EBQ:CRASH-3 Trial

Incomplete Journal Club Article

The Crash 3 Trial Collaborators. "Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.". The Lancet. 2019. {{{volume}}}:{{{pages}}}.
PubMed Full text

Clinical Question

Is tranexamic acid beneficial in patients with TBI?

Conclusion

"Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 hours of injury reduces head injury-related death. Patients should be treated as soon as possible after injury"

Major Points

Intracranial Hemorrhage Types

• Intra-axial
  • Hemorrhagic stroke (Spontaneous intracerebral hemorrhage)
  • Traumatic intracerebral hemorrhage
• Extra-axial
  • Epidural hemorrhage
  • Subdural hemorrhage
  • Subarachnoid hemorrhage (aneurysmal intracranial hemorrhage)

AHA Spontaneous ICH BP Guidelines 2015

1. If SBP is 150-220mmHg without contraindication to BP lowering, it is safe to acutely lower BP to 140mmHg and can be effective for improving functional outcome. (Class I Level A)
2. For ICH patients presenting with SBP >220 mm Hg, it may be reasonable to consider aggressive reduction of BP with a continuous intravenous infusion and frequent BP monitoring (Class IIb; Level of Evidence C)

AHA Aneurysmal SAH BP Guidelines

1. No well-controlled studies exist that answer whether BP control influences rebleeding
2. BP should be controlled to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure (Class I, Level of Evidence B).
3. Nicardipine, labetalol, and esmolol are appropriate choices for BP control (Sodium nitroprusside may raise intracranial pressure and cause toxicity with prolonged infusion and should be avoided)

AHA ICH Coagulopathy Guidelines 2015

1. Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor replacement therapy or platelets, respectively (Class I; Level of Evidence C). (Unchanged from the previous guideline)
2. Patients with ICH whose INR is elevated because of VKA should have their VKA withheld, receive therapy to replace vitamin K–dependent factors and correct the INR, and receive intravenous vitamin K (Class I; Level of Evidence C). PCCs may have fewer complications and correct the INR more rapidly than FFP and might be considered over FFP (Class IIb; Level of Evidence B). rFVIIa does not replace all clotting factors, and although the INR may be lowered, clotting may not be restored in vivo; therefore, rFVIIa is not recommended for VKA reversal in ICH (Class III; Level of Evidence C). (Revised from the previous guideline)
3. For patients with ICH who are taking dabigatran, rivaroxaban, or apixaban, treatment with FEIBA, other PCCs, or rFVIIa might be considered on an individual basis. Activated charcoal might be used if the most recent dose of dabigatran, apixaban, or rivaroxaban was taken <2 hours earlier. Hemodialysis might be considered for dabigatran (Class IIb; Level of Evidence C). (New recommendation)
4. Protamine sulfate may be considered to reverse heparin in patients with acute ICH (Class IIb; Level of Evidence C). (New recommendation)
5. The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain (Class IIb; Level of Evidence C). (Revised from the previous guideline)
6. Although rFVIIa can limit the extent of hematoma expansion in noncoagulopathic ICH patients, there is an increase in thromboembolic risk with rFVIIa and no clear clinical benefit in unselected patients. Thus, rFVIIa is not recommended (Class III; Level of Evidence A). (Unchanged from the previous guideline)

Design

• Randomized, placebo controlled trial of 12,737 patients done in 175 hospitals in 29 countries on patients with TBI.

Population Studied

Inclusion Criteria

• Adults with TBI were within 3 hours of injury, GCS 12 or lower or any intracranial bleeding on CT scan.

Baseline Characteristics

• 80% men, 19% female
• Mean age 41.7 years
• Bilateral nonreactive pupils 9%

Interventions

Loading dose 1 g over 10 min then infusion of 1g over 8 hours

Outcomes/Results

Primary Outcomes

Head injury-related death in hospital within 28 days of injury

• Among patients treated within 3 hours of injury, risk of head injury-related death was 18.5% in TXA group versus 19.8% in placebo group (CI 0.86-1.02).

Prespecified sensitivity analysis that excluded patients with a GCS of 3 and those with bilateral unreactive pupils at baseline

• There was a 12.5% risk of head injury related death compared to 14% in placebo (CI 0.80-1.00)

Secondary Outcomes

• Early head injury-related death (within 24 h after injury)
• All-cause and cause-specific mortality
• Disability
• Vascular occlusive events (MI, CVA, DVT, PE) - Similar in TXA vs. placebo
• Seizures
• complications
• Neurosurgery days in ICU
• Adverse events within 28 days

Funding

National institute for health research health technology assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Welcome Trust (Joint Global Health Trials Scheme)