WILL lOWer Dose Aspirin be Better With Rivaroxaban in Patients With Chronic Coronary Syndromes?

NCT04990791 | Completed Phase 4 Results

• 1 other identifier: STH20412
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

The trial is a pharmacodynamic study to determine the effect of a novel regimen of aspirin 20 mg BD plus rivaroxaban 2.5 mg BD on haemostasis, fibrin clot dynamics, inflammatory markers, platelet function and arachidonic acid metabolites when compared to standard regimens of aspirin 75 mg OD and aspirin 75 mg OD plus rivaroxaban 2.5 mg BD. In a randomised open-label three-period crossover design, patient participants receiving aspirin 75 mg OD for secondary prevention of IHD will be randomised 1:1 to receive one of two sequences of aspirin: aspirin 75 mg OD, then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD, then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD; or aspirin 75 mg OD, then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD, then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD. At the end of each 14(-2) day medication period, they will attend a study visit at which blood and urine samples will be obtained, and bleeding time measured, before and 2 hours after the last dose of IMP of the treatment period. The samples will be tested for fibrin clot dynamics; inflammatory markers and cytokines; prostanoids; and platelet function. Participants will be transitioned back to standard-of-care aspirin 75 mg OD at the end of the third treatment period and followed up by telephone call 14(-2) days later.

Conditions

Coronary Syndrome

Outcome Measures

Primary Outcomes (1)

• Bleeding Time Difference

  The primary endpoint will be difference in bleeding time, measured at 2 hours post-dose, assessed between aspirin (aspirin lysine) 75 mg once-daily alone vs. aspirin (aspirin lysine) 20 mg twice-daily plus rivaroxaban 2.5 mg twice-daily and aspirin (aspirin lysine) 75 mg once-daily alone vs. aspirin (aspirin lysine) 75 mg once-daily plus rivaroxaban 2.5 mg twice-daily.

  after 14(-2) days on each treatment schedule, bleeding time (seconds) performed 2 hours after the latest dose of aspirin +/- rivaroxaban.

Study Arms (2)

Aspirin 20mg

OTHER

Aspirin 75 mg OD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD

Drug: Aspirin 75mg; Drug: Aspirin 20mg; Drug: Rivaroxaban 2.5 mg

Asprin 75mg

OTHER

Aspirin 75 mg OD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD

Drug: Aspirin 75mg; Drug: Aspirin 20mg; Drug: Rivaroxaban 2.5 mg

Interventions

Aspirin 20mg DRUG

Aspirin 20mg BD for 14 days

Aspirin 20mg; Asprin 75mg

Aspirin 75mg DRUG

Aspirin 75mg OD for 14 days

Aspirin 20mg; Asprin 75mg

Rivaroxaban 2.5 mg DRUG

Rivaroxaban 2.5mg BD

Aspirin 20mg; Asprin 75mg

Eligibility Criteria

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

You may qualify if:

• Provision of informed consent prior to any study specific procedures
• Male or female aged greater than 18 years
• Existing diagnosis of a chronic coronary syndrome:
• (i) History of stable angina or (ii) History of an acute coronary syndrome event \>1 year ago or (iii) Previous evidence on imaging of either at least one stenosis \>50% in an epicardial coronary artery or a myocardial perfusion defect
• Receiving single antiplatelet therapy with aspirin 75 mg once daily

You may not qualify if:

