Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients

Background

Venous thromboembolism (VTE), to include both deep venous thrombosis (DVT) and pulmonary embolism (PE), represents a potential major cause of morbidity and mortality experienced by trauma patients after their initial injury.1–3 Despite extensive efforts designed to mitigate the risk of VTE development, a wide degree of variability in practice patterns persist.4 5 VTE chemoprophylaxis within the traumatically injured patient population is widely accepted as the standard of care; however, multidisciplinary opinions on the optimal medication regimen, dosing, and timing of initiation are controversial within individual medical specialties involved.

Although traumatic bleeding initially results in the consumption of coagulation factors, impaired platelet function, and hyperfibrinolysis, a rebound hypercoagulable state subsequently predominates following successful hemorrhage control and resuscitation that is characterized by supraphysiologic levels of thrombin and fibrinogen which predisposes critically injured trauma patients for increased risk of VTE.6–9 Current chemoprophylaxis regimens largely target the inhibition of thrombin, which in turn reduces the functional capacity of the plasma-based coagulation cascade and thrombin-induced platelet activation. Despite this, ongoing platelet activation through alternative pathways is hypothesized to play a critical role in post-injury VTE formation.10–13 Viscoelastic testing parameters in post-injury patients have demonstrated hypercoagulable states that may be resistant to standard low molecular weight heparin (LMWH)-based regimens and suggest that platelets may represent the dominant contributing factor for overall clot strength.10 13 This theory is further supported by a growing body of evidence that suggests that VTE rates are not affected by alterations in LMWH dosing strategies based on anti-Xa activity.14–16 Further complicating the picture, the classic teaching that PE in trauma patients arise from DVT has been challenged as recent evidence suggests a large cohort of pulmonary clots are secondary to primary pulmonary thrombosis. This phenomenon demonstrates a different set of associated risk factors than traditionally taught and may benefit from alternative chemoprophylactic management strategies.17 18

Aspirin, an oral antiplatelet agent, has demonstrated efficacy in VTE prevention within the medical and orthopedic literature.19–22 Recently, the use of aspirin as a sole prophylactic agent has been shown to be non-inferior to LMWH for VTE prophylaxis in isolated orthopedic trauma patients, highlighting the potential benefit of its use within this specific population; however, the role of antiplatelet medications for VTE prophylaxis in polytrauma patients remains largely understudied.23 24 Due to the complex nature of post-injury clot formation, along with the continued high rates of post-injury VTE despite longstanding and intensive efforts with LMWH chemoprophylaxis, we sought to assess the addition of platelet inhibition to decrease the rates of VTE formation. We hypothesized that incorporating aspirin to traditional VTE chemoprophylaxis regimens would decrease the risk of developing VTE after traumatic injury.

Methods

Results

Patient demographics

total of hen, figure 1 represents a flow diagram of the study population. The 2662 patients that did not receive sCP and did not have a VTE POA were either discharged (88%) or died (12%) within a median of 1 (1, 2) day of admission.

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Figure 1

Flow diagram of subjects included within the study. DVT, deep venous thrombosis; PE, pulmonary embolism; POA, present on admission; sCP, standard chemoprophylaxis; VTE, venous thromboembolism.

Table 1 demonstrates the demographic, injury, and VTE risk factors of the patients that received sCP compared with sCP+A. Patients that received sCP+A were older, had a higher rate of obesity, were more severely injured, had a longer length of stay, and more ventilator days. In addition, they had a higher TESS. There were no differences in the incidences of elevated thromboelastography (TEG) maximum amplitude (MA) levels. Patients that received sCP+A had higher rates of preadmission antiplatelet and vitamin K antagonist use (table 1).

Table 1

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Demographic, injury, and VTE risk factors by chemoprophylaxis regimen

Patients that received sCP+A had more known risk factors for VTE.2 28 Patients who received sCP+A were more likely to have had operations lasting longer than 2 hours, central venous lines, venous injuries requiring repair, blood transfusions of greater than four units, spine fractures, spinal cord injuries, cardiovascular disease, smoking history, or chronic obstructive pulmonary disease (COPD) (table 1).

