Tranexamic acid, a cheap and widely available generic drug, has been shown to safely improve the chances of trauma patients' surviving bleeding injuries, according to findings from a trial enrolling more than 20,000 patients in 40 countries.

The findings suggest that infusions of tranexamic acid, an antifibrinolytic agent used in surgery, also could be used in trauma care settings to help counter deaths from vehicular accidents and violence. Middle and lower-income countries account for more than 90% of the world's trauma deaths, the study's authors noted.

For their research, an international group of investigators, coordinated by Ian Roberts, Ph.D., of the London School of Hygiene and Tropical Medicine, recruited 20,211 adult trauma patients from 274 hospitals, all of whom had, or were at risk of developing, significant bleeding. Many of the study centers were located in India, Latin America, and Africa, as “that's where so much of the trauma is,” Dr. Roberts said in an interview.

Patients were randomized to receive either tranexamic acid (a loading dose of 1 g over 10 minutes followed by an infusion of 1 g over 8 hours) or placebo, with patients and clinicians blinded to treatment allocation. Although the dosing of tranexamic acid in surgery is adjusted according to a patient's body weight, the study investigators decided on a fixed dose of 2 g, which is effective over a range of body weights, because of the difficulty of weighing patients in a trauma setting (doi:10.1016/S0140-6736[10]60835-5).

Tranexamic acid had been shown to reduce the need for blood transfusions by a third in patients undergoing elective surgery (Cochrane Database Syst Rev 2007; CD001886), without increasing the risk of postoperative complications, and the study investigators hypothesized that because the hemostatic responses to surgery and trauma are similar, tranexamic acid might reduce bleeding-related mortality in trauma patients as well.

The study's primary outcome was death within 4 weeks of injury, whether from bleeding, vascular occlusion (myocardial infarction, stroke, and pulmonary embolism), multi-organ failure, head injury, or other causes, and analysis was by intention to treat.

All-cause mortality was shown to be significantly reduced with tranexamic acid: 1,463 (14.5%) of patients in the treatment group died within 4 weeks compared with 1,613 (16%) in the placebo group. The risk of death caused by bleeding was significantly reduced: 489 (4.9%) in the treatment arm compared with 574 (5.7%) in the placebo arm.

“The results show that the early administration of tranexamic acid to trauma patients with, or at risk of, significant bleeding reduces the risk of death from hemorrhage with no apparent increase in fatal or nonfatal vascular occlusive events,” the investigators concluded in their analysis. The investigators did not see statistically significant differences in transfusion rates between the two groups—transfusions were given to 50.4% of patients in the treatment arm and 51.3% in the placebo arm.

One of the trial's limitations, the investigators acknowledged, was its “limited insight into how tranexamic acid reduces the risk of death in bleeding trauma patients.” However, they said, it is the first scientific evidence that it can save lives and, at about £3 (U.S. $9) per 2-mg dose, “it would be considered a good buy in Boston or Bangalore,” Dr. Roberts said.

But despite the drug's affordability and generic status, it is still little known in trauma settings, Dr. Roberts said. “There has been off-label use of this drug [for trauma] in the past but not a lot. … If they do this tomorrow they could save millions of lives,” he said.

In an accompanying editorial, anesthesiologist Jerrold H. Levy of Emory University in Atlanta called the study “an important example of the complex relations between coagulation, fibrinolysis, inflammation, and outcomes after tissue injury … The similarities of tissue injury after trauma and surgery create a novel model for antifibrinolytic therapy with tranexamic acid.” However, Dr. Levy cautioned, the trauma findings from the tranexamic acid should not be extrapolated to other antifibrinolytic agents “until they have been studied in a similarly robust manner” (doi:10.1016/S0140-6736[10]60939-7).

Disclosures: The study was funded by the United Kingdom's National Institute for Health Research, Pfizer, BUPA Foundation, and the J.P. Moulton Charitable Foundation. Its investigators declared no conflicts of interest. Dr. Levy said that he has received grants from and been an adviser to Novo Nordisk.

My Take

Details Lacking

The use of tranexamic acid may hold promise as a way to reduce bleeding in injured patients. The authors showed lower mortality for patients who received the medication vs. a placebo, but there was no statistically significant difference in the transfusion requirements. This may seem unexpected, but details for this huge patient population are lacking. For example, factors that contribute to bleeding include hypothermia, crush injury, metabolic acidosis, and medications such as aspirin or clopidogrel. And about a third of the patients at high risk for bleeding received tranexamic acid more than 3 hours after injury, so it's likely that bleeding was an ongoing process during that time. Without knowing patients' details, it is difficult to tell who will most benefit from tranexamic acid.

DR. GRACE S. ROZYCKI is chief of the division of trauma/surgical critical care, department of surgery, Emory University, Atlanta.

70213_fx1.sml

Generic Tranexamic Acid Cut Bleeding Deaths