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Walter Ageno
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Bleeding, Thrombosis and Vascular Biology
venous thromboembolism
Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question
Text.Serial.Journal
https://www.btvb.org/btvb
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Mini-reviews
2023-05-17
2023-04-18
2023-04-30
2023-06-12
Bleed Thromb Vascul Biol
Walter Ageno
2023/05/17
10.4081/btvb.2023.82
Department of Medicine and Surgery, University of Insubria, Varese
2785-5309
2
venous thromboembolism
en
Samama CM, Laporte S, Rosencher N, et al. Rivaroxaban or enoxaparin in nonmajor orthopedic surgery. N Engl J Med 2020;382:1916-25.
Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question
https://www.btvb.org/btvb/article/download/82/67
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                                                                                                                          MINI-REVIEW

Aspirin or low-molecular weight heparin for thromboprophylaxis after
a fracture? That is the question
Giuseppe Camporese,1 Paolo Prandoni,2 Walter Ageno3
1
 General Medicine Unit – Thrombotic and Hemorrhagic Disorders Unit, Department of Internal Medicine, Padua University Hospital;
2
 Arianna Anticoagulazione Foundation, Bologna; 3Department of Medicine and Surgery, University of Insubria, Varese, Italy




    The recent publication of the PREVENT CLOT study in the                    each of the 21 participating trauma centers in the USA and
New England Journal of Medicine has renewed the interest                       Canada. The administration of aspirin or enoxaparin was man-
about the use of aspirin for prevention of venous thromboem-                   dated by the protocol only during the hospital stay. The mean
bolism (VTE) in orthopedic surgery that, at least in Europe, was               hospital duration was 5.3 days, and the mean number of in-pa-
virtually abandoned.1 The PREVENT CLOT is an open-label,                       tients doses of trial drugs was 8.6 in the aspirin group and 9.1 in
randomized controlled trial designed to test the role of aspirin,              the enoxaparin group. The decision to extend treatment after dis-




                                                                                                  ly
administered at the dose of 81 mg twice-daily, compared to                     charge was left to the discretion of the investigators according




                                                                                          on
enoxaparin, administered at the dose of 30 mg twice-daily for                  to existing local protocols and the median duration of thrombo-
the prevention of VTE in more than 12,000 patients candidate                   prophylaxis after hospital discharge was 21 days in both groups.
to surgery for fracture of the lower limbs and/or the upper limbs,                  The overall 3-month mortality rate for any cause (indicated




                                                                                    e
and for any pelvic or acetabular fracture. The trial presented                 as the primary efficacy outcome) resulted similarly low in the two
pragmatic characteristics, respectful of any procedure in use in
                                                                              us
                                                                               groups, either in the intention to treat analysis (0.78% in aspirin
                                                                               group, 0.73% in enoxaparin group; difference 0.05-96.2% confi-
                                                                               dence interval –0.27 to 0.38; P<0.001 for non-inferiority) or in
                                                                              al
                                                                               the per-protocol analysis (0.75% in aspirin group, 0.72% in enoxa-
    Correspondence: Walter Ageno, Department of Medicine and Sur-              parin group; difference 0.03-96.2% confidence interval –0.31 to
                                                           ci

    gery, University of Insubria, Varese, Italy.
                                                                               0.38; P<0.001 for non-inferiority). Likewise, the mortality rate re-
    E-mail: walter.ageno@uninsubria.it
                                                                               lated to fatal and non-fatal pulmonary embolism, major bleedings,
                                                         er


    Citation: Camporese G, Prandoni P, Ageno W. Aspirin or low-mol-            surgical wound complications, or infections were low and similar
                                                                               in the two arms. Even if the incidence of post-operative sympto-
                                                        m



    ecular weight heparin for thromboprophylaxis after a fracture? That
    is the question. Bleeding, Thrombosis, and Vascular Biology                matic deep-vein thrombosis (DVT) resulted higher in aspirin
                                            om




    2023;2:82.                                                                 group, and the difference was statistically significant for the inci-
                                                                               dence of distal DVT, the authors concluded that for opportunity
    Key words: aspirin; low-molecular weight heparin; fracture; sur-           and cost reasons aspirin should be preferred compared to enoxa-
    gery; venous thromboembolism.
                                      -c




                                                                               parin for VTE prevention in these patients.
    Contributions: the authors contributed equally.                                 The role of aspirin for the prevention of VTE in major or-
                             on




                                                                               thopedic surgery (total hip and total knee replacement) has long
    Conflict of interest: the authors declare no potential conflict of in-     been controversial. Historical studies using systematic venog-
    terest.                                                                    raphy of the lower limbs after 1-2 weeks from surgery found as-
                       N




