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 RESEARCH AND PERFORMANCE SUPPORT JUNE 1, 2015 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 RESEARCH AND PERFORMANCE SUPPORT JUNE 1, 2015 Tranexamic Acid Abdominal Aortic Aneurysms 3 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, RESEARCH AND PERFORMANCE SUPPORT JUNE 1, 2015 Tranexamic Acid Abdominal Aortic Aneurysms 4 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 RESEARCH AND PERFORMANCE SUPPORT JUNE 1, 2015 Tranexamic Acid Abdominal Aortic Aneurysms 5 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 RESEARCH AND PERFORMANCE SUPPORT JUNE 1, 2015 Tranexamic Acid Abdominal Aortic Aneurysms 6 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.