Effects of Edoxaban on Platelet Aggregation

NCT05122455 | Completed Phase 2

• 1 other identifier: SDC 5189/20/218
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: The interaction between nonvitamin K oral anticoagulants (NOACs) and platelet aggregation is complex. The direct activated factor X inhibitors (factor Xa inhibitors) an NOAC antagonizes thrombin generation, one of most important platelet agonist, so that, factor Xa inhibitors has a potential effect in decreasing thrombin-mediated platelet aggregation. On the other hand, patients who experience ACS continue to have a hypercoagulable state for long periods after the index event. The COMPASS trial showed that, in patients with stable coronary artery disease (SCAD), Rivaroxaban (a direct anti-Xa inhibitor) in addition to antiplatelet agent, compared to antiplatelet therapy alone, reduced the composite endpoint of myocardial infarction, stroke and death. Objective: Analyze the role of edoxaban on platelet aggregation in SCAD patients. Methods and Results: This is a prospective, non-randomized, interventional study of SCAD patients taking low-dose acetylsalicylic acid (ASA). Subjects initially will receive in the following sequence: ASA 100 mg once daily (QD) plus edoxaban 60 mg QD, clopidogrel 75 mg QD alone, clopidogrel 75 mg QD plus edoxaban 60 mg QD, and edoxaban 60 mg QD alone. Platelet function will be assessed by standard of care technology, at baseline and after each intervention phase, by Multiplate-ADP® (primary endpoint), Multiplate-Aspi® and Multiplate-TRAP®. In addition to immature platelets fraction (% IPF) and count (IPC). Coagulability will be assessed, at baseline and after each intervention phase, by thromboelastogram (TEG) assessment. Specifically, after the phases in which edoxaban will be administered activated factor X (FXa) level and Plasminogen activator inhibitor-1 (PAI-1) will be evaluated in addition to previous. Finally, inflammatory markers will be, at same way, assessed at baseline and after intervention each phase: ultrasensitive C-reactive protein (us-PCR). Keywords: edoxaban, direct factor Xa inhibitor, stable coronary artery disease, aspirin, clopidogrel, platelet aggregation.

Conditions

SCAD; AMI

Keywords

edoxaban; direct factor Xa inhibitor; stable coronary artery disease; aspirin; clopidogrel; platelet aggregation

Outcome Measures

Primary Outcomes (1)

• Main objective:

  To compare platelet aggregability in patients with CAD using the Multiplate-TRAP® method at the start of ASA use and after 10 ± 2 days of the association of edoxaban and ASA.

  24 months

Secondary Outcomes (5)

• Platelet reactivity after edoxaban plus ASA vs ASA

  24 months

• Platelet reactivity after edoxaban plus Clopidogrel vs Clopidogrel

  24 months

• Platelet reactivity after edoxaban vs after ASA

  24 months

• Platelet reactivity after edoxaban vs after Clopidogrel

  24 months

• Platelet reactivity after edoxaban plus ASA vs after edoxaban plus Clopidogrel

  24 months

Other Outcomes (1)

• Other secondary goals

  24 months

Study Arms (5)

ASA baseline

EXPERIMENTAL

Patients in chronic use of ASA

Drug: ASA

ASA + Edoxaban

EXPERIMENTAL

During this intervention phase, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days.

Drug: ASA; Drug: Edoxaban

Clopidogrel

EXPERIMENTAL

Subsequently, ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 ± 2 days (washout period of the ASA).

Drug: Clopidogrel

Clopidogrel + Edoxaban

EXPERIMENTAL

Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days

Drug: Clopidogrel; Drug: Edoxaban

Edoxaban

EXPERIMENTAL

Finally, only edoxaban 60 mg once a day for 10 ± 2 days will be administered.

Drug: Edoxaban

Interventions

ASA DRUG

During the intervention phases, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days. Subsequently, ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 ± 2 days (washout period of the ASA). Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days and, finally, only edoxaban 60 mg once a day for 10 ± 2 days will be administered. After the end of the interventions, the ASA 100 mg once a day will be restarted.

ASA + Edoxaban; ASA baseline

Clopidogrel DRUG

During the intervention phases, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days. Subsequently, ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 ± 2 days (washout period of the ASA). Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days and, finally, only edoxaban 60 mg once a day for 10 ± 2 days will be administered. After the end of the interventions, the ASA 100 mg once a day will be restarted.

Clopidogrel; Clopidogrel + Edoxaban

Edoxaban DRUG

During the intervention phases, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days. Subsequently, ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 ± 2 days (washout period of the ASA). Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days and, finally, only edoxaban 60 mg once a day for 10 ± 2 days will be administered. After the end of the interventions, the ASA 100 mg once a day will be restarted.

