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  • 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.
  • 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.
  • 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

    <p>Dr Antony Palmer, University of Oxford. </p> <p>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.</p>

    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.
  • Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
    British Journal of Anaesthesia. 2015;114(4):623-33

    Abstract

    BACKGROUND In early postpartum haemorrhage (PPH), a low concentration of fibrinogen is associated with excessive subsequent bleeding and blood transfusion. We hypothesized that pre-emptive treatment with fibrinogen concentrate reduces the need for red blood cell (RBC) transfusion in patients with PPH. METHODS In this investigator-initiated, multicentre, double-blinded, parallel randomized controlled trial, we assigned subjects with severe PPH to a single dose of fibrinogen concentrate or placebo (saline). A dose of 2 g or equivalent was given to all subjects independent of body weight and the fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes were total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g litre(-1), RBC transfusion within 4 h, 24 h, and 7 days, and as a composite outcome of 'severe PPH', defined as a decrease in haemoglobin of >40 g litre(-1), transfusion of at least 4 units of RBCs, haemostatic intervention (angiographic embolization, surgical arterial ligation, or hysterectomy), or maternal death. RESULTS Of the 249 randomized subjects, 123 of 124 in the fibrinogen group and 121 of 125 in the placebo group were included in the intention-to-treat analysis. At inclusion the subjects had severe PPH, with a mean blood loss of 1459 (sd 476) ml and a mean fibrinogen concentration of 4.5 (sd 1.2) g litre(-1). The intervention group received a mean dose of 26 mg kg(-1) fibrinogen concentrate, thereby significantly increasing fibrinogen concentration compared with placebo by 0.40 g litre(-1) (95% confidence interval, 0.15-0.65; P=0.002). Postpartum blood transfusion occurred in 25 (20%) of the fibrinogen group and 26 (22%) of the placebo group (relative risk, 0.95; 95% confidence interval, 0.58-1.54; P=0.88). We found no difference in any predefined secondary outcomes, per-protocol analyses, or adjusted analyses. No thromboembolic events were detected. CONCLUSIONS We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov: http://clinicaltrials.gov/show/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.Copyri ght The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

    Clinical Commentary

    Dr Akshay Shah, Adult Intensive Care Unit, John Radcliffe Hospital, Oxford

    What is known?

    Post-partum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide. Fibrinogen is an essential component of haemostasis and fibrinogen levels of <2 g.L-1, in patients with PPH, have been shown to predict further severe bleeding and requirement for blood and blood products. Current guidelines recommend using fibrinogen concentrate to correct acquired hypofibrinogenaemia although high quality evidence for this is lacking. A recent Cochrane review demonstrated weak evidence for fibrinogen concentrate in reducing transfusion requirements in bleeding patients undergoing elective cardiac surgery.

    What did this paper set out to examine?

    This was a multicentre randomised placebo-controlled study aimed to assess the efficacy of pre-emptive treatment with fibrinogen concentrate early in PPH without any laboratory evidence of hypofibrinogenaemia. This is different to previous studies that have examined the use of fibrinogen concentrate once coagulopathy and a fibrinogen deficit have been established. Patients aged >18 years with a PPH, defined as bleeding from the uterus and/or birth canal with 24 hours of delivery were randomised to receive a fixed dose of 2g of fibrinogen concentrate or placebo (isotonic saline). The primary outcome was red blood cell (RBC) transfusion during a 6-week follow-up period postpartum.

    What did they show?

    Data from 244 patients were available for final analysis; 123 in the fibrinogen group and 121 in the placebo group. There was no difference in the primary outcome RBC transfusion was given to 25 patient (20.3%) in the fibrinogen group and 26 patients (21.5%) in the placebo group. There was also no difference in clinically important secondary outcomes such as estimated blood loss, adverse effects and progression to severe PPH between both groups. An important limitation of this study is that patients who may stand to benefit the most from fibrinogen therapy were either under-represented or not included only 2.2% of patients had a critical fibrinogen level of <2 g.L-1 and 46 patients 15% of the bleeding population in this study, could not be randomised because they were bleeding too heavily and therefore informed consent could not be obtained. Furthermore, the difference in fibrinogen concentrate between the treated and placebo group was only 0.4 g.L-1 which suggests that a larger dose may be required.