                                                                               pirin significantly less effective than anticoagulant prophylaxis
    Funding: none.                                                             for post-operative DVT prevention.2 However, subsequent stud-
                                                                               ies focusing on clinical endpoints reported favorable results, and
    Received: 18 April 2023.
    Accepted: 20 April 2023.                                                   the use of aspirin increased in this setting in some countries.3
                                                                                    The American College of Chest Physicians guidelines rec-
    Publisher’s note: all claims expressed in this article are solely those    ognized aspirin as a beneficial antithrombotic treatment (if com-
    of the authors and do not necessarily represent those of their affili-     pared to the absence of any kind of thromboprophylaxis) and
    ated organizations, or those of the publisher, the editors and the re-     aspirin was included in the list of potential strategies, but rec-
    viewers. Any product that may be evaluated in this article or claim        ommended the low-molecular-weight heparin as the first line
    that may be made by its manufacturer is not guaranteed or endorsed         treatment for VTE prevention in patients undergoing major or-
    by the publisher.                                                          thopedic surgery.4 The more recent guidelines of the American
                                                                               Society of Hematology also included aspirin in the list of an-
    ©
     Copyright: the Author(s), 2023
    Licensee PAGEPress, Italy
                                                                               tithrombotic drugs for patients undergoing major elective sur-
    Bleeding, Thrombosis and Vascular Biology 2023; 2:82                       gery, but only suggested low-molecular-weight heparin for
    doi:10.4081/btvb.2023.82                                                   patients undergoing fracture repair.5
                                                                                    Two randomized controlled studies (EPCAT I and II) com-
    This work is licensed under a Creative Commons Attribution-                pared the role of aspirin for VTE prevention in patients under-
    NonCommercial 4.0 International License (CC BY-NC 4.0).                    going major orthopedic surgery after an initial 10-day course of
                                                                               enoxaparin or 5-day course of rivaroxaban, against extended


                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:82
6                                                             G. Camporese et al.




enoxaparin or rivaroxaban, respectively.6,7 Both studies only re-          ture, at the same time highlighted some characteristics of the pa-
ported symptomatic VTE events, which occurred in similarly                 tients investigated in the PREVENT CLOT study, which placed
low rates between treatment groups.                                        them at low risk of developing thrombosis (e.g. relatively young
     The findings of the PREVENT CLOT and of the EPCAT I                   patients with a mean age of 45 years, absence of history of previ-
and II trials share similar conclusions and seem to indicate aspirin       ous VTE event, etc), wishing for further studies supporting an ef-
as an effective and safe thromboprophylactic agent in the setting          fective role of aspirin in VTE prevention in those patients.12
of orthopedic surgery. In this sense, should we reconsider our                  In summary, we believe that evidence is not sufficiently
guidance, in light of the practical use and the low cost of aspirin?       strong to justify the use of aspirin in patients undergoing ortho-
     The assumption that aspirin is a valid alternative to antico-         pedic surgery, in the light of the superior efficacy of low molec-
agulant drugs, either low-molecular-weight heparin or direct oral          ular weight heparin for the prevention of VTE, with similarly
anticoagulants, originates from the low incidence of sympto-               low bleeding risk. The only advantage of aspirin is represented
matic, major VTE events after major orthopedic surgery and the             by the lower costs, is this enough? Based on available evidence
absence of statistically significant differences between treatment         aspirin should not be prescribed immediately after major ortho-
arms. However, aspirin is clearly less effective than any antico-          pedic surgery, and its use in any case should be considered after
agulant (including low-molecular-weight heparin, fondaparinux,             an initial course of low molecular weight heparin or rivaroxaban.
direct anti-Xa oral anticoagulants) when asymptomatic events               Aspirin should likely not even be considered in other surgical
are included. These events were usually assessed by venography             settings after the recent publication of the results of the
of the lower limbs, and mainly included distal DVT. Are we sure            PRONOMOS trial, that showed the superiority of rivaroxaban




                                                                                                     ly
that this finding is so irrelevant? In most cases, symptomatic             over enoxaparin for the prevention of symptomatic and asymp-




                                                                                              on
DVT of the lower limbs start in the distal veins, where it can             tomatic VTE events in minor orthopedic surgery of the lower
also remain asymptomatic for a long time. In other words, we               limbs.13 Also in this setting, aspirin should not be considered as
can state that there is no symptomatic proximal DVT without a              an alternative thromboprophylactic agent.




                                                                                        e
preceding stage of asymptomatic distal thrombosis. A systematic                 We still believe that the common European practice to use
review of all the studies on post-operative VTE prevention after
major orthopedic surgery published 15 years ago reported a con-
sistent and reproducible relationship between the rate of asymp-
                                                                                us
                                                                           parenteral (low molecular weight heparin, fondaparinux) or oral
                                                                           anticoagulants (rivaroxaban, apixaban) is widely justified and
                                                                           well supported by current evidence.
                                                                         al
tomatic DVT in the studies using venography and the rate of
symptomatic DVT in those not using venography.8 As a result,
                                                             ci

the only way to properly protect from symptomatic VTE is to                References
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                                                           er


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                                                          m




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                                         -c




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                                 on




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                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:82
                Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question             7



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                                       Bleeding, Thrombosis and Vascular Biology 2023; 2:82
