Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery

Abstract

Major bleeding during complex surgery increases the need for blood transfusions, prolongs the patient’s stay in the intensive care unit (ICU), and is associated with increased morbidity and mortality.1,2The standard treatment of perioperative bleeding involves the transfusion of allogeneic blood components (erythrocytes, fresh frozen plasma [FFP], platelet concentrate, or cryoprecipitate). Although these components have become safer, there is evidence that the transfusion of allogeneic blood components may be associated with a risk of serious adverse events.3–5Thus, treatment approaches that can reduce transfusion appear desirable.Clot strength increases with increasing concentrations of fibrinogen, and fibrinogen levels higher than 200 mg/dl have been suggested for optimal clot formation.6–8Immediately after cardiopulmonary bypass (CPB), fibrin formation is impaired to a greater extent than either thrombin generation or the platelet component of clot strength.9The plasma concentration of fibrinogen10,11and the firmness (elasticity/strength) of the fibrin-based clot9have been reported to decrease by an average of 34–42% in response to CPB. Furthermore, low levels of fibrinogen are associated with an increased risk of postoperative bleeding.10,12,13Overall, there is considerable evidence to support fibrinogen supplementation as a first-line treatment for coagulopathic bleeding among patients undergoing CPB. Several studies have suggested that fibrinogen concentrate therapy may be effective in controlling perioperative bleeding, reducing transfusion requirements as well as blood loss.11,14–19Fibrinogen concentrate is derived from human plasma and does not contain relevant levels of other coagulation factors.20Our group has developed and validated a model for individualized dosing of fibrinogen concentrate,17,18by measuring firmness of the fibrin-based clot, which is mainly dependent on plasma fibrinogen levels.13,21,22Maximum clot firmness (MCF) of the fibrin-based clot can be monitored using a commercially available fibrin-based thromboelastometry test (FIBTEM).11,23A clinical study is needed to investigate the efficacy and safety of fibrinogen concentrate in managing severe perioperative bleeding. We hypothesized that fibrinogen concentrate can reduce the need for blood transfusions without increasing the rate of serious adverse events when given intraoperatively as individualized first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery.This phase 2, prospective, randomized, double-blind, placebo-controlled, parallel-group, stratified, clinical study was conducted at a single center (Hannover Medical School, Hannover, Germany). It was approved by the Local Ethics Committee in Hannover, Germany, and by the German Regulatory Authorities; it was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The study was assigned Local Ethics Committee reference code no. 4891M-mono, EudraCT trial no. 2007-004612-31, and ClinicalTrials.govidentifier no. NCT00701142.Patients aged 18 yr or older for whom elective aortic replacement surgery involving CPB was planned and who provided signed informed consent were enrolled between June 2008 and April 2010. All aortic valve operations with root/ascending aorta replacement (thoracic aortic aneurysm [TAA]), with or without aortic arch replacement, and thoracoabdominal replacements were eligible. Patients were excluded from the study if they had undergone previous surgery at the same aortic site, if they had a congenital or acquired coagulation disorder, if they had a myocardial infarction or stroke in the previous 2 months, or if they used aspirin, clopidogrel, or vitamin K antagonists in the previous 2–5 days. All patients received antifibrinolytic prophylaxis with tranexamic acid (30 mg/kg bodyweight as a preoperative loading dose, followed by 1 mg/kg bodyweight/h throughout surgery). CPB was established after aortic cannulation and administration of 400 IU/kg heparin (Heparin-Natrium-25000-ratiopharm®; Merckle GmbH, Blaubeuren, Germany).Before surgery, patients were randomized to receive either fibrinogen concentrate or placebo; study medication was administered if clinically relevant bleeding occurred. This was defined as a 5-min bleeding mass of 60–250 g immediately after removal from CPB, neutralization of heparin with protamine sulfate (Protamin Valeant, Valeant Pharmaceuticals GmbH, Eschborn, Germany; protamine–heparin ratio of 1:1), and completion of surgical hemostasis, which includes suture placement and electrocautery (or diathermy) (fig. 1). Completion of surgical hemostasis consisted of surgical control of focal bleeding. Surgical hemostasis was deemed