Discussion

Despite targeted efforts to reduce the incidence of VTE after traumatic injury through risk stratification, improved and earlier chemoprophylaxis dosing, and the use of various mechanical mitigation strategies, the rate of VTE within trauma populations remains high among severely injured patients and VTE prevention is regarded one of the top priorities toward improving patient safety.2 29 30 In the current study, we demonstrated that adjunctive use of aspirin with standard chemoprophylaxis was independently associated with a 43% reduction in the hazard rate of developing VTE in trauma patients without an increased risk of associated bleeding complications. Moreover, this reduction in VTE was observed despite sCP+A patients having a greater number of risk factors and higher calculated baseline risk for VTE, compared with sCP only patients. These findings support our hypothesis that antiplatelet therapy may have a role as an adjunct to standard chemoprophylaxis regimens for decreasing the risk of developing VTE after traumatic injury.

Antiplatelet therapy has long been implicated in the risk reduction of arterial thrombosis (myocardial infarction, stroke, acute limb ischemia, etc); however, its role in the prevention of venous thrombosis, particularly following non-orthopedic trauma, has not been fully examined.31 32 The Antiplatelet Trialist’s Collaboration meta-analysis of over 50 trials in medical and surgical patients demonstrated a 10% decreased rate of DVT and a 64% relative risk reduction in PE with the use of antiplatelet therapy for 2 weeks postoperatively.31 33 The Pulmonary Embolism Prevention (PEP) trial, a multicenter, randomized controlled trial conducted in over 13,000 orthopedic surgical patients, also demonstrated that perioperative aspirin resulted in a 43% reduction in PE and 23% reduction in DVT when used in combination with additional chemoprophylaxis at the discretion of the operating surgeon.20 Aspirin alone was subsequently found to be non-inferior to LMWH for VTE prevention in patients after unilateral total hip arthroplasty over their standard course of postoperative monitoring (1.3% vs 0.3%, p=0.22).19 As a result of these studies, the American College of Chest Physicians, American Academy of Orthopedic Surgeons, and European Society of Anesthesiology have stated that aspirin is an acceptable component of multimodal VTE prophylaxis for patients undergoing major elective orthopedic operation.34–36

Trauma patients, however, represent a unique patient population with the potential to display altered platelet function based on viscoelastic testing. Previous studies have demonstrated that patients within this population who display elevated TEG MA and G values, markers for increased platelet activity and fibrin activity, are at increased risk for VTE despite appropriate VTE prophylaxis.10 37–39 Taken together, these data suggest a unimodal approach to VTE chemoprophylaxis focusing solely on the thrombin-based component of clot formation may be insufficient.10 11 Despite this, there remains a paucity of literature assessing the effects of antiplatelet medication on VTE formation in trauma patients.

Brill et al assessed the relationship between preinjury aspirin use with DVT formation and concluded that preinjury aspirin use in trauma patients was associated with a lower odds of in hospital DVT formation for those receiving heparinoid chemoprophylaxis (OR 0.35, 95% CI 0.13 to 0.93).12 The proposed protective effect of preinjury aspirin use displayed by Brill et al is in agreement with our findings suggesting antiplatelet medication may safely help to decrease VTE risk.

Of particular interest, Haac et al assessed aspirin versus LMWH as the sole VTE chemoprophylaxis regimen in orthopedic trauma patients and found no evidence of superiority on Global Rank test for either regimen.23 The Major Extremity Trauma Research Consortium subsequently followed with their multicenter, randomized control trial (PREVENT CLOT trial) which similarly found aspirin to be safe and non-inferior to LMWH with regard to mortality.24 Despite these studies being the first randomized trials to compare aspirin as a sole agent with LMWH for VTE mitigation, their focus on isolated orthopedic trauma patients yields findings that cannot be directly translated to the critically ill polytrauma patient, especially those that survive hemorrhagic shock.

