1. 1 CBS Journal Club CBS Journal Club Christopher Sharpe MD, FRCPC R6 Transfusion Medicine May 3, 2011

2. 2Objectives to discuss the role of tranexamic acid in coagulation/fibrinolysis to discuss the role of tranexamic acid in the prevention of bleeding during surgery and other clinical settings to discuss the role of tranexamic acid in the treatment of bleeding trauma patients

3. Focus of Journal Club “Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomised, placebo-controlled trial ” “Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomised, placebo-controlled trial ” CRASH-2 trial collaborators Lancet 2010; 376:23-32 CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2)

4. 4Introduction trauma is a significant cause of mortality, especially in the developing world 33% of trauma deaths in-hospital are attributed to bleeding the hemostatic responses to trauma and major surgery are similar (fibrinolysis and hyper-fibrinolysis are stimulated)

5. 5Introduction tranexamic acid: a synthetic derivative of lysine lysine binding sites on plasminogen are required for the binding of plasminogen and tPA to fibrin tranexamic acid competitively inhibits these interactions and inhibits fibrinolysis

6. 6 The Fibrinolytic System Initiation Phase - release of tPA from endothelial cells initiates limited conversion of plasminogen (Plg) to plasmin (Plm) - binding of tPA and plasminogen to C-terminal lysine (Lys) residues of partially-degraded fibrin increases the rate of plasmin formation tPA Plg Plm Lys Lys

7. 7 The Fibrinolytic System Propagation Phase - continuous cleavage of fibrin by plasmin generates new C-terminal lysine (Lys) residues which act as additional templates to bind tPA and plasminogen. Plasmin generation is accelerated Plm LysLys Lys Lys Lys Lys Lys

8. 8 Introduction Antifibrinolytic drugs used in cardiac surgery can reduce: - blood loss - the need for transfusion - the need for re-operation due to continued or recurrent bleeding

9. 9 Introduction Antifibrinolytic drugs: - tranexamic acid (lysine analogue) - epsilon-aminocaproic acid (EACA; lysine analogue) - aprotinin (withdrawn in May 2008 due to concerns of increased risk of death and cardiovascular complications)

10. 10 Introduction tranexamic acid, through its antifibrinolytic properties, can be used to reduce bleeding in certain clinical settings: - menorrhagia - dental surgery - elective surgery (knee/hip arthroplasty, spinal surgery, pediatric craniosynostosis reconstruction surgery) no apparent increase in the risk of postoperative complications (ie. vaso-occlusive episodes) with the use of tranexamic acid has been observed

11. 11 Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion Henry DA, Carless PA, Moxey AJ, et al. Cochrane Database Syst Rev 2011 Mar 16; 3 PURPOSE: to assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid and epsilon aminocaproic acid (EACA) on: - blood loss during surgery - need for red blood cell transfusion - adverse events (vascular occlusion, renal dysfunction, death) SELECTION CRITERIA: - randomized controlled trials (RCTs) in adults undergoing non-urgent surgery which compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other

12. 12 Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion Henry DA, Carless PA, Moxey AJ, et al. Cochrane Database Syst Rev 2011 Mar 16; 3 RESULTS: 252 RCTs involving ~25000 patients relative risk (RR) for RBC transfusion with tranexamic acid was 0.61 (95% CI 0.53 to 0.70) tranexamic acid did not reduce the need for re-operation due to bleeding (RR 0.80, 95% CI 0.55 to 1.17) compared with no treatment, tranexamic acid did not increase the risk of myocardial infarction, stroke, renal dysfunction or overall mortality (based on limited data)

13. 13 Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion Henry DA, Carless PA, Moxey AJ, et al. Cochrane Database Syst Rev 2011 Mar 16; 3 CONCLUSIONS: - lysine analogues (tranexamic acid) are effective in reducing blood loss and the receipt of allogeneic red cell transfusion during and after surgery - lysine analogues (tranexamic acid) appear to be free of serious adverse effects

