The Effect of Tranexamic Acid in Ruptured Abdominal Aortic Aneurysms

Tranexamic Acid Abdominal Aortic Aneurysms 1

Regina Qu'Appelle Health Region The Effect of Tranexamic Acid in Ruptured Abdominal Aortic Aneurysms

Study Protocol Version 1.9 Protocol Number: RQHR070113

Dr. Jagadish Rao, Dr. Don McCarville, Dr. David Kopriva, Ms. Suzanne Gulka, Dr.Jennifer St.Onge, Dr. Michelle McCarron

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Tranexamic Acid Abdominal Aortic Aneurysms 2

TABLE OF CONTENTS

1. PROTOCOL A. BACKGROUND AND RATIONALE B. RESEARCH PURPOSE AND OBJECTIVES C. NULL HYPOTHESIS D. STUDY DESIGN AND DURATION E. SUBJECTS F. STUDY INCLUSION CRITERIA G. STUDY EXCLUSION CRITERIA H. STUDY PROCEDURES AND DRUG REGIMEN/DOSAGE I. INFORMED CONSENT & SUBJECT WITHDRAWAL J. SAFETY JUSTIFICATION K. RESCUE MEDICATION AND RISK MANAGEMENT L. RECORDING OF ADVERSE EVENTS M. STUDY OUTCOMES N. SAMPLE SIZE CONSIDERATIONS O. STATISTICAL ANALYSIS P. POTENTIAL SIGNIFICANCE Q. REFERENCES

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1. THE EFFECT OF TRANEXAMIC ACID IN RUPTURED ABDOMINAL AORTIC ANEURYSMS STUDY PROTOCOL

A. BACKGROUND AND RATIONALE

A1. Tranexamic Acid Excessive bleeding as a result of surgery, menstrual conditions and trauma is an important medical condition because it often requires blood transfusions, which can be costly and difficult to acquire1. However, a failure to slow or stop bleeding greatly increases the risk of mortality.

Antifibrinolytic drugs such as tranexamic acid (TXA) facilitate coagulation by stabilizing the fibrin clot and therefore, can reduce blood loss and the need for transfusion. TXA is used worldwide for a variety of conditions in which local hyperfibrinolysis is considered to be involved, such as elective cardiac, spinal, orthopedic, prostatic and gynecological surgery, pulmonary haemorrhage, epistaxis, vaginal haemorrhage, and renal haemorrhage among others.2-4

A2. Tranexamic Acid as Treatment for Bleeding in Major Surgery. Orthopedic Surgery TXA has been widely used in orthopedic surgery, primarily total hip and knee arthroplasty. In most studies, a bolus dose is given preoperatively and often a second dose is given around 3 hours post-operatively, but there is substantial variation in dosage.

Large scale, randomized, placebo-controlled trials have generally shown reductions in blood loss, frequency of patients requiring blood transfusions, and the number of units transfused when TXA is used compared to placebo.5-12 A systematic review found that the average standardized effect size for blood loss reduction was 1.02 in studies comparing TXA to placebo for hip and knee surgeries.13 Across the majority of studies, there was no increase in the risk of venous thromboembolism.

Recent meta-analyses of randomized controlled trials have confirmed the efficacy of TXA in reducing blood loss and transfusions required in total knee14,15 and hip16 arthroplasty. For example, TXA was associated with a reduction in the proportion of patients who required blood transfusion (RR 2.56, 95%CI 2.10-3.11, p<0.00001, I2=75%), as well as less post-operative and total blood losses (post-op: mean difference 591mL, 95%CI -646.82—536.06, p<0.00001,

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I2=78%; total: mean difference 245mL, 95%CI -278.19—212.68, p<0.00001, I2=89%). There was no significant difference in incidence of deep vein thrombosis between groups. Another meta-analysis also showed that TXA significantly reduced the proportion of patients requiring perioperative allogeneic red blood cell transfusions compared with placebo (odds ratio 0.17; 95% CI 0.11, 0.24).17

Cardiac Surgery The use of TXA has been effective in reducing excessive bleeding in patients undergoing different forms of non-urgent cardiac surgery, such as coronary artery bypass grafting (CABG) and valve replacement.18-27 In most of these trials, a bolus slow intravenous loading dose (1–2g or 10–30mg/kg) of TXA was administered before sternotomy followed by a constant intravenous infusion (0.4–1 g/h or 1–16 mg/kg/h) throughout the operation. There was variation in the use of bolus intravenous doses after the surgery.

