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Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials
Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, Monaco F, Vitiello C, Zangrillo A, Landoni G
Journal of Cardiothoracic and Vascular Anesthesia. 2016;30((5):):1196-204.
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Abstract
OBJECTIVES To investigate the efficacy and safety of fibrinogen concentrate (FC) in surgical patients. DESIGN Meta-analysis of randomized controlled studies (RCTs). SETTING Perioperative. PARTICIPANTS Adult and pediatric surgical patients. INTERVENTIONS A search of PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Transfusion Evidence Library, Google Scholar, and the proceedings from major international anesthesiology meetings up to February 1, 2016 for RCTs that compared FC with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS The primary outcome was all-cause mortality. Pooled risk ratios and mean differences (MDs) were computed with either fixed-effects or random-effects models. The study included 14 RCTs comprising 1,035 patients; the majority of patients underwent cardiac surgery. All-cause mortality was lower in the fibrinogen group (4/432 [0.9%] v 15/430 [3.5%]; risk ratio 0.26; 95% confidence interval [CI] 0.09-0.78; p = 0.02; heterogeneity statistic (l2) = 0%). The use of FC was associated with reduced bleeding (MD -127 mL; 95% CI -207 to -47; p = 0.002; I2= 54%) and a lower number of red blood cells units transfused versus comparator (MD -0.9; 95% CI -1.3 to -0.5; p<0.001; I2 = 42%). There were no differences in the rates of thrombotic events and myocardial infarction. CONCLUSIONS In surgical patients, FC was associated with reduced bleeding and a lower number of red blood cell units transfused, and it also might reduce mortality. However, none of the analyzed trials was powered for estimation of survival and adverse events with FC use. Half of the included studies were of high or moderate risk of bias. The evidence primarily came from cardiac surgery settings.
Clinical Commentary
Dr. MJR Desborough, Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK.
What is known?
Bleeding is an important and potentially preventable adverse event associated with surgery. Prevention, or treatment, of bleeding must be balanced against the risk of arterial or venous thrombotic events. Fibrin, which is formed from fibrinogen, is a key part of blood clot formation. In situations where a patient’s fibrinogen concentration is low, fibrinogen concentrate (or another source of fibrinogen such as cryoprecipitate) is often administered. However it is less clear whether fibrinogen concentrate is effective and safe for patients with a normal baseline fibrinogen level.
An alternate, or adjuvant approach, is the use of anti-fibrinolytic agents (which prevent fibrin from being broken down) such as tranexamic acid and epsilon aminocaproic acid. These drugs are increasingly used to prevent peri-operative blood loss and do not appear to be associated with significant adverse events.
A systematic review and meta-analysis published in 2013 on fibrinogen concentrate in surgical patients found no difference in mortality but found a significant reduction in the incidence of red cell transfusion (Wikkelsø et al. Cochrane Database Syst Rev 2013;8:CD008864).
What did this paper set out to examine?
The authors set out to compare efficacy and safety of fibrinogen concentrate in surgical patients in a systematic review and meta-analysis. Randomised controlled trials including adult or paediatric surgery were included. Trials were included if they compared fibrinogen concentrate to placebo or another haemostatic therapy (fresh frozen plasma, platelets, cryoprecipitate or coagulation factor concentrates). The only exclusion was congenital (inherited) fibrinogen deficiency.
The primary outcome was all-cause mortality. Secondary outcomes were blood loss; proportion of patients who received a red cell transfusion; number of red cell units used; surgical revisions for bleeding; and thrombotic complications.
What did they show?
The authors identified 14 randomised controlled trials with 1035 patients. The majority of trials were in the setting of cardiac surgery. There was a high level of variation in the comparators that were used, the trigger for infusion of fibrinogen concentrate; prophylactic or therapeutic use; the timing of administration; and the dose of fibrinogen concentrate. The authors reported that half of the included studies were at high or moderate risk of bias.
The risk of all-cause mortality was significantly lower in the group treated with fibrinogen concentrate. The event rate for mortality was very low with the majority of trials having no deaths in either arm. The meta-analysis included an unpublished paper and exclusion of this paper form the meta-analysis resulted in a non-significant difference in mortality (Mengoli et al. J Cardiothorac Vasc Anesth 2017;31:e33-5).
Blood loss; number of red cell units transfused; and proportion of patients who received a red cell transfusion were significantly lower for those treated with fibrinogen concentrate. No difference was found in the risk of surgical revisions for bleeding or thrombotic complications.
What are the implications for practice and for future work?
This meta-analysis suggests that fibrinogen concentrate may reduce peri-operative mortality, bleeding and transfusion requirements. However the considerable variation in triggers, comparators and settings suggests that further randomised controlled trial data will be necessary to demonstrate efficacy in this setting. It is unclear whether anti-fibrinolytic drugs such as tranexamic acid or epsilon aminocaproic acid were used in the trials included in this meta-analysis. Now that these agents have been widely adopted into clinical guidelines, the efficacy and risk profile of fibrinogen concentrate may differ and this should be taken into account in future randomised controlled trials.
References
Fibrinogen/*therapeutic use Humans Perioperative Care/*methods Randomized Controlled Trials as Topic *Surgical Procedures, Operative Treatment Outcome efficacy fibrinogen hemorrhage safety surgery
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Blood transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: a systematic review and meta-analysis
Kwok CS, Sherwood MW, Watson SM, Nasir SB, Sperrin M, NolanJ, Kinnaird T, Kiatchoosakun S, Ludman PF, de Belder MA, et al
JACC: Cardiovascular Interventions. 2015;8((3):):436-46.