Although no studies currently exist comparing standard regimens with aspirin monotherapy in polytrauma patients, the findings of our study, which suggest an additive benefit of adjunctive aspirin to standard chemoprophylaxis regimens for VTE reduction, support the need for ongoing prospective evaluation of the antiplatelet medications for VTE chemoprophylaxis in the broader trauma populations. Moreover, many authors have previously shown that VTE is most common within the first week of injury with continuation of subsequent risk for many weeks after discharge.3 20 40–42 Although our data suggest the benefits of early aspirin use in the polytrauma population, prospective study assessing continued aspirin administration following discharge should be assessed. If effective, the potential for decreased cost and ease of use associated with aspirin compared with LMWH may make it an attractive possibility.

Our current study does have several limitations. This analysis represents the largest evaluation of aspirin for VTE mitigation in non-orthopedic trauma patients; however, the retrospective nature of this study creates findings that can only be viewed as hypothesis generating, are at risk for the potential of type II error, and are inherently dependent on the reliability of the databases assessed. A subset of the patients from this study were on aspirin prior to arrival as a home medication and it remains plausible that the antiplatelet effects present at the time of injury may have played a role in VTE mitigation as opposed to post-injury aspirin initiation. Thus, future prospective analyses will be required to fully analyze the reported association.

Individual injury patterns were not directly assessed due to the granularity of the queried datasets. Further, traumatic brain injury (TBI) patients were included within our population and may represent a confounding factor due to the inherently different coagulation profiles associated with TBI patients. As patients were not randomized to distinct groups, aspirin administration was by in large left to the discretion of the attending physician, generating a selection bias, although toward sicker patients. Routine screening for VTE was not conducted during this study therefore the generalizability of our results to the rate of VTE in an institution that does screen for VTE may be misrepresented. Our findings, which reveal a lower rate of VTE compared with prior studies, further highlight that asymptomatic VTE in patients may not have been captured due to the lack of routine screening. That said, routine screening for VTE in trauma patients is not ubiquitous and, thus, our findings remain relevant for the multitude of trauma centers that do not routinely screen for VTE. Although the relationship between interruptions in chemoprophylaxis and the rate of DVT has been documented, we did not include this in our model due to inherent limitations within the dataset.43 Nevertheless, the institutional guidelines for VTE prophylaxis in this study included early administration of chemoprophylaxis immediately after admission in the absence of a contraindication or within 24 hours after cessation of bleeding. A subset of patients within this study, however, received heparin as their primary chemoprophylaxis. Although this strategy was used based on their associated clinical findings that restricted use of LMWH based on institutional policy, heparin is thought to be an inferior agent to LMWH with regard to VTE prophylaxis in trauma and may result in an altered risk factor profile compared with those who received LMWH. Beyond this, chemoprophylactic dosing adjustments based on clinical findings were not captured during this analysis, resulting in an inability to adjust for dosing changes within the statistical models. In addition, the use of thromboembolic deterrent hose and sequential compression devices in the absence of a wound that precludes their placement are routinely employed; however, compliance with these practices was not collected in these databases and was not verified through chart review. Although early walking may help decrease VTE occurrence, time to walking was unable to be captured within our dataset and therefore was also not assessed. The administration of tranexamic acid, which has been widely debated regarding its potential thrombogenicity, was also not evaluated within this study. Although 47% of patients were on 325 mg of aspirin, we could not elucidate a difference in the dosage of aspirin (81 mg vs 325 mg) that contributed to the reduced risk of VTE. Thus, optimal dosing strategies still need to be elucidated. Beyond identifying the optimal dosing regimen, it remains possible that only select patient cohorts may benefit from the addition of aspirin. We speculate that patients who display increased platelet activity via TEG-based analysis may derive the greatest potential benefit from aspirin administration. This concept, however, has yet to be formally evaluated. Finally, aspirin resistance was not assessed within this study.44

Conclusion

In this current study of over 10,000 trauma patients, we demonstrated that the addition of aspirin to standard VTE chemoprophylaxis regimens was associated with a 43% reduction in the hazard rate of developing a VTE after injury without an increase in bleeding complications. Further prospective analysis should be sought to effectively identify optimal patient populations and VTE chemoprophylaxis strategies prior to routine incorporation in clinical practice.