Comments Off on Dabigatran Reversal Agent – Idarucizumab
Thanks to Rob MacSweeney‘s fantastic Critical Care Reviews I learned of Idarucizumab, a monoclonal antibody fragment that binds the (pesky) anticoagulant dabigatran. Two industry-supported studies this week show rapid, complete reversal of anticoagulation in healthy volunteers(1) and patients who were either bleeding or undergoing procedures(2). The dose given to patients was 5g intravenously.
An accompanying editorial(3) highlights that the clinical study did not have a control group, and these patients had a high mortality. Further controlled studies examining patient-orientated outcomes will be helpful.
Of interest, another editorialist(4) lists other potential antidotes for Non-vitamin-K antagonist oral anticoagulants (NOACs) that have been or are being tested: an antidote against all oral direct factor Xa inhibitors called andexanet alpha (a recombinant activated factor X that binds direct factor Xa inhibitors), and a modified thrombin has been shown to be effective in vitro and in animals for reversal of dabigatran and potentially also other direct thrombin inhibitors.
1. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial
The Lancet Volume 386, No. 9994, p680–690, 15 August 2015
BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.
METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m2 into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.
FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.
INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.
2. Idarucizumab for Dabigatran Reversal
N Engl J Med. 2015 Aug 6;373(6):511-20
BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.
METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.
CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
3. Targeted Anti-Anticoagulants
N Engl J Med. 2015 Aug 6;373(6):569-71
4. Antidotes for anticoagulants: a long way to go
The Lancet Volume 386, No. 9994, p634–636, 15 August 2015
Comments Off on Alternative ‘universal’ plasma donor
The group usually considered the universal donor for fresh frozen plasma because it contains no anti-A or anti-B antibodies is Type AB. Due to its limited availability the trauma service of the Mayo Clinic in Minnesota has been issuing thawed group A plasma to its flight crews who retrieve major trauma casualties from rural centres. This is given with packed group O red cells to patients who meet their prehospital massive transfusion protocol criteria. Some patients will inevitably receive ABO-incompatible plasma (namely patients with Group B or AB blood) which could theoretically give rise to haemolytic transfusion reactions, in which donor antibodies bind host red cells, activate complement, and give rise to anaemia, disseminated intravascular coagulation, acute kidney injury, and death. However:
- the transfusion of platelets containing ABO-incompatible plasma is common, with up to 2 units of incompatible plasma per apheresis platelet unit, whereas haemolytic reactions to platelets are rare (1 in 9,000 incompatible platelet transfusions);
- all reports of haemolytic reactions are caused by products that contain Group O plasma and there has never been a documented case of haemolysis as a result of products containing Group A plasma
A retrospective review showed no increased rates of adverse events with Type A compared with AB or ABO-compatible plasma. Since only a small absolute number of patients received an ABO-incompatible plasma transfusion, it could be argued that the study is underpowered (a point acknowledged by the authors). However this is very important and useful information for resource-limited settings.
Emergency use of prethawed Group A plasma in trauma patients
J Trauma Acute Care Surg. 2013 Jan;74(1):69-74
BACKGROUND: Massive transfusion protocols lead to increased use of the rare universal plasma donor, Type AB, potentially limiting supply. Owing to safety data, with a goal of avoiding shortages, our blood bank exploited Group A rather than AB for all emergency release plasma transfusions. We hypothesized that ABO-incompatible plasma transfusions had mortality similar to ABO-compatible transfusions.
METHODS: Review of all trauma patients receiving emergency release plasma (Group A) from 2008 to 2011 was performed. ABO compatibility was determined post hoc. Deaths before blood typing were eliminated. p < 0.05 was considered statistically significant.