to be complete if no obvious sources of bleeding were identified. A 5-min bleeding mass was subsequently determined by weighing dry surgical cloths and compresses, applying them to the surgical area for 5 min and weighing them again. No irrigation of the operative field was performed during the measurement of bleeding mass. Bleeding mass in the range 60–250 g was considered to be clinically relevant and coagulopathic in nature; an upper limit was included because of the life-threatening nature of massive bleeding. The thresholds of 60 and 250 g were chosen based on clinical experience at the authors’ center.17,18Randomized patients not eligible for treatment or withdrawn from the study before 24 h after the administration of study medication were replaced until there were sufficient patients to provide primary efficacy endpoint data for each study arm. Stratification was done according to surgery type (thoracoabdominal aortic aneurysm or TAA).Study medication was prepared in 50-ml opaque syringes by the pharmacist, according to a randomization code generated by the contract research organization (Accovion GmbH, Eschborn, Germany) using SAS (SAS Institute, Cary, NC) (the investigator initially assigned a randomization number to each patient). The randomization ratio of the treatment arms in each stratum (thoracoabdominal aortic aneurysm and TAA) was 1:1, with a block size of 4. Each 50-ml syringe contained either 1 g fibrinogen concentrate (Haemocomplettan P®, RiaSTAPTM; CSL Behring, Marburg, Germany) diluted in 50 ml sterile water, or an equivalent volume of 0.9% saline as placebo. The medication was delivered to the operation room upon request of the study investigator (anesthesiologist) and administered intravenously within 5 min of bleeding measurement. In order for study medication to be administered, patients had to fulfill the following conditions: activated clotting time less than 150 s, body temperature higher than 36°C, pH more than 7.3, and hemoglobin level higher than 8.5 g/dl. To ensure blinding, only the pharmacist had access to the randomization code; the use of opaque syringes ensured that fibrinogen concentrate and placebo were visually identical.Doses were determined from the MCF of the FIBTEM test, using a model developed in previous studies for individualizing fibrinogen concentrate dosing.17,18The FIBTEM test was performed by point-of-care thromboelastometry (ROTEM®device; TEM International, Munich, Germany), using blood samples taken 20 min before the end of CPB. The time taken to obtain the MCF value was 15 min. The fibrinogen concentrate dose was calculated by the unblinded point-of-care laboratory staff as follows: Fibrinogen concentrate dose (g) = (target FIBTEM MCF − actual FIBTEM MCF) (mm) × (bodyweight [kg]/ 70) × 0.5 g/mm.11,17,18The target FIBTEM MCF was 22 mm. None of the blinded personnel (investigator and staff of the operating room and ICU) had access to FIBTEM or fibrinogen concentration values after the administration of study medication.Approximately 5 min after the administration of study medication, bleeding mass was measured again. A transfusion algorithm was initiated in patients with a bleeding mass of 60–250 g as follows: if, upon removal of the aortic clamp, platelet count was lower than 100,000/µl, 2 U of apheresis platelet concentrate was administered; if platelet count was 100,000/µl or higher, 4 U FFP was administered in approximately 10 min. Subsequently, 5-min bleeding mass was reevaluated. If clinically relevant bleeding continued, the patient was given the blood component (platelet concentrate/FFP) not administered after the first bleed, and 5-min bleeding mass was again measured. Transfusion packages of 1 U platelet concentrate and 2 U FFP were administered until the 5-min bleeding mass was less than 60 g. Upon completion of hemostatic therapy, the thorax was closed (last suture = end of surgery), and the patient was transferred to the ICU. In the event of blood drainage higher than 400 ml during 1 h in the ICU, 1 U platelet concentrate and 2 U FFP were administered. Erythrocytes were also administered after CPB to maintain a hemoglobin level higher than 8·5 g/dl. Fibrinogen levels were measured using the Clauss assay, before and after the administration of study medication.The primary endpoint was the total number of units of allogeneic blood components (erythrocytes plus FFP plus platelet concentrate) given to patients between the administration of study medication and 24 h thereafter. Secondary endpoints included the number of units of each individual allogeneic blood component given (erythrocytes, FFP, and platelet concentrate), the proportion of patients who received no allogeneic blood components (total