ASA for postoperative venous thromboembolism prevention in patients with extremity or hip fractures: A critical appraisal of the PREVENT CLOT trial

ABSTRACT: The open-label PREVENT CLOT trial compared ASA with low-molecular-weight heparin (LMWH) for thromboprophylaxis in extremity fractures. ASA was noninferior to LMWH in reducing all-cause mortality but was associated with more frequent symptomatic thrombotic events. The study findings should be cautiously interpreted due to the clinical relevance of the outcomes and the restricted population studied. The PREVENT CLOT trial consisted primarily of healthy young patients with nonmajor trauma. These patients have inherently lower risk of venous thromboembolism than other patient cohorts of interest, such as frail, elderly, and polytrauma patients, limiting the generalizability of the results. Further, a more fulsome analysis of another higher-risk group, such as patients with proximal lower limb trauma, was lacking. No significant difference in bleeding was found between the ASA and LMWH arms, supporting LMWH use in patients with higher risk of thromboembolism. Ultimately, thromboprophylaxis choice for extremity fractures should be individualized based on patient risk factors and preferences.

The PREVENT CLOT trial demonstrated that ASA is noninferior to low-molecular-weight heparin in reducing all-cause mortality for extremity fractures. However, caution is necessary due to the limited representation of the patient population and the increased risk of symptomatic thrombotic events with ASA, underscoring the need for personalized thromboprophylaxis based on patient risk factors and preferences.


The baseline risk of symptomatic venous thromboembolism (VTE) in the first 35 days after major orthopaedic surgery has been estimated at 4.3%.[1] This burden of VTE, along with a much higher incidence of asymptomatic cases and potential complications, is the basis for the numerous clinical trials that have investigated pharmaceutical options for thromboprophylaxis in this patient population, including antiplatelet agents such as ASA and anticoagulants such as vitamin K antagonists, direct-acting anticoagulants, and low-molecular-weight heparin (LMWH). With these interventions, rates of VTE are reduced to 0.4% to 1.8% in patients with lower extremity surgeries; fatal VTE is very uncommon.[1,2] Therefore, thromboprophylaxis after major orthopaedic procedures that are associated with a higher risk of VTE is recommended as the standard of care by evidence-based clinical practice guidelines.

Although the total body of evidence supports a greater reduction of VTE with anticoagulants than with ASA, it is common practice for patients with orthopaedic fractures undergoing arthroplasties or fixations (e.g., nail insertions) to receive ASA for postoperative VTE prophylaxis, likely because of its lower cost and ease of administration compared with injections.[3-6] Enthusiasm for ASA use has been further amplified by favorable results in recent large trials.[7,8] In the EPCAT II trial, a multicentre double-blinded randomized controlled trial conducted in Canada, extended prophylaxis with low-dose ASA was noninferior to low-dose rivaroxaban in patients undergoing elective total hip or knee arthroplasties; both treatment arms had similar rates of symptomatic deep vein thrombosis, pulmonary embolism, and bleeding events.[7] In the PREVENT CLOT trial, a large open-label randomized controlled trial at 21 trauma centres in Canada and the United States, ASA was noninferior to LMWH (enoxaparin) in preventing postoperative all-cause mortality in patients with upper or lower extremity fractures.[8] While both trials have the potential to significantly influence clinical practice and guidelines, careful and selective application of the study findings to patients undergoing major orthopaedic surgery is warranted given the study designs and patient populations studied.[9] Here, we outline our concerns about extrapolating the findings of the PREVENT CLOT trial and applying them to unselected patients with orthopaedic fractures, particularly those who are considered at higher risk for VTE.

Study summary

The PREVENT CLOT trial included 12 211 adult patients with limb fractures surgically treated in trauma centres across North America, including those with pelvic or acetabular fractures who did not undergo surgery. Patients were randomized to receive ASA 81 mg orally twice daily or LMWH (enoxaparin) 30 mg twice daily by subcutaneous injection, with dose adjustment for weight and kidney function consistent with standards of care. During the 90-day follow-up period, the primary outcome of all-cause mortality occurred in 0.78% of the ASA arm and 0.73% of the LMWH arm. The authors concluded that ASA was noninferior to LMWH in preventing all-cause mortality when given as thromboprophylaxis for extremity fractures.

