Delaying Treatment Reduces Survival Benefits of Antifibrinolytics in Patients With Acute Severe Bleeding

Administration of antifibrinolytic agents, such as tranexamic acid, reduces patients’ risk of death from trauma-related or postpartum bleeding, but delaying time to treatment for more than one hour after bleeding onset significantly decreases treatment effectiveness (p<0.001), according to results from a meta-analysis published in the Journal of Clinical Oncology.

“Most deaths from bleeding occur on the day of onset, and many occur within the first few hours,” wrote Angèle Gayet-Ageron, MD, of the Division of Clinical Epidemiology at the University Hospitals of Geneva in Switzerland, and co-authors. “Patients with acute severe bleeding should receive antifibrinolytic treatment as soon as possible after bleeding onset.”

The researchers examined medical literature databases for randomized, placebo-controlled trials of more than 1,000 patients that evaluated the effects of antifibrinolytics (including aprotinin, tranexamic acid, aminocaproic acid, and aminomethylbenzoic acid) in acute severe bleeding. Only two trials met the inclusion criteria: the WOMAN trial and the CRASH-2 trial, both of which assessed the effects of tranexamic acid in a total of 40,138 patients.

WOMAN measured the effects of tranexamic acid treatment on death, hysterectomy, and other outcomes in 20,011 women (median age = 28 years; range = 24-32 years) with postpartum hemorrhage. CRASH-2 measured the drug’s effects on death and vascular occlusive events in 20,127 patients (median age = 30 years; interquartile range = 24-43 years) with traumatic bleeding.

Among the total cohort, 20,094 patients received tranexamic acid, and 20,044 received placebo. A total of 3,558 deaths were reported; 1,408 (40%) were related to bleeding, and 884 (63%) occurred within 12 hours of bleeding onset.

The time to treatment initiation varied among patients in each trial:

  • ≤1 hour: 7,452 (37.0%) in CRASH-2 and 9,572 (48.1%) in WOMAN
  • 1-3 hours: 6,033 (30.0%) and 5,356 (26.9%)
  • >3 hours: 6,634 (33.0%) and 4,974 (25.0%)

Data were missing for 117 patients.

The investigators found no heterogeneity in the treatment effect between trials (p=0.7243). Tranexamic acid significantly increased the number of patients with absence of death from bleeding (primary endpoint; odds ratio [OR] = 1.20; 95% CI 1.08-1.33; p=0.001).

When tranexamic acid was given immediately, it significantly improved survival, compared with any delay in administration (OR=1.72; 95% CI 1.42-2.10; p<0.0001). “Those who received treatment within the first hour were more often women and were younger, with a higher proportion of penetrating injuries (for trauma patients),” the authors wrote.

Data on time to death were available for the WOMAN trial but not the CRASH-2 trial. When looking at the data from WOMAN, the researchers found that deaths from bleeding peaked at two to three hours after onset in untreated women.

The treatment benefit of antifibrinolytics was estimated to be null starting at 135 minutes, with no treatment benefit actually observed at 180 minutes. In addition, for every 15-minute delay in treatment, the treatment benefit decreased by 10 percent.

To measure the relative treatment benefit (defined as the OR for absence of death from bleeding) of immediate tranexamic acid, the authors accounted for up to 60 minutes of treatment delay in the CRASH-2 study and  up to30 minutes of treatment delay in the WOMAN trial. The benefit varied between 70 percent (OR=1.70; 95% CI 1.38-2.11) and 82 percent (OR=1.82; 95% CI 1.47-2.25) among all patients, for an average benefit of 77 percent (OR=1.77; 95% CI 1.43-2.18).

There was no evidence of increased adverse events (AEs) associated with tranexamic acid. Although vascular occlusive events were more frequent in patients with traumatic bleeding than those with postpartum hemorrhage, fatal events were not increased with tranexamic acid treatment (OR=0.73; 95% CI 0.49-1.09; see TABLE). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events.

The study has limitations related to the methods of the included trials, including missing time of death and time of bleeding onset for patients with traumatic bleeds in CRASH-2. Deaths related to bleeding and vascular events could have been misclassified, the authors added.

Pfizer contributed to the funding of this study.

The authors report no financial conflicts.


Reference

Gayet-Ageron A, Prieto-Merino D, Ker K, et al. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet. 2017 November 7. [Epub ahead of print]

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