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Surgery 169 (2021) 470e476

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Surgery

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Anticoagulation therapy in patients with traumatic brain injury: An Eastern Association for the Surgery of Trauma multicenter prospective study

Kazuhide Matsushima, MDa,*, Stefan W. Leichtle, MDb, Jeffrey Wild, MDc, Katelyn Young, BSc, Grace Chang, MDd, Demetrios Demetriades, MD, PhDa, EAST ACT-TBI Multicenter Study Group*

a Division of Acute Care Surgery, LACþUSC Medical Center, Los Angeles, CA b Division of Acute Care Surgical Services, VCU Medical Center, Richmond, VA c Section of Trauma and Emergency General Surgery, Geisinger Medical Center, Danville, PA d Division of Trauma and Surgical Critical Care, Mount Sinai; Division of Surgical Critical Care, University of Chicago, Chicago, IL

a r t i c l e i n f o

Article history: Accepted 12 July 2020 Available online 12 September 2020

Presented at the 32nd Annual Scientific Assembly the Surgery of Trauma, January 17, 2019. * Reprint requests: Kazuhide Matsushima, MD, A

University of Southern California, LACþUSC Medical Inpatient Tower (C), C5L100, Los Angeles, CA 90033,

E-mail address: [email protected] * The EAST ACT-TBI Multicenter Study Group: Cara

nifer Massetti, ACNP, R Adams Cowley Shock Trauma Medical Center, Baltimore, MD. Nina E. Glass, MD, David Trauma and Acute Care Surgery, Rutgers-New Jersey Me O’Bosky, MD, Julie L. Chan, MD, PhD, Division of Tr University Medical Center, Loma Linda, CA. Daniel C. Surgery, Marshfield Clinic, Marshfield, WI. Kelly A. Ri Division of Trauma, Surgical Critical Care and Injury Pre

https://doi.org/10.1016/j.surg.2020.07.040 0039-6060/© 2020 Elsevier Inc. All rights reserved.

a b s t r a c t

Background: Trauma care providers often face a dilemma regarding anticoagulation therapy initiation in patients with traumatic brain injury owing to the associated risks of traumatic brain injury progression. The aims of this study were the following: (1) to describe the current practice of anticoagulation therapy in traumatic brain injury patients and their outcomes and (2) to identify factors associated with the progression of traumatic brain injury after anticoagulation therapy. Methods: In this multicenter prospective observational study, we included computed tomography eproven traumatic brain injury patients who received anticoagulation therapy within 30 days of hos- pital admission. Our primary outcome was the incidence of clinically significant progression of traumatic brain injury after anticoagulation therapy initiation. Results: A total of 168 patients were enrolled more than 22 months. Atrial fibrillation and venous thromboembolism were the most common pre-injury and postinjury anticoagulation therapy in- dications, respectively. Overall, 16 patients (9.6%) experienced clinically significant traumatic brain injury progression after anticoagulation therapy, out of which 9 (5.4%) patients subsequently required neurosurgical interventions. Between patients with clinical progression of traumatic brain injury and patients who showed no such progression, there were no significant differences in the baseline demographics and severity of traumatic brain injury. However, anticoagulation therapy was initiated significantly earlier in patients of the deterioration group than those of the no- deterioration group (4.5 days vs 11 days, P ¼ .015). In a multiple logistic regression model, pa- tients who received anticoagulation therapy later after injury had significantly lower risk of clini- cally significant traumatic brain injury progression (odds ratio: 0.915 for each day, 95% confidence interval: 0.841e0.995, P ¼ .037).

of the Eastern Association for

ssistant Professor of Surgery, Center, 2051 Marengo Street, USA. u (K. Matsushima). Diaz Lomangino, ACNP, Jen-

center, University of Maryland H. Livingston, MD, Division of

dical School. Newark, NJ. Karen auma/Acute Care, Loma Linda Cullinane, MD, Department of ppey, MD, Jyoti Sharma, MD, vention, Hackensack University

