Abstract

IMPORTANCE Excessive 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. OBJECTIVE To determine cost-effectiveness of fibrinogen concentrate vs cryoprecipitate for managing active bleeding in adult patients who underwent cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS A 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. INTERVENTIONS Fibrinogen concentrate (4 g per dose) or cryoprecipitate (10 units per dose) randomized (1:1) up to 24 hours postcardiopulmonary bypass. MAIN OUTCOMES AND MEASURES Effectiveness 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. RESULTS Patient 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 RELEVANCE Fibrinogen 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.

Abstract

BACKGROUND AND OBJECTIVES This sub-study of the FIBRES trial sought to examine the patterns of ABO-compatible cryoprecipitate administration and to identify adverse consequences of ABO-incompatible cryoprecipitate. MATERIALS AND METHODS This was a post hoc analysis of data collected from the FIBRES randomized clinical trial comparing fibrinogen concentrate with cryoprecipitate in the treatment of bleeding related to hypofibrinogenemia after cardiac surgery. The primary outcome was the percentage of administered cryoprecipitate that was ABO-compatible. Secondary outcomes were adverse events at 28 days. A follow-up survey was distributed to the FIBRES participating sites to examine the rationale behind the identified cryoprecipitate ABO-matching practice patterns. RESULTS A total of 363 patients were included: 53 (15%) received ABO-incompatible cryoprecipitate and 310 (85%) received ABO-compatible cryoprecipitate. There was an increased incidence of post-operative anaemia in the ABO-incompatible group (15; 28.3%) in comparison to the ABO-compatible (44; 14.2%) group (p = 0.01) at 28 days, which was unrelated to haemolysis, without a significant difference in transfusion requirement. In the multivariable logistic regression models accounting for clustering by site, there was no observed statistically significant association between the administration of ABO-incompatible cryoprecipitate and any other adverse outcomes. Nine out of 11 sites did not have a policy requiring ABO-matched cryoprecipitate. CONCLUSION This sub-study demonstrated that most cryoprecipitate administered in practice is ABO-compatible, despite the absence of guidelines or blood bank policies to support this practice. A signal towards increased risk of post-operative anaemia may be explained by higher rates of urgent surgery (vs. elective) in the ABO-incompatible group. Future studies should prospectively examine the impact of ABO-compatible versus incompatible cryoprecipitate to conclusively establish if there is a meaningful clinical impact associated with the administration of ABO-incompatible cryoprecipitate.

Abstract

BACKGROUND Coagulopathy in cardiac surgery is frequently associated with acquired hypofibrinogenaemia, which can be treated with either purified fibrinogen concentrate (FC) or cryoprecipitate. Because the latter is not purified and therefore contains additional coagulation factors, it is thought to be more effective for treatment of coagulopathy that occurs after prolonged cardiopulmonary bypass (CPB). We examined the impact of CPB duration on the efficacy of the two therapies in cardiac surgery. METHODS This was a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) RCT comparing FC (4 g) to cryoprecipitate (10 U) in adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia (n=735). The primary outcome was allogeneic blood products transfused within 24 h after CPB. Subjects were stratified by CPB duration (≤120, 121-180, and >180 min). The interaction of treatment assignment with CPB duration was tested. RESULTS Subjects with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n=134; cryoprecipitate, n=146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 h was 0.90 (one-sided 97.5% confidence interval [CI]: 0.00-1.12); P=0.004. For subjects with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI: 0.00-1.22]; P=0.03], and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI: 0.00-1.12]; P=0.005). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes. CONCLUSIONS The haemostatic efficacy of FC was non-inferior to cryoprecipitate irrespective of CPB duration in cardiac surgery. CLINICAL TRIAL REGISTRATION NCT03037424.

