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Factor VIII inhibitor bypass activity (FEIBA) for the reduction of transfusion in cardiac surgery: a randomized, double-blind, placebo-controlled, pilot trial
Sera VA, Stevens AE, Song HK, Rodriguez VM, Tibayan FA, Treggiari MM
Pilot and feasibility studies. 2021;7(1):137
Abstract
BACKGROUND Uncontrolled bleeding after cardiac surgery can be life-threatening. Factor eight inhibitor bypassing activity (FEIBA) is a prothrombin complex concentrate empirically used as rescue therapy for correction of refractory bleeding diathesis post-cardiopulmonary bypass (CPB). FEIBA used as rescue therapy for bleeding diathesis after CPB has been associated with a low incidence of complications and a reduction in transfusion requirement and re-exploration. The feasibility and efficacy of early administration of FEIBA after the termination of CPB have not been studied in a prospective randomized trial. METHODS We designed a small randomized, double-blinded, placebo-controlled pilot trial to determine the feasibility of a larger trial testing the hypothesis that FEIBA decreases transfusion requirements after CPB. The study was designed to evaluate the feasibility of a larger pivotal trial to determine the effectiveness of FEIBA in reducing the total volume of blood products transfused perioperatively, and its safety profile. Study participants were adult patients undergoing elective major aortic cardiovascular surgery at a tertiary referral hospital, who were equally randomized to receive a single dose of either FEIBA or matched placebo intraoperatively at the end of CPB. RESULTS Twenty patients were screened and 12 were randomized and included in the analysis. Protocol adherence was high, and all patients received the study drug per intention-to-treat except one patient. There were no protocol deviations or events of unblinding, and adverse events were not different between groups. Patients in the FEIBA group were older and more likely to be female and had higher BMI, lower hematocrit, and longer hypothermic circulatory arrest. There were no differences in post-randomization blood product transfusions (difference FEIBA vs. placebo -899 mL; 95% CI -5206 to 3409) or in the administration of open-label FEIBA. CONCLUSIONS This pilot trial confirmed the adequacy of the trial design that involved the early, blinded administration of FEIBA, by demonstrating excellent protocol adherence. We conclude that a larger trial establishing the effectiveness of early prothrombin complex concentrate administration to reduce the use of blood products in the setting of high-risk cardiac surgery is feasible. TRIAL REGISTRATION ClinicalTrials.gov, NCT02577614 . Registered 16 October 2015.
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2.
The effect of intravenous administration of active recombinant factor VII on postoperative bleeding in cardiac valve reoperations: a randomized clinical trial
Payani N, Foroughi M, Dabbagh A
Anesthesiology & Pain Medicine. 2015;5((1):):e22846.
Abstract
BACKGROUND Postoperative bleeding after cardiac reoperations is among the most complicating problems, both for the physicians and for the patients. Many modalities have been used to decrease its adverse effects and the need for blood products administration. OBJECTIVES In a randomized double-blinded clinical trial of redo cardiac valve surgery in adult, the effect of active recombinant factor VII (rFVIIa) on postoperative bleeding was compared with placebo. Chest tube drainage was used for comparison of bleeding between the two groups. PATIENTS AND METHODS Two groups of 18 patients undergoing redo valve surgeries were treated and compared regarding chest tube drainage, need for blood products, prothrombin time (PT), partial thromboplastin time (PTT), hemoglobin and hematocrit, platelet count, and international normalized ratio (INR) in first 24 hours after surgery. Bleeding was assessed at 3rd, 12th, and 24th hour after operation. In rFVIIa group, 40 micro g/kg of AryoSeven was administered before end of surgery and same volume of normal saline was administered as placebo in the control group. RESULTS Study groups showed no difference regarding baseline variables. Three patients in rFVIIa group (16.67%) and 13 in placebo group (72.23%) received blood products (P < 0.01). Chest tube blood drainage at 24th hour after operation was 315 +/- 177 mL in rFVIIa group and 557 +/- 168 mL in control group (P = 0.03). At third and 12th hour after operation, the difference was not statistically significant (P = 0.71 and P = 0.22, respectively). Postoperative ICU stay was not different; while extubation was longer in the placebo group (352 +/- 57 vs. 287 +/- 46 minutes; P = 0.003). CONCLUSIONS Our study demonstrated the efficacy of rFVIIa in controlling postoperative bleeding in redo cardiac valve surgeries regarding subsequent blood loss and transfusion requirement; however, outcome results remains to be defined.
