Jamaica Conference 3/30/15 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 2 nd generation Ukato and Shosuke Okamoto 1953 Okamotos (Japan) Melander et al (Sweden) 1960s 1 st generation3 rd generation Lysine Aminocaproic Acid (Amicar) 4-amino-methyl- cyclohexane carbonic acid (TXA)

TXA Origins, setting the stage for CRASH-2 Okamodo et al. (Japan) TXA is discovered 1962 CRASH-2 (International) Inspired by work from elective surgeries Hemorrhagic trauma Nisson et al. (Sweden) Explores human pharmacokinetics Mid 1960s Oral surgery in hemophiliacs 52 RCTs examined rates of allogeneic blood transfusion (3778 patients in total) Before 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

20211 trauma patients 274 hospitals in 40 countries 84% Men Mean age ~35 Mean time to injury ~ 2.5h 33% 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 BP 3.GCS 4.Penetrating only vs Blunt/Penetrating injury Inclusion Criteria 1. Risk of significant hemorrhage HR 3. Within 8h of injury 4. Uncertainty principle

CRASH-2 Trial (27%) (19%) >44 (23%) (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%) (16%) </=75 (16%) <77 (9%) (17%) (25%) >107 (48%) Severe 3-8 (18%) Moderate 9-12 (13%) Mild (69%)

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)

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 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)