Clinical practice guidelines recommend the use of thromboprophylaxis following the occurrence of orthopedic trauma to prevent the development of deep vein thromboses (DVT) and pulmonary embolisms (PEs). However, no head-to-head clinical trials exist comparing the use of aspirin, an inexpensive oral antiplatelet agent, to the use of LMWH for venous thromboembolic (VTE) prophylaxis.

The Prevention of Clot in Orthopaedic Trauma (PREVENT CLOT) study, a pragmatic, randomized trial, was conducted from April 2017 to August 2021 in 21 trauma centers in the United States and Canada to examine the noninferiority of aspirin compared with LMWH in terms of effectiveness and safety for thromboprophylaxis in patients following orthopedic trauma resulting in fracture.

The goal of this noninferiority study was to show that the effect of aspirin (the test drug) was not inferior to the effect of the active control (LMWH). The noninferiority margin for death from any cause utilized in this study was 0.75 percentage points, which represented the largest clinically acceptable difference allowed between aspirin and LMWH. Noninferiority was demonstrated when the upper limit of the confidence interval did not exceed the noninferiority margin.

Patients aged 18 years or older who had an extremity fracture that was treated either surgically or a fracture of the pelvis or acetabulum that was treated either operatively or nonoperatively were included in the study. Patients were excluded if they had fractures of the hand, forefoot, presented >48 hours post injury, received three or more doses of thromboprophylaxis prior to randomization, had a history of VTE in the past 6 months, were therapeutically anticoagulated, or if they had a chronic blood clotting disorder.

Patients were randomized to receive either aspirin 81 mg twice daily or SC enoxaparin 30 mg twice daily (dose adjusted for obesity or renal disease). Thromboprophylaxis was continued to hospital discharge or based upon hospital protocol. Adherence was assessed.

The primary outcome of the study was death from any cause at 90 days. Secondary efficacy outcomes were cause-specific death, nonfatal PE, and DVT. Secondary safety outcomes included bleeding events, wound complications, and surgical-site infections.

At the conclusion of the study in February 2022, 12,211 patients had been randomly assigned to either the aspirin (6,101 patients) or the LMWH (6,110 patients) group. The mean age of the study population was 44.6 years, with over 60% of patients being male. The majority of injuries (almost 90%) involved the lower extremities (LE), with over two-thirds of fractures affecting the LE only and approximately one-fifth involving both LE and upper extremities.

Noninferiority was demonstrated for death during the 90-day follow-up period with a probability of death of 0.78% in the aspirin group (47/6,101 patients) and 0.73% in the LMWH group (45/6,110; difference 0.05 percentage points; 96.2% CI, –0.27 to 0.38). Although aspirin was noninferior to LWMH in preventing death from any cause, it was not superior to LMWH. Noninferiority was also established in patients aged <60 years (difference 0.02 percentage points; 95% CI, –0.21 to 0.25) but not for those aged >60 years (difference 0.16 percentage points; 95% CI, –0.94 to 1.25).

For the secondary outcomes, the 90-day probability of DVT and distal DVT were lower in the LMWH group than in the aspirin group. The 90-day probability of DVT occurred in 151 aspirin-treated patients (2.51%) and in 103 LMWH-treated patients (1.71%) with a difference of 0.80 percentage points (95% CI, 0.28-1.31). A between-group difference of 0.58 percentage points (95% CI, 0.20-0.96) was found for distal DVT. The probability of proximal DVT was similar between both treatment groups (between-group difference 0.25% percentage points; 95% CI, –0.12 to 0.62). The incidence of nonfatal PE was the same in both treatment groups (90-day probability of 1.49%).

While the majority of nonfatal PE occurred within 7 days of randomization, the median time for the occurrence of DVT was 16 days following enrollment in the study.

The incidence of bleeding complications was similar between the aspirin and LMWH groups (13.72% for aspirin vs. 14.27% for LMWH, difference –0.54 percentage points; 95% CI, –1.78 to 0.69). Bleeding occurred shortly after initiation of therapy the median time to an event of 2 days. Wound complications and deep surgical-site infections were similar between the groups.

The authors concluded that in patients with extremity fractures who either underwent surgery or who had a pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to the use of LWMH in preventing death. The oral antiplatelet agent was also associated with a low incidence of DVT, PE, and 90-day mortality.

This study provides useful information for pharmacists who are involved in managing thromboprophylaxis of orthopedic surgical patients.

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