10.4081/btvb.2023.90
A strategy of oral anticoagulants (OAC) in addition to single or dual antiplatelet therapy, known as dual-pathway inhibition (DPI), has shown to reduce thrombotic events in patients with cardiovascular disease. However, despite its efficacy, its use in clinical practice has been hindered by the fact this strategy is also associated with increased bleeding, including major bleeding. The use of low dose direct oral anticoagulant (i.e. rivaroxaban 2.5 mg twice daily) on top of antiplatelet therapy has been associated with reduced bleeding, but some safety concerns still exists. The availability of a novel class of OACs selectively targeting the intrinsic coagulation pathway and potentially uncoupling thrombosis and hemostasis has sparked the interest towards the use of a new generation DPI strategy associated with enhanced safety. Several phase II trials using factor XI (FXI) inhibitors on top of antiplatelet therapy in patients with coronary artery or cerebrovascular disease have been recently published and others are under investigation. We here discuss the available evidence and future perspectives of DPI with FXI inhibitors in patients with cardiovascular disease.
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Dominick J. Angiolillo
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Bleeding, Thrombosis and Vascular Biology
intrinsic pathway
Factor XI inhibitors in adjunct to antiplatelet therapy: the ultimate dual-pathway inhibition?
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Bleed Thromb Vascul Biol
Dominick J. Angiolillo
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Donadini MP, Ageno W. Milvexian and other drugs targeting Factor XI: a new era of anticoagulation? Bleeding, Thrombosis, and Vascular Biology 2022;1:22.
Factor XI inhibitors in adjunct to antiplatelet therapy: the ultimate dual-pathway inhibition?
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                                                                                                                         MINI-REVIEW

Factor XI inhibitors in adjunct to antiplatelet therapy:
the ultimate dual-pathway inhibition?
Mattia Galli,1 C. Michael Gibson,2 Dominick J. Angiolillo3
1
 Maria Cecilia Hospital GVM Care and Research, Cotignola, Italy; 2Division of Cardiology, Department of Medicine, Beth Israel
                                                                    Deaconess Medical Center, Boston, MA, USA; 3University of
                                                                    Florida College of Medicine, Jacksonville, FL, USA

    Correspondence: Dominick J. Angiolillo, University of Florida
    College of Medicine-Jacksonville, 655 West 8th Street, Jack-
    sonville, Florida 32209, United States.                                    ABSTRACT
    Tel.: +1.904-244-3933 - Fax: +1.904-244-3102.                                  A strategy of oral anticoagulants (OAC) in addition to single
    E-mail: dominick.angiolillo@jax.ufl.edu                                    or dual antiplatelet therapy, known as dual-pathway inhibition
                                                                               (DPI), has shown to reduce thrombotic events in patients with
    Citation: Galli M, Gibson CM, Angiolillo DJ. Factor XI inhibitors
                                                                               cardiovascular disease. However, despite its efficacy, its use in
    in adjunct to antiplatelet therapy: the ultimate dual-pathway inhi-
    bition? Bleeding, Thrombosis, and Vascular Biology 2023;2:90.
                                                                               clinical practice has been hindered by the fact this strategy is
                                                                               also associated with increased bleeding, including major bleed-




                                                                                                 ly
    Key words: hemostasis inhibitor, antiplatelet therapy, cardiovas-          ing. The use of low dose direct oral anticoagulant (i.e. rivarox-




                                                                                         on
    cular diseases, intrinsic pathway.                                         aban 2.5 mg twice daily) on top of antiplatelet therapy has been
                                                                               associated with reduced bleeding, but some safety concerns still
    Contributions: the authors contributed equally.                            exists. The availability of a novel class of OACs selectively tar-




                                                                                   e
                                                                               geting the intrinsic coagulation pathway and potentially uncou-
    Conflict of interest: MG declares that he has received consulting
                                                                               pling thrombosis and hemostasis has sparked the interest
    fees or honoraria from Terumo, outside the present work. CMG re-
    ceives research support from Johnson & Johnson. He receives con-
    sulting support from Astra-Zeneca, Johnson & Johnson, Janssen &
                                                                              us
                                                                               towards the use of a new generation DPI strategy associated
                                                                               with enhanced safety. Several phase II trials using factor XI
                                                                               (FXI) inhibitors on top of antiplatelet therapy in patients with
                                                                              al
    Bayer, outside the submitted work. DJA declares that he has re-
    ceived consulting fees or honoraria from Abbott, Amgen, As-                coronary artery or cerebrovascular disease have been recently
                                                           ci

    traZeneca, Bayer, Biosensors, Boehringer Ingelheim,                        published and others are under investigation. We here discuss
    Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli             the available evidence and future perspectives of DPI with FXI
                                                         er


    Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma,                  inhibitors in patients with cardiovascular disease.
    Pfizer, Sanofi and Vectura. DJA also declares that his institution
                                                        m



    has received research grants from Amgen, AstraZeneca, Bayer,
    Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli
                                            om




    Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck,
    Novartis, Osprey Medical, Renal Guard Solutions and Scott R.
                                                                               Dual pathway inhibition
    MacKenzie Foundation.                                                           The persistence of elevated rates of ischemic recurrences,
                                      -c




                                                                               despite the use of antiplatelet therapy in patients with cardio-
    Ethics approval and consent to participate: not applicable.
                                                                               vascular disease (CVD), together with the understanding of the
                             on




    Availability of data and material: data and materials are available        pivotal role of coagulation factors on thrombo-inflammatory
    by the authors.                                                            processes involved in the pathogenesis of atherosclerosis and
                                                                               its complications have represented the rationale for the use of
                       N




    Acknowledgments: BioRender platform and templates were used                oral anticoagulants (OAC) in addition to standard antiplatelet
    for creating the Figure.                                                   therapy, a strategy known as dual-pathway inhibition (DPI).1,2
                                                                               Over the years, a DPI strategy has been tested using different
    Received: 20 July 2023.
                                                                               OAC regimens (Figure 1). Thus far, a DPI with a low dose of a
    Accepted: 20 July 2023.
                                                                               direct OAC (DOAC, i.e. rivaroxaban 2.5 mg twice daily) has
    Publisher’s note: all claims expressed in this article are solely those    been associated with the most favorable safety and efficacy pro-
    of the authors and do not necessarily represent those of their affili-     file, although the reduction of ischemic events occurred at the
    ated organizations, or those of the publisher, the editors and the re-     expense of increased major bleeding, underscoring the need to
    viewers. Any product that may be evaluated in this article or claim        identify alternative targets.3
    that may be made by its manufacturer is not guaranteed or endorsed              The recent development of a novel class of OACs, selec-
    by the publisher.                                                          tively targeting the intrinsic coagulation pathway, has been pro-
                                                                               posed as an opportunity to uncouple thrombosis and hemostasis.4
    ©
     Copyright: the Author(s), 2023                                            To this extent, several molecules with different routes of admin-
    Licensee PAGEPress, Italy
                                                                               istration and mechanisms of action, ranging from gene silencing
    Bleeding, Thrombosis and Vascular Biology 2023; 2:90
    doi:10.4081/btvb.2023.90                                                   to the direct inhibition of factor XI (FXI) by monoclonal anti-
                                                                               body or small molecules have been developed over the last few
    This work is licensed under a Creative Commons Attribution-                years.5,6 Early phase II trials have suggested FXI inhibitors to be
    NonCommercial 4.0 International License (CC BY-NC 4.0).                    an effective and potentially safer strategy compared with low-
                                                                               molecular-weight-heparin or a DOAC among patients undergo-


                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:90
8                                                                M. Galli et al.




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Figure 1. Temporal evolution of dual-pathway inhibition.
                                                          m
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ing total knee arthroplasty or with atrial fibrillation (AF), respec-       bleeding and ischemic events at 90 days were also found in the
tively.5,7 The favorable safety profile of this novel class of OAC          AXIOMATIC-SSP trial randomizing 2366 patients with non-
                                         -c




has stimulated interest towards their use in high risk scenarios,           cardioembolic ischemic stroke or transient ischemic attack (TIA)
including those that have traditionally exposed patients to an in-          to milvexian at the dose of 25 mg od, 25 mg bis in die (bid), 50
                                 on




creased risk of bleeding such as in patients treated with other an-         mg bid, 100 mg bid, 200 mg bid or placebo. Background an-
tiplatelet agents (i.e., DPI). The first phase II trials using a DPI        tiplatelet therapy consisted in DAPT with clopidogrel for the
strategy with FXI inhibitors have been recently published and               first 21 days followed by aspirin alone.
                            N




