5 Tranexamic acid and bleeding Activators of plasminogen from injured tissue convert it to plasmin.Plasmin binds to fibrin via its lysine binding sites to cause fibrinolysis.Bleeding and increased fibrinolysis are often found together.After the extensive tissue injury that occurs with trauma, the equilibrium is shifted and fibrinolysis which is ongoing is considered to be an important contributor to bleeding.Although the activation of fibrinolysis is complex, one of the pathway which leads to fibrinolysis is the conversion of plasminogen to plasmin which then binds to fibrin via its lysine binding sites.
7 Tranexamic acid and bleeding Tranexamic Acid (TXA) is a synthetic derivative of the amino acid lysine.It has a very high affinity for the lysine binding sites of plasminogen.It blocks these sites and prevents binding of plasmin to the fibrin surface, thus exerting its antifibrinolytic effect.The use of an anti-fibrinolytic agent aimed at blocking the lysine binding site such as tranexamic acid could potentially help reduce bleeding which occurs in trauma patients.
8 TXA reduces bleeding in surgery (Henry et al, 2011) TXA and bleedingTXA reduces bleeding in surgery (Henry et al, 2011)TXATXA better TXA worse0.61 ( )RR (95% CI)0.40.81.21.6TransfusionTXARR (95% CI)TXA better TXA worse0.40.81.21.60.57 ( )MortalityThere is good evidence that antifibrinolytics are useful in elective surgery. A systematic review of the randomised trials of tranexamic acid in patients undergoing elective surgery identified 53 studies which included about 3800 participants.Tranexamic acid reduced the need for blood transfusion by a third. And where transfusion was needed, it reduced the amount of blood transfused by about one unit.Death is a rare event in elective surgery so although there was a trend to reduction, this was not statistically significant.65 trials (4,842 patients) 30 trials (2,917 patients)
9 Does TXA reduce mortality in trauma (Coats, 2004)? TXA and bleedingDoes TXA reduce mortality in trauma (Coats, 2004)?Insufficient evidence to either support or refute a clinically important treatment effect.Further RCTs of tranexamic acid in trauma are needed.Because the haemostatic responses to surgery and trauma are similar, we hypothesised that antifibrinolytics might reduce bleeding in trauma patients.However, the systematic review we conducted showed that there was insufficient evidence to support or refute a clinically important effect and that further randomised controlled trials of antifibrinolytics were needed.
11 The CRASH-2 trialA randomized, placebo controlled trial among trauma patients with significant hemorrhage, of the effects of tranexamic acid on death and vascular occlusive events
12 Potentially eligible RANDOMISE INELIGIBLE INELIGIBLE Adult trauma patients, within 8 hours injurywith significant hemorrhage orat risk of significant hemorrhageDoctor is “certain” thattranexamic acid is indicatedINELIGIBLEGive tranexamic acidDoctor is “certain” thattranexamic acid is not indicatedINELIGIBLEDon’t give tranexamic acidDoctor is “SUBSTANTIALLY UNCERTAIN” as to the appropriateness of tranexamic acid in this patientAdult trauma patients (minimum 16 years); within 8 hours of injury, with or at risk of significant haemorrhage were eligible.The diagnosis of ‘with or at risk of significant haemorrhage’ was based on the treating doctor’s clinical diagnosis. The use of clinical inclusion criteria is appropriate in the context of traumatic bleeding in which a range of clinical signs need to be assessed when establishing the presence or absence of haemorrhage, while taking into account remedial measures, such as fluid resuscitation.Where an antifibrinolytic was clearly indicated or contraindicated, these patients were not randomised – otherwise all other patients were included after the appropriate consent procedure was completed.Consent procedures were established by local regulation and the appropriate ethics committees.RANDOMISETRANEXAMIC ACIDPLACEBO
13 Dose (Tranexamic Acid or placebo) MethodsTreatmentDose (Tranexamic Acid or placebo)Loading1 gram /10 minutes(IV infusion)Maintenance1 gram /8 hoursPatients received all other clinically indicated treatments and additionally received the trial treatment. - Which consisted of either 1 gram of tranexamic acid loading dose followed by a gram maintenance dose over 8 hours – or matched placebo.We chose a dose shown to be effective at inhibiting fibrinolysis in cardiac surgery and used a fixed dose because in the emergency situations, the administration of a fixed dose is practicable since determining the weight of a seriously injured patient can be difficult.
14 Methods Primary outcome Death in hospital within four weeks of injury Cause of death to be described: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism combined and separately), multi-organ failure, head injury, otherWe collected outcome at death, discharge or at 4 weeks whichever occurred first.