Abstract

PURPOSE The mainstay of therapy for coagulation factor deficiency in cardiac surgical patients is frozen plasma (FP); however, prothrombin complex concentrates (PCCs) may offer logistical and safety advantages. As there is limited comparative evidence, we conducted this study to explore the association of comparable PCC or FP doses with transfusion and outcomes. METHODS This was a post hoc analysis of a multicentre randomized trial comparing fibrinogen concentrate with cryoprecipitate (FIBRES trial) in bleeding cardiac surgical patients. This analysis included 415 patients who received only PCC (n = 72; 17%) or only FP (n = 343; 83%) for factor replacement. The main outcomes of interest were red blood cell (RBC) and platelet transfusion within 24 hr of cardiopulmonary bypass. Secondary outcomes included postoperative adverse events. Associations were examined by hierarchical generalized estimating equation models adjusted for demographic and surgical characteristics. RESULTS The median [interquartile range (IQR)] PCC dose was 1,000 [1,000-2,000] units, while the median [IQR] FP dose was 4 [2-6] units. Each unit of FP was independently associated with increased adjusted odds of RBC (1.60; 95% confidence interval [CI], 1.36 to 1.87; P < 0.01) and platelet transfusion (1.40; 95% CI, 1.15 to 1.69; P < 0.01) while each 500 units of PCC was independently associated with reduced adjusted odds of RBC (0.67; 95% CI, 0.50 to 0.90; P < 0.01) and platelet transfusion (0.80; 95% CI, 0.70 to 0.92; P < 0.01). Adverse event rates were comparable. CONCLUSIONS In cardiac surgical patients with post-cardiopulmonary bypass bleeding, PCC use was associated with lower RBC and platelet transfusion than FP use was. Prospective, randomized clinical trials comparing FP with PCC in this setting are warranted.

Abstract

PURPOSE Intravascular fluids are a necessary and universal component of cardiac surgical patient care. Both crystalloids and colloids are used to maintain or restore circulating plasma volume and ensure adequate organ perfusion. In Canada, human albumin solution (5% or 25% concentration) is a colloid commonly used for this purpose. In this narrative review, we discuss albumin supply in Canada, explore the perceived advantages of albumin, and describe the clinical literature supporting and refuting albumin use over other fluids in the adult cardiac surgical population. SOURCE We conducted a targeted search of PubMed, Embase, Medline, Web of Science, ProQuest Dissertations and Theses Global, the Cochrane Central Register of Controlled trials, and the Cochrane Database of Systematic Reviews. Search terms included albumin, colloid, cardiac surgery, bleeding, hemorrhage, transfusion, and cardiopulmonary bypass. PRINCIPAL FINDINGS Albumin is produced from fractionated human plasma and imported into Canada from international suppliers at a cost of approximately $21 million CAD per annum. While it is widely used in cardiac surgical patients across the country, it is approximately 30-times more expensive than equivalent doses of balanced crystalloid solutions, with wide inter-institutional variability in use and no clear association with improved outcomes. There is a general lack of high-quality evidence for the superiority of albumin over crystalloids in this patient population, and conflicting evidence regarding safety. CONCLUSIONS In cardiac surgical patients, albumin is widely utilized despite a lack of high- quality evidence supporting its efficacy or safety. A well-designed randomized controlled trial is needed to clarify the role of albumin in cardiac surgical patients.

Abstract

PURPOSE Albumin solution is a colloid used for resuscitation in cardiac surgical patients, but it is unclear if it offers advantages over crystalloids. We examined current clinical practice across 11 cardiac surgical centres and the association of albumin with outcomes in a cohort of bleeding cardiac surgical patients. METHODS This was a post hoc analysis of data from the Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery (FIBRES) trial. Multivariable regression models adjusted for demographic and surgical characteristics were used to examine predictors of early albumin administration (within the initial 24 perioperative hours), late albumin administration (from 24 hr to seven days after cardiopulmonary bypass), and the association of albumin use with 28-day acute kidney injury, mortality, and length of hospital and intensive care unit (ICU) stay. RESULTS Of the 735 patients included, 525 (71%) received albumin, ranging from 4.8% to 97.4% of patients across institutions, with 475 (64.6%) receiving albumin early (5% or 25% solution). In the adjusted models, female sex and preoperative hospital admission were associated with early use, while heart failure, female sex, bleeding severity, older age, and prior albumin use were predictors of later administration. Early albumin use was not associated with differences in acute kidney injury (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI], 0.96 to 3.27; P = 0.07), mortality (aOR 1.66; 95% CI, 0.99 to 2.78; P = 0.05), or length of ICU stay (P = 0.11) or hospital stay (P = 0.67). CONCLUSIONS Albumin use is common but highly variable within and across sites. Albumin use was not associated with improved outcomes. High quality randomized controlled trials should clarify its role in cardiac surgical patients.