In three large, randomized, placebo-controlled trials, intravenous TXA significantly reduced either post-operative blood loss or both intra- and post-operative blood loss, as well as transfusion requirements compared to placebo.20, 24, 28, 29 In smaller randomized trials, the effects of TXA have been more variable, potentially due to a lack of power. Four trials30-33 demonstrated significant reductions in both blood loss and transfusion requirements compared with placebo, while eight trials34-40 showed significant reductions in blood loss, but not in transfusion requirements.

A recent meta-analysis including 25 randomized trials of TXA use in cardiac surgery revealed that TXA significantly reduced postoperative blood loss, reoperations for bleeding and transfusion requirements of packed red blood cells or haemostatic blood products (fresh frozen plasma, platelets and cryoprecipitates) compared with control (placebo or no treatment).41 In another recent Cochrane meta-analysis of over 250 studies examining multiple types of antifibrinolytics in cardiac surgery, they identified an overall RR for transfusion with TXA of 0.61 (95% CI 0.53 to 0.70).42

Spinal In patients undergoing spinal surgery (spinal fusion, spinal fixation, discectomy, laminectomy, intersegmental decompression and tumour excision), TXA significantly reduced total perioperative blood loss in two randomized, double-blind, placebo-controlled trials,43,44 but only

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one44 found a significant reduction in the proportion of patients transfused. Patients in these trials received a bolus intravenous dose of TXA during anaesthesia followed by a maintenance infusion during surgery until skin closure43 or until 5 hours after surgery.44

In other smaller, randomized trials, TXA was also significantly more effective than placebo or control in reducing postoperative blood loss in cervical laminoplasty45, 46 and scoliosis surgery47 and reduced transfusion requirements compared to placebo in craniosynostosis surgery.48,49

A2. Tranexamic Acid in Trauma In addition to elective surgeries, antifibrinolytic agents have also begun to be assessed for their use in urgent conditions, including trauma. A large, randomized, double-blind, placebo- controlled trial in patients with subarachnoid haemorrhage demonstrated a significant reduction in the incidence of rebleeding compared with placebo when TXA was given 4–6g/day for up to 4 weeks (9% vs 24%).50 However, there was no difference in outcomes at 3 months due to a slight increased incidence of cerebral ischemia in the TXA group. Another study found similar reductions in rebleeds but without a difference between groups in cerebral ischemic manifestations.51 TXA is also effective in preventing secondary hemorrhage in traumatic hyphema.52-55

In 2010, a large (n=20,127), international, double-blind, randomized controlled trial of TXA in trauma patients with significant hemorrhage was conducted (CRASH-2).56 TXA 1g bolus was given over 10 min followed by an infusion of 1g over 8hr. TXA was associated with a lower incidence of 28-day death by any cause (14.5% vs. 16.0%, RR 0.91, 95%CI 0.85-0.97, p=0.0035) with an RR of death due to bleeding of 0.85 (95% CI 0.76, 0.96; p = 0.0077). Moreover, TXA was associated with a significant increase in the number of survivors with no dependency symptoms (14.7% vs. 13.3%, RR 1.11, 95%CI 1.04-1.19, p=0.0023). However, TXA did not significantly reduce the proportion of patients requiring blood product transfusion or the amount of blood products transfused. The safety of TXA was replicated in this study with no significant difference in incidence of any vascular occlusive event (1.7% vs. 2.0%, RR 0.84, 95%CI 0.68-1.02, p=0.084). It was estimated that potentially 2206 premature deaths in the US could be avoided with TXA (RR for death due to bleeding with TXA in Western nations determined to be 0.63, 95%CI 0.42-0.94).57,58

A further evaluation of the CRASH-2 trial data59 in patients who died due to bleeding emphasizes the importance of early administration of the drug. The estimated RRs of death due

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to bleeding compared with placebo were 0.68 (95% CI 0.57, 0.82; p < 0.0001) when TXA was administered within 1 hour of injury, 0.79 (95% CI 0.64, 0.97; p = 0.03) when administered between 1 and 3 hours, and 1.44 (95% CI 1.12, 1.84; p = 0.004) when administered more than 3 hours after injury, suggesting that the risk of mortality can increase if TXA is given after 3 hours. However, the increased mortality rate after 3 hours may have been inflated because of long transportation times to hospital in the developing countries in the trial. Therefore, it is currently unclear what the optimal time window is for TXA in urgent trauma.