16 Methods Statistical analysis Intention-to-treat analysis Relative Risks (RR)95% confidence intervals for overall results99% confidence intervals for subgroup resultsThe effect measures were relative risk.Precision was quantified with 95% confidence intervals for the overall risk, and with 99% confidence intervals for the results of subgroups.The relative risk is the risk of death in the TXA group divided by the risk of death in the placebo group.
17 Results Patient enrolment 20,211 patients from 274 hospitals in 40 countries
18 CRASH-2 trial profile 20,211 randomised 10,096 allocated TXA 10,115 allocated placebo3 consent withdrawn1 consent withdrawn10,093 baseline data10,114 baseline datapatients were randomly assigned to tranexamic acid or placebo.The data from four patients were removed from the trial because their consent was withdrawn after randomisation.Primary outcome data were available for 20,127 (99·6%) randomised patients.33 lostto follow-up47 lostto follow-upFollowed up = 10,060 (99.7%)Followed up = 10,067 (99.5%)
19 Baseline characteristics TXA n (%)Placebo n (%)GenderMale8,439 (83.6)8,496 (84.0)Female1,654 (16.4)1,617 (16.0)[not known]1Age (years)<252,783 (27.6)2,855 (28.2)25–343,012 (29.8)3,081 (30.5)35–441,975 (19.6)1,841 (18.2)>442,321 (23.0)2,335 (23.1)2The trial was very well balanced for the key baseline characteristics.Serious injury was much more common in men than women. This is because in general men have higher rates of car crashes and serious violence.77% of patients were under 45 years old.
20 Baseline characteristics TXA n (%)Placebo n (%)Time since injury (hours)≤1 hour3,756 (37.2)3,722 (36.8)>1 to ≤3 hours3,045 (30·2)3,006 (29·7)>3 hours3,380 (33.4)[not known]56Type of injuryBlunt6,812 (67.5)6,843 (67.7)Penetrating3,281 (32.5)3,271 (32.3)The majority of patients were randomised within 3 hours of injury.
21 Baseline characteristics TXA n (%)Placebo n (%)Systolic Blood Pressure (mmHg)>896,901 (68.4)6,791 (67.1)76–891,615 (16.0)1,697 (16.8)≤751,566 (15.5)1,608 (15.9)[not known]1118Respiratory rate (breaths per minute)>291,491 (14.8)1,429 (14.1)10–298,355 (82.8)8,436 (83.4)<10160 (1.6)149 (1.5)87 (0.9)100 (1.0)
22 Baseline characteristics TXA n (%)Placebo n (%)Capillary Refill Time (seconds)2 or less3,432 (34.0)3,406 (33.7)3–44,665 (46.2)4,722 (46.7)>41,699 (16.8)1,672 (16.5)[not known]297 (2.9)314 (3.1)Heart rate (beats per minute)>1074,872 (48.3)4,853 (48.0)92–1072,556 (25.3)2,546 (25.2)77–911,727 (17.1)1,770 (17.5)<77875 (8.7)871 (8.6)63 (0.6)74 (0.7)
23 Baseline characteristics TXA n (%)Placebo n (%)Glasgow Coma ScoreSevere (3–8)1,799 (17.8)1,839 (18.2)Moderate (9–12)1,353 (13.4)1,351 (13.4)Mild (13–15)6,934 (68.7)6,908 (68.3)[not known]716
24 Death: When patients die Another reason why early treatment is needed – if you look at this bar chart – you will see that:Of the 3076 patients who died, 35% died on the day of randomisation.There were 1063 deaths due to bleeding, 60% was on the day of randomisation.
25 Cause of death Cause of death TXA Placebo RR for death P value 10, ,067Bleeding ·85 (0·76–0·96) 0·0077Vascular occlusion ·69 (0·44–1·07) 0·096Multiorgan failure ·90 (0·75–1·08) 0·25Head injury ·97 (0·87–1·08) 0·60Other ·94 (0·74–1·20) 0·63Any death ·91 (0·85–0·97) 0·0035We believed from the information on mechanism of action and the results from surgery that TXA might work by reducing bleeding – so what was the effect on deaths from bleeding?We saw a highly significant reduction on death from bleeding – a 15% relative reduction.One of the concerns we had was that there might be an increase in vascular occlusive deaths, bearing in mind that TXA acts by stabilising clots – so what did we see? There was no increase in vascular occlusive deaths .What was the effect on deaths from multiorgan failure? We saw a non-significant reduction.Deaths from head-injury and other – again all going in the same direction.So the effect on all cause mortality was a significant reduction. In the trial there was 150 less deaths in the treatment group compared to placebo.
