Subscribe to RSS
DOI: 10.1055/a-2755-1789
Dual Pathway Inhibition: Redefining the Secondary Prevention COMPASS in Chronic Coronary Artery Disease
Authors
Abstract
Chronic coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide, despite advances in pharmacological and interventional therapies. Aspirin has long been the cornerstone of secondary prevention; however, residual cardiovascular risk persists in many patients, especially those with additional high-risk features such as diabetes, polyvascular disease, or renal dysfunction. The concept of dual pathway inhibition (DPI) combining low-dose anticoagulation with antiplatelet therapy has emerged as a novel strategy to enhance vascular protection. The COMPASS trial provided pivotal evidence supporting the use of low-dose rivaroxaban (2.5 mg twice daily) in combination with aspirin (100 mg daily), demonstrating significant reductions in major adverse cardiovascular events without a corresponding increase in fatal or intracranial bleeding. While the COMPASS study enrolled patients with sinus rhythm (oral anticoagulation naive) and used a special dose of DAOC, the recently published AQAUTIC study looked at CAD with prior oral anticoagulation. There was no benefit of adding aspirin to standard dose anticoagulation, and hence, such patients are not candidates for DPI. This review explores the rationale behind DPI, key findings from the COMPASS trial in chronic CAD patients, and the implications for clinical practice. It also discusses patient selection strategies, drug interactions, safety considerations, and current guideline recommendations. A proposed clinical algorithm is presented to guide the practical application of DPI in appropriately selected patients with stable CAD, aiming to redefine secondary prevention and improve long-term cardiovascular outcomes.
Keywords
chronic coronary artery disease - rivaroxaban - aspirin - antithrombotic therapy - high-risk CAD - cardiovascular outcomesPublication History
Received: 11 July 2025
Accepted: 24 November 2025
Article published online:
22 December 2025
© 2025. International College of Angiology. This article is published by Thieme.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Mafrica D, Franculli G, Esposito A. et al. Chronic coronary syndromes: diagnosis, management and gaps in evidence. HVT 2024; 8 (03) 391-410
- 2 Mant J, Hobbs FD, Fletcher K. et al; BAFTA investigators, Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370 (9586) 493-503
- 3 National Institute for Health Care Excellence (NICE). NG196: atrial fibrillation: diagnosis and management. 2021 . Accessed March 27, 2025 at: https://www.nice.org.uk/guidance/ng196.c
- 4 Hindricks G, Potpara T, Dagres N. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42 (05) 373-498
- 5 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
- 6 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
- 7 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
- 8 Cabral KP, Ansell JE. The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag 2015; 11: 117-123
- 9 Kvasnicka T, Malikova I, Zenahlikova Z. et al. Rivaroxaban-metabolism, pharmacologic properties and drug interactions. Curr Drug Metab 2017; 18 (07) 636-642
- 10 Ajmal M, Friedman J, Sipra QUAR, Lassar T. Rivaroxaban: expanded role in cardiovascular disease management—a literature review. Cardiovasc Ther 2021; 2021 (01) 8886210
- 11 Knuuti J, Wijns W, Saraste A. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
- 12 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324 (7329) 71-86
- 13 Cosentino F, Grant PJ, Aboyans V. et al; ESC Scientific Document Group. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41 (02) 255-323
- 14 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
- 15 Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015; 11: 967-977
- 16 Saljoughian M. Assessing novel oral anticoagulants. US Pharm 2018; 43 (02) 13-17
- 17 Samama MM. The mechanism of action of rivaroxaban–an oral, direct Factor Xa inhibitor–compared with other anticoagulants. Thromb Res 2011; 127 (06) 497-504
- 18 Mujer MTP, Rai MP, Atti V. et al. An update on the reversal of non-vitamin K antagonist oral anticoagulants. Adv Hematol 2020; 2020 (01) 7636104
- 19 Testa A, Morello A, Corcione N, Biondi-Zoccai G. Dual pathway inhibition of coagulation and inflammation with rivaroxaban: a new therapy paradigm against atherosclerosis. J Cardiovasc Pharmacol 2023; 81 (02) 117-119
- 20 Russo V, Fabiani D, Leonardi S. et al. Dual pathway inhibition with rivaroxaban and aspirin reduces inflammatory biomarkers in atherosclerosis. J Cardiovasc Pharmacol 2023; 81 (02) 129-133
- 21 Kubitza D, Perzborn E, Berkowitz SD. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Front Pharmacol 2013; 4: 145
- 22 Connolly SJ, Eikelboom JW, Bosch J. et al; COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 205-218
- 23 Zinman B, Wanner C, Lachin JM. et al; EMPA-REG Outcome Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22) 2117-2128
- 24 Schwartz GG, Steg PG, Szarek M. et al; Odyssey Outcomes Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379 (22) 2097-2107
- 25 Fulcher J, O'Connell R, Voysey M. et al; Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015; 385 (9976) 1397-1405
- 26 Collins R, Reith C, Emberson J. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388 (10059): 2532-2561
- 27 Ettehad D, Emdin CA, Kiran A. et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387 (10022): 957-967
- 28 Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet 2006; 368 (9535) 581-588