avoidance), the number of days not in the ICU or hospital during the 45 days after surgery (assumed to be zero for patients dying within that period), and mortality at 45 days after surgery.Safety was assessed principally by treatment-emergent adverse events occurring within 10 days of treatment. The follow-up period for serious adverse events was 45 days. Patients were monitored for viral seroconversion by hepatitis A virus, hepatitis B virus, hepatitis B core, hepatitis B surface antigen, hepatitis C virus, human immunodeficiency virus 1 and 2, and parvovirus B19 testing (enzyme immunoassays and polymerase chain reaction were used). In accordance with Good Clinical Practice, the study sponsor evaluated safety data throughout the study.Sixty patients were planned for the primary endpoint based on an assumed difference between the treatment group means of 4·25 ± 5.3 U (where 5.3 is the SD) with a two-sided type I error rate of 5% and more than 80% power for the nonparametric Wilcoxon rank sum test. These assumptions were derived from a previously reported average transfusion of 8·5 ± 5.3 U during TAA surgery.17We assumed that the use of fibrinogen concentrate would reduce transfusion of allogeneic blood products by 50% compared with the standard-of-care group. The efficacy and safety analyses included all patients who were randomized and received study treatment. This was not strictly an intention-to-treat analysis because of the need to randomize patients before ascertaining whether they met the study inclusion criteria (if randomization had been performed after establishing that patients met the study inclusion criteria, hemostatic therapy would have been delayed unethically).Inferential testing of the primary efficacy endpoint was based on a nonparametric Wilcoxon rank sum test with a two-sided type I error rate of 5%, testing the null hypothesis of no difference between the treatment groups. An unstratified Hodges–Lehman point estimate and the corresponding two-sided 95% CI for the treatment difference were also calculated. The primary endpoint was found to have a positively skewed nonnormal distribution. The proportion of patients receiving no allogeneic blood components within the first 24 h after start of infusion of study medication was analyzed in an exploratory manner applying a chi-square test.Exploratory analysis was performed for selected secondary endpoints (24-h transfusion of erythrocytes, FFP, and platelet concentrate [each component analyzed separately]). Additional analyses were performed for fibrinogen and hemoglobin using the two-sample t test for normally distributed outcomes and the Wilcoxon rank sum test for outcomes with a skewed distribution.All other secondary efficacy endpoints were analyzed by descriptive statistics, with values typically presented as mean ± SD. For the between-group comparison of safety outcomes, risk ratios with 95% CIs were calculated where possible (nonzero incidence).Data for the main efficacy endpoints are presented as median (with interquartile range, between the 25th and the 75th percentiles) values because the data were not normally distributed. SAS version 9.1.3 (SAS Institute) was used for all of the statistical analyses, except the Wilcoxon rank sum test, which was performed using StatXact (version 8.1; Cytel, Cambridge, MA).Of 80 patients screened, 61 were randomized and treated (fig. 2). Of these, 18 patients underwent thoracoabdominal aortic aneurysm surgery, 22 underwent TAA with arch surgery, and 21 underwent TAA without arch surgery (table 1). The two treatment groups had similar perioperative characteristics, and the population was typical for patients undergoing aortic surgery (table 1). Preoperative mean ± SD FIBTEM MCF was 17.9 ± 6.1 mm in the fibrinogen concentrate group and 16.4 ± 3.8 mm in the placebo group.On the basis of MCF values from the FIBTEM test performed during CPB, a median dose of 8 g (interquartile range [IQR], 6–9 g) of fibrinogen concentrate was administered to patients in the fibrinogen concentrate group (median volume, 400 ml; IQR, 300–450 ml). The median volume of study medication administered to the placebo group was also 400 ml (IQR, 300–450 ml). These doses were calculated from the FIBTEM MCF of samples taken approximately 20 min before removal from CPB; the mean MCF was 9.7 ± 3.1 mm in the fibrinogen concentrate group and 9.5 ± 2.7 mm in the placebo group. As shown in table 1, the two study groups were also comparable immediately before the administration of study medication (after removal from CPB, administration of protamine, and completion of surgical hemostasis), in terms of 5-min bleeding mass and activated clotting time.During the 24-h period after start of study