What was the research about?
After the fracture of certain bones, like the hip, thigh, or the long bones in the arms or legs, people have a high risk of getting blood clots. Blood clots form in the veins of the arms and legs and can be fatal if they travel to the lungs. A blood thinner called low molecular weight heparin, or LMWH, can help prevent clots. LMWH is injected under the skin. Aspirin is another medicine that can prevent clots; it is taken by mouth and is an inexpensive medicine.
In this study, the research team compared aspirin versus LMWH to prevent blood clots after treatment for a fracture in the hip, thigh, or the long bones in the arms and legs. The team wanted to learn if aspirin wasn’t any worse than LMWH in preventing deaths after treatment for a fracture.
What were the results?
At three months, the group of patients who received LMWH and the group who received aspirin didn’t differ in:
- The percentage of patients who died for any reason
- The percentage of patients who had blood clots in the lungs, bleeding, infections, or wound issues
- Patient out-of-pocket costs
Compared with the group of patients who were prescribed LMWH, the group of patients who were prescribed aspirin was more likely to be satisfied with and continue taking their medicine. But they had slightly higher rates of blood clots in the leg. It is unclear if this difference in blood clot rates—1.7 percent versus 2.5 percent—is clinically meaningful.
Who was in the study?
The study included 12,211 adults receiving treatment for fractures at one of 21 trauma centers in the United States. The average age was 45, and 62 percent were men.
What did the research team do?
The research team assigned patients by chance to receive a prescription for either LMWH or aspirin. Patients took LMWH by injection twice a day. Patients took aspirin by mouth twice a day. Doctors decided how long patients should be on each medicine.
After three months, the research team reviewed health records for deaths and other health outcomes. The team interviewed patients about how satisfied they were with their treatment. They also tracked how often patients took their medicine and their out-of-pocket costs.
What were the limits of the study?
All patients could receive up to two doses of LMWH before starting the study. Results may have differed if all patients had only received either aspirin or LMWH.
Future studies could compare aspirin with other blood thinners for preventing blood clots after a fracture.
How can people use the results?
Patients and doctors can use the results when considering medicines to prevent blood clots after a fracture in the hip, thigh, or the long bones in the arm or legs.
To compare the effectiveness of low molecular weight heparin (LMWH) versus aspirin in reducing all-cause mortality and blood clots in patients treated for fractures
|Study Design||Randomized controlled trial|
|Population||12,211 adult patients with operative extremity fractures proximal to the metatarsal or carpal bones or pelvic or acetabular fractures treated operatively or nonoperatively at 1 of 21 trauma centers in the United States|
Primary: all-cause mortality
Secondary: pulmonary embolism-related death, pulmonary embolism, deep vein thrombosis events, bleeding events, wound complications, infection of a deep surgical site, patient satisfaction with medication, patient out-of-pocket costs, inpatient medication adherence
|Timeframe||3-month follow-up for primary outcome|
This randomized controlled non-inferiority trial compared the effectiveness of LMWH with aspirin in reducing all-cause mortality and blood clots in patients who were treated for fractures.
Researchers randomized patients to receive either LMWH or aspirin after receiving treatment for a fracture. Patients receiving LMWH were prescribed a 30-milligram (mg) dose of the medication as a shot subcutaneously twice a day. Patients receiving aspirin were asked to take an 81-mg pill twice a day. Clinicians decided how long the patient should take medications on a case-by-case basis.
Three months after patients received their prescriptions, researchers recorded mortality and health outcomes. They also conducted interviews with patients about their satisfaction with the medication and tracked medication adherence and out-of-pocket costs.
The study included 12,211 adult patients receiving treatment for fractures at one of 21 trauma centers in the United States. The average age of patients was 45, and 62% were male.
Patients, clinicians, and representatives from professional organizations and insurers helped design the study.
The study found that, at three months, aspirin was not inferior to LMWH in reducing all-cause mortality among patients (difference, 0.05%; 96.2% confidence interval [CI]: -0.27%–0.38%; p<0.001 for a non-inferiority margin of 0.75%).
Compared with patients who were prescribed LMWH, patients who were prescribed aspirin were more likely to be satisfied with and adhere to their medication (both p<0.001) but they were also more likely to have deep vein thrombosis in the leg (difference, 0.80%; 95% CI: 0.28%–1.31%). Of note, this relatively small difference was driven by blood clots that were lower in the leg and may be less clinically important. The two medications did not differ significantly in other outcomes.
All patients were eligible to receive two doses of LMWH at the discretion of their doctors before study enrollment. However, only a third of the patients in the aspirin group received two doses of LMWH, and this medication represented a small part of the patients’ treatment. It is unknown whether these doses affected study results.
Conclusions and Relevance
Aspirin was not inferior to LMWH in reducing all-cause mortality in patients who were treated for fractures. Outcomes were similar for other health complications except for blood clots in the lower leg, which were more common with aspirin than with LMWH. Patients had higher satisfaction with and better adherence to aspirin than LMWH.
Future Research Needs
Future research could compare aspirin with other commonly used oral blood thinners, such as rivaroxaban, to prevent blood clots in patients who were treated for fractures.
Final Research Report
This project's final research report is expected to be available by November 2023.
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Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers noted that the report did not include some of the statistical analyses proposed in the original study protocol, specifically non-inferiority tests of non-fatal pulmonary embolism or deep-vein thrombosis and superiority tests of rate of complications. The researchers explained that their statistical analysis plan evolved and recommended that the reviewers compare the final report to the final study protocol and statistical analysis plan found in the report’s appendix.
- The reviewers also noted that the report did not include the two planned interim analyses and asked for those to be added since the interim analyses could have led the data and safety monitoring board to end the study early. The researchers added a summary of the interim analyses, which were reviewed only by the data and safety monitoring board and resulted in no study protocol changes.
- Reviewers requested more rationale for comparing aspirin to low-molecular-weight heparin rather than other oral anticoagulants for thromboprophylaxis in orthopedic trauma patients. The researchers explained they wanted to focus on treatments currently in clinical use.
Patient / Caregiver Partners
- Peter W. Thomas
- Debra Marvel
- Larry Cutsail
- Dave Wells
- Jeremy Palmer
- Ian Weston, MBA, American Trauma Society/Trauma Survivors Network
- Randolf Fenninger, National Blood Clot Alliance
Other Stakeholder Partners
- Stephen Fisher, MD, PhD, Chesapeake Employers' Insurance Company
- Stephen Breazeale, CRNP, R Adams Cowley Shock Trauma Center
- Grace S. Rozycki, MD, MBA, American Association for the Surgery of Trauma
- Kevin J. Bozic, MD, MBA, American Association of Orthopaedic Surgeons
- Nicole Stassen, MD, FACS, FCCM, Eastern Association for the Surgery of Trauma
- Bryce Robinson, MD, MS, FACS, FCCM, Eastern Association for the Surgery of Trauma's Practice Management Guideline Section
- Theodore Miclau, MD, Orthopaedic Trauma Association
- William Obremskey, MD, MPH, MHHC, Chair of the Orthopaedic Trauma Association's Evidence-Based Medicine Resource List
- Thomas Scalea, MD, FACS, MCCM, Western Trauma Association
Study Registration Information
- Has Results