Medical Center, Hackensack, NJ. Jeffry Nahmias, MD, MHPE, Areg Grigorian, MD, Di- vision of Trauma, Burns and Surgical Critical Care, University of California, Irvine, Or- ange, CA. Steven Allen, MD, Scott B. Armen, MD, Division of Trauma, Acute Care & Critical Care Surgery, Penn State Hershey Medical Center, Hershey, PA. John D. Berne, MD, Dalier Mederos, MD, Division of Trauma and Critical Care, Broward Health Medical Center, Fort Lauderdale, FL. Jose L. Pascual, MD, PhD, Division of Trauma & Surgical Critical Care, University of Pennsylvania, Philadelphia, PA. Shelby Resnick, MD, Department of Trauma Surgery, Kaiser Permanente-South Sacramento, Sacramento, CA. Omar Bholat, MD, Lauren Ostry, MD, Division of Acute Care Surgery, North Shore University Hospital, Manhasset, NY. Luis J. Garcia, MD, Rafael Ramos Vecchio, MD, Division of Acute Care Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA. Eleanor S. Winston, MD, Division of Trauma and Acute Care Surgery, Baystate Medical Center, Springfield, MA. Andrew F. Sabour, MD, Division of Acute Care Surgery, LAC+USC Medical Center, Los Angeles, CA.

K. Matsushima et al. / Surgery 169 (2021) 470e476 471

Conclusion: Our results suggest that early anticoagulation therapy is associated with higher risk of traumatic brain injury progression, thus a balance between bleeding and thromboembolic risks should be carefully evaluated in each case before initiating anticoagulation therapy.

© 2020 Elsevier Inc. All rights reserved.

Introduction

Anticoagulation therapy (ACT) is considered the primary treat- ment for venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism.1 ACT is also indicated for patients with medical conditions, such as atrial fibrillation (AF), which are associated with thromboembolic complications and for those with mechanical heart valves.2,3 Studies have demonstrated significant outcome benefits in patients with these conditions treated with ACT despite the associated risk of bleeding complications.4e6 As a result, an increasing number of patients currently receive ACT for various indications.7

Severely injured trauma patients are at a high risk for devel- opment of VTE. Despite aggressive mechanical and chemical pro- phylaxis, the incidence of VTE in such patients is reported to be as high as 40%.8 Patients with traumatic brain injury (TBI) are at particularly high risk for VTE.9 In addition, the number of trauma patients who are on ACT for a pre-existing medical condition is expected to increase as the population ages.10

However, adverse events associated with ACT, most importantly the progression of hemorrhagic TBI, can be catastrophic and life- threatening. Consequently, trauma care providers often face a dilemma regarding ACT initiation in the setting of TBI, owing to both the major bleeding risks of ACT and the thromboembolic complications associated with a recent TBI. Currently, the decision on ACT initiation is often based on expert opinions, as only scarce data are available regarding the safety of ACT after a TBI.11e14

Therefore, we sought the following: (1) to describe the current practice of ACT in TBI patients and associated outcomes, and (2) to identify factors associated with TBI progression after initiation of ACT. We hypothesized that earlier initiation of ACT would be associated with increased risk for clinically significant TBI progression.

Methods

Study design and patient selection

This was a prospective, multicenter, observational study spon- sored by the Eastern Association for the Surgery of Trauma (EAST) Multicenter Trial Committee. The Institutional Review Board (IRB) at the University of Southern California (Los Angeles, CA) as the coordinating center approved this study. Subsequently, this study was approved by the IRBs at the other 15 participating centers. A waiver of informed consent was granted by the IRB because of the observational nature of this research. From April 2016 to January 2018, patients who sustained computed tomography (CT)eproven hemorrhagic TBI (epidural hematoma, subdural hematoma, intra- parenchymal hemorrhage, subarachnoid hemorrhage) and received ACT during a hospital stay within 30 days of injury were selected for the study. Anticoagulants administered during the ACT included unfractionated heparin, low molecular weight heparin (LMWH), vitamin K antagonist, direct thrombin inhibitor, and direct factor Xa inhibitor. No standardized protocol was used for TBI management in the selected patients, and ACT was initiated at the discretion of clinicians and/or as per the institutional guidelines. Patients under the age of 18 years, prisoners, pregnant patients, and

transferred patients who were already on ACT were excluded from the study.