medication, patients treated with fibrinogen concentrate received fewer units of allogeneic blood components (median, 2 U; IQR, 0–8 U) than patients treated with placebo (median, 13 U; IQR, 8–21 U); the treatment difference (−9 U; 95% CI, −13 to −6 U) was statistically significant (P <0.001, table 2). A sensitivity analysis was performed, excluding patients who dropped out within 24 h of the administration of study medication (one patient in the placebo group). This showed a similar treatment difference (−8 U; 95% CI, −13 to −6 U). The treatment difference was also generally similar for each of the aortic replacement procedures included in the study. The number of units of erythrocytes, FFP, and platelet concentrate administered during the 24 h after start of study medication was lower in the fibrinogen concentrate group than that in the placebo group (table 2). These treatment differences were statistically significant for erythrocytes (reduction, −2 U; P = 0.007), FFP (reduction, −5 U; P < 0.001) and platelet concentrate (reduction, −2 U; P < 0.001).Total avoidance of transfusion was achieved in 13 of 29 patients (45%) in the fibrinogen concentrate group; in contrast, 32 of 32 patients (100%) in the placebo group received treatment with allogeneic blood components to control their coagulopathic bleeding (P < 0·001). The mean fibrinogen concentration and the mean FIBTEM MCF were similar in the two study groups at all time points except for the first measurement after the administration of study drug (at the “last suture” time point, i.e. , end of surgery), when higher values were observed in the fibrinogen concentrate group (fibrinogen level, 260 vs. P < table FIBTEM ± vs. ± P < was no between-group difference in hemoglobin at time point (table of days and days were also similar in the two study groups (table of patients in each treatment group reported treatment-emergent adverse events table The of treatment-emergent adverse events reported were typical for patients undergoing surgery, the and None of the treatment-emergent adverse events reported in the study was considered to be to study medication, and to from the study. because of bleeding was in patients in the fibrinogen concentrate group and patients in the placebo group. Although a risk of there was no significant between-group In all a surgical of bleeding was during of serious adverse events was similar in study groups serious adverse events to in the placebo group the fibrinogen concentrate group patients vs. Although the risk was there was no significant between-group None of the serious adverse events was considered to study and to and myocardial infarction were reported in a fibrinogen concentrate patient with a previous of myocardial and who underwent of TAA and was reported the patient was transferred for a with was for no events were reported in the fibrinogen concentrate group. In the placebo two events were reported (one and were no viral in either study study that fibrinogen concentrate, administered intraoperatively as first-line hemostatic the need for transfusion of allogeneic blood products in patients undergoing complex aortic The median transfusion of allogeneic blood components was by among patients receiving fibrinogen concentrate U compared with placebo U avoidance of allogeneic blood components in 13 of 29 patients (45%) treated with fibrinogen concentrate is of clinical that all patients in the placebo group received allogeneic blood outcomes may be to plasma fibrinogen concentration more and to higher levels among patients receiving fibrinogen concentrate compared with who received placebo. The use of fibrinogen concentrate of allogeneic blood products has clinical Fibrinogen concentrate is immediately available for with no need for or blood group and has a low administration can be administered in less time than either FFP or the time to control bleeding. In the of severe bleeding, the administration of g fibrinogen concentrate in min has been reported contrast, FFP administration and the concentration of fibrinogen in FFP 200 the extent to which fibrinogen levels can be a higher concentration of fibrinogen in to a range of concentration is more than with fibrinogen concentrate, that doses be as as with FFP, blood group is before use of fibrinogen concentrate with other coagulation as complex concentrate, in the of a treatment algorithm based on point-of-care coagulation was shown to decrease blood transfusion and events among surgery is of because it the treatment of using coagulation with the for in allogeneic blood transfusions than can be achieved with fibrinogen data that the in fibrinogen to the placebo was only than 24 and may be positively from a safety The safety of fibrinogen