RESULTS: Of the 254 patients, 35 (14%) received ABO-incompatible and 219 (86%) received ABO-compatible transfusions. There was no difference in age (56 years vs. 59 years), sex (63% vs. 63% male), Injury Severity Score (ISS) (25 vs. 22), or time spent in the trauma bay (24 vs. 26.5 minutes). Median blood product units transfused were similar: emergency release plasma (2 vs. 2), total plasma at 24 hours (6 vs. 4), total red blood cells at 24 hours (5 vs. 4), plasma-red blood cells at 24 hours (1.3:1 vs. 1.1:1), and plasma deficits at 24 hours (2 vs. 1). Overall complications were similar (43% vs. 35%) as were rates of possible transfusion-related acute lung injury (2.9% vs. 1.8%), acute lung injury (3.7% vs. 2.5%), adult respiratory distress syndrome (2.9% vs. 1.8%), deep venous thrombosis (2.9% vs. 4.1%), pulmonary embolism (5.8% vs. 7.3%), and death (20% vs. 22%). Ventilator (6 vs. 3), intensive care unit (4 vs. 3), and hospital days (9 vs. 7) were similar. There were no hemolytic reactions. Mortality was significantly greater for the patients who received incompatible plasma if concurrent with a massive transfusion (8% vs. 40%, p = 0.044). Group AB plasma use was decreased by 96.6%.
CONCLUSION: Use of Group A for emergency release plasma resulted in ABO-incompatible transfusions; however, this had little effect on clinical outcomes. Blood banks reticent to adopt massive transfusion protocols owing to supply concerns may safely use plasma Group A, expanding the pool of emergency release plasma donors.
LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III.
The highlight for me was Mr Jonny Morrison speaking on Resuscitative Emergency Balloon Occlusion of the Aorta (REBOA). He is a British military surgeon currently out in Texas studying balloon occlusion of the aorta on pigs. Looking at trauma deaths, the next unexpected survivors will come from the uncontrollable haemorrhage group (truncal and junctional zones). This is by no means a new technique – described in the 1950’s during the Korean War – but like the early Star Wars chapters, needed to wait for technology to advance to make it feasible. It has the effect of cross clamping the aorta which provides afterload support, increases cerebral and coronary perfusion and provides proximal inflow control – without the mess of a resuscitative thoracotomy and greater access.
The placement of the balloon is determined by the location of the injury (see photo) and falls into two zones. Zone 1 is the thoracic aorta and is used for truncal haemorrhage control, avoid Zone 2 where the celiac axis etc originates and Zone 3 is infrarenal, used for junctional bleeding and pelvic haemorrhage.
His studies have determined that for Zone 3 amenable bleeds balloon occlusion up to 60min is the optimal time. Any longer and the debt of the metabolic load is paid by increased inotropic support requirements. He also compared REBOA to the current standard treatment for junctional injuries, Celox™ gauze. If coagulation is normal then both treatments perform similarly, the benefit is seen in coagulopathic patients where REBOA outperforms the gauze.
Has REBOA been used on humans? Yes a case series of 13 – the technique improved the BP allowing time to get to definitive surgery (blogged here 2.5 years ago!).
The Zone 1 studies are looking at continuous vs intermittent balloon occlusion. The jury is still out as to which is better. With the intermittent occlusion (20min on, 1min off) there are inevitably some losses when the balloon is deflated, conversely the metabolic debt generated by continuous occlusion is too great in some also leading to deaths.
What was very clear is that for this technique to have an impact it must be delivered proactively and pre-hospital. The challenges that need to be overcome are access to the femoral artery and blind accurate placement.
Prof Karim Brohi brought the conference to a close with a summary of what we have learned about coagulation in trauma this year. Here are three things;
- FFP is good but as 43% deaths due to trauma in the UK are secondary to bleeding and occur in the first 3hr we are failing our patients by administering the treatment on average at 2.5hrs.
- Fibrinogen levels are low in coagulopathic trauma patients; we should give cryoprecipitate early and aim for Fib ≥2.0
- And finally whilst TEG is recommended to guide treatment and can provide results within 5 min, there are some aspects of coagulation it does not detect i.e. fibrinolysis was only detected in 8% of coagulopathic trauma patients – when measured in the plasma it was then detectable in 80%.
These are the highlights of the 2012 London Trauma Conference. I hope this whistle stop tour through these days has been informative and though provoking. I can assure you telephone hacking was not used to bring you this information and to my knowledge is correct.
