Outcome measures in clinical trials of treatments for acute severe haemorrhage

Abstract

Background: Acute 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 body: We 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.

Conclusions: All-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.

Keywords: Blood transfusion; Clinical trial; Haemorrhage; Haemostasis; Mortality; Outcome measure; Trial methodology.

Fig. 1

Primary cause of death by site of acute severe haemorrhage. Other causes of death in traumatic haemorrhage include head injury (39.8%). Other causes of death in gastrointestinal haemorrhage include cancer (10.3%) and liver disease (2.3%). Other causes of death in postpartum haemorrhage include eclampsia (2.1%) and pulmonary oedema (1.5%)

Fig. 2

Hypothetical model of the effect of a haemostatic treatment on all-cause and cause-specific mortality. The treatment reduces the risk of death due to bleeding by 25% (relative risk (RR) = 0.75) but has no effect on non-bleeding deaths (RR = 1.00). The effect on all-cause mortality (RR = 0.90) is a weighted average of the effect on cause-specific deaths, weighted according to the relative contributions of each cause. Assuming the same number of patients in each trial arm, the RR can also be calculated as the ratio of events in the treatment and placebo groups

Fig. 3

Effect of tranexamic acid on all-cause mortality and death due to bleeding in traumatic haemorrhage by time to treatment