concentrate was similar to that of placebo. This study was not to differences between fibrinogen concentrate and placebo in morbidity or the of between-group differences in safety is with the previously reported safety of fibrinogen concentrate, a low risk of an of virus patients in the fibrinogen concentrate group underwent compared with in the placebo group. Surgical bleeding was in all of these In the possible for are and there is no in study that the were to study The data are with the in the use of allogeneic blood products in the fibrinogen concentrate group. all allogeneic blood products administered within 24 h of study medication were included in the primary used during and after and all patients the operating room with a 5-min bleeding mass less than 60 is the randomized, double-blind, study of fibrinogen concentrate It is the first study of fibrinogen concentrate administered intraoperatively as first-line hemostatic therapy, and the first study of fibrinogen concentrate among patients undergoing complex two previous randomized clinical studies of fibrinogen concentrate have been the first patients undergoing = with blood by a significant in MCF after fibrinogen supplementation placebo. Transfusion and blood were similar in the two groups during surgery, erythrocytes were administered to patients in the placebo group two in the fibrinogen group (P < The performed in 20 bypass showed that the administration of fibrinogen concentrate g) blood by (P = transfusions were in patient in the fibrinogen group compared with in the placebo group. The study was and the of operation were distributed between the two treatment that they were as fibrinogen concentration and time the of the two groups before the administration of study study medication patients received study medication during a period if treatment consisted only of allogeneic blood the patient would only have been monitored blood products are study may also be considered as a comparison of fibrinogen concentrate with standard hemostatic treatment based on FFP and platelet in study was based on point-of-care coagulation testing to obtain more than standard laboratory are to the use of is as to which are data showed that of , and is to than a single is a test to firmness of a clot in the of a platelet , fibrin-based clot FIBTEM does not provide a measurement of fibrinogen of the fibrin-based clot is measured in units that are from of fibrinogen concentration as to or studies have shown between FIBTEM MCF and of fibrinogen was to FIBTEM MCF to 22 higher than the mean preoperative level of mm and at the end of the range This target was chosen to fibrinogen concentrate to be effective as a hemostatic is evidence that fibrinogen is the primary associated with that fibrinogen supplementation may for platelet typically to a fibrinogen level of approximately is within the range of similar to the value of mg/dl reported for patients older than 60 the plasma concentration for fibrinogen supplementation was at as more than 150 higher target may be because clot firmness to with fibrinogen concentration throughout the study has analysis does not strictly the for to To patients were randomized to treatment before the of clinically significant coagulopathic bleeding was was not because to the study was based on criteria as to clinical and because the criteria were the same for study groups. The use of 5-min bleeding mass as a study inclusion and as a for the transfusion of allogeneic blood products an of bleeding the that it is not the standard for hemostatic and that it may not be in all clinical are and measurement of blood in the Patients with preoperative coagulation or therapy were that the of the to patients may be of the study was comparison of the two treatment groups. This study is also by size and use of a single the of safety , adverse is not the size was determined statistically from an that the use of allogeneic blood products would be by a of clinical and the use of a single center may limit to other it also have in personnel and clinical is a need for studies of fibrinogen concentrate in surgical in patients with preoperative and in of patients to that may efficacy and to the observed safety studies would be randomized and with intention-to-treat also study in patients undergoing aortic replacement surgery has shown that first-line treatment with fibrinogen concentrate is to reduce the transfusion of allogeneic blood If in fibrinogen concentrate administration would provide a means of reducing or has the to the treatment for perioperative bleeding in patients with life-threatening support was provided by and GmbH, Germany). The for and Medical School, Hannover, Germany) for to blood of coagulation and data