Tranexamic acid: A Savior for Trauma Patients?

Patrick B Gregory, PharmDWakeMed Health & Hospitals

September 16, 2010

Objectives

• Review fibrinolysis • Understand role of antifibrinolytics in trauma

patients• Review CRASH-2 trial and its significance• Discuss the clinical impact CRASH-2 will have

on trauma patients

Fibrinolysis

http://en.wikipedia.org/wiki/File:Fibrinolysis.png

http://www.acta-ortho.gr/v55t4_4/Figure1.jpg

Antifibrinolytics

• Tranexamic acid (TXA), aminocaproic acid• Lysine-like drugs that interfere with the

formation of the fibrinolytic enzyme plasmin from its precursor plasminogen activators

• Block the binding sites of the enzymes of plasminogen respectively and thus stops plasmin formation

• May help to avoid the use of blood products such as fresh frozen plasma (FFP)

Antifibrinolytic drug use in surgery

• Cardiac surgery– Risk of death is lower in patients treated with

antifibrinolytics• Perioperative surgery– Antifibrinolytic drugs provide reductions in blood loss

and the need for allogeneic red cell transfusion• Spine surgery– Antifibrinolytic agents are often used for spinal

procedures in which a large amount of blood loss can be expected

Tranexamic acid: Mechanism of Action

Dunn CJ, Goa KL: Tranexamic acid: A review of its use in surgery and other indications. Drugs 1999;57:1005-1032.

Rationale for TXA use in trauma patients

• Bleeding is a leading cause of trauma death• Blood transfusion can be risky• Antifibrinolytics reduce blood loss after

surgery• Surgery and trauma produce similar

hemostatic responses• Henry et al showed TXA may be as effective as

aprotinin (direct plasmin inhibitor)

Henry DA, Carless PA, Moxey JA, et al. Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 4: CD001886.

Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2)

CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in

trauma patients with significant haemorrhage (CRASH-2: a randomised, placebo-controlled trial. Lancet 2010; published

online June 15. DOI:10.1016/S0140-6736(10)60835-5

CRASH-2: Methods

• Randomized, placebo-controlled, multi-centered trial

• Eligibility– Adult trauma patients with ongoing significant

hemorrhage or at risk of significant hemorrhage– Must be within 8 hours of injury – Excluded if antifibrinolytic agents were clearly

indicated or contraindicated

CRASH-2: Methods

• Treatment groups were balanced with respect to all baseline characteristics (see Table 1)

• Patients groups– Loading dose of 1 gram of tranexamic acid infused

over 10 minutes, followed by IV infusion of 1 gram over 8 hours

– Matching placebo (0.9% saline)

CRASH-2: Methods

• Primary– Death in hospital within 4 weeks of injury

• Secondary– Vascular occlusive event – Surgical intervention – Receipt of blood transfusion– Units of blood products transfused

CRASH-2: Trial profile

CRASH-2: Primary Outcome

CRASH-2: Secondary Outcome

CRASH-2: Discussion

• Early administration of TXA to trauma patients with, or at the risk of, significant bleeding reduces the risk of death from hemorrhage with no apparent increase in fatal or non-fatal vascular occlusive events

CRASH-2: Strengths & Limitations (From Authors)

• Strengths– Randomized– Balanced baseline

statistics– Analyses were on an

intention-to-treat basis– Primary endpoint was

both statistically significant and clinically important

• Limitations– Diagnosis of traumatic

hemorrhage can be difficult and misdiagnosis would have reduced the power of the trial

– Occlusive events were recorded only when there was clear clinical evidence

– Limited insight into how TXA reduces the risk of death in bleeding trauma patients

CRASH-2: Conclusions

• TXA could be given in a wide range of health-care settings, and safely reduced the risk of death in bleeding trauma patients

• The option to use TXA should be available to doctors treating trauma patients in all countries

Clinical Considerations

• No statistical difference in transfusion between the groups….how was mortality reduced?– Reduced bleeding event– Reduction of proinflammatory responses

• Warning: postoperative convulsive seizures– Associated with TXA doses 2-10 fold higher than

those used in CRASH-2– Proposed mechanism: TXA is structurally similar to γ-

aminobutyric acid as a potential cause of neurotoxicity.

Clinical Impact

• CRASH-2 shows that TXA should at least be a therapeutic option for trauma patients– Standard of care internationally?– More trials needed in US?

• Use caution before extrapolating these results of CRASH-2 to other antifibrinolytic agents

Questions???

Thank you for your time!