Abstract
This paper considers how results from clinical trials should be applied in the care of patients, using the results of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial of tranexamic acid in bleeding trauma patients as a case study. We explain why an understanding of the mechanisms of action of the trial treatment, and insight into the factors that might be relevant to this mechanism, is critical in order to properly apply (generalise) trial results and why it is not necessary that the trial population is representative of the population in which the medicine will be used. We explain why cause (mechanism)-specific mortality is more generalizable than all-cause mortality and why the risk ratio is the generalizable measure of the effect of the treatment. Overall, we argue that a biological insight into how the treatment works is more relevant when applying research results to patient care than the application of statistical reasoning.
Highlights
In September 1962, writing in the Keio Journal of Medicine, Japanese researchers Shosuke and Utako Okamoto reported the invention of a new chemical entity that inhibited the enzymatic breakdown of fibrin by plasmin [1]
A total of 20,211 adult trauma patients with significant bleeding, who were within 8 h of their injury, were randomly allocated to receive tranexamic acid (TXA, 1 g over 10 min followed by an infusion of 1 g over 8 h) or matching placebo
Using data from a large UK-based trauma registry, we showed that if TXA use is limited to patients with a baseline risk of more than 20%, we would miss most of the benefit, since 53% of TXA preventable deaths are in patients who had a baseline risk of death of less than 20% [16]
Summary
In September 1962, writing in the Keio Journal of Medicine, Japanese researchers Shosuke and Utako Okamoto reported the invention of a new chemical entity that inhibited the enzymatic breakdown of fibrin by plasmin [1]. A working group set up by the UK Royal College of Paediatrics and Child Health, aware of the evidence that TXA reduces bleeding in paediatric surgery, was prepared to generalise the CRASH-2 trial results to paediatric trauma [13]. They recommended that an adult TXA dose is used in children over 12 and a weight-related dose for younger children. The effect of TXA on death due to bleeding should be generalizable since this reflects the biological mechanism of action of TXA which we would expect to be broadly similar (i.e. generalizable) in different patients. Since TXA is highly cost-effective, with no serious side effects, it could be used in all trauma patients at risk of bleeding to death [24]
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