A3. Ruptured Abdominal Aortic Aneurysms The aorta normally supplies blood to the abdomen, pelvis, and legs). An abdominal aortic aneurysm (AAA) refers to an aorta that becomes abnormally large or balloons outward. Aneurysms commonly occur below the renal arteries, and are called infrarenal. They can develop in anyone, but are most often present in males over age 60 who have one or more risk factors (e.g. obesity, high blood pressure, smoking, high cholesterol). As the aneurysm grows, it is more likely to rupture and cause a hemorrhage once it reaches 5.5 cm in diameter. The wall of the aneurysm can become thinner and less pliant, resulting in increased risk for rupture. Aneurysm rupture can be contained within the retroperitoneum or freely rupture into the peritoneal cavity. Hemodynamic instability occurs with the latter, necessitating an open laparotomy and repair of the aneurysm. Patient survival is compromised as a result of urgent surgery. The aneurysms that are detected before rupture are typically followed with routine imaging such as CT scans or ultrasounds to determine the diameter of the aneurysm and the rate of growth.

Unlike mortality rates for cerebrovascular and cardiovascular disease, which have declined over the past few decades, death rates for AAA’s overall have remained relatively stable.60 For those over age 55, the incidence of AAA in men is 30.7 per 100,000 and women 8.5 per 100,000. Although improvements in screening and elective treatment have been made, ruptured AAA’s still pose a significant health problem. The survival rate for patients with ruptured AAA’s is very low. Even with surgery, mortality rates of 50 to 70% are common in Canadian hospitals. Some estimates are even as high as 95%.61 Over 50% of patients die before they even reach a hospital and of those who do, only 50% to 70% may be saved by emergency surgery. 62

Treating emergent ruptured AAA’s is also very costly. The direct cost of ruptured AAA repair was found to be significantly larger ($15,854) compared to elective repair ($9673). 61 The costs were primarily attributable to ICU stay and use of blood products. Therefore, any improvement

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in treatment of ruptured AAA’s would also be cost-effective as well as benefiting patient care. Administration of TXA as early as possible following diagnosis of the ruptured aneurysm has the potential to reduce the number of patients that even require surgery to repair the aneurysm. Instead, it is hypothesized in this study that the administration of TXA would result in stabilization of the aneurysmal clot and of vital signs, allowing for a less invasive repair with endovascular stenting. There is one case report of TXA reducing severe bleeding in a patient undergoing surgery to repair an abdominal aortic aneurysm.63

Therefore, given the substantial evidence of the efficacy of TXA in reducing blood loss, the need for blood transfusions, and mortality when used in different types of surgery, this drug may provide the same benefits to patients with ruptured AAA’s and ultimately reduce morbidity and mortality rates in this population. Although there are small risks of hypotension or thrombosis with TXA, we believe the benefit of preventing death in patients with ruptured AAA’s outweighs the potential risks.

B. RESEARCH PURPOSE AND OBJECTIVES:

The primary purpose of this study is to examine the effectiveness of TXA in reducing clinically significant bleeding in a novel patient population (ruptured abdominal aortic aneurysm). The first phase of this study will involve a small pilot project, consisting of ~25 patients who will be administered TXA during their treatment for a ruptured AAA. We will compare the amount of clinically significant bleeding (see section M) from a group of patients treated prospectively with TXA to data collected retrospectively over the previous year from a matched control group of patients who were treated for a ruptured AAA but not given TXA.

The pilot project is expected to take approximately two years to complete. At the conclusion of this pilot, if the data reveal that administration of TXA in patients with ruptured AAA reduces the incidence of clinically significant bleeding, then we will proceed to a multicenter national trial to determine the generalizability of TXA use to treat ruptured AAA across multiple hospitals in Canada.

C. NULL HYPOTHESIS: The primary null hypothesis is that there will be no difference in clinically significant bleeding in patients administered TXA while being treated for a ruptured AAA compared to patients who were not administered TXA during their treatment.