    What are the implications for practice and for future work?

    This study highlights the lack of benefit of fibrinogen concentrate in patients with early PPH and a normal fibrinogen level, which may help, limits it use. Future research should be directed towards developing fast and accurate tests for measuring fibrinogen levels and developing 'goal-directed’ therapy towards patients who may benefit the most such as those with severe PPH and/or acquired hypofibrinogenaemia.
  • Transfusion-related adverse events in the Platelet Dose study
    Transfusion. 2015;55(1):144-53

    Abstract

    BACKGROUND How platelet (PLT) product characteristics such as dose, source (whole blood derived [WBD] vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs after PLT transfusion. STUDY DESIGN AND METHODS In the multicenter Platelet Dose ("PLADO") study, pediatric and adult hematology-oncology patients with hypoproliferative thrombocytopenia were randomized to receive low-dose (LD), medium-dose (MD), or high-dose (HD) PLT prophylaxis for a pretransfusion PLT count of not more than 10x10(9) /L. All PLT units (apheresis or WBD) were leukoreduced. Post hoc analyses of PLADO data were performed using multipredictor models. RESULTS A total of 5034 PLT transfusions to 1102 patients were analyzed. A TRAE occurred with 501 PLT transfusions (10.0%). The most common TRAEs were fever (6.6% of transfusions), allergic or hypersensitivity reactions (1.9%), and sinus tachycardia (1.8%). Patients assigned HD PLTs were more likely than LD or MD patients to experience any TRAE (odds ratio for HD vs. MD, 1.50; 95% confidence interval, 1.10-2.05; three-group comparison p=0.02). PLT source and ABO matching status were not significantly related to overall TRAE risk. Compared to a patient's first PLT transfusion, subsequent PLT transfusions were less likely to have a TRAE reported, primarily due to a lower risk of allergic or hypersensitivity reactions. CONCLUSION The most important PLT unit characteristic associated with TRAEs was PLT dose per transfusion. HD PLTs may increase the risk of TRAEs, and LD PLTs may reduce the risk.Copyright 2014 AABB.

    Clinical Commentary

    What is known?

    Patients with severe thrombocytopenia (very low platelet count) due to a hypoproliferative bone marrow (markedly reduced platelet production) receive prophylactic (given to prevent bleeding) platelet transfusions. This usually occurs when the platelet count drops below a certain threshold (the current standard is a platelet count of 10 x 109/l). Platelet transfusions are known to be associated with risks. Mild to moderate reactions to platelet transfusions include rigors (severe shivering accompanied by a feeling of coldness), fever, and urticaria (hives). These reactions are not life-threatening but can be extremely distressing for the patient. Rarer, but more serious side effects include: transfusion-transmitted infections (bacterial and viral infections) and transfusion-related acute lung injury (TRALI).

    What did this paper set out to examine?

    This is a secondary analysis of the PLADO Study (Slichter et al, 2010). The authors set out to show whether the characteristics of the patient receiving the platelet transfusion (patient’s age, sex, type of treatment, number of previous platelet transfusions) or of the platelet component itself (whether the platelets were ABO matched with the patient, how the platelet component had been produced, number of platelets within the transfusion, number of days the platelets had been stored for) affected the frequency of transfusion-related adverse events (TRAEs) after platelet transfusions. In this study TRAEs were any event that occurred within 4 hours of the platelet transfusion irrespective of whether medical staff at the time thought the event was related to the transfusion. TRAEs consisted of at least one of the following: allergic or hypersensitivity reaction; slow or fast heart rate; high or low blood pressure; shortness of breath; low oxygen levels; wheezing; cough; rigors or chills, fever, infection, or haemolysis (breakdown of red blood cells). The severity of TRAEs were graded. Multivariable analyses were carried out that compared any TRAE versus none, any TRAE of Grade 2 or above versus none, and any TRAE of Grade 3 or above versus none. As well as analyses of specific TRAEs that occurred in at least 50 (1%) of transfusions in the analysis.

