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)