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  • Review Article
  • Published:

Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease

Abstract

Advances in antiplatelet therapies for patients with cardiovascular disease have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial. Moreover, many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. Therefore, novel strategies are needed to prevent clinical events through mechanisms beyond platelet inhibition and with an acceptable associated risk of bleeding. The advent of non-vitamin K antagonist oral anticoagulants, which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in dual-pathway inhibition strategies that combine an antiplatelet agent with an anticoagulant drug. In this Review, we highlight the emerging pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with different manifestations of cardiovascular disease, such as coronary artery disease, cerebrovascular disease and peripheral artery disease.

Key points

  • Aspirin has been the standard of care for chronic atherosclerosis, in which a residual risk of ischaemic events remains despite the availability of established therapies for limiting atherosclerosis progression and stabilizing existing plaques.

  • Secondary and tertiary prevention of atherothrombotic complications with antithrombotic strategies that are not restricted to aspirin alone is an emerging paradigm.

  • The combination of antiplatelet drugs with the non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban at a low dose was effective in two large-scale, randomized trials across the spectrum of atherosclerotic cardiovascular disease.

  • This strategy might have clinical benefit in a broad group of individuals with coronary or peripheral artery disease, but patient selection should balance the baseline residual risk of ischaemia and the expected increased risk of bleeding.

  • Further work is required to determine whether the use of novel, low-dose regimens of other NOACs in a dual antithrombotic pathway inhibition strategy provides a similar benefit–risk profile to that of rivaroxaban in these patients.

  • Similarly, the use of antiplatelet drugs other than aspirin in dual antithrombotic pathway inhibition strategies requires careful study.

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Fig. 1: Residual risk of cardiovascular events in patients with coronary artery disease receiving medical therapy.
Fig. 2: Mechanisms of platelet activation.
Fig. 3: Stages of prevention of cardiovascular disease.
Fig. 4: Role of factor Xa and thrombin in the pathophysiology of atherothrombosis.
Fig. 5: Synergy of dual-pathway inhibition.
Fig. 6: Coagulation factor-mediated activation of proteinase-activated receptors.
Fig. 7: Proposed algorithm for the choice of antithrombotic strategy in patients with chronic coronary syndrome.

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References

  1. Antithrombotic Trialists’ (ATT) Collaboration et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

    Google Scholar 

  2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348, 1329–1339 (1996).

    Google Scholar 

  3. Bhatt, D. L. et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N. Engl. J. Med. 354, 1706–1717 (2006).

    CAS  PubMed  Google Scholar 

  4. Bonaca, M. P. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 372, 1791–1800 (2015).

    PubMed  Google Scholar 

  5. Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012).

    CAS  PubMed  Google Scholar 

  6. Bhatt, D. L. et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 295, 180 (2006).

    CAS  PubMed  Google Scholar 

  7. Steg, P. G. et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 297, 1197–1206 (2007).

    CAS  PubMed  Google Scholar 

  8. Bhatt, D. L. et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J. Am. Coll. Cardiol. 49, 1982–1988 (2007).

    PubMed  Google Scholar 

  9. Libby, P. et al. Inflammation, immunity, and infection in atherothrombosis. J. Am. Coll. Cardiol. 72, 2071–2081 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fox, K. A. A., Metra, M., Morais, J. & Atar, D. The myth of ‘stable’ coronary artery disease. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-019-0233-y (2019).

    Article  PubMed  Google Scholar 

  11. Angiolillo, D. J., Ueno, M. & Goto, S. Basic principles of platelet biology and clinical implications. Circ. J. 74, 597–607 (2010).

    CAS  PubMed  Google Scholar 

  12. Ueno, M., Kodali, M., Tello-Montoliu, A. & Angiolillo, D. J. Role of platelets and antiplatelet therapy in cardiovascular disease. J. Atheroscler. Thromb. 18, 431–442 (2011).

    CAS  PubMed  Google Scholar 

  13. Angiolillo, D. J., Capodanno, D. & Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31, 17–28 (2010).

    CAS  PubMed  Google Scholar 

  14. Angiolillo, D. J. & Ferreiro, J. L. Antiplatelet and anticoagulant therapy for atherothrombotic disease: the role of current and emerging agents. Am. J. Cardiovasc. Drugs 13, 233–250 (2013).

    CAS  PubMed  Google Scholar 

  15. Moon, J. Y., Nagaraju, D., Franchi, F., Rollini, F. & Angiolillo, D. J. The role of oral anticoagulant therapy in patients with acute coronary syndrome. Ther. Adv. Hematol. 8, 353–366 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cho, S. W., Franchi, F. & Angiolillo, D. J. Role of oral anticoagulant therapy for secondary prevention in patients with stable atherothrombotic disease manifestations. Ther. Adv. Hematol. 10, 2040620719861475 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Roffi, M. et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Heart J. 37, 267–315 (2016).

    CAS  PubMed  Google Scholar 

  18. Ibanez, B. et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehx393 (2017).

    Article  PubMed  Google Scholar 

  19. Valgimigli, M. et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur. Heart J. 39, 213–260 (2018).

    PubMed  Google Scholar 

  20. Aboyans, V. et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur. Heart J. https://doi.org/10.1093/eurheartj/ehx095 (2017).