Data collection and statistical analysis

The following variables were collected at each participating center: patient baseline demographics, admission physiology, severity of injuries, head CT findings, the Rotterdam score, TBI management parameters (intracranial pressure monitoring, surgi- cal interventions including craniotomy and craniectomy), ACT pa- rameters (indications, type, and timing), and patient outcomes.15

All the data from the coordinating center and the other partici- pating centers were collected through REDCap (Research Electronic Data Capture, Harvard Catalyst, Boston, MA), a secure online data entry and management system. The primary outcome was the incidence of clinically significant deterioration of TBI after initiation of ACT characterized by any of the following: (1) a decrease in Glasgow Coma Scale (GCS) >2 points, (2) transfer to higher level of care, or (3) need for neurosurgical intervention. Other outcomes of interest included the incidence of radiographic progression of TBI as determined by repeat head CT after initiation of ACT. In addition, other hemorrhagic complications resulting in transfusion require- ment, radiologic interventions, or other surgical interventions, as well as in-hospital mortality, discharge functional status (GOS), and discharge location were collected.

Our study cohorts were divided into two groups, namely, the clinical deterioration group and the no-deterioration group. Clinical factors associated with clinical progression of TBI and patient outcomes were compared using univariate and multivariate ana- lyses. In univariate analyses, we used Student’s t-test or Mann- Whitney U test for continuous variables, and the c2 test or Fisher exact test for categorical variables as appropriate. Subsequently, multiple logistic regression analysis was performed for clinical progression of TBI after initiation of ACT, adjusting for clinically significant potential confounders. We reported odds ratios (OR) and 95% confidence intervals (CI) for each covariate. A P value < .05 was considered significant. Our sample size estimates were based on the previous retrospective study given the lack of prospective studies.12 We assumed that the incidence of clinically significant TBI progression would be up to 5%. Thus, for this prospective observational study, we anticipated requiring 126 TBI patients who receive ACT (confidence level: 99%, expected proportion: 0.05, total width of the CI: 0.1). All statistical analyses were performed using STATA 13.0 (StataCorp LP, College Station, TX).

Results

During the 22-month study period, a total of 168 patients from 16 centers met our inclusion criteria. Because of missing data for one of the patients, 167 patients were included for the analysis (Fig). The median age was 62 years (interquartile range [IQR]: 43e75) and 68.5% of patients were male. The median time for ACT was 10 days (IQR: 5e17 days). Clinical signs of neurologic deterio- ration were observed in 16 patients (9.6%) after initiation of ACT, and the median number of days from the ACT initiation to clinical deterioration was 3 days (IQR: 2e6 days). Patient characteristics and injury severity were compared between the clinical

Total patients from 16 centers

(n=168)

Patients included in the analysis

(n=167)

Incomplete data

(n=1)

Clinical deterioration observed

(n=16)

No clinical deterioration observed

(n=151)

No surgical interventions

(n=7)

Death

(n=3)

Death

(n=3)

Death

(n=5)

Surgical interventions

(n=9)

Fig. 1. Patient flow diagram.

K. Matsushima et al. / Surgery 169 (2021) 470e476472

deterioration group and the no-deterioration group (Table I). No significant difference was observed between the 2 groups with respect to basic demographics, including comorbid medical con- ditions. However, although fewer than 50% of patients in the no- deterioration group were >65 years of age, 68.8% of patients in the clinical deterioration group were >65 years of age (P ¼ .063). The majority of the patients included in the study were admitted after blunt trauma, and subdural hematoma was the most common type of TBI. The severity of TBI (radiographic and clinical signs) was similar between the 2 study groups. Neurosurgical interventions were performed within 24 h after admission in 36% of patients, distributed evenly between both study groups.

