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Aspirin Toe-to-Toe With LMWH Injections in Orthopedic Trauma

For patients with a variety of traumatic bone fractures, plain old oral aspirin provided just as good thromboprophylaxis as traditional low-molecular-weight heparin (LMWH) injections in the large PREVENT CLOT randomized trial.

Aspirin met noninferiority criteria against enoxaparin for all-cause mortality at 90 days (0.78% vs 0.73%, P<0.001 for noninferiority under a margin of 0.75 percentage points), according to the trial of over 12,000 patients from researchers led by Robert O’Toole, MD, an orthopedic trauma surgeon at University of Maryland School of Medicine in Baltimore.

Also comparable between treatments were the incidence of bleeding complications (13.72% vs 14.27%, respectively), nonfatal pulmonary embolism (1.49% for both), and other serious adverse events. Only rates of deep-vein thrombosis (DVT) were significantly worse with aspirin (2.51% vs 1.71% with LMWH), the investigators reported in the New England Journal of Medicine.

“Many patients with fractures will likely strongly prefer to take a daily aspirin over receiving injections after we found that both give them similar outcomes for prevention of the most serious outcomes from blood clots,” said O’Toole in a press release. “We expect our findings from this large-scale trial to have an important impact on clinical practice that may even alter the standard of care.”

Standard thromboprophylaxis with LMWH takes the form of injections that bring pain and bruising in some patients. In contrast, oral aspirin is relatively easy to administer and inexpensive to boot.

Matthew Costa, PhD, of the University of Oxford in England, suggested in an accompanying editorial that PREVENT CLOT should prompt guidelines to be updated to include aspirin as an option for venous thromboembolism (VTE) prevention in patients with traumatic injuries. He called this study “by far the largest trial to date” providing “compelling evidence that a readily available, inexpensive drug, taken orally, is a viable alternative to an injectable pharmacologic prophylaxis.”

Nevertheless, Costa drew attention to the small excess of DVTs in the oral aspirin arm.

“Although DVT is clearly not as serious as a fatal pulmonary embolism, it is not an inconsequential problem. Post-thrombotic syndrome affects some people who have had a DVT of the leg, and this condition can cause chronic pain and swelling,” he warned.

The CDC estimates that up to 100,000 people die from VTE each year in the U.S. These blood clots are a well-recognized complication after surgery; outside cases acquired from healthcare, they are also associated with long-distance travel, pregnancy, and cancer.

O’Toole and colleagues conducted PREVENT CLOT at 21 trauma centers in the U.S. and Canada. Participants were recruited from 2017 to 2021 and included 12,211 hospitalized adults with pelvic fractures or leg or arm fractures requiring surgery — excluding fractures of the hand and forefoot.

The study cohort had a mean age of 44.6 years, with 62.3% being men. Orthopedic trauma was the only known risk factor for VTE in a quarter of patients; 0.7% had a history of VTE and 2.5% a history of cancer.

Individuals were randomly assigned to enoxaparin (30 mg twice daily) or aspirin (81 mg twice daily). After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital — the duration of thromboprophylaxis was therefore not mandated, O’Toole’s group acknowledged.

Even so, prescribed durations of aspirin and LMWH were comparable. Patients received a mean of 8.8 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Adherence reached 87.4%, according to the study authors.

They also noted that the open-label conduct of the study may have affected secondary outcomes. Additionally, the primary endpoint had been changed from death related to pulmonary embolism to all-cause death (a change made after enrollment but without any knowledge of the trial outcomes).

Nonetheless, in the surgical setting, the benefit of aspirin thromboprophylaxis appears to extend beyond total joint arthroplasty, where it is still challenged.

“More work is needed to determine whether aspirin should also be considered for VTE prophylaxis after other types of surgeries and for nonsurgical patients who have risk factors for VTE,” Costa commented.

  • Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow


The study was funded by the Patient-Centered Outcomes Research Institute.

O’Toole reported personal ties to Imagen, Stryker Corporation, Zimmer, and Lincotek.

Costa had no disclosures.

Primary Source

New England Journal of Medicine

Source Reference: O’Toole RV, et al “Aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture” New Engl J Med 2023; DOI: 10.1056/NEJMoa2205973.

Secondary Source

New England Journal of Medicine

Source Reference: Costa M “Thromboprophylaxis after extremity fracture — time for aspirin?” New Engl J Med 2023; DOI: 10.1056/NEJMe2214045.

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