Dataset Information

Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial.

ABSTRACT:

Importance

Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired hypofibrinogenemia (fibrinogen level <1.5-2.0 g/L), for which guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The 2 products have important differences, but comparative clinical data are lacking.

Objective

To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to hypofibrinogenemia after cardiac surgery.

Design, setting, and participants

Randomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018.

Interventions

Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass.

Main outcomes and measures

Primary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, <1.2).

Results

Of 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, -∞ to 1.09; P < .001 for noninferiority] [2-sided 95% CI, 0.84 to 1.09; P = .50 for superiority]). Thromboembolic events occurred in 26 patients (7.0%) in the fibrinogen concentrate group and 35 patients (9.6%) in the cryoprecipitate group.

Conclusions and relevance

In patients undergoing cardiac surgery who develop clinically significant bleeding and hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired hypofibrinogenemia in cardiac surgery.

Trial registration

ClinicalTrials.gov Identifier: NCT03037424.

SUBMITTER: Callum J

PROVIDER: S-EPMC6822637 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceExcessive bleeding requiring fibrinogen replacement is a serious complication of cardiac surgery. However, the relative cost-effectiveness of the 2 available therapies-fibrinogen concentrate and cryoprecipitate-is unknown.ObjectiveTo determine cost-effectiveness of fibrinogen concentrate vs cryoprecipitate for managing active bleeding in adult patients who underwent cardiac surgery.Design, setting, and participantsA within-trial economic evaluation of the Fibrinogen Replenishment in Surgery (FIBERS) randomized clinical trial (February 2017 to November 2018) that took place at 4 hospitals based in Ontario, Canada, hospitals examined all in-hospital resource utilization costs and allogeneic blood product (ABP) transfusion costs incurred within 28 days of surgery. Participants included a subset of 495 adult patients from the FIBERS trial who underwent cardiac surgery and developed active bleeding and acquired hypofibrinogenemia requiring fibrinogen replacement.InterventionsFibrinogen concentrate (4 g per dose) or cryoprecipitate (10 units per dose) randomized (1:1) up to 24 hours postcardiopulmonary bypass.Main outcomes and measuresEffectiveness outcomes included number of ABPs administered within 24 hours and 7 days of cardiopulmonary bypass. ABP transfusion (7-day) and in-hospital resource utilization (28-day) costs were evaluated and a multivariable net benefit regression model built for the full sample and predefined subgroups.ResultsPatient level costs for 495 patients were evaluated (mean [SD] age 59.2 [15.4] years and 69.3% male.) Consistent with FIBERS, ABP transfusions and adverse events were similar in both treatment groups. Median (IQR) total 7-day ABP cost was CAD $2280 (US dollars [USD] $1697) (CAD $930 [USD $692]-CAD $4970 [USD $3701]) in the fibrinogen concentrate group and CAD $2770 (USD $1690) (IQR, CAD $1140 [USD $849]-CAD $5000 [USD $3723]) in the cryoprecipitate group. Median (interquartile range) total 28-day cost was CAD $38 180 (USD $28 431) $(IQR, CAD $26 350 [USD $19 622]-CAD $65 080 [USD $48 463]) in the fibrinogen concentrate group and CAD $38 790 (USD $28 886) (IQR, CAD $26 180 [USD $19 495]-CAD $70 380 [USD $52 409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2000 (USD $1489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness.Conclusions and relevanceFibrinogen concentrate is cost-effective when compared with cryoprecipitate in most bleeding adult patients who underwent cardiac surgery with acquired hypofibrinogenemia requiring fibrinogen replacement. The generalizability of these findings outside the Canadian health system needs to be verified.

