72% of the standard treatment patients (95% treatment group had 44 transfusions. Most transfusions CI: 0.60—0.83). There was no evidence of a centre effect at consisted of packed red blood cell (RBC) transfusions (38 in either 3 or 6 min. the TachoSil group and 35 in the standard treatment group). Three (5%) TachoSil patients compared with 17 (28%) Other postoperative complications were reported in 13 standard treatment patients failed to achieve haemostasis at TachoSil-treated patients (22%) and 16 standard treatment 6 min and received rescue treatment. In the three TachoSil patients (27%). patients, rescue treatment was fibrin glue, suture alone or suture plus TachoSil. In the standard treatment patients, 3.6. Safety rescue treatment was suture alone (n = 11), fibrin glue (n = 4), suture and oxidised cellulose (n = 1) or electrocoa- A total of 328 AEs were reported, 149 events in 46 (74%) gulation (n = 1). TachoSil-treated patients and 179 events in 44 (77%) 712 F. Maisano et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 708—714

There were no differences between the groups in mean body temperature in the evening after surgery and from days 1 to 5. A body temperature >38.5 8C was reported in two TachoSil patients and three standard treatment patients. Pyrexia (including postoperative fever) was reported as an AE in four patients in each group. One case of mild pyrexia in the TachoSil group was considered possibly related to trial treatment by the investigator. There were no significant differences between the groups with regard to vital signs or clinical laboratory measurements.