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3.
Prophylactic administration of recombinant activated factor VII in coronary revascularization surgery
Abdel-Meguid ME
Saudi Journal of Anaesthesia. 2013;7((3):):301-4.
Abstract
OBJECTIVE The objective of this clinical trial is to study the effectiveness of administering recombinant activated factor VII (rFVIIa) in reducing the amount of bleeding and the need for homologous blood and products transfusion in cardiac surgical coronary revascularization procedures done under cardiopulmonary bypass (CPB). METHODS In a randomized controlled prospective observational study, 30 patients were scheduled for elective cardiac revascularization under CPB. Patients were randomly allocated into two groups. In Group I (Control group), no rFVIIa was administered following CPB. In Group II (Study group), a dose of 90 ug/Kg of rFVIIa was administered following weaning off CPB. The total amount of chest tube drain during the 1(st) 24 h following surgery was recorded as well as the qualitative and quantitative assessments of homologous blood and products transfusion. Serial analysis of hematological parameters including hemoglobin level and coagulation test in a definite data points was done. T0=baseline readings prior to CPB, T1=off CPB after protamine administration and before administration of the study drug, T2=on Cardiac Intensive Care Unit (CICU) admission, T3=12 h post-CICU admission, and T4=24 h post-CICU admission. RESULTS Considering the total chest tube drainage, mean values showed statistically significant results with a P value of 0.001. Homologous blood and products transfusion were statistically lower in the study group. Regarding the mean values for hematological assessment, results showed statistically lower International Normalized Ratio values at CICU admission and 12 h post-CICU admission with a P value of 0.018 and 0.004, respectively. Also, the Partial Thromboplastin Time mean values were statistically lower at same timings with estimated P values of 0.04 and 0.001, respectively. CONCLUSION It is concluded that the prophylactic use of rFVIIa in patients undergoing coronary revascularization surgery under the management of CPB had a remarkable significant results on both the amount of post-operative bleeding and the amount of blood and products transfusion.
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4.
Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: A randomized, placebo-controlled, multicenter clinical trial
Karkouti K, von Heymann C, Jespersen CM, Korte W, Levy JH, Ranucci M, Sellke FW, Song HK
Journal of Thoracic & Cardiovascular Surgery. 2013;146((4):):927-39.
Abstract
OBJECTIVES Cardiac surgery with cardiopulmonary bypass frequently leads to excessive bleeding, obligating blood product transfusions. Because low factor XIII (FXIII) levels have been associated with bleeding after cardiac surgery, we investigated whether administering recombinant FXIII after cardiopulmonary bypass would reduce transfusions. METHODS In this double-blinded, placebo-controlled, multicenter trial, 409 cardiac surgical patients at moderate risk for transfusion were randomized to receive an intravenous dose of recombinant FXIII, 17.5 IU/kg (n=143), 35 IU/kg (n=138), or placebo (n=128) after cardiopulmonary bypass. Transfusion guidelines were standardized. The primary efficacy outcome was avoidance of allogeneic blood products for 7 days postsurgery. Secondary outcomes included amount of blood products transfused and reoperation rate. Serious adverse events were measured for 7 weeks. RESULTS Study groups had comparable baseline characteristics and an approximately 40% decrease in FXIII levels after cardiopulmonary bypass. Thirty minutes postdose, FXIII levels were restored to higher than the lower 2.5th percentile of preoperative activity in 49% of the placebo group, and 85% and 95% of the 17.5- and 35-IU/kg recombinant FXIII groups, respectively (P<.05 for both treatments vs placebo). Transfusion avoidance rates were 64.8%, 64.3%, and 65.9% with placebo, 17.5 IU/kg, and 35 IU/kg recombinant FXIII (respective odds ratios against placebo, 1.05 [95% confidence interval, 0.61-1.80] and 0.99 [95% confidence interval, 0.57-1.72]). Groups had comparable adverse event rates. CONCLUSIONS Replenishment of FXIII levels after cardiopulmonary bypass had no effect on transfusion avoidance, transfusion requirements, or reoperation in moderate-risk cardiac surgery patients (ClinicalTrials.gov identifier: NCT00914589). Copyright 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
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5.
Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery
Gill R, Herbertson M, Vuylsteke A, Olsen PS, von Heymann C, Mythen M, Sellke F, Booth F, Schmidt TA
Circulation. 2009;120((1):):21-7.
Abstract
BACKGROUND Blood loss is a common complication of cardiac surgery. Evidence suggests that recombinant activated factor VII (rFVIIa) can decrease intractable bleeding in patients after cardiac surgery. Our objective was to investigate the safety and possible benefits of rFVIIa in patients who bleed after cardiac surgery. METHODS AND RESULTS In this phase II dose-escalation study, patients who had undergone cardiac surgery and were bleeding were randomized to receive placebo (n=68), 40 microg/kg rFVIIa (n=35), or 80 microg/kg rFVIIa (n=69). The primary end points were the number of patients suffering critical serious adverse events. Secondary end points included rates of reoperation, amount of blood loss, and transfusion of allogeneic blood. There were more critical serious adverse events in the rFVIIa groups. These differences did not reach statistical significance (placebo, 7%; 40 microg/kg, 14%; P=0. 25; 80 microg/kg, 12%; P=0. 43). After randomization, significantly fewer patients in the rFVIIa group underwent a reoperation as a result of bleeding (P=0. 03) or required allogeneic transfusions (P=0. 01). CONCLUSIONS On the basis of this preliminary evidence, rFVIIa may be beneficial for treating bleeding after cardiac surgery, but caution should be applied and further clinical trials are required because there is an increase in the number of critical serious adverse events, including stroke, in those patients randomized to receive rFVIIa.
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6.
Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report
Levy JH, Gill R, Nussmeier NA, Olsen PS, Andersen HF, Booth FV, Jespersen CM
Thrombosis and Haemostasis. 2009;102((4):):765-71.
Abstract
Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A(2)) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A(2) (11. 9, 25, 35 or 50 IU/kg) or placebo in a 4:1 ratio. Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5-7. The primary end-point was incidence and severity of adverse events. Thirty-five patients were randomised to rFXIII-A(2) and eight to placebo. Eighteen serious adverse events were reported. These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/kg rFXIII-A(2) was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25-50 IU/kg rFXIII-A(2) restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A(2), in doses from 11. 9 IU/kg up to 50 IU/kg, was well tolerated. For post-operative FXIII replenishment, 35 IU/kg of rFXIII-A(2) may be the most appropriate dose.
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7.
A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures
Weaver FA, Lew W, Granke K, Yonehiro L, Delange B, Alexander WA, Study Investigators
Journal of Vascular Surgery. 2008;47((6):):1266-73.
Abstract
OBJECTIVES Recombinant thrombin (rThrombin) is a potential hemostatic alternative to bovine and human plasma-derived thrombin. This report examines the clinical results for the vascular surgery subgroup of patients enrolled in a larger double-blind, randomized, multicenter trial, which evaluated the comparative safety and efficacy of rThrombin and bovine plasma-derived thrombin (bThrombin) when used as adjuncts to surgical hemostasis. METHODS Data from the 164 vascular patients who underwent either a peripheral arterial bypass (PAB) or arteriovenous graft (AV) procedure are included in this analysis. Time to hemostasis at proximal and distal anastomotic sites at 1. 5-, 3-, 6-, and 10-minute intervals was determined by procedure (PAB or AV) and overall (PAB + AV). Baseline and day 29 immunologic sera were analyzed. The incidences of postoperative adverse events were compared between treatment groups. Categorical adverse events were evaluated in relation to thrombin product antibody formation. RESULTS Patients were randomized to either bThrombin (n = 82) or rThrombin (n = 82). Procedures included PAB (n = 88) and AV (n = 76). The bThrombin and rThrombin groups were well matched for demographics and baseline characteristics. A comparable incidence of anastomotic hemostasis was observed in both treatment groups at 10 minutes (94% bThrombin, 91% rThrombin). The incidence of hemostasis was lower at all time points for PAB procedures compared with AV procedures. In the PAB group, a significantly greater proportion of patients receiving rThrombin (55%) achieved hemostasis at 3 minutes compared with bThrombin (39%; P < . 05). Adverse event profiles and laboratory findings were similar between groups. No patients in the rThrombin group developed anti-rThrombin product antibodies at day 29, whereas 27% of patients in the bThrombin group developed antibodies to bThrombin product (P < . 0001). CONCLUSIONS rThrombin or bThrombin used as a hemostatic ancillary for anastomotic bleeding was equally effective at 10 minutes; however, rThrombin compared with bThrombin may provide a more rapid onset of hemostasis at 3 minutes in PAB procedures. Adverse events were similar between the two thrombins. In patients undergoing vascular surgery, both treatments were similarly well tolerated, although rThrombin demonstrated a superior immunogenicity profile.