This is Lou Chan, roving reporter for Resus ME! signing off.
‘London raises her head, shakes off the debris of the night from her hair, and takes stock of the damage done. The sign of a great fighter in the ring is can he get up from a fall after being knocked down… London does this every morning.’
Comments Off on Red cell transfusion guidelines
The AABB (formerly the American Association of Blood Banks has issued guidelines on red blood cell transfusion1, providing some number-based targets which may be helpful for some practitioners or organisations. Editorialist and heavyweight intensivist Jean-Louis Vincent argues for a more individual patient-based assessment2, and highlights some of the weaknesses of existing studies, in particular the often quoted but now fairly old TRICC study3 which suffered from poor recruitment and the possible lack of applicability to modern practice now that leucodepleted products are used.
Prof Vincent states:
“Transfusion decisions need to consider individual patient characteristics, including age and the presence of CAD, to estimate a specific patient’s likelihood of benefit from transfusion. The decision to transfuse is too complex and important to be guided by a single number.“
Description: Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children.
Methods: These guidelines are based on a systematic review of the literature on randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay.
Recommendation 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence).
Recommendation 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence).
Recommendation 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence).
Recommendation 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).
1. Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB
Ann Intern Med. 2012 Mar 26. [Epub ahead of print] Full Text
2. Indications for Blood Transfusions: Too Complex to Base on a Single Number?
Ann Intern Med. 2012 Mar 26. [Epub ahead of print] Full Text
3. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care
N Engl J Med 1999; 340:409-417 Full Text
Comments Off on Clotbusting wisdom on tap – your questions answered
The prevention and management of venous thromboembolic disease is a huge topic, which generates questions for emergency, critical care, and acute physicians during many shifts:
- How long should someone requiring cardioversion for atrial fibrillation be anticoagulated for?
- How should I provide thromboprophylaxis for this intubated patient?
- This patient with submassive pulmonary embolism isn’t hypotensive yet. Can I thrombolyse them? Can I?
- There’s a large superficial vein thrombosis in that limb – is anticoagulation indicated?
- This asymptomatic patient on warfarin has an INR of 9.0 – should I reverse them?
- Do I need to add Vitamin K if I’ve reversed warfarin with prothrombin complex concentrate?
The answers to these – and many, many more – questions are provided in one of the most comprehensive guidelines I’ve ever come across. I can see myself clicking on the link below in future when on duty in the ED.
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Chest. 2012 Feb;141(2 Suppl) Full Text
Comments Off on Xigris withdrawn
Pharmaceutical company Eli Lilly has announced the withdrawal of its severe sepsis drug activated protein C, or drotrecogin alfa (proprietary name Xigris). This is because the PROWESS-SHOCK study, now complete, showed no benefit in its primary endpoint of 28 day mortality when compared with placebo in septic shock patients. There was also no benefit in a subgroup of patients with protein C deficiency, and no significant increased risk of severe bleeding.
At this stage physicians should not initiate treatment with Xigris in new patients and should stop ongoing treatment
Xigris treatment should not be started in new patients. Xigris treatment should be stopped in patients being treated with Xigris.
All remaining Xigris product should be returned to the supplier from whom it was purchased.
The UK Intensive Care Society’s Announcement contains a link to Eli Lilly’s press release.
Comments Off on Reversing new oral anticoagulants
A small study on normal volunteers examined reversal of the new oral anticoagulants, Rivaroxaban and Dabigatran.
Rivaroxaban is a Factor Xa inhibitor and Dabigatran is a direct thrombin inhibitor.
We should note that this was a study on the reversal of effects on various coagulation tests, not on reversal of bleeding, which is what we would be interested in for our ED/critical care patients.
Nevertheless, it’s helpful to note that prothrombin complex concentrate appeared to reverse the effects of Rivaroxaban, but not of Dabigatran.
Background Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs.
Methods and Results In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests.
Conclusion Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.
Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate
Circulation. 2011 Oct 4;124(14):1573-9
So what do we do about bleeding patients who are taking Dabigatran? If you haven’t seen it already, take a look at this video from HQMEDED.com made by my heroes at Hennepin County Medical Centre:
They have an algorithm for the patient who is bleeding on dabigatran therapy that you can download a PDF of here
Comments Off on Score to predict traumatic coagulopathy
Acute traumatic coagulopathy (ATC) is present in up to 25% of major trauma patients by the time they arrive in hospital. A predictive tool called the coagulopathy of severe trauma (COAST) score was retrospectively derived and then prospectively validated in major trauma patients in the state of Victoria, Australia. The definition of ATC was INR > 1.5 (1.0–1.3) or aPTT of > 60 s (25–38 s) on hospital presentation.
The study claims that a subgroup of patients with acute traumatic coagulopathy can be accurately identified based on simple observations in the pre-hospital phase or immediately on presentation to the ED, and that this could improve the feasibility of prospective interventional studies. Perhaps this will lead on to evaluation of pre-hospital tranexamic acid or even blood products?
At the cutoff score of ≥3, 40 coagulopathic patients would have been missed with 60 patients correctly predicted. The authors argue that while the low sensitivity of the score missed these coagulopathic patients, they had significantly better outcomes (and contained a significantly higher proportion of patients with isolated severe head injury).
Introduction: The inability to accurately predict acute traumatic coagulopathy (ATC) has been a key factor in the low level of evidence guiding its management. The aim of this study was to develop a tool to accurately identify patients with ATC using pre-hospital variables without the use of pathology or radiological testing.
Methods: Retrospective data from the trauma registry on major trauma patients were used to identify vari- ables independently associated with coagulopathy. These variables were clinically evaluated to develop a scoring system to predict ATC, which was prospectively validated in the same setting.
Results: There were 1680 major trauma patients in the derivation dataset, with 151 patients being coagulopathic. Pre-hospital variables independently associated with ATC were entrapment (OR 1.85; 95% CI: 1.12–3.06), temperature (OR 0.60; 95% CI: 0.60–0.72), systolic blood pressure (OR 0.99; 95% CI: 0.98–0.99), abdominal or pelvic content injury (OR 2.0; 95% CI: 1.27–3.12) and pre-hospital chest decompression (OR 4.99; 2.77–8.99). The COAST score was developed, scoring points for entrapment, temperature <35 ◦ C, systolic blood pressure <100 mm Hg, abdominal or pelvic content injury and chest decompression. Prospectively validated using 1225 major trauma patients, a COAST score of ≥3 had a specificity of 96.4% with a sensitivity of 60.0%, with an area under the receiver operating characteristic curve of 0.83 (0.78–0.88).
Conclusions: The COAST score accurately identified a group of patients with ATC using pre-hospital obser- vations. This predictive tool can be used to select patients for inclusion into prospective studies examining management options for ATC. Mortality in these patients is high, potentially improving feasibility of outcome studies.
Comments Off on CRASH-2 and head injury
The overall effect of the antifibrinolytic drug tranexamic acid on outcome from major trauma was assessed in the CRASH-2 trial, reported here and here. Its effect on a nested cohort of 270 patients from the trial who had traumatic brain injury has now been published1.
Previous evaluation in nontraumatic subarachnoid haemorrhage patients showed tranexamic acid to be associated with cerebral ischaemia, whereas in CRASH-2 (in which a lower dose of tranexamic acid was used) there was a trend to fewer ischaemic lesions as well as smaller haematoma growth and decreased mortality. None of these outcomes were statistically significant so further research is warranted.
An accompanying editorial2 states:
…the CRASH-2 study also justifies a re-evaluation of the possible benefit of low dose short term TXA in patients with other types of intracranial haemorrhage. Many patients with aneurysmal subarachnoid haemorrhage still have to wait for one or two days before the aneurysm is occluded. In addition, at least 30% of patients with spontaneous intracerebral haemorrhage experience substantial haematoma growth in the first 24 hours after the onset of the haemorrhage. As well as the CRASH-2 trial we therefore need new trials investigating short course low dose TXA in patients with aneurysmal subarachnoid haemorrhage and intracerebral haemorrhage.
