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  • Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials
    Journal of Cardiothoracic and Vascular Anesthesia. 2016

    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.
  • The safety of intravenous iron preparations: systematic review and meta-analysis.
    Mayo Clinic Proceedings. 2015;90(-1):12-23

    Abstract

    OBJECTIVE To amass all available evidence regarding the safety of intravenous (IV) iron preparations to provide a true balance of efficacy and safety. METHODS Systematic review and meta-analysis of all randomized clinical trials comparing IV iron to another comparator. All electronic databases until January 1, 2014, were reviewed. Primary outcome was occurrence of severe adverse events (SAEs). Secondary outcomes included all-cause mortality and other adverse events (AEs). Subgroup analysis was performed on the basis of type of IV iron, comparator, treated condition, and system involved. RESULTS A total of 103 trials published between 1965 through 2013 were included. A total of 10,390 patients were treated with IV iron compared with 4044 patients treated with oral iron, 1329 with no iron, 3335 with placebo, and 155 with intramuscular iron. There was no increased risk of SAEs with IV iron (relative risk [RR], 1.04; 95% CI, 0.93-1.17; I(2)=9%). Subgroup analysis revealed a decreased rate of SAEs when IV iron was used to treat heart failure (RR, 0.45; 95% CI, 0.29-0.70; I(2)=0%). Severe infusion reactions were more common with IV iron (RR, 2.47; 95% CI, 1.43-4.28; I(2)=0%). There was no increased risk of infections with IV iron. Gastrointestinal AEs were reduced with IV iron. CONCLUSION Intravenous iron therapy is not associated with an increased risk of SAEs or infections. Infusion reactions are more pronounced with IV iron.Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved. RN E1UOL152H7 (Iron).

    Clinical Commentary

    Dr Amy E. Schmidt, University of Rochester Medical Center

    What is known?

    Iron deficiency anemia (IDA) occurs in many patients particularly those with chronic kidney disease, cancer, and chronic heart failure. Treatment typically consists of iron supplementation and erythropoiesis-stimulating agents (ESAs). Usually, oral iron is given first. However, many patients do not have a sufficient response to oral iron or are unable to tolerate it. Thus, IV iron is typically used to treat these individuals. IV iron has been found to be superior to oral iron in several areas including sustained hemoglobin response, decreased need for RBC transfusion, and patient tolerance. Several IV iron complexes are available including iron sucrose, low-and-high-molecular weight dextrans, ferric gluconate (FG), ferric citrate (FC), ferric carboxymaltose (FCM), iron isomaltoside 1000 (II), and ferumoxytol (F). The newer iron complexes (FCM, II, and F) can be given at higher doses and do not require test doses. IV iron is likely still underutilized due to historic concerns for increased rates of adverse events (AEs).

    What did this paper set out to examine?

    The authors set out to perform a systematic review and meta-analysis of all randomized controlled trials comparing IV iron to another comparator. They searched numerous databases until December 31, 2013. The primary outcome examined was severe AEs (SAEs) and the secondary outcomes examined included mortality, AEs requiring discontinuation, treatment related AEs, and any AEs. They sought to elucidate if IV iron is associated with an increased risk of SAEs, mortality, infection, or other AEs.

    What did they show?

    The authors examined 103 trials with a total of 10,390 patients treated with IV iron, 4,044 patients treated with oral iron, 1,329 with no iron, and 3,335 with placebo. Notably, they found that there was no increased risk of SAEs with IV iron. Particularly, IV iron was not associated with increased risk of cardiovascular, respiratory, neurologic, thromboembolic, or constitutional SAEs. They also found that IV iron is not associated with increased mortality or infection. They also found that IV iron had decreased gastrointestinal AEs. As expected, they found that IV iron was associated with serious infusion reactions. This association was particularly seen with FG (RR 5.32). They also found a decrease in cardiovascular AEs and discontinuation of therapy with FCM. Overall, this large meta-analysis showed that IV iron formulations are safe.

    What are the implications for practice and for future work?

    Based upon this large meta-analysis and other studies, newer IV iron formulations such as FCM are likely to become more widely used in treating IDA.
  • Topical and intravenous tranexamic acid reduce blood loss compared to routine hemostasis in total knee arthroplasty: a multicenter, randomized, controlled trial
    Archives of Orthopaedic & Trauma Surgery. 2015;135(-7):1017-25