14. 14 The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial Shakur H, Elbourne D, Gulmezoglu M, et al. Trials 2010; 11:40 obstetrical hemorrhage is the leading cause of maternal mortality (most occurs in the postpartum period) PURPOSE : - to determine the effect of early administration of tranexamic acid in women with clinically diagnosed postpartum haemorrhage on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events)

15. 15 The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial Shakur H, Elbourne D, Gulmezoglu M, et al. Trials 2010; 11:40 METHOD: - a randomized, double blind, placebo controlled trial is ongoing in 15000 women with a clinical diagnosis of postpartum hemorrhage following vaginal delivery or c-section - eligibility criterion: clinician's uncertainty whether or not to use an antifibrinolytic agent in the setting of postpartum hemorrhage - patients will be randomization to tranexamic acid (1 g IV) or placebo (NaCl 0.9%)

16. 16 The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial Shakur H, Elbourne D, Gulmezoglu M, et al. Trials 2010; 11:40 ANALYSES: intention to treat PRIMARY ENDPOINT: mortality or hysterectomy

17. 17 Introduction Question yet to be answered: - does tranexamic acid reduce mortality and bleeding in trauma patients who are bleeding?

18. Focus of Journal Club “Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomised, placebo-controlled trial ” “Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomised, placebo-controlled trial ” CRASH-2 trial collaborators Lancet 2010; 376:23-32 CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2)

19. 19 CRASH-2 placebo-controlled trial placebo-controlled trial to assess the effects of the early administration of a short course of tranexamic acid in trauma patients with, or at risk of, significant hemorrhage on: - death - vascular occlusive events - the receipt of blood transfusion

20. 20 CRASH-2: Methods 274 hospitals in 40 countries involved in trial Eligibility criteria: - adult trauma patients with significant hemorrhage (SBP 110 BPM, or both) within 8 hours of injury - adult trauma patients who were considered to be at risk of significant hemorrhage within 8 hours of injury

21. 21 CRASH-2: Methods patient entry into study was “governed by the uncertainty principle” if a clear indication for tranexamic acid was felt to be present by the responsible doctor, trauma patients were not randomized into the study if a clear contraindication to tranexamic acid treatment was felt to be present by the responsible doctor, trauma patients were not randomized into the study patients were eligible for randomization when the responsible doctor was “substantially uncertain” as to whether or not to treat a patient with tranexamic acid

22. 22 CRASH-2: Methods informed consent was obtained from trauma patients if possible (or a relative or representative if this was not possible) consent was deferred or waived if above option not available (and obtained later if possible)

23. 23 CRASH-2: Methods randomization was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator the telephone randomization service used a minimization algorithm balancing for: - sex - age - time since injury - Glasgow Coma Score - systolic blood pressure - country of origin - central capillary refill time - respiratory rate - type of injury (blunt or penetrating)

24. 24 CRASH-2: Methods Randomization options: - telephone randomization using the University of Oxford Clinical Trial Service Unit (CTSU) - local treatment pack system (the pack number was sent to the international trial coordinating centre in London, UK)

25. 25 CRASH-2: Methods once the treatment pack number was recorded, the patient was included in the trial whether or not the treatment pack was opened or the allocated treatment started (intention to treat analysis)

26. 26 CRASH-2: Methods Random assignment to receive either: - a loading dose of 1 g of tranexamic acid IV over 10 min followed by 1 g IV over 8 hours OR - matched placebo (0.9% saline IV) each treatment pack was numbered and contained four IV doses of either tranexamic acid 500 mg or IV placebo (0.9% saline) tranexamic acid and placebo were indistinguishable (IV amps)

27. 27 CRASH-2: Methods study participants, site investigators, and trial coordinating centre staff were masked to treatment allocation emergency unblinding was available by calling the University of Oxford Clinical Trial Service Unit (CTSU)

28. 28 CRASH-2: Methods Primary outcome: death in hospital within 4 weeks of injury Cause of death categories: - bleeding - vascular occlusion (stroke, myocardial infarction, pulmonary embolism) - multiorgan failure - head injury - other