ACT was indicated for various pre-injury and postinjury co- morbid conditions (Table II). AF was the most common preinjury indication, and VTE was the most common postinjury indication. ACT was initiated significantly earlier in the clinical deterioration group than in the no-deterioration group (4.5 days vs 11.0 days, P ¼ .015). Unfractionated heparin infusion was the most commonly used agent for ACT, followed by LMWH. Direct oral anticoagulants ([DOACs] direct factor Xa inhibitor and direct thrombin inhibitor) were used in only 16 patients, all of whom were in the no-deterioration group (10.6%).

Of 151 patients in the no-deterioration group, 9 patients demonstrated radiographic progression of TBI on repeat head CT (6.0%) (Table III). No additional invasive procedures were required in these patients, but ACT was discontinued in 6 patients (66.7%). Of 16 patients with clinical deterioration, 9 patients (56.3%) required further invasive procedures (6 intracranial pressure monitoring, 2 craniectomy, 1 burr hole drainage). GCS was decreased >2 points in 14 patients (87.5%) and 8 patients (50.0%) required transfer to the intensive care unit.

A total of 11 patients (5 in the clinical deterioration group and 6 in the no-deterioration group) developed other hemorrhagic complications on ACT, including airway and gastrointestinal bleeding, retroperitoneal hematoma, and wound-related hemor- rhage. Of those, 6 patients required surgical, endovascular, or endoscopic interventions for hemorrhage control. In-hospital mortality was significantly higher in the clinical deterioration group than the no-deterioration group (37.5% vs 3.3%, P < .001). Similarly, functional outcomes upon discharge were significantly worse in the clinical deterioration group than in the no-deterioration group. In a multiple logistic regression model for analysis of clinical deterioration after ACT, the following covariates were adjusted: age (>65 years), days from injury to ACT, and the

Table I Patient characteristics and injury severity

Variables No deterioration group (N ¼ 151) Clinical deterioration group (N ¼ 16) P value Median age (IQR) 60 (42e74) 68.5 (41e74.5) .399 Age >65 y (%) 64 (42.38%) 11 (68.75%) .063 Sex (male) 104 (68.87%) 10 (62.50%) .584 Mean body mass index (SD) 27.6 (0.50) 31.7 (2.17) .088 Comorbid conditions (%) Coronary artery disease 44 (29.14) 4 (25.00) 1.000 Congestive heart failure 16 (10.60) 3 (18.75) .398 Diabetes mellitus 27 (17.88) 4 (25.00) .502 COPD 7 (4.64) 3 (18.75) .057 Liver cirrhosis 3 (1.99) 0 (0.00) 1.000 ESRD 2 (1.32) 0 (0.00) 1.000 Mechanism of injury (%) .751 Motor vehicle accident 33 (21.85) 2 (12.50) Motorcycle accident 9 (5.96) 2 (12.50) Auto versus pedestrian 25 (16.56) 2 (12.50) Blunt assault 3 (1.99) 0 (0.00) Fall 68 (45.03) 8 (50.00) Gunshot wound 3 (1.99) 0 (0.00) Stab wound 1 (0.66) 0 (0.00) Others 9 (5.96) 2 (12.50) mGCS on admission (%) .561 1 18 (11.92) 2 (12.50) 2 3 (1.99) 0 (0.00) 3 7 (4.64) 0 (0.00) 4 16 (10.60) 0 (0.00) 5 18 (11.92) 4 (25.00) 6 89 (58.94) 10 (62.50) Types of TBI (%) Epidural hematoma 14 (9.27) 2 (12.50) .654 Subdural hematoma 94 (62.25) 13 (81.25) .174 Subarachnoid hemorrhage 93 (61.59) 9 (56.25) .789 Intraparenchymal hemorrhage 34 (22.52) 4 (25.00) .762 Others 11 (7.28) 1 (6.25) 1.000 AIS head (%) .841 1 9 (5.96) 2 (12.50) 2 26 (17.22) 2 (12.50) 3 34 (22.52) 4 (25.00) 4 44 (29.14) 4 (25.00) 5 38 (25.17) 4 (25.00) Median ISS (IQR) 24 (16e33) 21.5 (15e26.5) .451 CT findings on admission Midline shift >5mm (%) 29 (19.21) 2 (12.50) .739 Rotterdam CT score (%) .781 1 37 (24.50) 5 (31.25) 2 55 (36.42) 6 (37.50) 3 36 (23.84) 2 (12.50) 4 18 (11.92) 3 (18.75) 5 4 (2.65) 0 (0.00) 6 1 (0.66) 0 (0.00) Neurosurgical interventions <24 h after admission (%) External ventricular drainage 19 (12.58) 1 (6.25) .696 Bolt 9 (5.96) 3 (18.75) .093 Craniotomy 20 (13.25) 1 (6.25) .696 Craniectomy 17 (11.26) 2 (12.50) 1.000 None 96 (63.58) 11 (68.75) .789