ASA + Edoxaban; Clopidogrel + Edoxaban; Edoxaban

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged between 18 and 75 years
• Confirmed diagnosis of CAD using ASA 100 mg once a day. The following will be considered for CAD diagnosis: previous history of type 1 AMI (at least one year ago), according to the fourth universal definition of myocardial infarction (Thygesen, Alpert et al. 2018) and/or coronary angioplasty and/or coronary artery bypass graft surgery myocardium and/or coronary angiography showing at least 50% obstruction in one of the main epicardial vessels.
• Agreement to sign the free and informed consent form.

You may not qualify if:

• Clinically active bleeding or clinically significant bleeding in the last year.
• Peptic ulcer active in the last 60 days
• Previous history of high gastrointestinal bleeding
• Hemoglobin \<10 g / dl at randomization;
• Platelets \<100,000 or \>500,000 µ/L
• Need for lumbar puncture
• Atrial fibrillation
• Metal valve prosthesis
• Percutaneous coronary intervention (PCI) in the last 3 months with conventional stent and in the last 6 months with drug-eluting stent.
• Surgical myocardial revascularization (CABG) in the last 90 days
• Percutaneous coronary intervention (PCI) or surgical myocardial revascularization (CABG) planned within the next 60 days;
• Previous hemorrhagic stroke;
• Moderate or severe liver failure associated with coagulation disorders (Child-Pugh B or C)
• Hypersensitivity to edoxaban or formula components;
• Pregnant women or women of childbearing potential;

Sponsors & Collaborators

• University of Sao Paulo: lead
• Daiichi Sankyo: collaborator

Study Sites (1)

Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo

São Paulo, São Paulo, 05403-900, Brazil

Location

Related Publications (24)

• Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011 Aug 25;365(8):699-708. doi: 10.1056/NEJMoa1105819. Epub 2011 Jul 24.

  PMID: 21780946 BACKGROUND

• Angiolillo DJ, Bhatt DL, Cannon CP, Eikelboom JW, Gibson CM, Goodman SG, Granger CB, Holmes DR, Lopes RD, Mehran R, Moliterno DJ, Price MJ, Saw J, Tanguay JF, Faxon DP. Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update. Circulation. 2021 Feb 9;143(6):583-596. doi: 10.1161/CIRCULATIONAHA.120.050438. Epub 2021 Feb 8.

  PMID: 33555916 BACKGROUND

• Arantes FBB, Menezes FR, Franci A, Barbosa CJDG, Dalcoquio TF, Nakashima CAK, Baracioli LM, Furtado RHM, Nomelini QSS, Ramires JAF, Kalil Filho R, Nicolau JC. Influence of Direct Thrombin Inhibitor and Low Molecular Weight Heparin on Platelet Function in Patients with Coronary Artery Disease: A Prospective Interventional Trial. Adv Ther. 2020 Jan;37(1):420-430. doi: 10.1007/s12325-019-01153-8. Epub 2019 Nov 22.

  PMID: 31758517 BACKGROUND

• Ardissino D, Merlini PA, Bauer KA, Galvani M, Ottani F, Franchi F, Bertocchi F, Rosenberg RD, Mannucci PM. Coagulation activation and long-term outcome in acute coronary syndromes. Blood. 2003 Oct 15;102(8):2731-5. doi: 10.1182/blood-2002-03-0954. Epub 2003 Jul 3.

  PMID: 12843003 BACKGROUND

• Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-e492. doi: 10.1161/CIR.0000000000000558. Epub 2018 Jan 31. No abstract available.

  PMID: 29386200 BACKGROUND

• Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, Metsarinne K, O'Donnell M, Dans AL, Ha JW, Parkhomenko AN, Avezum AA, Lonn E, Lisheng L, Torp-Pedersen C, Widimsky P, Maggioni AP, Felix C, Keltai K, Hori M, Yusoff K, Guzik TJ, Bhatt DL, Branch KRH, Cook Bruns N, Berkowitz SD, Anand SS, Varigos JD, Fox KAA, Yusuf S; COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Jan 20;391(10117):205-218. doi: 10.1016/S0140-6736(17)32458-3. Epub 2017 Nov 10.

  PMID: 29132879 BACKGROUND

• Freeman MR, Williams AE, Chisholm RJ, Armstrong PW. Intracoronary thrombus and complex morphology in unstable angina. Relation to timing of angiography and in-hospital cardiac events. Circulation. 1989 Jul;80(1):17-23. doi: 10.1161/01.cir.80.1.17.

  PMID: 2736749 BACKGROUND

• Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008 Sep;6(9):1542-9. doi: 10.1111/j.1538-7836.2008.03064.x. Epub 2008 Jul 4.

  PMID: 18624979 BACKGROUND

• Gibson CM, Mega JL, Burton P, Goto S, Verheugt F, Bode C, Plotnikov A, Sun X, Cook-Bruns N, Braunwald E. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J. 2011 May;161(5):815-821.e6. doi: 10.1016/j.ahj.2011.01.026.

