Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results

Abstract

Background: Early treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects.

Methods: The CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors.

Results: Clinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI - 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28).

Conclusions: Accurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results.

Trial registration: ClinicalTrials.gov NCT01402882 . Registered on 25 July 2011.

Keywords: Antifibrinolytic; Monitoring; Tranexamic acid; Traumatic brain injury; measurement error.

Fig. 1

Histogram showing digit preference in time to treatment for mild to moderately injured patients in CRASH-3. N = 8107. Time is from monitoring where available else clinician-recorded

Fig. 2

Bland-Atman graphs by country income level. The graph on the left is for low- and middle-income countries (N = 319, bias = − 10 min, upper limit of agreement = 74 min, lower limit of agreement = − 93 min). The graph on the right is for high-income countries (N = 137, bias = − 9 min, upper limit of agreement = 44 min, lower limit of agreement = − 61 min). The magnitude of the bias and the gap between the limits of agreement are larger in low- to middle-income compared to high-income countries

Fig. 3

Tranexamic acid effectiveness in preventing death due to TBI versus time to treatment. Mild and moderately injured patients only. N = 8107, number of head injury deaths = 537. Time to treatment is from monitoring where available else clinician-recorded

Fig. 4

The effect of monitoring and statistical adjustment methods on the treatment effectiveness of tranexamic acid verses time to treatment. N = 8107, number of head injury deaths = 537. CRASH-3 monitored time consists of monitored time where available else clinician-recorded