    What did they show?

    Fever (6.6%) and allergic reactions (1.9%) were the most common TRAEs. A multipredictor logistic regression model for any TRAE versus no TRAE, which adjusted for all other variables in the model and for within-person correlation. This study found that a high number of platelets within the component increased the risk of a TRAE (odds ratio for high platelet number vs. intermediate platelet number, 1.50; 95% confidence interval, 1.10-2.05). This effect was no longer seen when only grade 2 or above TRAEs were considered, however this may be due to the small number of episodes observed. Compared to a patient’s first platelet transfusion, participants who had more than five platelet transfusions were less likely to have a TRAE reported during subsequent transfusions. This was primarily due to a lower risk of allergic or hypersensitivity reactions.

    What are the implications for practice and for future work?

    The primary publication of the PLADO study showed that a large number of platelets within a transfusion does not decrease the risk of WHO grade 2 or above bleeding, and does not reduce the number of transfusion episodes compared to an intermediate number of platelets within a component. This study now shows that platelet components that contain a large number of platelets may put patients at a higher risk of developing a TRAE. This study provides an additional reason why platelet components that contain a high number of platelets should not be used routinely.
  • Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial
    Anesthesiology. 2015;122(1):29-38

    Abstract

    BACKGROUND Several studies have indicated that a restrictive erythrocyte transfusion strategy is as safe as a liberal one in critically ill patients, but there is no clear evidence to support the superiority of any perioperative transfusion strategy in patients with cancer. METHODS In a randomized, controlled, parallel-group, double-blind (patients and outcome assessors) superiority trial in the intensive care unit of a tertiary oncology hospital, the authors evaluated whether a restrictive strategy of erythrocyte transfusion (transfusion when hemoglobin concentration <7 g/dl) was superior to a liberal one (transfusion when hemoglobin concentration <9 g/dl) for reducing mortality and severe clinical complications among patients having major cancer surgery. All adult patients with cancer having major abdominal surgery who required postoperative intensive care were included and randomly allocated to treatment with the liberal or the restrictive erythrocyte transfusion strategy. The primary outcome was a composite endpoint of mortality and morbidity. RESULTS A total of 198 patients were included as follows: 101 in the restrictive group and 97 in the liberal group. The primary composite endpoint occurred in 19.6% (95% CI, 12.9 to 28.6%) of patients in the liberal-strategy group and in 35.6% (27.0 to 45.4%) of patients in the restrictive-strategy group (P = 0.012). Compared with the restrictive strategy, the liberal transfusion strategy was associated with an absolute risk reduction for the composite outcome of 16% (3.8 to 28.2%) and a number needed to treat of 6.2 (3.5 to 26.5). CONCLUSION A liberal erythrocyte transfusion strategy with a hemoglobin trigger of 9 g/dl was associated with fewer major postoperative complications in patients having major cancer surgery compared with a restrictive strategy.

    Clinical Commentary

    What is known?

    Thresholds for red cell transfusion are currently under much scrutiny with a growing number of randomised controlled trials (RCTs) supporting the safety of restrictive transfusion practices in specified patient groups e.g. patients treated on the intensive care unit (TRICC) [1], following hip (FOCUS) [2] and cardiac surgery (TRACS) [3, 4], and patients with acute upper gastrointestinal bleeding [5] and sepsis (TRISS) [6]. Patients with cancer who are anaemic have poorer outcomes than those who are not [7] but there are no previous RCTs examining risks and benefits of transfusion in surgical patients with malignancy.

    What did this paper set out to examine?

    This paper describes 198 critically ill patients following surgery for abdominal malignancy randomised to restrictive (threshold 7 g/dl) and liberal (9 g/dl) transfusion strategies [8]. The primary outcome was a composite 30-day endpoint of all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock and reoperation.

    What did they show?