others are under investigation.                                                  Although these phase II trials were underpowered for clinical
                                                                            outcomes, especially efficacy events, and larger phase III trials
                                                                            are warranted to support the efficacy of DPI with FXI inhibitors
Dual pathway inhibition with FXI inhibitors                                 in different clinical scenarios, the observed safety profile – includ-
                                                                            ing in patients treated DAPT with prasugrel/ticagrelor – in the in-
    Specifically, PACIFIC-MI randomized 1601 patients with                  dividual trials appears promising. Nevertheless, a recent
recent (<5 days) acute myocardial infarction treated with stan-             meta-analysis pooling data from phase II trials and performing a
dard dual antiplatelet therapy (DAPT, prasugrel/ticagrelor 80%,             pre-specified analysis according to the dose of the FXI inhibitor
clopidogrel 20%) to oral asundexian 10, 20, or 50 mg or placebo             used on top of antiplatelet therapy found that, compared with
once-daily (od). Of note, asundexian 20 and 50 mg correspond                placebo, DPI may increase the risk of bleeding, including major
to the therapeutic dose used for stroke prevention in patients              bleeding, especially when high doses are used.10 Indeed, large
with AF. At 1 year, there was no difference in ischemic or bleed-           scale phase III clinical testing will allow to better unravel both
ing events with any dose of asundexian compared with placebo.8              safety and efficacy data associated with DPI using FXI inhibitors
PACIFIC-Stroke found similar results at 26 weeks in 1880 pa-                in combination with standard-of-care antiplatelet treatment regi-
tients with acute (<48 hours) non-cardioembolic ischemic stroke             mens.5,7 The LIBREXIA-ACS trial (NCT05754957) is aiming at
randomized to either oral asundexian 10, 20, or 50 mg or                    randomizing 16,000 ACS patients receiving antiplatelet therapy
placebo od. All patients were treated with standard of care an-             standard-of-care to either milvexian orally or placebo and will
tiplatelet therapy (aspirin alone 57%, DAPT with clopidogrel                provide important information on the safety and efficacy of DPI
43%, lasting in average 70 days).9 Finally, no differences in               in the ACS setting. Indeed, an important component of this trial


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:90
                       Factor XI inhibitors in adjunct to antiplatelet therapy: the ultimate dual-pathway inhibition?                      9



will be the understanding of the safety and efficacy of milvexian          3. Galli M, Capodanno D, Benenati S, et al. Efficacy and safety
according to antiplatelet treatment regimens which may vary over              of dual-pathway inhibition in patients with cardiovascular dis-
the course of the study time course (up to 42 months) in line with            ease: a meta-analysis of 49 802 patients from 7 randomized
recent updates in the field.11 Similarly, other studies will be eval-         trials. Eur Heart J Cardiovasc Pharmacother 2022;8:519-28.
uating DPI using FXI inhibitors in combination with standard-of-           4. Hsu C, Hutt E, Bloomfield DM, et al. Factor XI inhibition to
care antiplatelet treatment regimens in other clinical setting.               uncouple thrombosis from hemostasis: JACC review topic of
Among patients with recent acute ischemic stroke or high-risk                 the week. J Am Coll Cardiol 2021;78:625-31.
TIA, LIBREXIA-STROKE (NCT05702034) will randomize                          5. Greco A, Laudani C, Spagnolo M, et al. Pharmacology and
15,000 patients to either milvexian or placebo and OCEANIC-                   clinical development of factor XI inhibitors. Circulation
STROKE (NCT05686070) will randomize 9300 patients to either
                                                                              2023;147:897-913.
asundexian or placebo, in addition to single or DAPT.12
                                                                           6. Prisco D, Mattioli I, De Caterina R, Bettiol A. The new era of
                                                                              anticoagulation: factor XI and XII inhibitors. Bleeding,
                                                                              Thrombosis, and Vascular Biology 2023;2:76.
Conclusions                                                                7. De Caterina R, Prisco D, Eikelboom JW. Factor XI inhibitors:
    Overall, a DPI strategy using a FXI inhibitor in adjunct to               cardiovascular perspectives. Eur Heart J 2023;44:280-92.
antiplatelet therapy may represent a paradigm shift for the treat-         8. Rao SV, Kirsch B, Bhatt DL, et al. A multicenter, phase 2,
ment of high-risk patients with cardiovascular and cerebrovas-                randomized, placebo-controlled, double-blind, parallel-group,




                                                                                            ly
cular disease, with the potential to reduce the risk of thrombotic            dose-finding trial of the oral factor XIa inhibitor asundexian




                                                                                    on
complications while mitigating the risk of bleeding which has                 to prevent adverse cardiovascular outcomes after acute my-
been the major drawback of more aggressive antithrombotic                     ocardial infarction. Circulation 2022;146:1196-206.
combination strategies. Ongoing trials will unravel the safety             9. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibi-
and efficacy of FXI inhibitors in adjunct to antiplatelet therapy




                                                                               e
                                                                              tion with asundexian after acute non-cardioembolic ischaemic
in various clinical scenarios and define whether this will consti-            stroke (PACIFIC-Stroke): an international, randomised, dou-
tute the ultimate DPI strategy.                                         us    ble-blind, placebo-controlled, phase 2b trial. Lancet 2022;400:
                                                                              997-1007.
                                                                   al
                                                                          10. Galli M, Laborante R, Ortega-Paz L, et al. Factor XI inhibitors
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                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:90