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OBJECTIVES This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices.Copyright 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Clinical Commentary
What is known?
Allogenic red cell transfusion is associated with adverse clinical outcomes in many clinical settings.
What did this paper set out to examine?
The authors conducted a systematic review of the evidence that relates to the relationship between red cell transfusion and adverse clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The study is timely because the increasingly elderly population referred for PCI are at increased risk of anaemia and acute haemorrhage, the two key indications for red cell transfusion.
What did they show?
The authors conducted a robust and well described systematic review of relevant databases. They identified 19 observational analyses that included 2,258,711 patients met their eligibility criteria; reporting of transfusions, death and Major Adverse Cardiac Events (MACE). The included studies were of mixed quality and showed differences in their design, definitions of primary and secondary exposures, duration of follow up, and type of analyses. Pooled effect estimates demonstrated strong associations between transfusion, mortality and MACE, although these analyses also demonstrated significant heterogeneity. Sub group analyses that included only studies with longer follow-up, or that contained adjustment for confounders such as transfusion volume or anaemia showed consistent associations between transfusion and harm, with some reduction in heterogeneity.
What are the implications for practice and for future work?
Implications for future research: The authors conclude that their data cannot demonstrate a causal relationship between transfusion and adverse outcomes in these patients. However they do discuss the possible pathological effects of transfusion and conclude that their data should support more restrictive transfusion practice. Implications for future practice: This study generates the hypothesis that reduced exposure to red cells may have benefits in these high risk patients. This hypothesis should be tested in a randomised controlled clinical trial. It is premature to suggest that the evidence presented here makes a case for restrictive practice.
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Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: A randomized pilot trial
Galas FR, de Almeida JP, Fukushima JT, Vincent JL, Osawa EA, Zeferino S, Camara L, Guimaraes VA, Jatene MB, Hajjar LA
Journal of Thoracic & Cardiovascular Surgery. 2014;148((4):):1647-55.
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OBJECTIVES Acute acquired hypofibrinogenemia in children undergoing cardiac surgery is a major concern because it often results in perioperative bleeding and high rates of allogeneic blood transfusion. Fibrinogen concentrate has been proposed as an alternative to cryoprecipitate (the gold standard therapy), with minimal infectious and immunologic risks. Our objective was to investigate the efficacy and safety of fibrinogen concentrate in children undergoing cardiac surgery. METHODS In this randomized pilot study, patients were allocated to receive fibrinogen concentrate (60 mg/kg) or cryoprecipitate (10 mL/kg) if bleeding was associated with fibrinogen levels <1 g/dL after cardiopulmonary bypass weaning. The primary outcome was postoperative blood losses during the 48 hours after surgery. RESULTS A total of 63 patients were included in the study, 30 in the fibrinogen concentrate group and 33 in the cryoprecipitate group. The median 48-hour blood loss was not significantly different between the 2 groups (320 mL [interquartile range, 157-750] vs 410 mL [interquartile range, 215-510], respectively; P = .672). After treatment, plasma fibrinogen concentration increased similarly following administration of both products. There were no differences in allogeneic blood transfusion after intervention treatment. CONCLUSIONS A large trial comparing fibrinogen concentrate and cryoprecipitate in the management of children with acute acquired hypofibrinogenemia during heart surgery is feasible. The preliminary results of our study showed that the use of fibrinogen concentrate was as efficient and safe as cryoprecipitate in the management of bleeding children undergoing cardiac surgery. Copyright 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Clinical Commentary
Dr Simon Stanworth - NHS Blood & Transplant, Oxford, UK
What is known?
There are several different sources of fibrinogen for use in patients with major bleeding such as trauma or postpartum or surgery. The two main concentrated sources are fibrinogen concentrate or cryoprecipitate. Cryoprecipitate is the standard method of fibrinogen supplementation in UK. The evidence relating to the clinical effectiveness of cryoprecipitate is very limited; with very few randomised controlled trials (RCTs) completed to date. Fibrinogen concentrate (FgC) is increasingly available and a recent Cochrane review evaluating the effectiveness of FgC for patients with bleeding found limited data (six small trials, none in trauma) but reported no effect on overall mortality but did find a reduction in allogeneic transfusion.
What did this paper set out to examine?
Pilot trials are needed to inform the design of larger definitive trials which can answer fundamental questions about effectiveness of fibrinogen supplementation in patients with major bleeding. This study describes a pilot study of fibrinogen concentrate or cryoprecipitate to reduce bleeding in children undergoing cardiac surgery. Patients younger than 7 years and admitted for elective cardiac surgery and cardio-pulmonary bypass were screened and eligible for randomisation to receive fibrinogen concentrate (60mg/kg) or cryoprecipitate (10ml/kg) if they developed diffuse bleeding at wound surfaces and a fibrinogen concentration < 1g/L/.
What did they show?
A total of 63 patients were included in the pilot, 30 received fibrinogen concentrate and 33 cryoprecipitate. There were no differences in post-operative blood losses (primary outcome), and the median 48 hour blood loss was not significantly different between the two groups. Rises in plasma fibrinogen concentration were similar between the two groups, and there were no significant differences between the groups for adverse events and a range of other clinical outcomes.
What are the implications for practice and for future work?
In addition to documenting feasibility of recruitment, the pilot study supports the need for larger trials, not just to understand how different sources of fibrinogen should be used, but also to evaluate comparative differences between products. Cryoprecipitate is a pooled blood component) that has a variable, but high Fg concentration (15-20 g/L), but also contains other plasma proteins (FVIII, FXIII, von Willebrand’s factor and fibronectin) which may confer additional haemostatic benefits.