    This is the first RCT to demonstrate a worse outcome for patients assigned a restrictive threshold. There is an almost two-fold increase in the composite 30-day endpoint in the restrictive group (35.6% versus 19.6%, p=0.012). Thirty day mortality was 8.2% (liberal) versus 22.8% (restrictive), p= 0.005. The most common causes of death were septic shock and multisystem organ failure. Cardiovascular events and intra-abdominal sepsis were more frequent in the restrictive group.

    The extent of the worse outcomes in the restrictive group is unexpected following larger RCTs supporting the safety of restrictive transfusion practice. The least supportive of this strategy was the recently published cardiac surgery RCT which concluded that a restrictive threshold was not superior to a liberal threshold [4]; they showed no difference in the primary outcome (serious infection or ischaemic event at 3 months). However, there was an increased mortality in the restrictive group (4.2% versus 2.6%, p=0.045).

    There are significant differences in outcomes between the 2 groups in Almeida’s study and so we must consider whether these are attributable to differences in transfusion practice. Importantly, 57.7% of those even in the liberal group (79.2% in the restrictive group) were not transfused during the randomisation period. The reported difference in haemoglobin between the groups relates to the pre-transfusion haemoglobin and therefore does not include haemoglobins of those not transfused (68.9% of total study population).

    Although the target thresholds were 7.0 and 9.0 g/dl, patients were transfused on average at 6.8 g/dl (restrictive group) and 7.9 g/dl (liberal). Compared to the preceding large RCTs there is a lack of separation in haemoglobin levels between groups [2, 6]. All 13 protocol deviations in the liberal group occurred when patients with haemoglobin <9.0 g/dl were not transfused; all 7 deviations in the restrictive group were for transfusions given with haemoglobin >7.0 g/dl.

    The median duration for which patients remained randomised (i.e. length of ICU stay) was 4 days, compared to 11 days in the TRICC trial and until discharge or death in the Villanueva and FOCUS trials. In this study the small difference in haemoglobin between the groups only emerges at 4 days.

    These factors together call into doubt whether the differences in outcomes can be attributed to differences in transfusion alone, and so an alternative explanation for the differences in outcomes must be sought. One possible reason is the small excess in major operations (oesophagectomy, gastroduodenopancreatectomy) as compared to cystectomy and hysterectomy in the restrictive group; this may also explain the excess of abdominal sepsis. There was a small, non-significant, excess of patients with diabetes, chronic obstructive pulmonary disease and congestive heart failure in the restrictive group.

    The question addressed in the study is important and there are positive aspects to the trial which should be highlighted. This is the first randomised study specifically assessing post-operative patients with malignancy; the FOCUS study is the only other large RCT to include significant numbers of cancer patients (18.0 and 18.8% in the two arms) but the types, stage or remission status are not given. In the current study there were attempts to blind patients and investigators and the clinical practice described is deliverable on most ICUs. There were small numbers of protocol deviations and follow-up to the primary endpoint was complete.

    What are the implications for practice and for future work?

    It is important to consider the limitations of this study if its findings are to be used to inform practice. In the presence of multiple other RCT data supportive of restrictive transfusion practice we would caution against changing practice based on this research. Despite its unexpected findings, this study questions the safety of restrictive transfusion practice and it is important that future trials continue to address the safety this approach among different patient groups.

    References

    1. Hébert PC, et al., A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med, 1999. 340(6): 409-17.

    2. Carson JL, et al., Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med, 2011. 365(26): 2453-62.

    3. Hajjar LA, et al., Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA, 2010. 304(14): 1559-67.

    4. Murphy GJ, et al., Liberal or restrictive transfusion after cardiac surgery. N Engl J Med, 2015. 372(11): 997-1008.

    5. Villanueva C, et al., Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med, 2013. 368(1): 11-21.

    6. Holst, LB, et al., Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med, 2014. 371(15): p. 1381-91.

    7. Caro JJ, et al., Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer, 2001. 91(12): aase4rd3eazS2A214-21.

    8. Pinheiro de Almeida J, et al., Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial. Anesthesiology, 2015. 122(1): 29-38.

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