Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial: Addressing the Knowledge Gaps.
ABSTRACT: Abstract Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes. Interest in the use of tranexamic acid (TXA) in hemorrhaging patients as an antifibrinolytic agent has grown recently. Additionally, several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions. A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage; however, questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality. We describe here the rationale, design, and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport (STAAMP) trial. The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage. This study is a multicenter, placebo-controlled, double-blind, randomized clinical trial. The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs. It includes a 2-phase intervention, with a prehospital and in-hospital phase to investigate multiple dosing regimens. The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process. It was designed to address several existing knowledge gaps and research priorities regarding TXA use in trauma.
Project description:Many trauma systems are examining whether to implement prehospital tranexamic acid (TXA) protocols since hemorrhage remains the leading cause of potentially preventable early trauma mortality, and early in-hospital administration of TXA within 3?hours of injury is associated with reduced mortality. But robust evidence regarding the efficacy of prehospital administration of the antifibrinolytic drug TXA on trauma outcomes is lacking. This review examines the current evidence available regarding prehospital TXA efficacy in both military and civilian trauma, and updates available evidence regarding in-hospital TXA efficacy in trauma.
Project description:The use of tranexamic acid (TXA) in the treatment of trauma patients was relatively unexplored until the landmark Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial in 2010 demonstrated a reduction in mortality with the use of TXA. Although this trial was a randomized, double-blinded, placebo-controlled study incorporating >20,000 patients, numerous limitations and weaknesses have been described. As a result, additional studies have followed, delineating the potential risks and benefits of TXA administration. A systematic review of the literature to date reveals a mortality benefit of early (ideally <1 hour and no later than 3 hours after injury) TXA administration in the treatment of severely injured trauma patients (systolic blood pressure <90 mm Hg, heart rate >110). Combined with abundant literature showing a reduction in bleeding in elective surgery, the most significant benefit may be administration of TXA before the patient goes into shock. Those trials that failed to show a mortality benefit of TXA in the treatment of hemorrhagic shock acknowledged that most patients received blood products before TXA administration, thus confounding the results. Although the use of prehospital TXA in the severely injured trauma patient will become more clear with the trauma studies currently underway, the current literature supports the use of prehospital TXA in this high-risk population. We recommend considering a 1 g TXA bolus en route to definitive care in high-risk patients and withholding subsequent doses until hyperfibrinolysis is confirmed by thromboelastography.
Project description:BACKGROUND:Trauma is the leading cause of morbidity and mortality in children in the United States. The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however, the drug has not been evaluated in a clinical trial in severely injured children. We designed the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting a confirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries. METHODS:Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized to one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. We will use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, and combined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers. We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life (PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), total amount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulation biomarkers, and adverse events (specifically thromboembolic events and seizures). DISCUSSION:This multicenter trial will provide important preliminary data and assess the feasibility of conducting a confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagic injuries to the torso and/or brain. TRIAL REGISTRATION:ClinicalTrials.gov registration number: NCT02840097 . Registered on 14 July 2016.
Project description:Hemorrhage and trauma induced coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. Interest in the use of prehospital plasma in hemorrhaging patients as a primary resuscitation agent has grown recently. Trauma center-based damage control resuscitation using early and aggressive plasma transfusion has consistently demonstrated improved outcomes in hemorrhaging patients. Additionally, plasma has been shown to have several favorable immunomodulatory effects. Preliminary evidence with prehospital plasma transfusion has demonstrated feasibility and improved short-term outcomes. Applying state-of-the-art resuscitation strategies to the civilian prehospital arena is compelling. We describe here the rationale, design, and challenges of the Prehospital Air Medical Plasma (PAMPer) trial. The primary objective is to determine the effect of prehospital plasma transfusion during air medical transport on 30-day mortality in patients at risk for traumatic hemorrhage. This study is a multicenter cluster randomized clinical trial. The trial will enroll trauma patients with profound hypotension (SBP ? 70 mmHg) or hypotension (SBP 71-90 mmHg) and tachycardia (HR ? 108 bpm) from six level I trauma center air medical transport programs. The trial will also explore the effects of prehospital plasma transfusion on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research with an investigational new drug approval from the U.S. Food and Drug Administration utilizing a multipronged community consultation process. It is one of three ongoing Department of Defense-funded trials aimed at expanding our understanding of the optimal therapeutic approaches to coagulopathy in the hemorrhaging trauma patient.