  PMID: 21570509 BACKGROUND

• Honda Y, Kamisato C, Morishima Y. Edoxaban, a direct factor Xa inhibitor, suppresses tissue-factor induced human platelet aggregation and clot-bound factor Xa in vitro: Comparison with an antithrombin-dependent factor Xa inhibitor, fondaparinux. Thromb Res. 2016 May;141:17-21. doi: 10.1016/j.thromres.2016.02.028. Epub 2016 Feb 26.

  PMID: 26962981 BACKGROUND

• Honda Y, Kamisato C, Morishima Y. Prevention of arterial thrombosis by edoxaban, an oral factor Xa inhibitor in rats: monotherapy and in combination with antiplatelet agents. Eur J Pharmacol. 2016 Sep 5;786:246-252. doi: 10.1016/j.ejphar.2016.06.011. Epub 2016 Jun 7.

  PMID: 27288116 BACKGROUND

• Huber K, Christ G, Wojta J, Gulba D. Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report 2001. Thromb Res. 2001 Sep 30;103 Suppl 1:S7-19. doi: 10.1016/s0049-3848(01)00293-6.

  PMID: 11567664 BACKGROUND

• Khalil P, Kabbach G. Direct Oral Anticoagulants in Addition to Antiplatelet Therapy for Secondary Prevention after Acute Coronary Syndromes: a Review. Curr Cardiol Rep. 2019 Jan 28;21(1):5. doi: 10.1007/s11886-019-1088-x.

  PMID: 30689068 BACKGROUND

• Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol. 2011 Jul 5;8(9):502-12. doi: 10.1038/nrcardio.2011.91.

  PMID: 21727917 BACKGROUND

• Orbe J, Zudaire M, Serrano R, Coma-Canella I, Martinez de Sizarrondo S, Rodriguez JA, Paramo JA. Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test. Thromb Haemost. 2008 Feb;99(2):382-7. doi: 10.1160/TH07-07-0443.

  PMID: 18278189 BACKGROUND

• Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010 Nov;138(5):1093-100. doi: 10.1378/chest.10-0134. Epub 2010 Mar 18.

  PMID: 20299623 BACKGROUND

• Sibbing D, Braun S, Jawansky S, Vogt W, Mehilli J, Schomig A, Kastrati A, von Beckerath N. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost. 2008 Jan;99(1):121-6. doi: 10.1160/TH07-07-0478.

  PMID: 18217143 BACKGROUND

• Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, Collet JP, Cuisset T, Franchi F, Gross L, Gurbel P, Jeong YH, Mehran R, Moliterno DJ, Neumann FJ, Pereira NL, Price MJ, Sabatine MS, So DYF, Stone GW, Storey RF, Tantry U, Trenk D, Valgimigli M, Waksman R, Angiolillo DJ. Updated Expert Consensus Statement on Platelet Function and Genetic Testing for Guiding P2Y12 Receptor Inhibitor Treatment in Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2019 Aug 26;12(16):1521-1537. doi: 10.1016/j.jcin.2019.03.034. Epub 2019 Jun 12.

  PMID: 31202949 BACKGROUND

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 BACKGROUND

• Hokusai-VTE Investigators; Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31.

  PMID: 23991658 BACKGROUND

• Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018 Oct 30;72(18):2231-2264. doi: 10.1016/j.jacc.2018.08.1038. Epub 2018 Aug 25. No abstract available.

  PMID: 30153967 BACKGROUND

• Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006 Apr 18;47(8 Suppl):C13-8. doi: 10.1016/j.jacc.2005.10.065.

  PMID: 16631505 BACKGROUND

• von Pape KW, Dzijan-Horn M, Bohner J, Spannagl M, Weisser H, Calatzis A. [Control of aspirin effect in chronic cardiovascular patients using two whole blood platelet function assays. PFA-100 and Multiplate]. Hamostaseologie. 2007 Aug;27(3):155-60; quiz 161-2. doi: 10.1007/978-3-540-36715-4_49. German.

  PMID: 17694222 BACKGROUND

• Wurtz M, Hvas AM, Christensen KH, Rubak P, Kristensen SD, Grove EL. Rapid evaluation of platelet function using the Multiplate(R) Analyzer. Platelets. 2014;25(8):628-33. doi: 10.3109/09537104.2013.849804. Epub 2013 Nov 18.

  PMID: 24246241 BACKGROUND

MeSH Terms

Interventions

Clopidogrel; edoxaban

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: This is a prospective, non-randomized, interventional study of SCAD patients

Study Record Dates

• First Submitted: October 19, 2021
• First Posted: November 16, 2021
• Study Start: September 14, 2021
• Primary Completion: June 24, 2024
• Study Completion: June 24, 2024
• Last Updated: April 27, 2025

Record last verified: 2025-04

Locations

BR (1)