It looks like considerable enthusiasm for this drug will be around for a while. I look forward to more outcome data, particularly in regard to this challenging group of patients with traumatic and non-traumatic intracranial bleeding.
OBJECTIVE: To assess the effect of tranexamic acid (which reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients) on intracranial haemorrhage in patients with traumatic brain injury.
METHODS: A nested, randomised, placebo controlled trial. All investigators were masked to treatment allocation. All analyses were by intention to treat. Patients 270 adult trauma patients with, or at risk of, significant extracranial bleeding within 8 hours of injury, who also had traumatic brain injury.
INTERVENTIONS: Patients randomly allocated to tranexamic acid (loading dose 1 g over 10 minutes, then infusion of 1 g over 8 hours) or matching placebo.
MAIN OUTCOME MEASURES: Intracranial haemorrhage growth (measured by computed tomography) between hospital admission and then 24-48 hours later, with adjustment for Glasgow coma score, age, time from injury to the scans, and initial haemorrhage volume.
RESULTS: Of the 133 patients allocated to tranexamic acid and 137 allocated to placebo, 123 (92%) and 126 (92%) respectively provided information on the primary outcome. All patients provided information on clinical outcomes. The mean total haemorrhage growth was 5.9 ml (SD 26.8) and 8.1 mL (SD 29.2) in the tranexamic acid and placebo groups respectively (adjusted difference -3.8 mL (95% confidence interval -11.5 to 3.9)). New focal cerebral ischaemic lesions occurred in 6 (5%) patients in the tranexamic acid group versus 12 (9%) in the placebo group (adjusted odds ratio 0.51 (95% confidence interval 0.18 to 1.44)). There were 14 (11%) deaths in the tranexamic acid group and 24 (18%) in the placebo group (adjusted odds ratio 0.47 (0.21 to 1.04)).
CONCLUSIONS: This trial shows that neither moderate benefits nor moderate harmful effects of tranexamic acid in patients with traumatic brain injury can be excluded. However, the analysis provides grounds for further clinical trials evaluating the effect of tranexamic acid in this population
1. Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study)
BMJ. 2011 Jul 1;343:d379 (free text available)
2. Tranexamic acid for traumatic brain injury
BMJ. 2011 Jul 1;343:d3958
Comments Off on Better than FFP in trauma?
Replacement of clotting factors in bleeding trauma patients seems to be of benefit, but are coagulation factor concentrates safer than fresh frozen plasma? This retrospective study suggests they might be; prospective studies are recommended.
INTRODUCTION: Clinical observations together with recent research highlighted the role of coagulopathy in acute trauma care and early aggressive treatment has been shown to reduce mortality.
METHODS: Datasets from severely injured and bleeding patients with established coagulopathy upon emergency room (ER) arrival from two retrospective trauma databases, (i) TR-DGU (Germany) and (ii) Innsbruck Trauma Databank/ITB (Austria), that had received two different strategies of coagulopathy management during initial resuscitation, (i) fresh frozen plasma (FFP) without coagulation factor concentrates, and (ii) coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrates) without FFP, were compared for morbidity, mortality and transfusion requirements using a matched-pair analysis approach.
RESULTS: There were no major differences in basic characteristics and physiological variables upon ER admission between the two cohorts that were matched. ITB patients had received substantially less packed red blood cell (pRBC) concentrates within the first 6h after admission (median 1.0 (IQR(25-75) 0-3) vs 7.5 (IQR(25-75) 4-12) units; p
CONCLUSION: Although there was no difference in overall mortality between both groups, significant differences with regard to morbidity and need for allogenic transfusion provide a signal supporting the management of acute post-traumatic coagulopathy with coagulation factor concentrates rather than with traditional FFP transfusions. Prospective and randomised clinical trials with sufficient patient numbers based upon this strategy are advocated.
The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion.
Injury. 2011 Jul;42(7):697-701