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8.
Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebo-controlled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy
Ekert H, Brizard C, Eyers R, Cochrane A, Henning R
Blood Coagulation & Fibrinolysis. 2006;17((5):):389-95.
Abstract
We investigated the effectiveness of prophylactic administration of recombinant activated factor VII (rFVIIa) for cardiopulmonary bypass surgery in children under 1 year old with congenital heart disease (CHD) in a double-blinded, placebo-controlled study. The rFVIIa dose was 40 microg/kg and all patients also received standard haemostatic replacement therapy. The primary endpoint was the time to chest closure from neutralization of heparin with protamine sulphate as this could be most objectively and accurately measured during surgery. Secondary endpoints were volumes of transfused blood, platelet concentrates and fresh-frozen plasma. All adverse events were recorded. In the intention-to-treat analysis there were 76 patients (40 in rFVIIa group and 36 in placebo group). The demographics and severity of CHD were similar in both groups. No benefit of rFVIIa prophylaxis was found in the time to chest closure, which was significantly prolonged in the rFVIIa group (rFVIIa mean +/- SE, 98. 8 +/- 27. 27 versus 55. 3 +/- 29. 15, P = 0. 0263). In the 41 patients available for a follow-up visit 6 weeks after discharge, the chest closure time was also prolonged in the rFVIIa group (P = 0. 0515). There were no significant differences in the secondary endpoints. Adverse events were similar in both groups.
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9.
Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study
Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS
British Journal of Anaesthesia. 2005;95((5):):596-602.
Abstract
BACKGROUND Receiving an allogeneic transfusion may be an independent predictor of mortality for patients undergoing cardiac surgery. Furthermore, these patients utilize 15% of all donated blood in the UK. In our unit, 80% of patients undergoing complex non-coronary cardiac surgery requiring cardiopulmonary bypass (CPB) receive an allogeneic transfusion. Activated recombinant FVII (rFVIIa) may be effective in reducing this need for transfusion. METHODS Twenty patients undergoing complex cardiac surgery were randomized to receive rFVIIa or placebo after CPB and reversal of heparin. RESULTS Two patients in the rFVIIa group received 13 units of allogeneic red cells and coagulation products compared with eight patients receiving 105 units of allogeneic red cells and coagulation products in the placebo group (relative risk of any transfusion 0. 26; confidence interval 0. 07-0. 9; P=0. 037). The groups did not differ for adverse events. CONCLUSION Despite major limitations (underpowered study and prone to type I error), we have shown that rFVIIa significantly reduces the need for allogeneic transfusion in complex non-coronary cardiac surgery without causing adverse events.
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10.
Recombinant activated factor VII in cardiac surgery
Herbertson M
Blood Coagulation & Fibrinolysis. 2004;15((Suppl 1):):S31-2.
Abstract
Adult cardiac surgery has an incidence of 1-1. 25 million procedures per year. Overall costs are in the range of 50 billion US dollars per year and are increasing. Included in these costs is an increasing burden from the use of blood and blood products. The central haemostatic problems associated with cardiac surgery are impaired platelet function associated with pre-operative medication and cardiopulmonary bypass, consumption of platelets, dilution of coagulation proteins and triggering of fibrinolysis. Anecdotal data suggest that recombinant activated factor VII (rFVIIa) has a possible role in cardiac surgery, but randomized, controlled trials are required to confirm this potential. We have undertaken a prospective, randomized, placebo-controlled trial in adult cardiac surgery with a high risk of serious haemorrhage. Drug (rFVIIa) or placebo is given after cardiopulmonary bypass and following the administration of protamine. The primary endpoints of the study are use of blood and blood products. Secondary endpoints are blood loss, length of stay in the intensive care unit and in the hospital, and survival. This study will give us further information on the potential efficacy and safety of rFVIIa in cardiac surgery.