By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: A three-year analysis of a prospectively maintained database with traumatic brain injury patients revealed that novel oral anticoagulant use is associated with increased risk of intracranial hemorrhage progression, neurosurgical intervention, and mortality.

SOURCE: Zeeshan M, Jehan F, O’Keeffe T, et al. The novel oral anticoagulants (NOACs) have worse outcomes compared with warfarin in patients with intracranial hemorrhage after TBI. J Trauma Acute Care Surg 2018;85:915-920.

Despite the increasing use of novel oral anticoagulants (NOACs) within the healthcare system, emergent reversal of these agents remains a management challenge. There is little data comparing the use of NOACs to warfarin in patients with intracranial hemorrhage (ICH) after traumatic brain injury (TBI). Zeeshan and colleagues conducted a three-year analysis of their prospectively maintained database examining the outcomes after TBI in patients taking NOACs compared to those taking warfarin. Researchers analyzed all adult trauma patients admitted to a single Level I trauma center with a diagnosis of TBI. Inclusion criteria were all adult TBI patients with ICH on initial head CT scans who received anticoagulation prior to injury. Anticoagulants included warfarin or NOACs, including direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (rivaroxaban and apixaban). Patients with documented bleeding diathesis, chronic liver disease, penetrating mechanisms of injury, or those who died within 24 hours of trauma were excluded. The primary outcomes were ICH progression and the need for surgical intervention. Progression was defined as an increase in the size of an existing hemorrhage or development of a new hemorrhage not previously seen on CT head. The need for surgical intervention was defined as intracranial pressure monitoring, craniotomy, or craniectomy that was performed as a result of ICH progression. Secondary outcomes included complications in the hospital, discharge to rehabilitation hospital or skilled nursing facility (SNF), hospital and ICU length of stay, and in-hospital mortality.

From the 1,459 eligible patients, 210 matched TBI patients were identified (70 patients on NOACs and 140 patients on warfarin). The matched groups were similar in age (P = 0.21), Glasgow Coma Scale (GCS) score (P = 0.54), mechanism of injury (P = 0.61), Injury Severity Score (P = 0.62), and type and size of ICH (P = 0.09). Compared to patients on warfarin, patients who had been treated with NOACs prior to injury had a higher rate of progression (P = 0.03), neurosurgical intervention (P = 0.04), mortality (P = 0.04), and longer ICU length of stay (P = 0.04). There was no difference in hospital length of stay (P = 0.22) or SNF disposition (P = 0.14). A sub-analysis for severe TBI patients (defined as GCS ≤ 8) revealed no difference in rate of progression (P = 0.59), neurosurgical intervention (P = 0.62), or mortality (P = 0.81). NOAC use was associated with an increased risk of ICH progression, neurosurgical intervention, and mortality after mild and moderate TBI. It is important to carefully keep these risks in mind when deciding on the optimal form of anticoagulation for each individual patient.

COMMENTARY

Patients on oral antithrombotics are at increased risk of ICH after trauma.1 Although vitamin K antagonists have been the only class of oral anticoagulants available for decades, many clinicians have substituted NOACs for warfarin because of the ease of use. NOACs have a rapid onset of action, fewer drug interactions, no dietary limitations, no laboratory monitoring requirements, and predictable pharmacokinetics.2 The difficulty in NOAC reversal in cases of serious, life-threatening hemorrhage, especially from ICH after TBI, remains an important clinical concern in the setting of growing use of these agents. The findings of Zeeshan and colleagues underscore this problem, finding that prior NOAC use was associated with an increased risk of ICH progression, neurosurgical intervention, and mortality after a mild and moderate TBI when compared to similar patients receiving warfarin.

Previous data regarding the outcomes of TBI patients on NOACs were published by Kobayashi and colleagues and conducted by the American Association for the Surgery of Trauma.3 Although in this study researchers found that TBI patients on NOACs were not at higher risk of ICH, ICH progression, or death, the study population was substantially different. These investigators included all trauma patients admitted to the hospital on prior dabigatran, rivaroxaban, apixaban, warfarin, aspirin, or clopidogrel. In the study by Kobayashi and colleagues, only 30% of the patients had ICH on presentation, while ICH was an inclusion criterion in the Zeeshan et al study. The Kobayashi study also included lower rates of subdural hematoma (SDH) (19% vs. 30%) and older patients with a lower Injury Severity Score. An additional limitation to the study was that only 10% of the study population was taking a NOAC.

Although NOACs often are favored for their attractive pharmacokinetic qualities previously discussed, the reversal strategies for these novel agents are still evolving.4 Ideally, most forms of anticoagulation have a specific reversal agent or antidote for episodes of serious or life-threatening bleeding. Dabigatran’s reversal agent is idarucizumab, but this anti-dabigatran monoclonal antibody fragment often is unavailable to many because of its cost.5 Andexanet alfa recently was approved as a reversal agent for the oral direct factor Xa inhibitors (apixaban, betrixaban, edoxaban, and rivaroxaban), but again, it is costly with limited availability. There are other promising antidotes under development, including a small molecule antidote, PER977, and a mutant form of factor Xa, FXa(I16L), but they are not currently available. As a result, clinicians often are left with less targeted interventions, such as four-factor prothrombin complex concentrate (4-factor PCC) and fresh frozen plasma in this setting.

The use of NOACs will continue to rise, and critical care providers should ensure that their hospitals have a systematic protocol available to treat patients receiving these agents who present with life-threatening or uncontrolled bleeding. Although the Zeeshan study appears to have been more deliberate in addressing the question of NOAC vs. warfarin in TBI, it also had limitations that warrant further consideration. The study was a single-center, observational study without a true control group. Because it was an observational study, there is an association between NOAC use and increased risk of progression of ICH, neurosurgical intervention, and mortality after mild and moderate TBI, but causation cannot be assigned. There also is concern for sampling bias, since the institution was a Level I trauma center serving as a quaternary referral hospital. Although the manuscript relays the details of the reversal agents (fresh frozen plasma, prothrombin complex concentrate, vitamin K) were recorded, the results of these data points were not mentioned again throughout the manuscript. Not knowing the frequency, timing, or type of reversal agent for each case is a major limitation. Despite these substantial limitations, this study challenges a provider to balance risks and benefits of a particular anticoagulant carefully and to be ready to intervene with rapid recognition and reversal in patients with ICH. These findings also highlight the need for future larger, multicenter studies to further explore the outcomes of patients on NOACs after traumatic brain injury. 

REFERENCES

  1. Siracuse JJ, Robich MP, Gautam S, et al. Antiplatelet agents, warfarin, and epidemic intracranial hemorrhage. Surgery 2010;148:724-729; discussion 729-730.
  2. Verdecchia P, Angeli F, Aita A, et al. Why switch from warfarin to NOACs? Intern Emerg Med 2016;11:289-293.
  3. Kobayashi L, Barmparas G, Bosarge P, et al. Novel oral anticoagulants and trauma: The results of a prospective American Association for the Surgery of Trauma Multi-Institutional Trial. J Trauma Acute Care Surg 2017;82:827-835.
  4. Dzeshka MS, Pastori D, Lip GYH. Direct oral anticoagulant reversal: How, when and issues faced. Expert Rev Hematol 2017;10:1005-1022.
  5. Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 2018;15:273-281.