Project description:INTRODUCTION:Coagulopathic bleeding is a serious complication of cardiac surgery to which an important contributor is acquired hypofibrinogenaemia (plasma fibrinogen <1.5-2.0?g/L). The standard intervention for acquired hypofibrinogenaemia is cryoprecipitate, but purified fibrinogen concentrates are also available. There is little comparative data between the two therapies and randomised trials are needed. METHODS AND ANALYSIS:FIBrinogen REplenishment in Surgery (FIBRES) is a multicentre, randomised (1:1), active-control, single-blinded, phase III trial in adult cardiac surgical patients experiencing clinically significant bleeding related to acquired hypofibrinogenaemia. The primary objective is to demonstrate that fibrinogen concentrate (Octafibrin/Fibryga; Octapharma) is non-inferior to cryoprecipitate. All patients for whom fibrinogen supplementation is ordered by the clinical team within 24?hours of cardiopulmonary bypass will receive 4?g of fibrinogen concentrate or 10 units of cryoprecipitate (dose-equivalent to 4?g), based on random allocation and deferred consent. The primary outcome is total red cell, platelet and plasma transfusions administered within 24?hours of bypass. Secondary outcomes include major bleeding, fibrinogen levels and adverse events within 28 days. Enrolment of 1200 patients will provide >90%?power to demonstrate non-inferiority. One preplanned interim analysis will include 600 patients. The pragmatic design and treatment algorithm align with standard practice, aiding adherence and generalisability. ETHICS AND DISSEMINATION:The study is approved by the local research ethics board and will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and regulatory requirements. Patient consent prior to treatment is waived, as per criteria in the Tri-Council Policy Statement. Results will be published in the scientific/medical literature, and at international congresses. Non-inferiority of purified fibrinogen concentrate would support its use in acquired hypofibrinogenaemia. The results are likely to improve care for cardiac surgical patients experiencing significant bleeding, an understudied yet high-risk population. TRIAL REGISTRATION NUMBER:NCT03037424; Pre-results.

Project description:BackgroundCardiac surgery is the most common setting for massive transfusion in medically advanced countries. Studies of massive transfusion after injury suggest that the ratios of administered plasma and platelets (PLT) to red blood cells (RBCs) affect mortality. Data from the Red Cell Storage Duration Study (RECESS), a large randomized trial of the effect of RBC storage duration in patients undergoing complex cardiac surgery, were analyzed retrospectively to investigate the association between blood component ratios used in massively transfused patients and subsequent clinical outcomes.MethodsMassive transfusion was defined as those who had ≥6 RBC units or ≥8 total blood components. For plasma, high ratio was defined as ≥1 plasma unit:1 RBC unit. For PLT transfusion, high ratio was defined as ≥0.2 PLT doses:1 RBC unit; PLT dose was defined as 1 apheresis PLT or 5 whole blood PLT equivalents. The clinical outcomes analyzed were mortality and the change in the Multiple Organ Dysfunction Score (ΔMODS) comparing the preoperative score with the highest composite score through the earliest of death, discharge, or day 7. Outcomes were compared between patients transfused with high and low ratios. Linear and Cox regression were used to explore relationships between predictors and continuous outcomes and time to event outcomes.ResultsA total of 324 subjects met the definition of massive transfusion. In those receiving high plasma:RBC ratio, the mean (SE) 7- and 28-day ΔMODS was 1.24 (0.45) and 1.26 (0.56) points lower, (P = .007 and P = .024), respectively, than in patients receiving lower ratios. In patients receiving high PLT:RBC ratio, the mean (SE) 7- and 28-day ΔMODS were 1.55 (0.53) and 1.49 (0.65) points lower (P = .004 and P = .022), respectively. Subjects who received low-ratio plasma:RBC transfusion had excess 7-day mortality compared with those who received high ratio (7.2% vs 1.7%, respectively, P = .0318), which remained significant at 28 days (P = .035). The ratio of PLT:RBCs was not associated with differences in mortality.ConclusionsThis analysis found that in complex cardiac surgery patients who received massive transfusion, there was an association between the composition of blood products used and clinical outcomes. Specifically, there was less organ dysfunction in those who received high-ratio transfusions (plasma:RBCs and PLT:RBCs), and lower mortality in those who received high-ratio plasma:RBC transfusions.