From Pages to Practice

By Robert Smyth, MD, MSc

Published March 15, 2023


Venous thromboembolism (VTE) is the most common cause of preventable death in hospitalized medical patients, yet pharmacologic prophylaxis remains underutilized. The Virchow’s triad of venous stasis, vascular injury, and hypercoagulability is key in the assessment of VTE risk. Based on the Padua Score — a validated risk assessment model that determines risk of VTE and need for anticoagulation in hospitalized patients — a score of ≥4 points is considered high risk, with decreased mobility assigned 3 points and recent trauma or surgery 2 points. Thus, patients with extremity fractures requiring surgery or pelvic or acetabular fractures are considered high risk and require thromboprophylaxis.

Low-molecular-weight heparin (LMWH), a drug that binds to and accelerates the activity of antithrombin III, is considered safe and effective for thromboprophylaxis. Although LMWH is associated with a low risk of bleeding, subcutaneous injections can be uncomfortable and leave local bruising, raising concerns about adherence, especially after surgery. Aspirin also has antithrombotic properties, (including reductions in thrombin and thromboxane A2, an important cofactor in platelet function) and has been shown to have similar efficacy as rivaroxaban in the prevention of VTE following total hip arthroplasty. Although clinical guidelines recommend LMWH for thromboprophylaxis after a fracture, patients may prefer aspirin given its lower cost and oral administration, but head-to-head comparisons are lacking.

To that end, the authors of the Prevention of Clot in Orthopaedic Trauma (PREVENT CLOT) trial compared the effectiveness and safety of thromboprophylaxis with aspirin or LMWH in patients with limb fracture or pelvic or acetabular fracture. They randomized 12,000 patients at 21 sites to receive enoxaparin (30 mg) or aspirin (81 mg) twice daily during hospitalization. Once discharged, thromboprophylaxis was continued according to local clinical protocols.

The primary outcome of death from any cause at 90 days was similar in the two groups: 47 patients (0.78%) in the aspirin group versus 45 patients (0.73%) in the LMWH group (P<0.001 for a noninferiority margin of 0.75 percentage points). Secondary outcomes, including incidence of nonfatal pulmonary embolism and serious bleeding, also did not differ significantly between the two groups, but patients who received aspirin had a higher incidence of DVT (2.51% vs. 1.71%). The authors concluded that thromboprophylaxis with aspirin was noninferior to LMWH in patients with extremity fractures requiring surgery or pelvic or acetabular fractures.

The following caveats should be noted when interpreting these results: Patients with a history of VTE in the past 6 months, receiving therapeutic anticoagulation at the time of admission, or with a chronic blood-clotting disorder were excluded. Transfusion of ≥2 units of blood was required in 13% to 14% of patients in both groups. The average duration of therapy was 3 to 4 weeks, requiring many LMWH injections.

Nonetheless, the results of this trial suggest that offering aspirin for thromboprophylaxis can safely alleviate some of the burden of illness resulting from LMWH. We will have to wait and see if guidelines change to incorporate aspirin into thromboprophylaxis recommendations.

Read the following NEJM Journal watch summary for more details of the PREVENT CLOT study.

Venous Thromboembolism Prophylaxis After Fractures

Allan S. Brett, MD, reviewing Major Extremity Trauma Research Consortium (METRC). N Engl J Med 2023 Jan 19

Patients with major fractures often receive antithrombotic drugs to prevent venous thromboembolism (VTE), but the optimal agent is unclear. This trial from 21 U.S. and Canadian trauma centers included 12,000 hospitalized patients with extremity fractures that were treated operatively or pelvic fractures treated operatively or nonoperatively; patients with fractures limited to hands or forefoot were excluded.

Patients were randomized to receive aspirin (81 mg twice daily) or enoxaparin (usually 30 mg subcutaneously, twice daily), starting during hospitalization. The duration of posthospitalization prophylaxis (median, 21 days) was left to clinician judgment. The lower and upper extremities were involved in 88% and 27% of patients, respectively; some patients had fractures in both locations. Outcomes at 90 days were as follows:

  • Overall mortality was not significantly different in the aspirin and enoxaparin groups (0.78% and 0.73%).

  • Incidence of nonfatal pulmonary embolism was identical in the two groups (1.5%).

  • Deep venous thrombosis (DVT) occurred significantly more often with aspirin than with enoxaparin (2.5% vs. 1.7%), but distal DVT accounted for most of the difference.

  • Serious bleeding and wound complications occurred with similar frequency in the two groups.

Comment: Aspirin and enoxaparin recipients had similar efficacy and safety outcomes. The slightly higher incidence of distal DVT with aspirin probably doesn't override the fact that aspirin — which requires no injections and is inexpensive — is more acceptable to most patients (BMJ Open 2017; 7:e016676. opens in new tab). These results will surely influence future guideline recommendations on VTE prophylaxis for patients who undergo surgery for major fractures.

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Robert Smyth, MD, MSc, is a 2022–2023 NEJM Editorial Fellow. He is currently an Assistant Professor of computational biomedicine at the Boston University School of Medicine.