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D. STUDY DESIGN AND DURATION: This study employs a 2-year prospective non-randomized intervention design. All patients that present to a Saskatchewan hospital that refers patients to Regina with a clinically- confirmed ruptured AAA during the 2-year enrollment period will be potential participants.

E. SUBJECTS: Twenty-five consecutive patients will be enrolled in the study. Potential participants will present to a hospital across southern Saskatchewan with a ruptured AAA. Based on data over the last 3 years, out of ~14 aneurysm patients per month, we expect that only 0-1 will have a ruptured AAA so it will take at least 2 years to obtain data from 25 patients.

F. STUDY INCLUSION CRITERIA Any patient with ruptured AAA, regardless of sex, age, ethnicity (including Aboriginals) who may or may not be on anticoagulant or antiplatelet medications for comorbid conditions.

G. STUDY EXCLUSION CRITERIA  Pregnancy  Hypersensitivity to TXA or any component of the formulation  Acquired defective color vision  Active intravascular clotting or disseminated intravascular coagulation  Subarachnoid hemorrhage  Patients with thromboembolic disease  Age less than 18 years  Known clotting disorder, such as factor 5 Leiden deficiency (if known)  Patients receiving thrombin or tretinoin  TXA administration in the last 24 hours

H. STUDY PROCEDURES AND DRUG REGIMEN/DOSAGE Sites Regina (Regina General Hospital) will be the primary site for this study. Rural hospitals in the surrounding area that refer patients to Regina for trauma surgery will be the secondary sites. Local Health Canada Qualified Investigators will be responsible for the managing the study at each hospital.

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Diagnosis Patients presenting to a Saskatchewan emergency room (ER) that refers patients to Regina with symptoms of a ruptured AAA might have an ultrasound or CT scan to confirm diagnosis as part of investigations. The current standard of care, however, is clinical assessment, which may be aided by prior imaging history of an unruptured AAA. Enrollment without radiologic confirmation at the time of presentation to the ER would take place upon the recommendation of the vascular surgeon in Regina. At that time, the patient’s pharmaceutical history will be examined using the Pharmaceutical Information Program (PIP) system to determine if the patient has any contradictions to TXA as listed above for patients in Saskatchewan. Since other provinces do not have the PIP program, the study will be restricted to patients with SK Health

Cards. For patients that meet the study inclusion criteria and none of the exclusion criteria, we will proceed with a three-part informed consent procedure (see Section I).

TXA Administration For the first dose (one gram IV over ten minutes), patients who have an ultrasound or CT in a hospital/care centre outside of the catchment area for Regina (rural patients) showing radiological confirmation of ruptured AAA will receive the first dose of TXA by the local attending physician (ER or family physician). These patients will be transferred to the trauma centre in Regina and the vascular surgeon will be notified that the patient is part of the study and has received TXA. For patients who are diagnosed in Regina, the vascular surgeon will be responsible for ordering TXA upon diagnosis in the emergency room.

The second dose of TXA (one gram IV will be administered over 8 hours) will be ordered by the vascular surgeon or anesthesiologist in the ER, the OR theatre or the intensive care unit in Regina. Dosing recommendations are based on data resulting from the CRASH-2 Trial.56 Since only a small proportion of TXA is metabolized, there is no need for dosage adjustment in patients with renal impairment.64

If the patient stabilizes as a result of the TXA administration, the patient will proceed to the angiogram suite (interventional radiology) where a vascular surgeon will perform endovascular stenting. If the patient becomes or remains hemodynamically unstable after arrival, the patient will proceed to the operating room for laparotomy and open repair of the aneurysm. Procedures and subsequent treatment will remain the same as the current standard of care for ruptured AAA’s.

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We will only collect data on the patient and his/her care during the patient’s stay in hospital. Given that there is little risk of adverse events occurring from administration of TXA after hospital stay, once the patient has been released from hospital, there will be no direct follow-up. The routine follow-up for these patients is within six weeks of discharge by the vascular surgeon.