IQR, interquartile range; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; mGCS, Glasgow Coma Scale (motor); AIS: abbreviated injury scale; ISS, injury severity score; CT, computed tomography.

K. Matsushima et al. / Surgery 169 (2021) 470e476 473

Rotterdam CT score (Table IV). Patients who had ACT initiated after a greater number of days after injury demonstrated significantly lower risk of clinical deterioration (OR: 0.915 for each day, P ¼ .037).

Discussion

The determination to initiate ACT after TBI is difficult with un- known risks to ideally counsel patients. In this prospective multi- center study, the largest to date, we observed that approximately 10% of TBI patients developed neurologic deterioration after the initiation of ACT. Although patient demographics and TBI severity were similar between the patients of the clinical deterioration group and the no-deterioration group, earlier initiation of ACT was

significantly associated with an increased risk of clinical deterio- ration. These results suggest that early initiation of ACT in patients with TBI confers a significant risk of adverse outcomes. Therefore, the indications for ACT should be carefully evaluated in each patient and the timing of the ACT should be determined on the basis of associated risks and benefits. Once ACT is initiated, the neurologic status of the patient needs be monitored closely for any signs of neurologic deterioration.

Although safety and efficacy of chemical thromboprophylaxis after a TBI have been extensively studied in the past decade, little is known regarding the safety of its therapeutic use after TBI.16

Pandya et al13 conducted a retrospective single-center study to describe the outcome of patients who received antithrombotic

Table II Anticoagulation therapy

Variables No deterioration group (N ¼ 151) Clinical deterioration group (N ¼ 16) P value Preinjury ACT indications (%) Atrial fibrillation 31 (20.53) 3 (18.75) 1.000 Deep venous thrombosis 9 (5.96) 1 (6.25) 1.000 Pulmonary embolism 12 (7.95) 0 (0) 0.608 Mechanical heart valve 19 (12.58) 4 (25.00) 0.242 Others 12 (7.95) 1 (6.25) 1.000

Postinjury ACT indications (%) Atrial fibrillation 30 (19.87) 5 (31.25) 0.332 Deep venous thrombosis 61 (40.40) 8 (50.00) 0.595 Pulmonary embolism 39 (25.83) 2 (12.50) 0.362 Mechanical heart valve 19 (12.58) 3 (18.75) 0.446 Others 36 (23.84) 3 (18.75) 0.766

Median days to ACT (IQR) 11 (5e18) 4.5 (2.5e12) 0.015 Patient location upon initiation of ACT (%) 0.017 ICU 81 (53.64) 14 (87.50) Monitored unit (stepdown, telemetry) 33 (21.85) 2 (12.50) General ward 37 (24.50) 0 (0) Stable TBI on head CT before ACT (%) 121 (80.13) 12 (75.00) 0.744 Types of ACT (%) 0.275 Unfractionated heparin infusion 68 (45.03) 12 (75.00) LMWH 27 (17.88) 3 (18.75) Vitamin K antagonist 35 (23.18) 1 (6.25) Direct factor Xa inhibitor 15 (9.93) 0 (0) Direct thrombin inhibitor 1 (0.66) 0 (0) Others 5 (3.31) 0 (0)

Supratherapeutic aPTT or PT-INR (%)* 29 (27.36) 4 (30.77) 0.753 Simultaneous antiplatelet therapy (%) 29 (19.21) 5 (31.25) 0.324

ICU, intensive care unit; aPTT, activated partial thromboplastin time; PT-INR, prothrombin time-international normalized ratio. * Supratherapeutic � 1 incident(s) of aPTT or PT-INR value twice as high as the target range.

