Abstract
BackgroundAcute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions.Main bodyWe use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment.ConclusionsAll-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.
Highlights
Time-specific mortality can be used as a proxy for cause-specific mortality
Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions
When a patient has acute severe bleeding, time is of the essence, and urgent care inevitably takes priority over the administration of a trial treatment
Summary
When a patient has acute severe bleeding, time is of the essence, and urgent care inevitably takes priority over the administration of a trial treatment. Because many deaths in patients with acute severe bleeding are from comorbidities that may be unaffected by the trial treatment, even large trials will have low power to detect changes in all-cause mortality. Both benefit and harm can be obscured in all-cause mortality, and because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. This file provides two tables showing the relationship between baseline characteristics and blood transfusion in postpartum and traumatic haemorrhage. This file provides two tables showing the relationship between baseline characteristics and blood transfusion in postpartum and traumatic haemorrhage. (DOCX 27 kb)
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