Ethics approval

This study was approved by the Institutional Review Board for Observation and Epidemiological Study of Kitasato University Medical Ethics Organization (KMEO B19-360). All procedures involving human participants were performed in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from the Kitasato University School of Medicine website by using an opt-out system. We informed or disclosed to the patients about the conduct of this study and provided them with ample opportunities to opt out. We anonymized all data used in this study.

Study design and population

This was a single-center retrospective observational cohort study. Data were extracted from the hospital information systems. The study population included trauma patients who received prophylactic anticoagulation therapy for VTE at Kitasato University Hospital Emergency and Disaster Medical Center between April 1, 2015, and August 31, 2020. The inclusion criteria were as follows: (1) age ≥ 18 years, (2) received initial prophylactic anticoagulants after admission, and (3) patients who had received initial anticoagulation postoperatively if surgery had been performed. The following patients were excluded: (1) patients receiving therapeutic anticoagulants for VTE (n = 16); (2) patients who died before or during prophylactic anticoagulation therapy (n = 236); (3) patients who initially received other anticoagulants, except for four prophylactic anticoagulants (heparin calcium, enoxaparin, fondaparinux, and edoxaban) (n = 1756); and (4) patients who discontinued prophylactic anticoagulation therapy due to changes in the patient’s condition after commencing prophylactic anticoagulation therapy (n = 8). In addition, among the 137 patients who met the inclusion criteria, we further excluded patients who received prophylactic anticoagulation therapy for < 7 days (n = 10) and those with missing data (n = 33). Finally, 94 patients were enrolled in this study, with 70 and 24 patients assigned to the non-BRSS and BRSS groups, respectively (Fig. 1). The BRSS group was defined as the BRSS group at the time of initial prophylactic anticoagulation therapy because the BRSS was implemented in a template on the electronic medical record.

VTE risk assessment

In our hospital, we used a computerized clinical decision support system (CCDSS) to assess the risk factors for VTE, including background factors, surgical type, and patient history [8]. CCDSS provides appropriate prophylaxis for VTE according to the VTE risk level. We assessed VTE prophylaxis at the time of admission, time of change in prophylaxis, before the start and end of prophylactic anticoagulation therapy, and further selected prophylaxis according to the VTE risk level. Mechanical prophylaxis is recommended when the risk level is low or moderate. When the VTE risk level is high, prophylactic anticoagulation therapy is recommended in addition to mechanical prophylaxis. When the VTE risk level is highest, both mechanical prophylaxis and prophylactic anticoagulation therapy are recommended. Prophylactic anticoagulation therapy was administered to all the patients if there were no contraindications. Mechanical prophylaxis, such as intermittent pneumatic compression (IPC) or compression stockings, has also been used. DVT was defined as a new thrombus within the venous system after admission, and was recorded after confirmation by vascular ultrasonography. Vascular ultrasonography was performed by a clinical laboratory technician and the results were evaluated by emergency department doctors.

Bleeding risk assessment

We created bleeding risk criteria associated with bleeding risk factors in other studies [7, 9, 10]. The bleeding risk score was determined based on bleeding risk factors associated with prophylactic anticoagulation therapy. We determined that the score would be higher if there were contraindications or if there was no experience with contraindicated medications, as the importance of avoiding these drugs was emphasized. We adjusted the distribution of BRSS to consider more than one dominant factor (Table 1). The BRSS was administered by emergency department doctors at the time of the initial prophylactic anticoagulation therapy after admission (Fig. 2). First, we evaluated eight contraindications and precautions to be considered prior to initial prophylactic anticoagulation therapy. Second, we examined five bleeding risk factors: age [7, 9, 10], body weight [11], creatinine clearance [10, 12], antiplatelet therapy [10], and P-glycoprotein inhibitors [11, 13]. The BRSS automatically calculates the bleeding risk score and displays the available information for prophylactic anticoagulation and the recommended dosage of prophylactic anticoagulation therapy. Finally, appropriate prophylactic anticoagulation was selected based on this information (Table 2). The following prophylactic anticoagulants were used: (1) UFH (Heparin calcium; Sawai); 5000 U twice daily subcutaneously, (2) enoxaparin (Clexane; Sanofi); 20 mg once or twice daily subcutaneously, (3) fondaparinux (Arixtra; Novartis); 1.5 mg or 2.5 mg once daily subcutaneously, (4) edoxaban (Lixiana; Daiichi-Sankyo); 15 mg or 30 mg once daily orally.