    Abstract

    INTRODUCTION Tranexamic acid (TXA) is becoming widely used in orthopedic surgery to reduce blood loss and transfusion requirements, but consensus is lacking regarding the optimal route and dose of administration. The aim of this study was to compare the efficacy and safety of topical and intravenous routes of TXA with routine hemostasis in patients undergoing primary total knee arthroplasty (TKA). MATERIALS AND METHODS We performed a randomized, multicenter, parallel, open-label clinical trial in adult patients undergoing primary TKA. Patients were divided into three groups of 50 patients each: Group 1 received 1 g topical TXA, Group 2 received 2 g intravenous TXA, and Group 3 (control group) had routine hemostasis. The primary outcome was total blood loss. Secondary outcomes were hidden blood loss, blood collected in drains, transfusion rate, number of blood units transfused, adverse events, and mortality. RESULTS One hundred and fifty patients were included. Total blood loss was 1021.57 (481.09) mL in Group 1, 817.54 (324.82) mL in Group 2 and 1415.72 (595.11) mL in Group 3 (control group). Differences in total blood loss between the TXA groups and the control group were clinically and statistically significant (p < 0.001). In an exploratory analysis differences between the two TXA groups were not statistically significant (p = 0.073) Seventeen patients were transfused. Transfusion requirements were significantly higher in Group 3 (p = 0.005). No significant differences were found between groups regarding adverse events. CONCLUSION We found that 1 g of topical TXA and 2 g of intravenous TXA were both safe strategies and more effective than routine hemostasis to reduce blood loss and transfusion requirements after primary TKA. LEVEL OF EVIDENCE I.

    Clinical Commentary

    Dr. Antony Palmer, University of Oxford

    What is known?

    Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, the optimal dosing strategy and route of delivery for TKA remains unknown. The vast majority of studies comparing intravenous and intraarticular delivery have not demonstrated a difference in efficacy or adverse event profile, however, the dose and mode of administration vary significantly between studies.

    What did this paper set out to examine?

    This manuscript presents the results of an open-label randomised controlled study comparing blood loss in patients receiving routine haemostasis (50 patients: control group) or routine haemostasis and tranexamic acid (100 patients: treatment group) at the time of primary total knee arthroplasty. Patients receiving tranexamic acid were divided into two groups: Group 1 received 1g of tranexamic acid applied topically across the surgical field after prosthesis cementation. Group 2 received 1g of tranexamic acid intravenously 15-30 minutes prior to tourniquet inflation and again once the tourniquet was deflated.

    What did they show?

    The primary outcome measure was total blood loss, and this was significantly lower in the intravenous and topical tranexamic acid groups compared with the control group. There was no statistically significant difference between intravenous and topical administration. The authors considered a 200ml reduction in blood loss within drains to be clinically significant, and this was demonstrated in both tranexamic groups compared with the control group, but again there was no difference between routes of administration. The frequency and nature of adverse events was comparable across groups.

    What are the implications for practice and for future work?

    The results from this study suggest that 1g of tranexamic acid administered topically to the surgical field after implant cementation, or 1g of tranexamic acid delivered intravenously prior to tourniquet inflation and on tourniquet deflation, are both safe and effective means of achieving a clinically-significant reduction in total blood loss associated with primary total knee arthroplasty surgery. As with the majority of previous studies, no difference was detected between the different routes of administration and the study may have lacked power for this analysis. The optimal dose and timing of tranexamic acid administration remains unknown and the regimes adopted in this study may be suboptimal. A recent meta-analysis suggested that the efficacy of topical tranexamic acid might be greater when doses exceeding 2g are administered. The role of intraarticular administration warrants further investigation given this route may overcome systemic contraindications. There are a number of benefits from reducing the blood loss associated with total knee arthroplasty surgery. These have not yet been demonstrated in terms of functional recovery or length of hospital stay and this represents a further area for future research.
  • Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial
    Archives of Orthopaedic & Trauma Surgery. 2015;135(4):465-71

    Abstract

    INTRODUCTION A randomised, double-blind clinical trial was conducted comparing the efficacy of tranexamic acid (TXA) as a single intravenous bolus or a continuous infusion to patients undergoing total knee arthroplasty (TKA). Study hypothesis was that a second dose of TXA would not offer any clinical benefits over the single infusion. MATERIALS AND METHODS One hundred and six patients were randomised to a single intraoperative dose of 30 mg/kg tranexamic acid (OS group, n = 54), or to a loading dose of 10 mg/kg tranexamic acid followed 2 h later by a continuous 2 mg/kg/h infusion for 20 h (OD group, n = 52). The primary outcome was blood loss calculated from haematological values and perioperative transfusions. Secondary outcomes included the occurrence of major complications within the first postoperative year. RESULTS All patients completed tranexamic acid therapy without adverse events. The mean blood loss was 1,148 +/- 585 ml in group OS and 1,196 +/- 614 ml in group OD (p = 0.68). No patients received a transfusion. There were no occurrences of major complications up to 6-weeks follow-up. CONCLUSIONS The study demonstrated that a single bolus of tranexamic acid 30 mg/kg is as effective as a continuous infusion in patients undergoing tranexamic acid. The single application of tranexamic acid as part of routine care is recommended.

    Clinical Commentary

    Dr Antony Palmer, University of Oxford.

    Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.

    What is known?

    Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.

    What did this paper set out to examine?

    These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.

    What did they show?

    The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.

    What are the implications for practice and for future work?

    Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
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