Project description:Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA's various sites and modes of action may further improve patient outcomes.
Project description:Essentials Delayed treatment with tranexamic acid results in loss of efficacy and poor outcomes. Increasing urokinase activity may account for adverse effects of late tranexamic acid treatment. Urokinase + tranexamic acid produces plasmin in plasma or blood and disrupts clotting. ?2 -Antiplasmin consumption with ongoing fibrinolysis increases plasmin-induced coagulopathy. SUMMARY: Background Tranexamic acid (TXA) is an effective antifibrinolytic agent with a proven safety record. However, large clinical trials show TXA becomes ineffective or harmful if treatment is delayed beyond 3 h. The mechanism is unknown but urokinase plasminogen activator (uPA) has been implicated. Methods Inhibitory mechanisms of TXA were explored in a variety of clot lysis systems using plasma and whole blood. Lysis by tissue plasminogen activator (tPA), uPA and plasmin were investigated. Coagulopathy was investigated using ROTEM and activated partial thromboplastin time (APTT). Results IC50 values for antifibrinolytic activity of TXA varied from < 10 to > 1000 ?mol L-1 depending on the system, but good fibrin protection was observed in the presence of tPA, uPA and plasmin. However, in plasma or blood, active plasmin was generated by TXA + uPA (but not tPA) and coagulopathy developed leading to no or poor clot formation. The extent of coagulopathy was sensitive to available ?2 -antiplasmin. No clot formed with plasma containing 40% normal ?2 -antiplasmin after short incubation with TXA + uPA. Adding purified ?2 -antiplasmin progressively restored clotting. Plasmin could be inhibited by aprotinin, IC50 = 530 nmol L-1 , in plasma. Conclusions Tranexamic acid protects fibrin but stimulates uPA activity and slows inhibition of plasmin by ?2 -antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when ?2 -antiplasmin is consumed by ongoing fibrinolysis. Additional direct inhibition of plasmin by aprotinin may prevent development of coagulopathy and extend the useful time window of TXA treatment.
Project description:Hyperfibrinolysis (HF) is a major contributor to coagulopathy and mortality in trauma patients. This study investigated (i) the rate of HF during the pre-hospital management of patients with multiple injuries and (ii) the effects of pre-hospital tranexamic acid (TxA) administration on the coagulation system.From 27 trauma patients with pre-hospital an estimated injury severity score (ISS) ?16 points blood was obtained at the scene and on admission to the emergency department (ED). All patients received 1 g of TxA after the first blood sample was taken. Rotational thrombelastometry (ROTEM) was performed for both blood samples, and the results were compared. HF was defined as a maximum lysis (ML) >15 % in EXTEM.The median (min-max) ISS was 17 points (4-50 points). Four patients (15 %) had HF diagnosed via ROTEM at the scene, and 2 patients (7.5 %) had HF diagnosed via ROTEM on admission to the ED. The median ML before TxA administration was 11 % (3-99 %) vs. 10 % after TxA administration (4-18 %; p?>?0.05). TxA was administered 37 min (10-85 min) before ED arrival. The ROTEM results before and after TxA administration did not significantly differ. No adverse drug reactions were observed after TxA administration.HF can be present in severely injured patients during pre-hospital care. Antifibrinolytic therapy administered at the scene is a significant time saver. Even in milder trauma fibrinogen can be decreased to critically low levels. Early administration of TxA cannot reverse or entirely stop this decrease.The pre-hospital use of TxA should be considered for severely injured patients to prevent the worsening of trauma-induced coagulopathy and unnecessarily high fibrinogen consumption.ClinicalTrials.gov ID NCT01938768 (Registered 5 September 2013).