K. Matsushima et al. / Surgery 169 (2021) 470e476474

therapy, including ACT and antiplatelet therapy. They reported the development of a clinically significant expansion of TBI in 1 patient out of the 35 patients who were only given ACT (2.9%) and in another patient out of the 11 patients who were given both ACT and antiplatelet therapy (9.1%). This low incidence of complications associated with ACT in TBI patients was also suggested in other single-center studies.11,12,14 In a retrospective study including 26 TBI patients who received ACT, Byrnes et al11 observed only 1 pa- tient (3.8%) with minor expansion of intraparenchymal hemor- rhage as revealed by a follow-up head CT. The average time from injury to ACT was 11.9 days and, notably, 2 patients were anti- coagulated within 24 hours of injury without any hemorrhagic complications. Shahan et al14 reviewed 93 TBI patients who underwent antithrombotic therapy for associated blunt cerebro- vascular injury. They used low-intensity heparin infusion (goal activated partial thromboplastin time: 45e60 seconds) and none of the 93 TBI patients developed clinical deterioration; however, 9% of them were observed to have expansion of TBI on repeat imaging. Another single-center study including 72 TBI patients also demonstrated that 8.3% of TBI patients on ACT developed hemor- rhagic TBI, as demonstrated by repeat head CT.12 However, none of them developed any signs of neurologic deterioration.

In contrast to earlier studies, 9.6% of our study patients devel- oped clinically significant neurologic deterioration after ACT initi- ation post TBI. Of those, 56.3% required further surgical interventions for the control of TBI progression. Overall, in-hospital mortality rate and functional outcomes upon discharge were significantly worse in the clinical deterioration group than in the no-deterioration group. The median time to ACT in the clinical deterioration group was 4.5 days (IQR: 2.5e12 days), but there were also 4 patients for whom ACT was initiated after 12 days after injury (13, 13, 17, 26 days). Although the heterogeneity between each study makes comparisons challenging, the results in our study suggest that the use of ACT is not always safe in patients with a recent TBI. Thus, clinicians should consider all the associated risks

and benefits of ACT for each case. In particular, patients should always be evaluated for their comorbid conditions before ACT administration. For example, the risk of thromboembolic compli- cations for patients with a mechanical mitral valve would be different from patients with AF and a low CHA2DS2-VASc score.

17,18

In a recent randomized trial, forgoing perioperative bridging ACT was found to be non-inferior to LMWH bridging for preventing arterial thromboembolism in AF patients undergoing elective surgery.19

The second aim of this study was to identify clinical factors associated with risk of clinically significant neurologic deteriora- tion after initiation of ACT. In one retrospective study, multiple logistic regression analysis was performed to identify significant predictors of hemorrhagic expansion following ACT with the help of repeat head CT.12 Age ˃65 years was observed to be a significant predictor; whereas the Rotterdam score on initial CT and the timing of ACT (<10 days after injury) were not significantly associated with expansion of hemorrhagic TBI. Another retrospective study sug- gested that subdural hematoma is a significant risk factor associ- ated with hemorrhagic expansion post antithrombotic therapy.13

However, our multivariate analysis found that age (>65 years) and the Rotterdam score on initial CT were not significantly asso- ciated with clinical deterioration post ACT. Rather, the timing of ACT appeared to be the most important risk factor for clinical deterioration. Although we were unable to provide specific recommendations for the timing of ACT initiation because of a relatively small sample size, the duration between injury and the initiation of ACT should be the major driving factor in discussions with the patient regarding the risk of TBI progression.