4. Discussion

Patients undergoing cardiovascular surgery represent a challenging group with regard to achieving haemostasis during surgery. Heparinisation and extracorporeal circulation compromise the coagulation capacity of the blood, while high arterial pressures predispose to bleeding [3,14]. As such, the coagulation system of patients during cardiopulmonary bypass is significantly impaired. TachoSil has previously been shown to be an effective and safe haemostatic and sealing agent in patients undergoing lung surgery [9,10], kidney resection [11] and liver resection [12]. However, this is the first controlled study of TachoSil in patients undergoing cardiovascular surgery. In this study, TachoSil was significantly superior to conventional haemostatic fleece material in achieving effective and fast intra-operative local haemostasis. Three-quarters of patients achieved haemostasis after 3 min with TachoSil, compared with only a third of the patients treated with compression or standard haemostatic fleece ( p < 0.0001). This difference between treatments remained after 6 min ( p = 0.0006). Compared with TachoSil, almost 6 times as many patients treated with the standard haemostatic fleece failed to achieve haemostasis and required rescue treatment (28% vs 5%). The limited haemostatic efficacy of standard treatment observed in this study is clinically significant, given that standard haemo- static fleeces are widely regarded as effective and are Fig. 2. Proportions of patients achieving haemostasis at 3 and 6 min by (a) site of bleeding (vessels vs heart) and (b) before or during/after protamine routinely used in cardiovascular surgery. infusion. The results of the present trial are comparable with the previous randomised studies assessing topical haemostatic standard-treated patients. The most frequently reported AEs agents in cardiovascular surgery [6—8,15—17]. In a rando- were supraventricular arrhythmias (including atrial fibrilla- mised controlled trial of 93 patients undergoing cardiac tion, atrial flutter and supraventricular tachycardia; TachoSil, surgery, significantly more patients achieved haemostasis n = 20; standard treatment, n=16), pleural effusion (n=14/ after 3 min (72% vs 23%) and 10 min (94% vs 60%) with a 14), nausea (n=8/5), hyperglycaemia (n=6/7) and haemor- gelatine-based haemostatic sealant (Floseal MatrixTM) than rhagic anaemia (n=5/6), all of which are known complications with thrombin-soaked Gelfoam [6]. Similarly, 88—90% of of the surgical procedure and underlying disease. One AE in the patients undergoing cardiac operations who received fibrin TachoSil group (mild pyrexia) was considered possibly related sealant (TISSEELW VH or TISSEEL VH S/D) as an adjunct to to trial . There were no major differences in the standard haemostatic techniques achieved haemostasis at occurrence of AEs between the trial treatments. Fifty-eight 5 min [8]. In another randomised trial, a 93% success rate for serious AEs were reported, 15 events in eight (13%) TachoSil fibrin sealant in controlling bleeding within 5 min was patients and 43 events in 18 (32%) standard treatment reported in patients undergoing either re-operative cardiac patients. No serious AEs were considered to be related to surgery or emergency re-sternotomy, compared with only trial treatment. Four deaths occurred, three as a result of 12% with conventional topical agents [16]. sepsis with multi-organ failure (two TachoSil patients and one The adhesive strength of TachoSil has been shown to be standard treatment patient) and one as a result of ventricular approximately twice that of other prepare-to-use treatments tachycardia, myocardial infarction and respiratory failure (fibrin glue coated onto fleece) and significantly higher than (standard treatment patient). fibrin glue alone [18—20]. Strong adhesion of the fibrin clot to F. Maisano et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 708—714 713 the application site combined with the mechanical support of The centralised randomisation procedure helped minimise the collagen patch and fibrin network result in a physically the risk of potential bias that can occur in a trial with an stable barrier capable of preventing bleeding. Fixation of the open-label design. However, use of the intra-operative IVRS local haemostatic effect may help prevent haemorrhage procedure had the disadvantage of introducing a delay of 2— caused by post-surgical hyperfibrinolytic activity of cut or 3 min before the application of trial treatment, during which severed cardiac parenchymal tissue. time compression of the target area may have been required. Patients who were screened for this trial tended to be high- During these 2—3 min of compression, the severity of the risk patients who were expected to bleed, such as those bleeding was to some extent reduced. This reduction in undergoing aortic surgery or re-operation. It is probable that bleeding before the application of trial treatment may have the EuroSCOREs of patients tended to be high, although data to potentially reduced the observed difference between the determine these were not routinely collected. Over half of the treatments. surgical procedures in randomised patients were combined or Combined or complex procedures that would be expected considered to be complex procedures necessitating prolonged to be associated with a higher risk of bleeding were more extracorporeal circulation. These procedures were more frequent in the standard group than the TachoSil group (59% frequent among patients who were randomised compared vs 44%). Despite this, there was a tendency towards greater with screening failures (52% vs 39%). This suggests that patients severity of bleeding in the target area in the TachoSil group, randomised in this trial may represent a higher-risk group than indicating that the difference in the proportion of combined a general cardiovascular surgery population. This is also or complex procedures did not affect the validity of the trial suggested by the high occurrence of postoperative transfu- results. There was no significant centre effect on the primary sions (approximately 40%). efficacy endpoint. It is conceivable that this observation is Two-thirds of bleedings occurred from a vessel, with one- due to uniform basic standard procedures used in cardiac third from the surrounding tissue. In a post-hoc analysis of surgery irrespective of centre. patients with vessel bleeding, significantly more patients in TachoSil was safe and well tolerated, with AEs generally the TachoSil group achieved haemostasis at 3 and 6 min similar in the two treatment groups. Most AEs were related to compared with those in the standard treatment group (69% vs the surgical procedure or the underlying disease. There was a 31%; p = 0.003, and 94% vs 67%; p = 0.004, respectively). slight tendency towards a higher occurrence of AEs in the Although suture support was not specifically assessed, this standard treatment group, although this was most likely a indicates that TachoSil is effective as a suture support in random finding. vascular surgery. Previous studies with TachoSil or Tacho- Raised body temperature has previously been reported to Comb have also demonstrated efficacy for the control of be more frequent with TachoSil than standard treatment [11]. suture hole bleeding in vascular reconstruction and aortic However, no differences were observed between treatments arch aneurysm repair [21—23]. Other haemostatic agents in mean body temperature or in the number of patients with have also been shown to be effective in the prevention of body temperature >38.5 8C. A single patient in the TachoSil suture hole bleeding [24]. group had pyrexia that was considered possibly related to Nearly three-quarters of bleedings were arterial with a treatment. However, this patient had postoperative inflam- slightly higher occurrence in the TachoSil group than the matory syndrome which may have accounted for the pyrexia. standard treatment group (81% vs 67%), and more than half of There was no evidence to suggest that pyrexia or postoperative bleedings were from the aorta. Arterial bleedings are fever increased with TachoSil treatment. haemostatically demanding because of the high arterial blood In conclusion, the results of the trial indicate that TachoSil pressure, especially in anti-coagulated patients. In this study, is safe and significantly more effective than conventional the ability of TachoSil to withstand high-pressure suture hole standard haemostatic fleece material for the control of local bleeding was shown by its effective application to the aorta bleeding during cardiovascular surgical procedures. and left ventricle. Venous bleedings are also a challenge because of the vulnerability of the venous tissue, which can be delicate and difficult to suture. TachoSil was shown to be Acknowledgements effective when applied to venous vessels, the right atrium and right ventricle. The ability of TachoSil to achieve haemostasis We thank the other study investigators: Dr Daniel A. after application to a variety of vascular structures suggests Steinbru¨chel, Rigshospitalet, Cardiovascular and Thoracic that it may also be useful in more peripheral vascular surgery. Surgery, Copenhagen, Denmark; Professor Jose´ Luis Pomar, TachoSil was also effective when given before protamine Hospital Clinic i Provincial Cardiovascular Surgery, Barcelona, reversion of heparinisation, indicating haemostatic and Spain; and Professor Mauro Rinaldi, Ospedale S. Giovanni sealing properties independent of blood coagulability. In a Battista — Le Molinette, Direzione di Cardiochirurgia, Torino, small subgroup of 19 patients (TachoSil, n=10; standard Italy. We also thank Christian Holm Hansen (Nycomed, treatment, n=9) who received trial treatment before Roskilde, Denmark) for statistical support. protamine infusion, 70% of the TachoSil patients compared with 56% of the standard treatment patients had haemostasis References at 3 min. Although the trial was not powered to detect a difference between treatments in this subgroup, and the difference was not statistically significant, these results [1] Harmon DE. Cost/benefit analysis of pharmacologic . 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