• Any history of haemorrhagic stroke or lacunar stroke
• History of ischaemic stroke or transient ischaemic attack in the last year
• Heart failure associated with NYHA class III or IV symptoms
• Estimated glomerular filtration rate \<15 ml/min
• Planned procedure for coronary revascularization
• Any planned surgery or other procedure that may require suspension or discontinuation of antiplatelet therapy expected to occur within 3 months of randomisation
• Prior intention by patient or physician to discontinue aspirin within the study period
• Receiving doses of aspirin other than 75 mg once daily
• Treatment or planned treatment with antiplatelet medication apart from aspirin (eg. clopidogrel, prasugrel, ticagrelor, dipyridamole, ticlopidine)
• Current use of a loop, thiazide or potassium sparing diuretic (affects prostanoid assays)
• Any acute coronary syndrome event, percutaneous coronary intervention or coronary artery bypass grafting within 1 year prior to randomisation
• Current or planned use of an oral anticoagulant (e.g. warfarin, dabigatran, rivaroxaban \[including 2.5 mg BD\], apixaban, edoxaban) or parenteral anticoagulant (eg. unfractionated heparin, low molecular weight heparin, bivalirudin)
• Current or planned use of a GPIIb/IIIa inhibitor (eg. abciximab, tirofiban)
• Current or planned use of a fibrinolytic agent (eg. tissue plasminogen activator)
• Requiring or likely to require treatment with a non-steroidal anti-inflammatory drug (NSAID), including COX2 inhibitors, and including regular or intermittent/as required use

Sponsors & Collaborators

• Sheffield Teaching Hospitals NHS Foundation Trust: lead

Study Sites (1)

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, South Yorkshire, S5 7AU, United Kingdom

Location

Related Publications (19)

• Task Force Members; Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ; ESC Committee for Practice Guidelines; Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document Reviewers; Knuuti J, Valgimigli M, Bueno H, Claeys MJ, Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O, Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K, Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S, Yildirir A, Zamorano JL. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013 Oct;34(38):2949-3003. doi: 10.1093/eurheartj/eht296. Epub 2013 Aug 30. No abstract available.

  PMID: 23996286 BACKGROUND

• Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020 Jan 14;41(3):407-477. doi: 10.1093/eurheartj/ehz425. No abstract available. Erratum In: Eur Heart J. 2020 Nov 21;41(44):4242. doi: 10.1093/eurheartj/ehz825.

  PMID: 31504439 BACKGROUND

• Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Stork S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330. doi: 10.1056/NEJMoa1709118. Epub 2017 Aug 27.

  PMID: 28844192 BACKGROUND

• Sumaya W, Wallentin L, James SK, Siegbahn A, Gabrysch K, Bertilsson M, Himmelmann A, Ajjan RA, Storey RF. Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy. Eur Heart J. 2018 Apr 1;39(13):1078-1085. doi: 10.1093/eurheartj/ehy013.

  PMID: 29390064 BACKGROUND

• Konigsbrugge O, Weigel G, Quehenberger P, Pabinger I, Ay C. Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation. Clin Exp Med. 2018 Aug;18(3):325-336. doi: 10.1007/s10238-018-0490-9. Epub 2018 Feb 7.

  PMID: 29417256 BACKGROUND

• Patrono C, Morais J, Baigent C, Collet JP, Fitzgerald D, Halvorsen S, Rocca B, Siegbahn A, Storey RF, Vilahur G. Antiplatelet Agents for the Treatment and Prevention of Coronary Atherothrombosis. J Am Coll Cardiol. 2017 Oct 3;70(14):1760-1776. doi: 10.1016/j.jacc.2017.08.037.

  PMID: 28958334 BACKGROUND

• Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994 May 5;330(18):1287-94. doi: 10.1056/NEJM199405053301808. No abstract available.

  PMID: 8145785 BACKGROUND

• Ajjan RA, Standeven KF, Khanbhai M, Phoenix F, Gersh KC, Weisel JW, Kearney MT, Ariens RA, Grant PJ. Effects of aspirin on clot structure and fibrinolysis using a novel in vitro cellular system. Arterioscler Thromb Vasc Biol. 2009 May;29(5):712-7. doi: 10.1161/ATVBAHA.109.183707. Epub 2009 Mar 12.

  PMID: 19286636 BACKGROUND

• Kiers D, van der Heijden WA, van Ede L, Gerretsen J, de Mast Q, van der Ven AJ, El Messaoudi S, Rongen GA, Gomes M, Kox M, Pickkers P, Riksen NP. A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia. Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6.