I. INFORMED CONSENT & SUBJECT WITHDRAWAL Given the urgency and seriousness of a ruptured AAA (e.g. most patients are unconscious when admitted), there will be a three-part informed consent procedure based on the individual case: 1) First, if the patient is conscious and capable of giving informed consent, the vascular surgeon will provide the patient with the “Pre-Treatment Consent Form”, a shortened version that covers the most pertinent information about TXA, for review and signature. When the patient is medically stable, a verbal review of the study will be conducted between the patient and physician, in order to obtain consent for the use of the patient’s data. 2) If the patient is incapable of giving informed consent, the patient’s next-of-kin or legally authorized representative will be contacted to provide verbal or written consent on behalf of the patient using the “Pre-Treatment Consent Form”. When the patient is medically stable, he/she will be given the “Post-Treatment Consent Form” which has the remaining information about the study and asks for permission to use the patient’s health data. We will also attempt to make contact with the NOK or substitute decision maker based on the available medical file/charts or any documents that arrive with the patient . and if the patient is still unable, post surgery, to provide consent for the use of data.

3) Finally, if the patient is incapable of giving consent and there is no next-of-kin or legally authorized representative that can be contacted in a timely manner (30 minutes), informed consent will be waived and the “Dual Physician Consent Form” will be used. These attempts to contact the legally authorized representative will include phone calls to those listed on the charts or other health documents. If the patient becomes medically stable, he/she will be approached for informed consent after the procedure using the “Post-Treatment Consent Form”.

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In the circumstance where patients die, either from surgical complications or for other reasons such as health care associated pneumonia, the data will still be used in the analysis. It is important to determine if the deaths suggest a correlation between the use of the drug and mortality and excluding the data can potentially lead to selection bias. For rural patients around Regina, pre-treatment consent will be obtained by the local attending physician in the ER, whereas patients from Regina will be approached by the vascular surgeon. Post-treatment consent will be obtained by the vascular surgeon. The study coordinator and/or primary investigator will provide adequate training in obtaining consent for the local sub- investigators at rural sites. Consent forms from the rural sites around Regina will be securely mailed (using secure, traceable means) to the Primary Investigator in Regina for secure long- term storage, within one week of consent being obtained. In the interim, the rural sub- investigator will be responsible for securely storing the consent form in his/her office.

J. SAFETY JUSTIFICATION Tranexamic acid is generally well tolerated and serious or severe adverse events are rare. TXA has a relatively innocuous drug interaction profile. Although there is some risk of potential thrombosis with other medications not listed in Section G (e.g. some oral contraceptives, antifibrinolytics, factor IX complex concentrates), the risk is still low and the potential benefits of TXA for ruptured AAA far outweigh the risk of thrombosis because of the high probability of death in these patients and the time-sensitive nature of the treatment. We are avoiding use of TXA in any patient taking drugs with a significant risk of thrombosis (e.g. tretinoin), although this is expected to be rare.

There is also a low risk of a patient experiencing adverse reactions to the drug. The most frequently reported adverse events in large, randomized controlled trials discussed in Section A were mostly of mild or moderate severity and included headache (50%), mild pain (20%), nausea, vomiting, diarrhea, dyspepsia, dysmenorrhea, dizziness, back pain, numbness, phosphenes and anemia (6%). There is a small risk of hypotension with rapid IV administration; however, patients may already be experiencing this as a result of the ruptured AAA. Very few cases of deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis and central retinal artery and vein obstruction have been reported in patients receiving tranexamic acid for a variety of indications.13-16, 56 Given the high probability of death, the risks associated with TXA are certainly less compared to no drug treatment at all, which is standard.

K. RESCUE MEDICATION AND RISK MANAGEMENT

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The greatest risk associated with TXA is thrombosis but any potential reversals for thrombosis caused by TXA (e.g. alteplase) would be contraindicated in a patient with a ruptured AAA. Any patient that develops a thrombosis would be treated in the same manner as any other individual who did not receive TXA. Moreover, the risk of thrombosis is more associated with prolonged administration of the drug (e.g. oral administration), which is not applicable to the two doses given in this study. There is no risk of dose dumping or immunogenicity in this situation.

L. RECORDING OF ADVERSE EVENTS (AE)

Any AE that occurs as a result of TXA treatment will be recorded. In order to avoid vague, ambiguous or colloquial expressions, the AE shall be recorded in standard medical terminology rather than the subject’s own words. The existence of an AE may be concluded from a spontaneous report of the subject, from a physical assessment or from special tests. Each AE will be evaluated for duration, severity, seriousness and causal relationship to the drug treatment. The action taken and the outcome will also be recorded. All AEs occurring during the study period will be followed up in accordance with good medical practice until resolved or judged no longer clinically significant, or if a chronic condition, until fully characterized. All follow-up results are to be documented in writing.