Patient inclusion

Patients enrolled in the PREVENT CLOT trial were young (mean age: 44.6 ± 17.8 years), and most of them sustained nonmajor trauma (85.6% had an Injury Severity Score of less than 15 out of 75). Cancer (2.5%), diabetes (8.3%), and a previous history of VTE (0.7%) were reported as comorbidities; the orthopaedic trauma event was the only known risk factor for thrombosis in 27.3% of patients. These characteristics suggest that patients in the PREVENT CLOT trial had a decreased baseline risk of thrombosis and were less likely to require (and therefore benefit from) pharmacologic thromboprophylaxis. In comparison, previous studies in patients with hip fracture surgeries have typically been composed of patients older than 70 years of age, with up to 63% of patients having a history of cardiovascular disease.[10-16] Patients enrolled in the PREVENT CLOT trial also had lower injury severity compared with cohorts in other trauma studies.[17,18] Given that advanced age, a history of cardiovascular disease, and higher injury severity are well-established risk factors for VTE, a large number of patients in the PREVENT CLOT trial likely had a lower risk of VTE than the typical trauma cohort with hip fracture or major injuries.[19]

The PREVENT CLOT trial also included only patients with upper extremity fractures, which made up 12% of patients in each of the treatment arms. As thromboprophylaxis is not the standard of care for these patients, we question the rationale for including them. The inclusion of such a low-risk group may also reduce the ability to detect a difference in outcomes between ASA and LMWH.[20]


The investigators of the PREVENT CLOT trial selected all-cause mortality as the primary outcome. While mortality rate is a significant outcome and a robust hard endpoint, it is neither a sensitive outcome for assessing the efficacy and safety of pharmacologic thromboprophylaxis nor a typical primary outcome in trauma-related thromboprophylaxis studies.[3,21,22] Furthermore, given the low-risk patient population, it is not surprising that 90-day mortality was low and was similar between the ASA and LMWH arms.

The secondary efficacy outcomes were more informative: cause-specific mortality, nonfatal pulmonary embolism, and deep vein thrombosis. Bleeding, wound complications, and surgical site infection were secondary safety outcomes. These outcomes are essential for assessing the efficacy and safety of thromboprophylaxis and are important determinants of quality of life and cost-effectiveness.[23] Consistent with previous orthopaedic trials with arthroplasties and lower limb fractures, a significantly lower incidence of symptomatic deep vein thrombosis was observed in the LMWH arm (1.71%) compared with the ASA arm (2.51%) in the PREVENT CLOT trial. Around 50% of these were proximal, which is a significant risk factor for pulmonary embolism.[24] Notably, the decreased rate of deep vein thrombosis in the LMWH arm was not accompanied by a statistically significant increased incidence of bleeding. The absence of a trade-off from a safety perspective adds reassurance of the value of LMWH as a safe choice of thromboprophylaxis compared with ASA in patients with a higher risk for VTE.

Additional concerns

Another factor that limits our confidence in generalizing the trial results is the lack of detail about the collective group of lower extremity fractures. Although the number of patients in this group is well balanced between the two treatment arms, the distribution of fractures was not reported. Considering that the risk of VTE after a lower extremity fracture is higher with more proximal locations than with more distal locations (e.g., hip versus ankle), an imbalance in the distribution of these fracture locations between treatment arms may impact the findings.[25,26] Furthermore, it would be highly informative to know the proportion of fractures at different locations, because the recommended indication and duration of postoperative VTE prophylaxis differ depending on the location and type. A more detailed breakdown of outcomes according to different sites of fracture (e.g., upper extremity vs pelvis, proximal femur vs distal lower limb) would also be welcome and hypothesis generating.