Table 1 Bleeding risk scores for prophylactic anticoagulationFig. 1

Flowchart of patients’ enrollment. There were 2153 trauma cases from April 1, 2015, to August 31, 2020. A total of 2016 patients met the following exclusion criteria:1) 16 patients received therapeutic anticoagulants for VTE, 2) 236 patients died before or during prophylactic anticoagulation, 3) 1756 patients initially received other prophylactic anticoagulants except for four prophylactic anticoagulants (heparin calcium, enoxaparin, fondaparinux, and edoxaban), and 4) eight patients discontinued the treatment due to changes in their condition after prophylactic anticoagulation therapy; therefore, 137 patients met the inclusion criteria. In addition, from the 137 patients who met the inclusion criteria, we further excluded patients who received prophylactic anticoagulation therapy for < 7 days (n  = 10) and those with missing data (n  = 33). Finally, 94 patients were enrolled in this study, with 70 and 24 patients assigned to the non-BRSS and BRSS groups, respectively

Fig. 2

Bleeding risk scoring system. The bleeding risk scoring system is an auto-calculation system for the bleeding risk scores. In the first step, we checked eight criteria: complications and precautions for prophylactic anticoagulation therapy. In the second step, we assessed the five bleeding risk factors. The bleeding risk scoring system calculates the bleeding risk score and displays the available information on prophylactic anticoagulation and the recommended dosage of prophylactic anticoagulation therapy. Finally, we selected appropriate prophylactic anticoagulation based on this information

Table 2 Bleeding risk scores and recommendation for prophylactic anticoagulationData collection

Data on age, sex, body weight, acute physiology and chronic health evaluation II (APACHE-II) score, sequential organ failure assessment (SOFA) score, injury severity score (ISS), major injury site, and complications were collected at the time of admission to the emergency and disaster medical center. Blood transfusions were collected during prophylactic anticoagulation therapy, if blood transfusions were performed. IPC or compression stockings for mechanical prophylaxis were collected between admission and discharge. Data on hemoglobin (Hb), platelet, creatinine clearance (CLcr), total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels were collected before the commencement of prophylactic anticoagulation therapy.

Outcome

The primary outcome was the rate of major bleeding events. Major bleeding events were defined as a decline in Hb to > 2 g/dL [14], bleeding from the digestive organs, and gastrointestinal bleeding due to the high frequency of gastrointestinal bleeding with anticoagulants such as direct oral anticoagulants [15]. The secondary outcomes were the rate of minor bleeding events, occurrence of VTE, rate of inappropriate prophylactic anticoagulation therapy, length of stay in the emergency center, length of hospital stay, and duration of prophylactic anticoagulation therapy. Minor bleeding events were classified as instances of hematuria or a shift from negative latent urinary blood before prophylactic anticoagulation to positive latent urinary blood during or after prophylactic anticoagulation. Minor bleeding events were defined based on the Bleeding Academic Research Consortium Definition for Bleeding (Type2 events) using A Consensus Report From the Bleeding Academic Research Consortium [16] and a previous study [17]. Inappropriate prophylactic anticoagulation therapy was defined as the use of contraindicated therapy, simultaneous administration of prophylactic anticoagulants with contraindicated medicines, off-label use, or overdosage or dosage of anticoagulants. The follow-up period for bleeding events was from the start of anticoagulant administration to the day after the end of administration. The follow-up period for VTE was from the time of admission to the hospital until the end of the VTE prophylactic anticoagulation therapy.

Main analysis

This study aimed to identify the effect of BRSS on major and minor bleeding events in trauma patients. Therefore, the effect of BRSS including APACHE-II score and ISS as explanatory variables on major or minor bleeding events was analyzed using multivariate logistic regression models in 94 patients finally enrolled in this study.

Sensitivity analysis

We also performed the following analysis to consider the differences in the analysis population or imbalances in patient characteristics.

1)

The effect of BRSS on major or minor bleeding events was analyzed using univariate logistic regression models in 137 patients that met the inclusion criteria with multiple imputations for missing values.

2)

The effect of BRSS on major or minor bleeding events was analyzed using univariate logistic regression models in 127 patients that met the inclusion criteria and prophylactic anticoagulation therapy for more than 7 days with multiple imputations for missing values.

3)

The effect of BRSS on major or minor bleeding events was analyzed using univariate logistic regression models in 122 patients that met the inclusion criteria and were excluded from the missing value of bleeding events.

4)

The effect of BRSS, including APACHE-II score and ISS as explanatory variables, on major or minor bleeding events was analyzed using multivariate logistic regression models in 137 patients that met the inclusion criteria with multiple imputations for missing values.

Statistical analysis

Fisher’s exact test was used to compare categorical variables between the BRSS and non-BRSS groups, while the Mann-Whitney U test was used to analyze continuous variables. Categorical data were presented as absolute values and percentages of the population, and quantitative data were presented as medians and interquartile ranges. Categorical and continuous variables were compared between the BRSS and non-BRSS groups, excluding patients with missing data from the primary analysis. However, considering the missing values in the sensitivity analysis, multiple imputations were performed using chained equations to create 100 sets of multiple imputation data in R version 4.2.2(R Development Core Team) after a Multivariate Imputation via Chained Equations (MICE) package was installed and loaded into the R library. All statistical analyses were conducted using EZR version 1.61 software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and a graphical user interface for R version 4.2.2, a modified R Commander version designed to add statistical functions frequently used in biostatistics [18]. All tests were two tailed. Statistical significance was set at p < 0.05. P-values for non-primary outcomes were nominal, to account for multiplicity.