Project description:Damage-associated molecular patterns, including mitochondrial DNA (mtDNA) are released during hemorrhage resulting in the development of endotheliopathy. Tranexamic acid (TXA), an antifibrinolytic drug used in hemorrhaging patients, enhances their survival despite the lack of a comprehensive understanding of its cellular mechanisms of action. The present study is aimed to elucidate these mechanisms, with a focus on mitochondria. We found that TXA inhibits the release of endogenous mtDNA from granulocytes and endothelial cells. Furthermore, TXA attenuates the loss of the endothelial monolayer integrity induced by exogenous mtDNA. Using the Seahorse XF technology, it was demonstrated that TXA strongly stimulates mitochondrial respiration. Studies using Mitotracker dye, cells derived from mito-QC mice, and the ActivSignal IPAD assay, indicate that TXA stimulates biogenesis of mitochondria and inhibits mitophagy. These findings open the potential for improvement of the strategies of TXA applications in trauma patients and the development of more efficient TXA derivatives.
Project description:The antifibrinolytic agent tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding, but its effectiveness in patients with traumatic brain injury (TBI) is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hemorrhage (ICH) secondary to TBI, does TXA compared to placebo improve patients' outcomes?MEDLINE, EMBASE, CINAHL, and other databases were searched for randomized controlled trial (RCT) or quasi-RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurologic function, hematoma expansion, and adverse effects. We used "Grading quality of evidence and strength of recommendations" to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate.Of 1030 references identified through the search, 2 high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk of 0.64 (95% confidence interval [CI], 0.41-1.02); on unfavorable functional status, a relative risk of 0.77 (95% CI, 0.59-1.02); and on ICH progression, a relative risk of 0.76 (95% CI, 0.58-0.98). No serious adverse effects (such as thromboembolic events) associated with TXA group were reported in the included trials.Pooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Further evidence is required to support its routine use in patients with TBI.
Project description:Postpartum hemorrhage (PPH) is a major cause of maternal mortality, accounting for one quarter of all maternal deaths worldwide. Estimates of its incidence in the literature vary widely, from 3 % to 15 % of deliveries. Uterotonics after birth are the only intervention that has been shown to be effective in preventing PPH. Tranexamic acid (TXA), an antifibrinolytic agent, has been investigated as a potentially useful complement to uterotonics for prevention because it has been proved to reduce blood loss in elective surgery, bleeding in trauma patients, and menstrual blood loss. Randomized controlled trials for PPH prevention after cesarean (n = 10) and vaginal (n = 2) deliveries show that women who received TXA had significantly less postpartum blood loss without any increase in their rate of severe adverse effects. However, the quality of these trials was poor and they were not designed to test the effect of TXA on the reduction of PPH incidence. Large, adequately powered, multicenter randomized controlled trials are required before the widespread use of TXA to prevent PPH can be recommended.A multicenter, double-blind, randomized controlled trial will be performed. It will involve 4000 women in labor for a planned vaginal singleton delivery, at a term ? 35 weeks. Treatment (either TXA 1 g or placebo) will be administered intravenously just after birth. Prophylactic oxytocin will be administered to all women. The primary outcome will be the incidence of PPH, defined by blood loss ?500 mL, measured with a graduated collector bag. This study will have 80 % power to show a 30 % reduction in the incidence of PPH, from 10.0 % to 7.0 %.In addition to prophylactic uterotonic administration, a complementary component of the management of third stage of labor acting on the coagulation process may be useful in preventing PPH. TXA is a promising candidate drug, inexpensive, easy to administer, and simple to add to the routine management of deliveries in hospitals. This large, adequately powered, multicenter, randomized placebo-controlled trial seeks to determine if the risk-benefit ratio favors the routine use of TXA after delivery to prevent PPH.ClinicalTrials.gov NCT02302456 (November 17, 2014).