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Jamaica Conference3/30/15
Sariah Khormaee
TRANEXAMIC ACID (TXA):The promise of a nearly perfect drug for the bleeding trauma patient
Outline
1. Origin
2. Pharmacology
3. Brief history of clinical application
4. CRASH-2 Trial
5. Implications
6. Future directions
Origins of TXA
“There was no such thing as plasmin then, but we knew that in certain conditions that blood will coagulate and then once coagulated will liquify” – Utako Okamoto
Pharmacology
TXA
Origin story of TXA
Bjorn Wiman
1950s
2nd generation
Ukato and Shosuke Okamoto
1953
Okamotos (Japan)Melander et al (Sweden)
1960s
1st generation 3rd generation
LysineAminocaproic Acid
(Amicar)
4-amino-methyl-cyclohexane carbonic
acid (TXA)
TXA Origins, setting the stage for CRASH-2Okamodo et al. (Japan)
TXA is discovered19
62
CRASH-2 (International)
Inspired by work from elective surgeries
Hemorrhagic trauma
2005
-201
1
1960 1970 1980 1990 2000 2010
Nisson et al. (Sweden)
Explores human pharmacokineticsM
id 1
960s
Oral surgery in hemophiliacs
52 RCTs examined rates of allogeneic blood transfusion (3778 patients in total)
Bef
ore
2007
Menorrhagia
29 cardiac surgery (2488 pts) RR 0.69 (0.60, 0.71)
21 ortho surgery (993 pts) RR 0.44 (0.33, 0.60)
2 liver surgery (296 pts) RR 0.16 (0.00, 32.47)
Briefly- side effects, dosing
Although it continues to be controversial, there is no good evidence that TXA is thrombogenic.
Some of these trials used a flat dose of TXA regardless of body weight
Most reported minimal to no side effects at doses sufficient to decrease perioperative blood transfusion (nausea, vomiting, dizziness)
CRASH-2 Trial
CRASH-2 Trial
20211 trauma patients
274 hospitals in 40 countries
84% MenMean age ~35
Mean time to injury ~ 2.5h33% penetrating trauma
Randomized
10,067 Patients
Placebo
10,060 patients
TXA
Primary Outcome: Death in hospital within 4 weeks
Secondary Outcomes: vascular occlusive events, surgical intervention, blood transfusion, units transfused, dependency
A priori analysis plan:
1. Hours since injury 2. Systolic BP3. GCS4. Penetrating only vs
Blunt/Penetrating injury
Inclusion Criteria
1. Risk of significant hemorrhage2. <90 mmHg systolic bp and/or >110 HR3. Within 8h of injury4. Uncertainty principle
CRASH-2 Trial
18-25 (27%)
35-44 (19%)
>44 (23%)
25-34 (30%)
Age (y) Time since Injury
<1 h (37%)
1-3 h (30%)
>3 h (33%)
Type of Injury
Penetrating (33%)
Penetrating + Blunt (67%)
SBP (mmHg) Heart Rate (BPM) GCS
>/= 90 (68%)
76-89 (16%)
</=75 (16%)
<77 (9%)
77-91 (17%)
92-107 (25%)>107 (48%)
Severe 3-8 (18%)
Moderate 9-12 (13%)
Mild 13-15 (69%)
CRASH-2
CRASH-2
There was no significant difference in vascular occlusion events (except MI, where RR 0.64 in favor of TXA), need for transfusion/surgery, dependency at discharge
CRASH-2
CRASH-2: The 3h rule (post-hoc analysis)
CRASH-2: The 3h rule (post-hoc analysis)Bleeding only deaths
CRASH-2: Implications
1 g TXA = $5.70
Since 1977, WHO has compiled a list of “Essential Medicines”. There are currently 340 compounds included on this list.
TXA was added to the list in 2009.
It is now widely used in the UK (funding country for the CRASH-2 trial) in both the emergency ambulance system of the NHS and the military
Adoption around the world has been more gradual, but is growing.
TXA: Expanding Indications/Future work
Current Large Clinical Trials
WOMAN (double blind, placebo controlled RCT on peripartum hemorrhage) 20,000 patients, Reporting in 2016/7.
CRASH-3 (double blind, placebo controlled RCT on traumatic brain injury) 8,000 patients. (3,856 patients currently randomized)
HALT-IT (placebo controlled RCT on acute upper GI hemorrhage) 8,000 patients.
Smaller Investigations
TXA in pediatric cardiac surgery
TXA during cystectomy trial (TACT) pilot
Many orthopedic trials
Summary
1. What it is: Synthetic enantiomer that binds lysine affinity sites of plasminogen
2. Brief history of clinical application: Used widely in elective surgery (especially cardiac and orthopedic surgeries)
3. Pharmacology: Very safe, can be given at a flat dose
4. CRASH-2 Trial: Largest trauma trial in history showing TXA can decrease all cause mortality in patients with hemorrhagic trauma
5. Implications: Extremely inexpensive drug with wide range of applications, a WHO essential medicine
6. Future directions: Many ongoing large RCT (WOMAN, CRASH-3, HALT-IT), potential for expanded general surgery RCTs (elective)