M. STUDY OUTCOMES: The primary outcomes of interest in this study are 1) Incidence of clinically significant bleeding. This is defined as: a. Hgb <100 g/L b. transfusion of 2 or more units of blood (packed red blood cells or PRBCs), 1 or more unit of fresh frozen plasma (FFP), 5 or more units of cryoprecipitate, or 1 or more unit of platelets 2) Rate of open repair surgery (laparotomy) 3) Rates of endovascular repair (EVAR) 4) Mortality from all causes (28 day mortality)

The secondary outcomes of interest are: 1) The need for transfusion/ blood product administration 2) Number of blood units given before, during and after surgery 3) Incidence of transfusion related reactions 4) Number of days requiring mechanical ventilation

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5) Length of stay (days) in Intensive Care Unit 6) Length of stay (days) in hospital 7) Incidence of abdominal compartment syndrome 8) Incidence of renal failure with need for renal replacement therapy or intermittent hemodialysis in patients who have never required dialysis or continuous renal replacement therapy prior to surgery. 9) Incidence of transfusion related lung injury 10) Cardiac outcomes such as arrest, myocardial ischemia, stroke or seizure 11) Time from initial presentation with symptoms to first dose of TXA

N. SAMPLE SIZE CONSIDERATIONS Randomized controlled trials of the effect of TXA on number units of PRBC’s transfused have revealed changes of 1.96 units with standard deviations of 3.46.29 With a one-sided type 1 error rate of 5%, a sample of 15 experimental subjects with a control group data set of 50 would have at least 80% power to detect a similar effect. If we use a more conservative estimate of only a 1.0 unit change with a standard deviation of 2.5, we would need approximately 80% power with 35 experimental subjects and 70 controls.24 Using the proportion of patients transfused, differences of 18%28 and 25%44 have been found. Again, a sample of 25 TXA subjects and 75 control subjects would be required with 80% power. Twenty subjects would be needed to detect a similar reduction of 28% in the proportion of patients experiencing major bleeding.29 Therefore, we are using a minimum sample size of 25 to have 80% power to detect significant changes in these outcomes.

O. STATISTICAL ANALYSES: We will compare data from the experimental group (TXA) to the data from the same number of matched control patients collected retrospectively (control group). The patients will be matched on age, sex, ethnicity, history of peripheral vascular disease, coronary artery disease, aneurysms, and current medications (antihypertensives, anticoagulants, NSAIDs). Continuous variables will be summarized by means with standard deviation and medians with interquartile range. Categorical variables will be presented using frequencies and percentages. Our primary analyses will compare outcomes that are measured on interval/ratio scales (e.g. between the two groups using independent t-tests or ANOVA’s or non-parametric Mann-Whitney/Kruskal- Wallis if the data are skewed). For categorical data, chi-square or Fisher’s Exact tests with effect size measures will be used to analyze the relationship between treatment and outcome (e.g. incidence of abdominal compartment syndrome in experimental vs. control group).. We

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will also examine the relationship between time elapsed between first ER presentation and first dose of TXA and the primary outcomes. We will use two-sided tests with alpha set at .05 to be able to detect if TXA produces worse outcomes than standard treatment.

P. POTENTIAL SIGNIFICANCE: To date, there is very limited patient specific research surrounding the use of TXA for the purpose of reducing clinically significant bleeding in patients with confirmed ruptured AAA. Other patient populations that have high risks of clinically significant bleeding have shown statistically significant benefit from the use of TXA, resulting in reduced overall mortality. The addition of the Shock Trauma Air Rescue Society (STARS) to current medical transportation in Southern Saskatchewan 2012 (fixed wing and road ambulance with Basic and Advance Life support crew) has increased the number of patients with traumas (including ruptured AAA’s) admitted to hospital, necessitating an appropriate treatment plan for these patients. The results of this study will provide valuable information about the effectiveness of this drug in this novel patient population. If we find a significant improvement in morbidity and mortality, we hope to extend this study to a multi-center national trial to determine if these effects can be generalized to the larger Canadian population. Given that TXA is inexpensive and widely available, it has the potential to be a very promising therapy for blood loss in traumas such as ruptured AAA’s as well as reduce hospital and patient costs associated with treating this condition.

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Q. REFERENCES:

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