The types of procedures and surgeries performed were also not available in the PREVENT CLOT publication. This is useful information for interpreting the results, because the type of surgery can have a significant influence on VTE risk, with arthroplasties being associated with lower risk compared with fracture surgeries such as nail insertions and cephalomedullary nailing.[27]

Finally, fewer patients were discharged on enoxaparin (88.8%) than ASA (93.6%). Both arms were prescribed thromboprophylaxis for a median of 21 days. However, the authors did not elaborate on compliance to these regimens at home. The uncertainty around medication adherence makes it challenging to determine what effect this had on the reported outcomes.

Other published commentaries

Our appraisal of the PREVENT CLOT trial aligns with other critical reviews, editorials, and letters to the editor.[28-30] Importantly, the underrepresentation of a higher-risk population limits the generalizability of the PREVENT CLOT trial to those patients at higher risk of VTE, such as elderly patients and those with hip fractures.


The PREVENT CLOT trial provided evidence that in patients with lower risk of VTE after extremity fractures, there appears to be little difference between twice-daily regimens of ASA or LMWH for primary thromboprophylaxis. However, given the patient population and the primary outcome that were studied, we caution against generalizing and extrapolating the results to higher-risk populations who were underrepresented, such as elderly patients, patients with moderate or severe injuries, and those with comorbidities that increase risk for VTE (e.g., cardiovascular disease, cancer, history of VTE, obesity). It remains paramount for clinicians to assess VTE risk in individual patients with orthopaedic fractures to determine the appropriateness of ASA versus LMWH for pharmacological thromboprophylaxis.

Competing interests

This research did not receive specific grant funding from agencies in the public, commercial, or not-for-profit sectors. Dr Lee has received consultancy fees and honoraria from Bayer, Bristol Myers Squibb, Janssen, LEO Pharma, and Pfizer.

This article has been peer reviewed.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


1.    Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e278S-e325S.

2.    Gade IL, Kold S, Severinsen MT, et al. Venous thromboembolism after lower extremity orthopedic surgery: A population-based nationwide cohort study. Res Pract Thromb Haemost 2021;5:148-158.

3.    CRISTAL Study Group. Effect of aspirin vs enoxaparin on symptomatic venous thromboembolism in patients undergoing hip or knee arthroplasty: The CRISTAL randomized trial. JAMA 2022;328:719-727.

4.    Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. Chest 2016;149:315-352. Erratum in: Chest 2016;150:988.

5.    Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: Prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv 2019;3:3898-3944.

6.    Sidhu V, Naylor JM, Adie S, et al. Post-discharge patient-reported non-adherence to aspirin compared to enoxaparin for venous thromboembolism prophylaxis after hip or knee arthroplasty. ANZ J Surg 2023;93:989-994.

7.    Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 2018;378:699-707.

8.    Major Extremity Trauma Research Consortium (METRC). Aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture. N Engl J Med 2023;388:203-213.

9.    Costa M. Thromboprophylaxis after extremity fracture—Time for aspirin? N Engl J Med 2023;388:274-275.

10.    Rosencher N, Vielpeau C, Emmerich J, et al. Venous thromboembolism and mortality after hip fracture surgery: The ESCORTE study. J Thromb Haemost 2005;3:2006-2014.

11.    Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) Investigators. Fracture fixation in the operative management of hip fractures (FAITH): An international, multicentre, randomised controlled trial. Lancet 2017;389(10078):1519-1527.

12.    The HEALTH Investigators. Total hip arthroplasty or hemiarthroplasty for hip fracture. N Engl J Med 2019;381:2199-2208.

13.    The HIP ATTACK Investigators. Accelerated surgery versus standard care in hip fracture (HIP ATTACK): An international, randomised, controlled trial. Lancet 2020;95(10225):698-708. Errata in: Lancet 2021;398(10315):1964; Lancet 2023;401(10382):1078.

14.    Beauchamp-Chalifour P, Belzile ÉL, Michael R, et al. The risk of venous thromboembolism in surgically treated hip fracture: A retrospective cohort study of 5184 patients. Orthop Traumatol Surg Res 2022;108:103142.

15.    Llopis-Cardona F, Armero C, Hurtado I, et al. Incidence of subsequent hip fracture and mortality in elderly patients: A multistate population-based cohort study in eastern Spain. J Bone Miner Res 2022;37:1200-1208.