26 Any cause of death TXA (n= 10,060) 1,463 (14.5%) Placebo (n= 10,067) 1,613 (16.0%)RR (95% CI)0.91 (0.85–0.97) 2P=0.0035This is just reiterating the main effect on all cause mortality.The bottom line is that this is very good news for trauma patients.The vertical line crossing 1 signifies the line of no-effect.0.80.91.01.1TXA betterTXA worse
27 Death due to bleeding TXA (n= 10,060) 489 (4.9%) Placebo (n= 10,067) 574 (5.7%)RR (95% CI)0.85 (0.76–0.96) 2P=0.0077This is just reiterating the main effect on all cause mortality.The bottom line is that this is very good news for trauma patients.The vertical line crossing 1 signifies the line of no-effect.0.80.91.01.1TXA betterTXA worse
28 Bleeding death: early treatment is better p=RR (99% CI)≤1 hour0.68 (0.54–0.86)>1 to ≤ 3 hours0.79 (0.60–1.04)>3 hours1.44 (1.04–1.99)0.85 (0.76–0.96).7.8.9126.96.36.199.41.5
31 Bleeding death: early treatment is better All causes of deathBleedingNon-bleedingRR (95%CI)20 1270·91 (0·85–0·97)p=0·00350·85 (0·76–0·96)p=0·00770·94 (0·86–1·02)p=0·13≤17 4510·87 (0·76–0·97)0·68 (0·57–0·82)1·04 (0·89–1·21)≥1–36 0330·87 (0·77–0·97)0·79 (0·64–0·97)0·91 (0·78–1·05)>36 6341·00 (0·90–1·13)1·44 (1·12–1·84)0·89 (0·78–1·02)2 test of homogeneity4·411 (p=0·11)23·516 (p=0·0000)2·537 (p=0·28)
32 Vascular occlusive events TXAallocated(10,060)Placeboallocated(10,067)RR (95% CI)DVT 40 (0.40%) 41 (0.41%)PE 72 (0.69%) 71 (0.70%)MI 35 (0.35%) 55 (0.52%)Stroke 57 (0.56%) 66 (0.65%)The concern that there might be an increase in vascular occlusive events was not realised. When we combine fatal and non-fatal events:There was no increase in Deep vein thrombosis, pulmonary embolism, myocardial infarction or stroke.There was no increased risk of having any of these events.Any 168 (1.63%) 201 (1.95%).188.8.131.521.11.2TXA betterTXA worse
33 Blood transfusion Blood transfusion 5,067 5,160 RR (95% CI) TXAallocated(10,060)Placeboallocated(10,067)RR (95% CI)Blood transfusion 5,067 5,160(50.4%) (51.3%)We did not see the significant reduction in blood transfusion which was observed with the use of Tranexamic acid in elective surgery. There are several potential explanations:(a) Fewer deaths occurred in patients allocated to tranexamic acid than to placebo, and the patients who survived as a result of tranexamic acid administration would have had a greater opportunity to receive a blood transfusion (competing risks).(b) It could be an indication of the difficulty of accurate estimation of blood loss in trauma patients when assessing the need for transfusion – in surgery blood transfusion is easily titrated to blood loss as it is directly observed by the surgeon.(c) Another possible explanation is that after the loading dose, tranexamic acid was infused over 8 hours, whereas decisions about transfusion are made soon after admission.(d) TXA might be working via some other mechanism..8.911.1TXA betterTXA worse
34 Death and Dependency TXA [n=10060] Placebo [n=10067] RR (95% CI) p-valueNo symptoms1,483 (17·3%)1,334 (15·8%)1·11 (1·04 – 1·19)0·0023Minor symptoms3,054 (30·4%)3,061 (30·4%)1.00 (0·96 – 1·04)0·94Some restriction2,016 (20.0%)2,069 (20.6%)0·97 (0·92 – 1·03)0·36Dependent1,294 (12.9%)1,273 (12.6%)1·02 (0·95 – 1·09)0·63Fully dependent696 (6.9%)676 (6.7%)1·03 (0·93 – 1·14)0·57Dead1,463 (14·5%)1,613 (16·0%)0·91 (0·85 – 0·97)0·0035With more patients alive in the tranexamic acid group, there was a possibility that there would be an increase in patients being more dependent.However, in addition to a reduction in death, there were more patients with no symptoms in the tranexamic acid treated group.
