Aspirin for venous thromboprophylaxis after fracture: ready for prime time?

Comment on the article ‘Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture’ which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2205973. The Prevention of Clot in Orthopaedic Trauma (PREVENT CLOT) trial was an investigator-initiated, pragmatic, multicenter, randomized trial aiming to test the noninferiority of aspirin as compared with low-molecular-weight heparin (LMWH) for venous thromboprophylaxis in patients with a fracture of an extremity.1 Adult patients with an acute extremity fracture (i.e. hip to midfoot or shoulder to wrist) who had been treated operatively, or with any pelvic/acetabular fracture regardless of surgical intervention, were randomized 1:1 to receive aspirin 81 mg twice daily or enoxaparin 30 mg twice daily while hospitalized. After discharge, the duration of therapy with the randomly assigned antithrombotic agent was decided based on each hospital protocol. Key exclusion criteria were hospital admission >48 h after injury or treatment with ≥3 doses of thromboprophylaxis agent before enrollment. The primary endpoint was death from any cause at 90 days. The original primary outcome was death related to pulmonary embolism (PE), with death from any cause as a secondary outcome. Secondary endpoints included: death related to PE, nonfatal PE, deep-vein thrombosis (DVT), and bleeding events at 90 days. A total of 12 211 patients (mean age, 45 years; 38% females) were enrolled from April 2017 to August 2021 at 21 trauma centers in the United States (USA) and Canada. Less than 1% of patients had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients were hospitalized for a mean of 5 days and received a mean of 9 in-hospital thromboprophylaxis doses. Inpatient protocol adherence was high in both groups (95% aspirin and 97% LMWH). The median duration of thromboprophylaxis prescribed at discharge was 21 days in both groups. On intention-to-treat analysis, the 90-day probability of all-cause death was 0.78% in the aspirin group and 0.73% in the LMWH group (difference, 0.05%; 96.2% confidence interval CI, −0.27 to 0.38; P < 0.001 for noninferiority). No differential treatment effect on all-cause death was observed based on age (<60 vs. ≥ 60 years). The 90-day probability of death related to PE was similar in the aspirin and the LMWH groups (0.07% vs. 0.08%), as well as that of nonfatal PE (1.49% vs. 1.49%). The 90-day probability of DVT was 2.51% in the aspirin group and 1.71% in the LMWH group (difference, 0.80%; 95% CI, 0.28–1.31). Bleeding events occurred in 13.7% in the aspirin group and in 14.3% in the LMWH group (difference, −0.54%; 95% CI, −1.78 to 0.69). The results of the prespecified per-protocol analysis were consistent with those of the intention-to-treat analysis. Venous thromboembolism is a major determinant of long-term morbidity in hospitalized patients, represents a preventable cause of mortality, and has a significant impact on health care costs.2 Patients hospitalized after an extremity fracture are at high risk of venous thromboembolism due to the traumatic injury itself, the duration of surgery, and the limited mobility during recovery.3 To reduce this risk, almost all patients receive up to ∼1 month of thromboprophylaxis after surgery.4 There has been intense debate about which thromboprophylaxis regimen should be preferred, given that the benefits of thromboprophylaxis must be balanced against bleeding risk and costs. Anticoagulant therapies for venous thromboprophylaxis include injectable agents (e.g. low-molecular-weight heparin, LMWH) and newer oral agents.5 Substantial evidence supports the notion that platelet activation along with neutrophil recruitment is implicated in the initiation and propagation of deep-vein thrombosis (DVT).6 Thus, it is not surprising that low-dose aspirin may exert a protective effect against venous thromboembolism through reduced platelet activation and, at least in part, via the acetylation of proteins involved in blood coagulation (e.g. fibrinogen and prothrombin), resulting in more efficient fibrinolysis and reduced thrombin generation.7 In fact, the seminal Pulmonary Embolism Prevention (PEP) trial has clearly demonstrated that, as compared to placebo, low-dose aspirin reduces the risk of pulmonary embolism (PE) and DVT by at least a third throughout a period of increased risk in patients undergoing surgery for hip fracture or elective arthroplasty.8 This evidence is in line with observational data and with the results of more recent trials and meta-analyses.9,10 Yet, anticoagulant thromboprophylaxis remains the preferred approach, and aspirin is currently used off-label for the prevention of venous thromboembolism in both the USA and Europe.5 Within the limitations of lower-than-expected 90-day mortality, as reflected by <100 events in the whole trial, PREVENT CLOT demonstrated the noninferiority of aspirin as compared with LMWH in preventing all-cause death in patients with extremity fractures.1 Although the primary outcome was changed from death related to PE to all-cause death during enrollment because of concern about competing risk with the outcome of cause-specific death, the results were consistent for outcomes of mortality related to PE and nonfatal PE. This represents by far the largest trial comparing aspirin and an anticoagulant for the prevention of venous thromboembolism, providing further evidence in support of low-dose aspirin as a valid option in patients with traumatic injuries. No difference in bleeding risk between the two regimens was found, and the incidence of DVT was low in both groups (∼2%), although it was higher in patients receiving aspirin, mostly driven by distal DVT. The open-label design of the trial might have favored a higher diagnostic suspicion in the experimental group (i.e. aspirin) at follow-up, so that surveillance bias cannot be completely excluded, in particular for secondary endpoints like DVT. Of note, the trial population was relatively young (mean age, 45 years) and without a history of previous episodes of venous thromboembolisms, therefore at relatively lower thrombotic risk among patients with extremity fractures. Yet, the prespecified age-related sub-group analysis showed consistent results in older and younger subjects. The findings of this trial might determine a reconsideration of current guidelines for the prevention of venous thromboembolism in hospitalized patients, including the option of aspirin in patients with extremity fractures, especially in those with ischemic heart disease and/or a history of coronary revascularization who are already on treatment with single or dual antiplatelet therapy at the time of traumatic injury.11 Whether this strategy for venous thromboprophylaxis might be beneficial to other patient categories, such as those at high thromboembolic risk without recent traumatic injuries and/or surgery, needs to be tested in future studies. No new data were generated or analyzed in support of this research.