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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
TABLE . Deaths and Vascular Occlusive Events Based on Treatment
Tranexamic Acid ( n = 10,060 )
Any cause of death 1,463 ( 14.5 %)
Death from bleeding 489 ( 4.9 %)
Death from nonbleeding
Vascular occlusive event 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
CRASH-2 Trial WOMAN Trial Total
974 ( 9.7 %)
168 ( 1.7 %)
Vascular death 33 ( 0.3 %)
Myocardial infarction *
35 ( 0.4 %)
Stroke * 57 ( 0.6 %)
Pulmonary embolism *
Deep vein thrombosis *
* Includes fatal and non-fatal events
72 ( 0.7 %)
40 ( 0.4 %)
Placebo ( n = 10,067 )
1,613 ( 16 %)
574 ( 5.7 %)
1,039 ( 10.3 %)
201 ( 2 %)
48 ( 0.5 %)
55 ( 0.5 %)
66 ( 0.7 %)
71 ( 0.7 %)
41 ( 0.4 %)
Tranexamic Acid ( n = 10,034 )
227 ( 2.3 %)
155 ( 1.5 %)
72 ( 0.7 %)
31 ( 0.3 %)
10 ( 0.1 %)
2 ( 0 %)
8 ( 0.1 %)
17 ( 0.2 %)
3 ( 0 %)
Placebo ( n = 9,977 )
255 ( 2.6 %)
190 ( 1.9 %)
65 ( 0.7 %)
34 ( 0.3 %)
11 ( 0.1 %)
3 ( 0 %)
6 ( 0.1 %)
20 ( 0.2 %)
7 ( 0.1 %)
Tranexamic Acid ( n = 20,094 )
1,690 ( 8.4 %)
644 ( 3.2 %)
1,046 ( 5.2 %)
199 ( 1 %)
43 ( 0.2 %)
37 ( 0.2 %)
65 ( 0.3 %)
89 ( 0.4 %)
43 ( 0.2 %)
Placebo ( n = 20,044 )
1,868 ( 9.3 %)
764 ( 3.8 %)
1,104 ( 5.5 %)
235 ( 1.2 %)
59 ( 0.3 %)
58 ( 0.3 %)
72 ( 0.4 %)
91 ( 0.5 %)
48 ( 0.2 %) delay in the CRASH-2 study and up to 30 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 ).
“Patients ... should receive antifibrinolytic treatment as soon as possible after bleeding onset .”
— ANGÈLE GAYET-AGERON , MD
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 ]
38 ASH Clinical News January 2018