29. 29 CRASH-2: Methods Treatment effects on the primary outcome were subdivided by four baseline characteristics: 1 ) estimated time since injury (<1h, 1-3h, 3-8h) 2) systolic blood pressure (≤75, 76-89, ≥90mmHg) 3) Glasgow Coma Scale (severe 3-8, moderate 9-12, mild 13-15) 4) type of injury (penetrating or blunt)

30. 30 CRASH-2: Methods Secondary Outcomes: - vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis) - surgical intervention (neuro/thoracic/abdominal/pelvic surgery) - receipt of blood transfusion - number of units of blood products transfused

31. 31 CRASH-2: Methods Other data collected: - level of dependency post-traumatic injury was measured using the 5-point Modified Oxford Handicap Scale at hospital discharge or on day 28 if still in hospital

32. 32 CRASH-2: Methods Categories of Oxford Handicap Scale: - dead - fully dependent requiring attention day and night - dependent but not requiring constant attention - independent (some restriction in lifestyle) - minor symptoms - no symptoms

33. 33 CRASH-2: Methods Other data collected: - use of recombinant factor VIIa - gastrointestinal bleeding complications - adverse events that were “serious, unexpected, and suspected to be related to the study treatment” outcomes were recorded if they occurred while the patient was still in hospital (up to 28 days after initial randomization) trial coordinating centre in London had central database

34. 34 CRASH-2: Statistics a trial of 20000 patients was planned in order to achieve a 95% chance of a two-sided p-value of < 0.05 (and a 2% survival difference) all analyses were on intention to treat basis for primary outcome analyses, relative risks were calculated with 99% CIs with two-sided p-values

35. 35 CRASH-2: Statistics heterogeneity in treatment effects across subgroups was assessed with chi-square (Χ 2 ) tests missing data was not imputed into the database

36. 36 Figure 1: Trial Profile

37. 37 Table 1: Baseline Data of Participants

38. 38 Table 1: Baseline Data of Participants

39. 39 Figure 2: Mortality by Days from Randomization

40. 40 Table 2: Death by Cause

41. 41 Table 3: Vascular Occlusive Events, need for transfusion and surgery, and level of dependency

42. 42 Figure 3: All-cause mortality by subgroup GCS (Glasgow Coma Scale) *95% CI

43. 3 3 Results CRASH-2: Results No emergency unblinding was required during the study No adverse events were recorded that were “serious, unexpected, or suspected to be related to the study treatment “ 4

44. 3 3 Discussion CRASH-2: Discussion trial inclusion criteria were clinically-based (not based on laboratory tests) - overt bleeding may be easily identified but judging patients at risk for bleeding in the setting of trauma is difficult - it is possible that some of the patients randomized may not have been bleeding at the time of randomization (reduced power of trial) vascular occlusive events were recorded in the study only when there was clear clinical evidence - under-reporting of events may have occurred 4

45. 3 3 Discussion CRASH-2: Discussion the mechanism of action of tranexamic acid in reducing all-cause mortality in the setting of traumatic bleeding is not fully clear from the trial design - ? prevention of hyperfibrinolyis vs. other mechanism ? fibrinolytic activity was not measured in this trial (ie. D-dimer, FDPs, plasmin-α2 antiplasmin complex, plasmin-α2 macroglobulin complex, Bβ 1-42 fragment, Bβ 14-42 fragment, euglobulin clot lysis time) further study is needed to define the mechanism of action of tranexamic acid in this setting 4

46. 3 3 Discussion CRASH-2: Discussion What is the optimal time to give tranexamic acid to a bleeding trauma patient post-injury? - most deaths due to trauma are from bleeding that occurs within the first few hours after injury - giving tranexamic acid when bleeding is most likely (ie. early on) and avoiding it when vascular occlusive event risk is highest (ie. later on) is likely appropriate and appears safe since there was no increase in the risk of fatal or non-fatal vascular occlusive events when tranexamic acid was given within eight hours of injury 4