- 29 Baigent C, Blackwell L, Collins R. et al; Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373 (9678) 1849-1860
- 30 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038) 1329-1339
- 31 Bhatt DL, Fox KA, Hacke W. et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354 (16) 1706-1717
- 32 Bonaca MP, Bhatt DL, Cohen M. et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
- 33 Eikelboom JW, Bhatt DL, Fox KAA. et al. Mortality benefit of rivaroxaban plus aspirin in patients with chronic coronary or peripheral artery disease. J Am Coll Cardiol 2021; 78 (01) 14-23
- 34 Korjian S, Braunwald E, Daaboul Y. et al. Safety and efficacy of rivaroxaban for the secondary prevention following acute coronary syndromes among biomarker-positive patients: insights from the ATLAS ACS 2-TIMI 51 trial. Eur Heart J Acute Cardiovasc Care 2019; 8 (02) 186-193
- 35 Würtz M, Olesen KKW, Mortensen MB. et al. Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score. Eur Heart J 2022; 43 (10) 996-1004
- 36 Würtz M, Olesen KKW, Bhatt DL. et al. Net clinical benefit of extended dual pathway inhibition according to baseline risk in patients with chronic coronary syndrome: a COMPASS substudy. Eur Heart J Cardiovasc Pharmacother 2024; 10 (03) 201-209
- 37 Bonaca MP, Bauersachs RM, Anand SS. et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020; 382 (21) 1994-2004
- 38 Bauersachs RM, Szarek M, Brodmann M. et al; VOYAGER PAD Committees and Investigators. Total ischemic event reduction with rivaroxaban after peripheral arterial revascularization in the VOYAGER PAD trial. J Am Coll Cardiol 2021; 78 (04) 317-326
- 39 Anand SS, Bosch J, Eikelboom JW. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 219-229
- 40 Sibbing D, Blaha MJ, Chawla R. et al. Dual-pathway inhibition with low-dose aspirin and rivaroxaban versus aspirin monotherapy in patients with coronary artery disease and peripheral artery disease: systematic literature review and meta-analysis. Eur Cardiol 2023; 19: e01
- 41 Bauer KA. Pros and cons of new oral anticoagulants. Hematology (Am Soc Hematol Educ Program) 2013; 2013 (01) 464-470
- 42 European Medicines Agency—Europa EU Xarelto. INN-Rivaroxaban—Summary of Product Characteristics. Accessed October 25, 2018 at: https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf
- 43 Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76 (03) 455-466
- 44 Haas S, Bode C, Norrving B, Turpie AG. Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk. Vasc Health Risk Manag 2014; 10: 101-114
- 45 Eriksson BI, Turpie AG, Lassen MR, Kakkar AK, Gent M. Pooled analysis of four rivaroxaban studies: NSAIDs, ASA and platelet inhibitors. J Thromb Haemost 2009; 7: 761
- 46 Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939)–an oral, direct factor Xa inhibitor–has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007; 63 (04) 469-476
- 47 Vrints C, Andreotti F, Koskinas KC. et al; ESC Scientific Document Group. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J 2024; 45 (36) 3415-3537
- 48 Virani SS, Newby LK, Arnold SV. et al; Peer Review Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. Circulation 2023; 148 (09) e9-e119 Erratum in: Circulation. 2023;148(13):e148. Erratum in: Circulation. 2023;148(23):e186
- 49 Abramson BL, Al-Omran M, Anand SS. et al; Primary Panel, Secondary Panel. Canadian Cardiovascular Society 2022 guidelines for peripheral arterial disease. Can J Cardiol 2022; 38 (05) 560-587
- 50 Bainey KR, Marquis-Gravel G, Belley-Côté E. et al. Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology 2023 focused update of the guidelines for the use of antiplatelet therapy. Can J Cardiol 2024; 40 (02) 160-181
- 51 Kazibwe J, Gheorghe A, Wilson D, Ruiz F, Chalkidou K, Chi YL. The use of cost-effectiveness thresholds for evaluating health interventions in low- and middle-income countries from 2015 to 2020: a review. Value Health 2022; 25 (03) 385-389
- 52 Lamy A, Eikelboom J, Tong W. et al. The cost-effectiveness of rivaroxaban with or without aspirin in the COMPASS trial. Eur Heart J Qual Care Clin Outcomes 2023; 9 (05) 502-510
- 53 Russo V, Fabiani D, Imbalzano E. et al. Clinical Performance and Persistence on Dual Pathway Inhibition with Rivaroxaban and Aspirin in Real-World Setting. J Cardiovasc Pharmacol 2024; 84 (02) 170-174
- 54 National Institute for Health and Care Excellence (NICE). Rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease. Technology appraisal guidance (TA607). London: NICE; , October 2019. Accessed August 2025 at: www.nice.org.uk/guidance/ta607
- 55 Pradhan A, Bhandari M, Vishwakarma P, Sethi R. Novel dual therapy: a paradigm shift in anticoagulation in patients of atrial fibrillation undergoing percutaneous coronary intervention. TH Open 2020; 4 (04) e332-e343
- 56 Lemesle G, Didier R, Steg PG. et al; AQUATIC Trial Investigators. Aspirin in patients with chronic coronary syndrome receiving oral anticoagulation. N Engl J Med 2025; 393 (16) 1578-1588
- 57 Bainey KR, Welsh RC, Connolly SJ. et al; COMPASS Investigators. Rivaroxaban plus aspirin versus aspirin alone in patients with prior percutaneous coronary intervention (COMPASS-PCI). Circulation 2020; 141 (14) 1141-1151
- 58 Roth GA, Mensah GA, Johnson CO. et al; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020; 76 (25) 2982-3021
- 59 Prajapathi S, Pradhan A, Mohta A, Sethi R. The third-generation anticoagulants: factors XI, XII, and XIII inhibitors. Egypt Heart J 2024; 76 (01) 137
- 60 Harrington J, Piccini JP, Alexander JH, Granger CB, Patel MR. Clinical evaluation of factor XIa inhibitor drugs: JACC review topic of the week. J Am Coll Cardiol 2023; 81 (08) 771-779