The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l s

Thromboprophylaxis after Extremity Fracture

— Time for Aspirin?
Matthew Costa, Ph.D.

Hospital-acquired venous thromboembolism re-
mains a common and preventable cause of
death, so many health care systems around the
world mandate that all patients who are admit-
ted to the hospital undergo a risk assessment for
venous thromboembolism.1,2 Patients who have
had traumatic injuries are at particular risk for
venous thromboembolism as a result of their
injuries, the surgeries that are often performed
to treat their broken bones, and the patients’
relative immobility during recovery.3 Therefore,
nearly all patients who undergo surgery for a
fracture are considered to be at high risk for
venous thromboembolism, and preventative in-
terventions are recommended.
Interventions to reduce the risk of venous
thromboembolism in patients who have under-
gone surgery for fractures fall into two broad
categories. The first is mechanical prophylaxis
(e.g., antiembolism stockings that compress the
legs to reduce pooling of venous blood in the
lower limbs and intermittent pneumatic com-
pression devices that actively squeeze the mus-
cles in the foot or leg to keep blood moving in
the veins). However, since the legs are com-
monly involved in traumatic injuries, mechanical
devices may be difficult or impossible to apply
in this group of patients. The other category of
prophylaxis is pharmacologic, which includes
oral drugs (e.g., aspirin and direct oral antico-
agulants) and injectable low-molecular-weight
heparin.
The choice of agent for pharmacologic pro-
phylaxis is made on the basis of balancing the
effectiveness of the therapy with regard to re-
ducing venous thromboembolism and the risk of
side effects, most notably bleeding.4 In many
countries, low-molecular-weight heparin that is
delivered by subcutaneous injection has become
the pharmacologic prophylaxis of choice for pa-
tients who have undergone surgery for a traumatic
injury because it is considered to be effective and
to have a low risk of bleeding complications.1,5
However, patients generally do not like receiving
the injections, which are painful and often cause
bruising at the site of injection, leading to con-
cerns about adherence.6 As the number of pa-
tients who are assessed to be at risk for venous
thromboembolism increases, more patients will
be treated with pharmacologic prophylaxis,
leading to an increase in health care costs.7 This
leads to the question: what type of pharmaco-
logic prophylaxis should clinicians and health
care systems recommend?
In this issue of the Journal, investigators in
the Major Extremity Trauma Research Consor-
tium8 go a long way toward answering this ques-
tion. In this trial, 12,211 participants 18 years of
age or older with an operatively treated limb
fracture or any pelvic or acetabular fracture were
randomly assigned to receive low-molecular-
weight heparin at a dose of 30 mg twice daily by
injection or aspirin at a dose of 81 mg taken
orally twice daily. The main finding of the trial
was that the occurrence of death from any cause
at 90 days was very similar in the two groups:
0.78% of patients in the aspirin group and 0.73%
in the heparin group. The authors concluded
that aspirin was noninferior to low-molecular-
weight heparin in preventing death in the trial
population.
Although this is not the first trial to address

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 Editorials

the choice of aspirin or heparin for venous be considered for venous thromboembolism pro-
thromboembolism prophylaxis among patients phylaxis after other types of surgeries and for
with operatively treated extremity fractures (or nonsurgical patients who have risk factors for
any pelvic or acetabular fracture), this is by far venous thromboembolism.
the largest trial to date and provides compelling Disclosure forms provided by the author are available with the
evidence that a readily available, inexpensive full text of this editorial at NEJM.org.
drug, taken orally, is a viable alternative to an From Oxford Trauma and Emergency Care, Nuffield Depart-
injectable pharmacologic prophylaxis. ment of Orthopedics, Rheumatology, and Musculoskeletal Sci-
Are there any caveats to this message? The ences, University of Oxford, Oxford, United Kingdom.
trial shows several secondary outcomes that 1. National Institute for Health and Care Excellence. Venous
support the main conclusion of the trial, includ- thromboembolism in over 16s: reducing the risk of hospital-
ing a similar risk of pulmonary embolism in the acquired deep vein thrombosis or pulmonary embolism. Au-
gust 13, 2019 (https://www​.­nice​.­org​.­uk/​­g uidance/​­ng89/​­chapter/​
two groups and, in terms of safety outcomes, no ­Recommendations).
evidence of a difference in the incidence of 2. Hegsted D, Gritsiouk Y, Schlesinger P, Gardiner S, Gubler
bleeding events, which occurred in 13.72% of KD. Utility of the risk assessment profile for risk stratification
of venous thrombotic events for trauma patients. Am J Surg
patients in the aspirin group and 14.27% in the 2013;​205:​517-20.
low-molecular-weight–heparin group. However, 3. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospec-
in keeping with previous trials, the authors tive study of venous thromboembolism after major trauma. N Engl
J Med 1994;​331:​1601-6.
noted that deep-vein thrombosis was more fre- 4. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales
quent in patients who had received aspirin than Uribe CH. Thromboprophylaxis for trauma patients. Cochrane
in those who had received heparin (2.51% vs. Database Syst Rev 2013;​3:​CD008303.
5. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette
1.71%), although the absolute difference was FA. Practice management guidelines for the prevention of ve-
small (0.80 percentage points). Although deep- nous thromboembolism in trauma patients: the EAST Practice
vein thrombosis is clearly not as serious as a Management Guidelines Work Group. J Trauma 2002;​53:​142-64.
6. Colwell CW Jr, Pulido P, Hardwick ME, Morris BA. Patient
fatal pulmonary embolism, it is not an inconse- compliance with outpatient prophylaxis: an observational study.
quential problem. Post-thrombotic syndrome Orthopedics 2005;​28:​143-7.
affects some people who have had a deep-vein 7. Horner D, Goodacre S, Pandor A, et al. Thromboprophylaxis
in lower limb immobilisation after injury (TiLLI). Emerg Med J
thrombosis of the leg, and this condition can 2020;​37:​36-41.
cause chronic pain and swelling. 9
8. Major Extremity Trauma Research Consortium (METRC).
The findings in this trial clearly indicate that Aspirin or low-molecular-weight heparin for thromboprophy-
laxis after a fracture. N Engl J Med 2023;​388:​203-13.
guidelines for the prevention of hospital-­ 9. Makedonov I, Kahn SR, Abdulrehman J, et al. Prevention of
acquired venous thromboembolism will need to the postthrombotic syndrome with anticoagulation: a narrative
be rewritten to include the option of aspirin in review. Thromb Haemost 2022;​122:​1255-64.
patients with traumatic injuries. More work is DOI: 10.1056/NEJMe2214045
needed to determine whether aspirin should also Copyright © 2023 Massachusetts Medical Society.

Growing Evidence and Remaining Questions

in Adolescent Transgender Care
Annelou L.C. de Vries, M.D., Ph.D., and Sabine E. Hannema, M.D., Ph.D.

This week in the Journal, a much-awaited pri-
mary report from Chen et al.1 on 2 years of
gender-affirming hormones (GAH) in transgen-
der adolescents appears. The approach to adoles-
cent transgender care with early treatment with
puberty blockers, and GAH in youth from 16
years of age, originated in the Netherlands (“the
Dutch model”) and became the dominant medi-
cal care model for transgender adolescents.2 Es-
pecially over the past decade, marked increases
in referrals but limited evidence as to long-term
outcomes have led to controversies and debate
regarding this approach. Indeed, some European
countries are adapting their guidelines and re-

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