47. 3 3 Discussion CRASH-2: Discussion What is the optimal dose of tranexamic acid to prevent bleeding? - results from studies in surgical patients showed no significant difference between high and low doses on blood loss and blood transfusion - low dose 2.5 mg/kg loading dose with 0.25 mg/kg/h over 1-12 hours - high dose 100 mg/kg loading dose with 4 mg/kg/h over 1-12 hours Tranexamic acid dose used in this trial (for a 70 kg patient): ~15 mg/kg loading dose with 1.8 mg/kg/h over 1-12 hours 4

48. 3 3 Discussion CRASH-2: Discussion What is the optimal dose of tranexamic acid to prevent bleeding? - the fixed dose that was given in the trial was chosen because it was within the range shown to inhibit fibrinolysis without producing adverse effects - giving a fixed dose is reasonable in the setting of traumatic bleeding (obtaining the weight of a patient is difficult) - would higher tranexamic acid doses be of benefit? 4

49. 3 3 Discussion CRASH-2: Discussion Is the use of tranexamic acid warranted in other bleeding settings? - traumatic brain injury with intracranial hemorrhage (studies are lacking) - post-partum hemorrhage (WOMAN Trial ongoing) 4

50. 3 3 Critical Appraisal Are the results valid ? YES - large numbers of patients were enrolled in the study - baseline characteristics of the patients were matched at the start of the trial - the assignment of patients to treatment was randomized which ensured that patients, clinicians, and study personnel who treated bleeding trauma patients were blinded as to the presence or absence of the intervention 4

51. 3 3 Critical Appraisal Are the results valid ? YES - groups were treated equally with the exception of the study intervention - all of the study subjects were accounted for by the end of the trial (and most were followed up) 4

52. 3 3 Critical Appraisal Are the results valid? - the decrease in all-cause mortality with tranexamic acid was statistically significant (14.5% in tranexamic acid group vs. 16.0% in placebo group; RR 0.91, 95% CI 0.85- 0.97; p=0.0035 ) - results are clinically relevant and widely generalizable - “uncertainty principle” which guided patient entry into the study is subjective (no explanation was provided as to what constitutes a clear indication for, or against, the use of tranexamic acid in the setting of traumatic) 4

53. 3 3 Critical Appraisal Are the results valid? - the use of intention to treat was appropriate in this trial since most of the patients randomized to receive treatment actually received what was intended 4

54. 3 3 Critical Appraisal What are the results? - tranexamic acid showed a reduction in all- cause mortality compared to placebo (14.5% vs. 16.0%; RR 0.91, 95% CI 0.85-0.97; p=0.0035) - tranexamic acid showed a reduction in the risk of death due to bleeding compared to placebo (4.9% vs. 5.7%; RR 0.85, 95% CI 0.76-0.96; p=0.0077) 4

55. 55 Critical Appraisal How can I apply the results to patient care? - encourage the use of tranexamic acid early on in the setting of trauma patients who are bleeding (or who may bleed) in order to reduce all-cause mortality and the risk of death due to bleeding (data shows that a substantial number of trauma patients die early after injury, and many die from bleeding) - monitor adverse events (such as vascular occlusion) when tranexamic acid is used in the setting of traumatic bleeding

56. 56 Critical Appraisal How can I apply the results to patient care? - the results can (and likely should) be applied to bleeding trauma patients worldwide since the trial involved patients from 40 countries - clinical inclusion criteria for tranexamic acid use in the setting of bleeding trauma patients are available and feasible worldwide

57. 57 Critical Appraisal How can I apply the results to patient care? - the benefits of treatment with tranexamic acid in the setting of traumatic bleeding are worth the cost - cost of 2 g IV of tranexamic acid: $54 in Canada - tranexamic acid is relatively simple to administer

58. 58 Critical Appraisal How can I apply the results to patient care? - the harms associated with tranexamic acid use in bleeding trauma patients appear to be acceptable: the vaso-occlusive event rate is not increased

59. 1616 Questions or Questions or comments? comments?