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The effect of time to international normalized ratio reversal on intracranial hemorrhage evolution in patients with traumatic brain injury

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Last updated:12th Mar 2020
Published:12th Feb 2020
This retrospective analysis of data collected from a US Level II trauma centre attempts to determine the effect of international normalised ratio (INR) reversal time on haemorrhage evolution in traumatic brain injury (TBI) patients taking prehospital anticoagulants (AC).

Currently, rapid reversal of INR by factor replacement therapy or platelet addition is recommended by both the American Heart Association and the American Stroke Association for TBI patients taking prehospital AC medication to minimise intracranial haemorrhage expansion. Several studies have shown the associated risks of taking prehospital AC medication in TBI patients: greater risk of intracranial haemorrhage evolution, a threefold increase in rate of worsening in repeat head computed tomographic (CT) scans, increased length of hospital stay and increased mortality (McMillian & Rogers, 2009; Peck et al., 2014; Joseph et al., 2014; Franko et al., 2006). One group of patients particularly at risk of intracranial haemorrhage due to TBIs are the elderly. Between 1992 and 2009, the incidence of TBIs within the elderly population of Pennsylvania almost doubled (Ramanathan et al., 2012). What’s more, this patient group are often taking prehospital AC medication, putting them at greater risk.

However, contradictory evidence has led to uncertainty of the benefits of rapid INR reversal in this patient population. Some cases have shown a positive increase in favourable patient outcomes (Ivascu et al., 2005), while others have shown that early reversal was not associated with an improved neurological outcome and may not be sufficient as a stand-alone treatment for TBI patients (Dowlatshahi et al., 2012; Goldstein et al., 2006).

Andrews et al., intended to add to the existing literature on INR reversal and attempt to determine the effect of time to INR reversal on intracranial haemorrhage evolution in TBI patients taking prehospital AC medication. At a suburban Level II trauma centre, 96 patients were identified between February 2011 and December 2013, as having had an intracranial haemorrhage caused by a TBI while taking prehospital AC medication. Initial INR, time of INR reversal, initial and subsequent CT results and presence of intracranial haemorrhage evolution data from patient charts were used to create this analysis. The study population had an initial INR of >2 and reversed to <1.5 during their hospital admission. The study population was predominantly geriatric trauma patients, with a median age of 83 years old (range 76–88).

Interestingly, the study found a significant association between INR reversal in less than 10 hours with a decreased odds ratio for intracranial haemorrhage evolution. 49 patients (51%) achieved reversal in less than 10 hours (AOR = 0.38; 95% CI [0.14, 0.98] p = 0.043). What’s more, age, Glasgow Coma Scale (GCS), Injury Severity Score (ISS) and Head Abbreviated Injury Scale (AIS) Score weren’t seen to have a significant effect on reversal time.

On the other hand, no association was seen when INR reversal was achieved in under 5 hours. As previous data has supported rapid reversal the non-significance within this study is likely due to the small number of patients who successfully achieved INR reversal in under 5 hours; 14 patients (14.6%) in comparison to the 49 patients (51%) who achieved reversal in less than 10 hours. This is certainly a limitation of the study and opens up the need for further research in a wider population.


Despite contradictory information, it has been previously demonstrated that earlier presentation to a physician and, therefore, quicker neurological intervention results in a decreased risk of intracranial haemorrhage evolution (Ivascu et al., 2005). During this study, protocol implementation was not evaluated and as a result, early identification and early surgical intervention were not significant confounding factors; supporting the association of early INR reversal time and decreased intracranial haemorrhage evolution.

While rapid response protocols have been seen to reduce the risk of intracranial haemorrhage evolution, this study found that the mean time for INR reversal was 13.3 hours - much longer than the desired rapid reversal time frame. This longer time to INR reversal ultimately leads to poorer outcomes for patients. A number of factors were identified that may have contributed to this delay: longer waiting times in triage, time from presentation to the diagnosis of intracranial haemorrhage, time to initial INR, and finally time to administration of reversal agent. The discovery of these combined factors leading to slower INR reversal time suggests a multidisciplinary team approach for timely treatment and an improvement of patient care is required.

These delays may well have impacted the results of this study with 34 patients (35.4%) having intracranial haemorrhage evolution during follow-up head CT scans. In addition, there was a mortality rate of 12.5% (12 patients). In order to establish the bigger picture of INR reversal time and determine if these results could have been prevented with quicker INR reversal further research is required.

To summarise, this study has demonstrated reversing elevated INR in AC-taking TBI patients in less than 10 hours may decrease the risk of intracranial haemorrhage evolution. However, as this study focuses on a single suburban Level II trauma unit in the USA, further studies are required globally with much larger study populations, as different local protocols may have an impact on time to INR reversal and the success of minimising intracranial haemorrhage expansion.