  PMID: 28692111 BACKGROUND

• Thomas MR, Outteridge SN, Ajjan RA, Phoenix F, Sangha GK, Faulkner RE, Ecob R, Judge HM, Khan H, West LE, Dockrell DH, Sabroe I, Storey RF. Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model. Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2562-70. doi: 10.1161/ATVBAHA.115.306528. Epub 2015 Oct 29.

  PMID: 26515417 BACKGROUND

• Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.

  PMID: 28845751 BACKGROUND

• Teng R, Maya J, Butler K. Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers. Platelets. 2013;24(8):615-24. doi: 10.3109/09537104.2012.748185. Epub 2012 Dec 18.

  PMID: 23249161 BACKGROUND

• Choi J, Hwang SY, Ahn K. Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition. Nucleic Acids Res. 2018 Feb 28;46(4):1912-1926. doi: 10.1093/nar/gkx1312.

  PMID: 29315404 BACKGROUND

• Ghys T, Malfait R, VAN den Bossche J. Performance evaluation of the Sysmex XS-1000i automated haematology analyser. Int J Lab Hematol. 2009 Oct;31(5):560-6. doi: 10.1111/j.1751-553X.2008.01081.x. Epub 2009 Jun 18.

  PMID: 18616754 BACKGROUND

• Parker WAE, Orme RC, Hanson J, Stokes HM, Bridge CM, Shaw PA, Sumaya W, Thorneycroft K, Petrucci G, Porro B, Judge HM, Ajjan RA, Rocca B, Storey RF. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome. Platelets. 2019;30(2):148-157. doi: 10.1080/09537104.2019.1572880. Epub 2019 Feb 13.

  PMID: 30759035 BACKGROUND

• Doroszko A, Szahidewicz-Krupska E, Janus A, Jakubowski M, Turek A, Ilnicka P, Szuba A, Mazur G, Derkacz A. Endothelial dysfunction in young healthy men is associated with aspirin resistance. Vascul Pharmacol. 2015 Apr-Jun;67-69:30-7. doi: 10.1016/j.vph.2015.02.001. Epub 2015 Feb 17.

  PMID: 25697550 BACKGROUND

• Olson MT, Kickler TS, Lawson JA, McLean RC, Jani J, FitzGerald GA, Rade JJ. Effect of assay specificity on the association of urine 11-dehydro thromboxane B2 determination with cardiovascular risk. J Thromb Haemost. 2012 Dec;10(12):2462-9. doi: 10.1111/jth.12026.

  PMID: 23072449 BACKGROUND

• Sanchez A, Mirabel JL, Barrenechea E, Eugui J, Puelles A, Castaneda A. Evaluation of an improved immunoturbidimetic assay for serum C-reactive protein on a COBAS INTEGRA 400 Analyzer. Clin Lab. 2002;48(5-6):313-7.

  PMID: 12071582 BACKGROUND

• Harrell FE Jr, Lee KL, Matchar DB, Reichert TA. Regression models for prognostic prediction: advantages, problems, and suggested solutions. Cancer Treat Rep. 1985 Oct;69(10):1071-77.

  PMID: 4042087 BACKGROUND

MeSH Terms

Conditions

Angina, Unstable

Interventions

Aspirin; Rivaroxaban

Condition Hierarchy (Ancestors)

Angina Pectoris; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Chest Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Thiophenes; Sulfur Compounds; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. William Parker
• Organization: The University of Sheffield

w.parker@sheffield.ac.uk

0114 226 6159

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised controlled open-label crossover study

Study Record Dates

• First Submitted: June 28, 2021
• First Posted: August 4, 2021
• Study Start: August 26, 2021
• Primary Completion: August 31, 2023
• Study Completion: December 1, 2023
• Last Updated: February 20, 2026
• Results First Posted: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)