36 Effect of early TXA on death due to bleeding (by geographical region)RR (95% CI) P=0.70TXA worseTXA better.184.108.40.2061.1.5HospitalsAsia 114Latin America 56Africa 52EU, Australia, Canada 48World0.72 (0.63–0.83)
37 Effect of early TXA on death due to bleeding (by baseline risk of death)RR (95% CI) p=0.090–10%10–20%>20%All0.72 (0.63–0.83).220.127.116.11.918.104.22.168TXA betterTXA worse
38 Effect of early TXA on vascular occlusion (by baseline risk of death)RR (95% CI) p=0.930–10%10–20%>20%All0.69 (0.53–0.89).22.214.171.124.9126.96.36.199TXA betterTXA worse
39 Conclusion TXA reduces mortality in bleeding trauma patients TXA should be given as soon as possible (<3 hours)No increased risk of vascular occlusive events
41 Methods Study design Double blind randomised placebo controlled trial nested in a subset of CRASH-2 trial participantsParticipantsPatients MUST fulfil eligibility criteria for the CRASH-2 trial+CT scan showing intracranial abnormality consistent with traumatic brain injury and GCS <15Intervention1 gram of TXA (10 min), 1 gram (eight hours)or matching placebo (sodium chloride 0·9%)
42 Flow diagram CRASH-2 eligibility criteria AND initial CT scan compatible with TBI AND GCS <15Patients randomisedTranexamic acidPlacebo24 to 48 hoursFollow-up CT scansFollow-up CT scansClinical follow-up as per CRASH-2Clinical follow-up as per CRASH-2
43 Outcomes CT scan outcomes Clinical outcomes Total haematoma growth Significant haematoma growth(increase >25% in size)New intracranial haemorrhageNew focal cerebral ischaemic lesionsMass effectTraumatic subarachnoid haemorrhageClinical outcomesMortalityNeed for neurosurgery
44 Methods Randomisation was balanced by centre Treatment allocation was concealedAll analyses were undertaken on an intention to treat basisAnalysis was adjusted for baseline variables(Initial volume, Time from injury to first and second CT scanGlasgow Coma Score , and Age)
45 Methods for CT scan reading Experienced radiologistProtocol for CT scan reading using validated methodsDouble reading of all the CT scansKappa and Intraclass correlation coefficient for reliability
46 Trial Profile Allocated to TXA (n=133) Allocated to placebo (n=137) Received loading dose (n=133)Received maintenance dose (n=133)Received loading dose (n=137)Received maintenance dose (n=136)Clinical follow up (n=133)Clinical follow up (n=137)Randomised (n= 270)Initial CT scan (n=127)3 patients diedFollow-up CT scan (n=123) (123/133)Initial CT scan (n=129)2 patients diedFollow-up CT scan (n=126) (126/137)
48 Mean total haemorrhage growth 1086428.1 ml (SD 29.2)5.9 ml (SD 26.8)TXAPlacebo
49 CT scan outcomes – Haematoma growth (ml) Unadjusted difference Total patientsUnadjusted difference(95% CI)Adjusteddifference ±P valueAll patients206-2.1 (-9.8 to 5.6)-3.79 (-11.5 to 3.9)0.33Neurosurgery46-6.3 (-35.0 to 22.4)-15.5 (-46.5 to 15.5)0.32No neurosurgery160-1.6 (-7.3 to 4.0)-2.11 (-7.1 to 2.9)0.40± Adjusted for age, GCS, size of initial bleeding, time since injury to first CT scanand time since first CT scan to second CT scan
50 CT scan outcomes TXA n (%) n=123 Placebo n (%) n=126 Adjusted ± OR (95% CI)Significant haematoma growth44 (36%)56 (44%)0.67(0.40–1.13)New haemorrhage13 (11%)20 (16%)0.62(0.28–1.35)Mass effect findings58 (47%)76 (60%)0.53(0.23–1.21)New focal ischaemic regions6 (5%)12 (9%)0.51(0.18–1.44)± Adjusted for age, GCS, size of initial bleeding, time since injury to first CT scanand time since first CT scan to second CT scan
51 Clinical outcomes TXA n (%) n=133 Placebo n (%) n=137 Adjusted ± OR (95% CI)Overall mortality14 (10%)24 (17%)0.47(0.21–1.04)Need for neurosurgery20 (15%)21 (15%)0.98(0.45–1.93)± Adjusted for age and GCS
52 TXA in isolated TBI trial (Surakrant et al) 240 patients with moderate or severe TBIWithin 8 hours of injurySame TXA dose as CRASH-2 trialOutcomes: Haemorrhage growth and mortality
53 Significant Haemorrhage growth Meta-analysisSignificant Haemorrhage growthCRASH-2 IBSThai study