Abstract

IMPORTANCE Approximately 15% of patients undergoing cardiac surgery receive frozen plasma (FP) for bleeding. Four-factor prothrombin complex concentrates (PCCs) have logistical and safety advantages over FP and may be a suitable alternative. OBJECTIVES To determine the proportion of patients who received PCC and then required FP, explore hemostatic effects and safety, and assess the feasibility of study procedures. DESIGN, SETTING, AND PARTICIPANTS Parallel-group randomized pilot study conducted at 2 Canadian hospitals. Adult patients requiring coagulation factor replacement for bleeding during cardiac surgery (from September 23, 2019, to June 19, 2020; final 28-day follow-up visit, July 17, 2020). Data analysis was initiated on September 15, 2020. INTERVENTIONS Prothrombin complex concentrate (1500 IU for patients weighing ≤60 kg and 2000 IU for patients weighing >60 kg) or FP (3 U for patients weighing ≤60 kg and 4 U for patients weighing >60 kg), repeated once as needed within 24 hours (FP used for any subsequent doses in both groups). Patients and outcome assessors were blinded to treatment allocation. MAIN OUTCOMES AND MEASURES Hemostatic effectiveness (whether patients received any hemostatic therapies from 60 minutes to 4 and 24 hours after initiation of the intervention, amount of allogeneic blood components administered within 24 hours after start of surgery, and avoidance of red cell transfusions within 24 hours after start of surgery), protocol adherence, and adverse events. The analysis set comprised all randomized patients who had undergone cardiac surgery, received at least 1 dose of either treatment, and provided informed consent after surgery. RESULTS Of 169 screened patients, 131 were randomized, and 101 were treated (54 with PCC and 47 with FP), provided consent, and were included in the analysis (median age, 64 years; interquartile range [IQR], 54-73 years; 28 [28%] were female; 82 [81%] underwent complex operations). The PCC group received a median 24.9 IU/kg (IQR, 21.8-27.0 IU/kg) of PCC (2 patients [3.7%; 95% CI, 0.4%-12.7%] required FP). The FP group received a median 12.5 mL/kg (IQR, 10.0-15.0 mL/kg) of FP (4 patients [8.5%; 95% CI, 2.4%-20.4%] required >2 doses of FP). Hemostatic therapy was not required at the 4-hour time point for 43 patients (80%) in the PCC group and for 32 patients (68%) in the FP group (P = .25) nor at the 24-hour time point for 41 patients (76%) in the PCC group and for 31 patients (66%) patients in the FP group (P = .28). The median numbers of units for 24-hour cumulative allogeneic transfusions (red blood cells, platelets, and FP) were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 14.0 U (IQR, 8.0-20.0 U) in the FP group (ratio, 0.58; 95% CI, 0.45-0.77; P < .001). After exclusion of FP administered as part of the investigational medicinal product, the median numbers of units were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 10.0 U (IQR, 6.0-16.0 U) in the FP group (ratio, 0.80; 95% CI, 0.59-1.08; P = .15). For red blood cells alone, the median numbers were 1.5 U (IQR, 0.0-4.0 U) in the PCC group and 3.0 U (IQR, 1.0-5.0 U) in the FP group (ratio, 0.69; 95% CI, 0.47-0.99; P = .05). During the first 24 hours after start of surgery, 15 patients in the PCC group (28%) and 8 patients in the FP group (17%) received no red blood cells (P = .24). Adverse event profiles were similar. CONCLUSIONS AND RELEVANCE This randomized clinical trial found that the study protocols were feasible. Adequately powered randomized clinical trials are warranted to determine whether PCC is a suitable substitute for FP for mitigation of bleeding in cardiac surgery. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04114643.

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, -infinity 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.