Our study has several limitations. First, owing to the observa- tional nature of the study, the decision to initiate ACT was made based on clinical judgment. As a consequence, there might be sig- nificant variations in selecting patients who received ACT between each participating center. As we did not include a group of patients for whom ACT was indicated but not initiated during their hospital

Table III Patient outcomes

Variables No deterioration group (N ¼ 151) Clinical deterioration group (N ¼ 16) P value Radiographic progression of TBI (%) < .001 Yes 9 (5.96) 10 (62.50) No 93 (61.59) 3 (18.75) No repeat CT imaging 49 (32.45) 3 (18.75)

Median days from ACT to radiographic progression (IQR) 2 (2e6) 2.5 (1e5) .617 ACT discontinuation (%) 6/9 (66.67) 12/16 (75.00) .673 Invasive interventions for progression of TBI (%) 0 (0.00) 9 (56.25) .008 Other hemorrhagic complications (%) 6 (3.97) 5 (31.25) .001 In-hospital mortality (%) 5 (3.31) 6 (37.50) < .001 Median length of ICU stay (IQR) 11.5 (2e23) 15 (11e21) .114 Median length of hospital stay (IQR) 21 (9e34) 21 (15e31) .535 Discharge disposition (%) .066 Home or back to prior living situation 42 (28.77) 0 (0.00) Rehabilitation facility 61 (41.78) 3 (33.33) Nursing home or long-term care facility 40 (27.40) 6 (66.67) Others 3 (2.05) 0 (0.00)

Glasgow Outcome Scale (%) < .001 1 5 (3.31) 6 (37.50) 2 8 (5.30) 0 (0.00) 3 48 (31.79) 9 (56.25) 4 31 (20.53) 1 (6.25) 5 59 (39.07) 0 (0.00)

ICU, intensive care unit.

Table IV Multiple logistic regression for clinically significant deterioration*

Variables Odds ratio 95% Confidence interval P value

Age >65 y 2.892 0.917e9.123 .070 Days from injury to ACT (1-day increment) 0.915 0.841e0.995 .037 Rotterdam CT score >3 2.450 0.570e10.527 .228

* Hosmer-Lemeshow goodness-of-fit test: P ¼ .59

K. Matsushima et al. / Surgery 169 (2021) 470e476 475

stay, thromboembolic risks in those patients remain unknown. Similarly, the decisions on obtaining the pre ACT and post-ACT head CTs to evaluate the progression of TBI were made at the clinicians’ discretion. Therefore, withholding ACT based on radiographic progression of TBI on a repeat CT might have prevented clinical progression for patients in the no-deterioration group. Second, the definition of clinically significant progression of TBI in our study can be subjective. For example, we did not implement a universal protocol for determining surgical indications in patients with worsening TBI. Third, the type of anticoagulant that should be considered for the first-line treatment in the patients with a recent TBI remains unknown. In the meantime, clinicians should be familiar with the pros and cons of commonly used anticoagu- lants.20 Our results suggest that DOACs might be safe to be used in patients with recent TBI (0 of 10 patients developed clinically sig- nificant progression of TBI). Although other retrospective studies demonstrated improved clinical outcomes related to the preinjury use of DOACs compared with vitamin K antagonists in patients with TBI, further prospective studies with a larger sample size are still required.21,22 Finally, we were unable to determine the long-term risk of hemorrhagic complications post ACT in TBI patients. In a retrospective cohort study using the administrative database in Denmark, resumption of warfarin therapy for AF in TBI patients was significantly associated with a lower relative risk of death in 1 years after their discharge.23 It is interesting to note that resuming warfarin therapy in TBI patients was also associated with a lower rate of recurrent intracranial hemorrhage.

In conclusion, patients with recent TBI who require ACT for indicated conditions must be carefully evaluated to determine both their risk for progression of TBI and thromboembolic complica- tions. The results of our study suggest that earlier initiation of ACT

is associated with an increased risk of clinically significant TBI progression. Therefore, the timing of ACT initiation should be tailored for each case based upon this risk and the risk for throm- boembolic complications without ACT.

Conflict of interest/Disclosure

All authors deny any potential conflict of interest.

Funding/Support

The authors declare that neither internal nor external financial support was used for this study.

Acknowledgments

The authors would like to thank Monica Wong for the technical support in conducting this multicenter prospective study.

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