    Article  PubMed  Google Scholar 

  21. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation https://doi.org/10.1161/CIR.0000000000000678 (2019).

    Article  PubMed  Google Scholar 

  22. Gerhard-Herman, M. D. et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J. Am. Coll. Cardiol. 69, e71–e126 (2017).

    PubMed  Google Scholar 

  23. Knuuti, J. et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehz425 (2019).

    Article  PubMed  Google Scholar 

  24. Piepoli, M. F. et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur. Heart J. 37, 2315–2381 (2016).

    PubMed  PubMed Central  Google Scholar 

  25. Gaziano, J. M. et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 392, 1036–1046 (2018).

    CAS  PubMed  Google Scholar 

  26. ASCEND Study Collaborative Group et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 379, 1529–1539 (2018).

    Google Scholar 

  27. McNeil, J. J. et al. Effect of aspirin on all-cause mortality in the healthy elderly. N. Engl. J. Med. 379, 1519–1528 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zheng, S. L. & Roddick, A. J. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA 321, 277–287 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Montalescot, G. A farewell to aspirin in primary prevention? Nat. Rev. Cardiol. 16, 76–77 (2019).

    PubMed  Google Scholar 

  30. Mahmoud, A. N., Gad, M. M., Elgendy, A. Y., Elgendy, I. Y. & Bavry, A. A. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur. Heart J. 40, 607–617 (2019).

    CAS  PubMed  Google Scholar 

  31. Capodanno, D. Oral antithrombotic therapy after acute coronary syndromes: ‘dual antiplatelet’ or ‘dual pathway’? EuroIntervention https://doi.org/10.4244/EIJV13I7A112 (2017).

    Article  PubMed  Google Scholar 

  32. ten Cate, H. Tissue factor-driven thrombin generation and inflammation in atherosclerosis. Thromb. Res. 129 (Suppl.), S38–S40 (2012).

    PubMed  Google Scholar 

  33. Esmon, C. T. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb. Haemost. 111, 625–633 (2014).

    CAS  PubMed  Google Scholar 

  34. Borissoff, J. I., Spronk, H. M. H. & ten Cate, H. The hemostatic system as a modulator of atherosclerosis. N. Engl. J. Med. 364, 1746–1760 (2011).

    CAS  PubMed  Google Scholar 

  35. Mostowik, M., Siniarski, A., Gołębiowska-Wiatrak, R., Nessler, J. & Gajos, G. Prolonged CRP increase after percutaneous coronary intervention is associated with high thrombin concentrations and low platelet’ response to clopidogrel in patients with stable angina. Adv. Clin. Exp. Med. 24, 979–985 (2015).

    PubMed  Google Scholar 

  36. Brummel-Ziedins, K. et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J. Thromb. Haemost. 6, 104–110 (2008).

    CAS  PubMed  Google Scholar 

  37. Becker, E. M. et al. Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. J. Thromb. Haemost. 10, 2470–2480 (2012).

    CAS  PubMed  Google Scholar 

  38. Perzborn, E., Heitmeier, S. & Laux, V. Effects of rivaroxaban on platelet activation and platelet-coagulation pathway interaction: in vitro and in vivo studies. J. Cardiovasc. Pharmacol. Ther. 20, 554–562 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Álvarez, E., Paradela-Dobarro, B., Raposeiras-Roubín, S. & González-Juanatey, J. R. Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium. Br. J. Clin. Pharmacol. 84, 280–291 (2018).

    PubMed  Google Scholar 

  40. Andreotti, F., Testa, L., Biondi-Zoccai, G. G. L. & Crea, F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur. Heart J. 27, 519–526 (2006).

    CAS  PubMed  Google Scholar 

  41. Kirchhof, P. et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur. Heart J. 37, 2893–2962 (2016).

    PubMed  Google Scholar 

  42. Sardar, P. et al. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLOS ONE 8, e77694 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wallentin, L. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 362, 789–797 (2003).

    CAS  PubMed  Google Scholar 

  44. Oldgren, J. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur. Hear. J. 32, 2781–2789 (2011).

    CAS  Google Scholar 

  45. Steg, P. G. et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur. Heart J. 32, 2541–2554 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Goldstein, S. et al. Phase 2 study of TAK-442, an oral factor Xa inhibitor, in patients following acute coronary syndrome. Thromb. Haemost. https://doi.org/10.1160/TH13-07-0543 (2014).

    Article  PubMed  Google Scholar 

  47. APPRAISE Steering Committee and Investigators et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the apixaban for prevention of acute ischemic and safety events (APPRAISE) trial. Circulation 119, 2877–2885 (2009).

    Google Scholar 

  48. Alexander, J. H. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365, 699–708 (2011).

    CAS  PubMed  Google Scholar 

  49. Mega, J. L. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29–38 (2009).

    CAS  PubMed  Google Scholar 

  50. Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366, 9–19 (2012).