Abstract

PURPOSE Thromboelastography and rotational thromboelastometry are point-of-care (POC) viscoelastic tests used to help guide blood product administration. It is unclear whether these tests improve clinical or transfusion-related outcomes. The objective of this study was to appraise data from randomized trials evaluating the benefit of POC testing in cardiac surgery patients. Primary outcomes were the proportion of patients transfused with blood products and all-cause mortality. SOURCE Medline (Ovid), EMBASE (Ovid), CENTRAL (the Cochrane Library-Wiley), Web of Science, Biosis, Scopus, and CINAHL databases, as well as clinical trial registries and conference proceedings were queried from inception to February 2018. PRINCIPAL FINDINGS We identified 1,917 records, 11 of which were included in our analysis (8,294 patients). Point-of-care testing was not associated with a difference in the proportion of patients transfused with any blood product (risk ratio [RR], 0.90; 95% confidence interval [CI], 0.79 to 1.02; I(2) = 51%; four trials, 7,623 patients), or all-cause mortality (RR, 0.73; 95% CI, 0.47 to 1.13; I(2) = 5%; six trials, 7,931 patients). Nevertheless, POC testing was weakly associated with a decrease in the proportion of patients receiving red blood cells (RBC) (RR, 0.91; 95% CI, 0.85 to 0.96; I(2) = 0%; seven trials, 8,029 patients), and heterogeneous reductions in frozen plasma (FP) (RR, 0.58; 95% CI, 0.34 to 0.99; I(2) = 87%; six trials, 7,989 patients) and platelets (RR, 0.66; 95% CI, 0.49 to 0.90; I(2) = 65%; seven trials, 8,029 patients). Meta-analysis of the number of units of RBCs and FP was not possible due to heterogeneity in reporting, however POC testing significantly reduced the units of platelets transfused (standard mean difference, -0.09; 95% CI, -0.18 to 0.00; four trials, 7,643 patients). CONCLUSION Our review indicates that in cardiac surgery patients, POC viscoelastic hemostatic testing is not associated with a reduction in the proportion of patients receiving any blood product or all-cause mortality. However, viscoelastic testing is weakly associated with a reduction in proportion of patients transfused with specific blood products. Presently, the benefits associated with viscoelastic testing in cardiac surgery patients are insufficiently robust to recommend routine implementation of this technology. TRIAL REGISTRATION PROSPERO (CRD4201706577). Registered 11 May 2017.

Abstract

BACKGROUND -Cardiac surgery is frequently complicated by coagulopathic bleeding that is difficult to optimally manage using standard hemostatic testing. We hypothesized that point-of-care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery and thereby reduce blood transfusions. METHODS -We conducted a pragmatic multi-centered stepped-wedge cluster randomized controlled trial of a POC-based transfusion algorithm in consecutive patients undergoing cardiac surgery with cardiopulmonary bypass at 12 hospitals from Oct 6, 2014 to May 1, 2015. Following a 1-month data collection at all participating hospitals, a transfusion algorithm incorporating point-of-care hemostatic testing was sequentially implemented at 2 hospitals at a time in 1-month intervals, with the implementation order randomly assigned. No other aspects of care were modified. The primary outcome was red cell transfusion from surgery to postoperative day seven. Other outcomes included transfusion of other blood products, major bleeding, and major complications. The analysis adjusted for secular time-trends, within-hospital clustering, and patient-level risk factors. All outcomes and analyses were pre-specified before study initiation. RESULTS -Among the 7402 patients studied, 3555 underwent surgery during the control phase and 3847 during the intervention phase. Overall, 3329 (45.0%) received red cells, 1863 (25.2%) received platelets, 1645 (22.2%) received plasma, and 394 (5.3%) received cryoprecipitate. Major bleeding occurred in 1773 (24.1%) patients and major complications occurred in 740 (10.2%) patients. The trial intervention reduced rates of red cell transfusion (adjusted relative risk [RR], 0.91; 95% CI, 0.85 to 0.98; P = 0.02; Number needed to treat [NNT] 24.7), platelet transfusion (RR, 0.77; 95% CI, 0.68 to 0.87; P < 0.001; NNT 16.7), and major bleeding (RR, 0.83; 95% CI, 0.72 to 0.94; P = 0.004; NNT 22.6), but had no effect on other blood product transfusions or major complications. CONCLUSIONS -Implementation of point-of-care hemostatic testing within the context of an integrated transfusion algorithm reduces red cell transfusions, platelet transfusions, and major bleeding following cardiac surgery. Our findings support the broader adoption of point-of-care hemostatic testing into clinical practice. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02200419.