16.    Sullivan KJ, Husak LE, Altebarmakian M, Brox WT. Demographic factors in hip fracture incidence and mortality rates in California, 2000–2011. J Orthop Surg Res 2016;11:4.

17.    Tarabadkar N, Alton T, Gorbaty J, et al. Trends in orthopedic fracture and injury severity: A level I trauma center experience. Orthopedics 2018;41:e211-e216.

18.    Girshausen R, Horst K, Herren C, et al. Polytrauma scoring revisited: Prognostic validity and usability in daily clinical practice. Eur J Trauma Emerg Surg 2022. doi: 10.1007/s00068-022-02035-5.

19.    Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107(23 Suppl 1):I9-I16.

20.    Flevas DA, Megaloikonomos PD, Dimopoulos L, et al. Thromboembolism prophylaxis in orthopaedics: An update. EFORT Open Rev 2018;3:136-148.

21.    Alsheikh K, Hilabi A, Aleid A, et al. Efficacy and safety of thromboprophylaxis post-orthopedic surgery. Cureus 2021;13:e19691.

22.    Shahi A, Bradbury TL, Guild GN III, et al. What are the incidence and risk factors of in-hospital mortality after venous thromboembolism events in total hip and knee arthroplasty patients? Arthroplast Today 2018;4:343-347.

23.    Hogg K, Kimpton M, Carrier M, et al. Estimating quality of life in acute venous thrombosis. JAMA Intern Med 2013;173:1067-1072.

24.    Kabashneh S, Singh V, Alkassis S. A comprehensive literature review on the management of distal deep vein thrombosis. Cureus 2020;12:e8048.

25.    Ricci WM, Broekhuyse H, Keating JF, et al. Thromboprophylaxis an update of current practice: Can we reach a consensus? OTA Int 2019;2:e027.

26.    Gouzoulis MJ, Joo PY, Kammien AJ, et al. Risk factors for venous thromboembolism following fractures isolated to the foot and ankle fracture. PLoS One 2022;17:e0276548.

27.    MacDonald DRW, Neilly D, Schneider PS, et al. Venous thromboembolism in hip fracture patients: A subanalysis of the FAITH and HEALTH trials. J Orthop Trauma 2020;34(Suppl 3):S70-S75.

28.    Vergallo R, Patrono C. Aspirin for venous thromboprophylaxis after fracture: Ready for prime time? Eur Heart J 2023;44:1299-1300.

29.    Sourmelis S, Zagoreos N. Aspirin for thromboprophylaxis after a fracture. N Engl J Med 2023;388:e57.

30.    Wu X-D, Min J. Aspirin for thromboprophylaxis after a fracture. N Engl J Med 2023;388:e57.

Mr Hong is a pharmacist at Vancouver General Hospital. Mr Haag is a clinical pharmacy specialist, nephrology, at the Kidney Clinic at Vancouver General Hospital and a clinical instructor in the Faculty of Pharmaceutical Sciences at the University of British Columbia. Mr Lau is a clinical pharmacy specialist, emergency medicine, at Vancouver General Hospital and a clinical instructor in the Faculty of Pharmaceutical Sciences at UBC. Dr Lee is a professor of medicine at UBC, medical director of the Thrombosis Program in Vancouver Coastal Health, and a scientist for the Centre for Advancing Health Outcomes.

Daniel Hong, PharmD, BCGP, Hans Haag, BSc, BSc (Pharm), ACPR, Anthony Lau, ACPR, PharmD, BCPS, CDCES, Agnes Y. Y. Lee, MD, MSc, FRCPC. ASA for postoperative venous thromboembolism prevention in patients with extremity or hip fractures: A critical appraisal of the PREVENT CLOT trial. BCMJ, Vol. 65, No. 10, December, 2023, Page(s) 372-375 - Premise.

Above is the information needed to cite this article in your paper or presentation. The International Committee of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

About the ICMJE and citation styles

The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.

An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.

BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:

  • Only the first three authors are listed, followed by "et al."
  • There is no period after the journal name.
  • Page numbers are not abbreviated.

For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit

BCMJ Guidelines for Authors

Leave a Reply