Blood-clot promoting drugs for acute traumatic injury

This is an update of an existing Cochrane review, the last version was published in 2012.

Background

Injury is the second leading cause of death for people aged five to 45 years. Over four million people worldwide die of injuries every year, often because of extensive blood loss. Antifibrinolytic drugs promote blood clotting by preventing blood clots from breaking down. Some examples of antifibrinolytic drugs are aprotinin, tranexamic acid (TXA), epsilon-aminocaproic acid and aminomethylbenzoic acid. Doctors sometimes give these drugs to patients having surgery to prevent blood loss. These drugs might also stop blood loss in seriously injured patients and, as a result, save lives.

The authors of this review searched for randomised trials assessing the effects of antifibrinolytics in trauma patients.

Search date

The evidence in this review is current to January 2015.

Study characteristics

We found three randomised trials which met inclusion criteria and included well data from over 20,000 patients recruited in 40 countries.

Of these, one small trial (n = 77) looked at the effect of aprotinin in patients aged 12 and older who had suffered trauma involving broken bones and shock.

Two trials assessed the effect of TXA in patients aged 16 and over. The largest (n = 20,211) involved patients suffering from a variety of types of trauma, and the other (n = 240) only those who had suffered traumatic brain injury.

Results

The trial assessing the effect of aprotinin was too small to provide reliable data.

Results for TXA suggest that, when given early, TXA reduces the risk of death compared to patients who do not receive TXA without increasing the risk of side effects.

However, there is still some uncertainty about the effect of TXA in patients who have bleeding inside the brain from a head injury, but are not bleeding from injuries elsewhere. It is possible that the effects of TXA are different in this specific patient group.

We have found two ongoing trials that are trying to answer this question.

The authors of this review conclude that TXA can safely reduce death in trauma patients with bleeding and should be given as soon as possible after injury. However, they cannot conclude whether or not TXA is also effective in patients with traumatic brain injury with no other trauma, until the ongoing trials have been completed.

Quality of the evidence

Evidence for important outcomes including mortality, need for further surgery and blood transfusion, came from high-quality evidence, meaning we have confidence in the findings. There was moderate-quality evidence for important adverse events including vascular occlusive events (including heart attacks, deep vein thrombosis, stroke and pulmonary embolism).

Authors' conclusions: 

TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.  TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains.

Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.

Read the full abstract...
Background: 

Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma.

Objectives: 

To assess the effect of antifibrinolytic drugs in patients with acute traumatic injury.

Search strategy: 

We ran the most recent search in January 2015. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), PubMed and clinical trials registries.

Selection criteria: 

Randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA], epsilon-aminocaproic acid and aminomethylbenzoic acid) following acute traumatic injury.

Data collection and analysis: 

From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria, and extracted data. One review author assessed the risk of bias for key domains.

Outcome measures included: mortality at end of follow-up (all-cause); adverse events (specifically vascular occlusive events [myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism] and renal failure); number of patients undergoing surgical intervention or receiving blood transfusion; volume of blood transfused; volume of intracranial bleeding; brain ischaemic lesions; death or disability.

We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach.

Main results: 

Three trials met the inclusion criteria.

Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only.

One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock.

The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high). This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data.

There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain.

There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population.

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