    CAS  PubMed  Google Scholar 

  51. Gibson, W. J. et al. Safety and efficacy of rivaroxaban when added to aspirin monotherapy among stabilized post‐acute coronary syndrome patients: a pooled analysis study of ATLAS ACS‐TIMI 46 and ATLAS ACS 2‐TIMI 51. J. Am. Heart Assoc. 8, e009451 (2019).

    PubMed Central  Google Scholar 

  52. Ohman, E. M. et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 389, 1799–1808 (2017).

    CAS  PubMed  Google Scholar 

  53. Capodanno, D. et al. Management of antithrombotic therapy in atrial fibrillation patients undergoing PCI: JACC state-of-the-art review. J. Am. Coll. Cardiol. 74, 83–99 (2019).

    PubMed  Google Scholar 

  54. Dewilde, W. J. et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 381, 1107–1115 (2013).

    CAS  PubMed  Google Scholar 

  55. Capodanno, D. et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat. Rev. Cardiol. 15, 480–496 (2018).

    CAS  PubMed  Google Scholar 

  56. Gibson, C. M. et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N. Engl. J. Med. 375, 2423–2434 (2016).

    CAS  PubMed  Google Scholar 

  57. Gibson, C. M. et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin k antagonist treatment strategy: clinical perspective. Circulation 135, 323–333 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cannon, C. P. et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N. Engl. J. Med. 377, 1513–1524 (2017).

    CAS  PubMed  Google Scholar 

  59. Lopes, R. D. et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1817083 (2019).

    Article  PubMed  Google Scholar 

  60. Vranckx, P. et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet https://doi.org/10.1016/S0140-6736(19)31872-0 (2019).

    Article  PubMed  Google Scholar 

  61. Capodanno, D. & Angiolillo, D. J. Dual antithrombotic therapy for atrial fibrillation and PCI. Lancet https://doi.org/10.1016/S0140-6736(19)31954-3 (2019).

    Article  PubMed  Google Scholar 

  62. Franchi, F. et al. Effects of edoxaban on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel: results of the EDOX-APT study. Thromb. Haemost. https://doi.org/10.1055/s-0039-1695772 (2019).

    Article  PubMed  Google Scholar 

  63. Golwala, H. B. et al. Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials. Eur. Heart J. 39, 1726–1735a (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lopes, R. D. et al. Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2019.1880 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Gargiulo, G. et al. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur. Heart H. 7, 3757–3767 (2019).

    Google Scholar 

  66. Eikelboom, J. W. et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N. Engl. J. Med. 377, 1319–1330 (2017).

    CAS  PubMed  Google Scholar 

  67. Sharma, M. et al. Stroke outcomes in the COMPASS trial. Circulation 139, 1134–1145 (2019).

    PubMed  Google Scholar 

  68. Moayyedi, P. et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 157, 682–691.e2 (2019).

    CAS  PubMed  Google Scholar 

  69. Moayyedi, P. et al. Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology 157, 403–412.e5 (2019).

    CAS  PubMed  Google Scholar 

  70. Anand, S. S. et al. Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial. J. Am. Coll. Cardiol. 73, 3271–3280 (2019).

    CAS  PubMed  Google Scholar 

  71. Branch, K. R. et al. Rivaroxaban with or without aspirin in patients with heart failure and chronic coronary or peripheral artery disease: the COMPASS trial. Circulation https://doi.org/10.1161/CIRCULATIONAHA.119.039609 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Fox, K. A. A. et al. Rivaroxaban plus aspirin in patients with vascular disease and renal dysfunction: from the compass trial. J. Am. Coll. Cardiol. 73, 2243–2250 (2019).

    CAS  PubMed  Google Scholar 

  73. Connolly, S. J. et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391, 205–218 (2018).

    CAS  PubMed  Google Scholar 

  74. Lamy, A. et al. Rivaroxaban, aspirin, or both to prevent early coronary bypass graft occlusion: the COMPASS-CABG study. J. Am. Coll. Cardiol. 73, 121–130 (2019).

    CAS  PubMed  Google Scholar 

  75. Anand, S. S. et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391, 219–229 (2018).

    CAS  PubMed  Google Scholar 

  76. Anand, S. S. et al. Major adverse limb events in lower extremity peripheral artery disease: COMPASS trial. J. Am. Coll. Cardiol. 71, 2306–2315 (2018).

    PubMed  Google Scholar 

  77. Borissoff, J. I., Spronk, H. M. H., Heeneman, S. & ten Cate, H. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze? Cardiovasc. Res. 82, 392–403 (2009).

    CAS  PubMed  Google Scholar 

  78. Zannad, F. et al. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N. Engl. J. Med. 379, 1332–1342 (2018).

    CAS  PubMed  Google Scholar 

  79. Greenberg, B. et al. Association of rivaroxaban with thromboembolic events in patients with heart failure, coronary disease, and sinus rhythm: a post hoc analysis of the COMMANDER HF trial. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2019.1049 (2019).

    Article  PubMed  Google Scholar 

  80. Capodanno, D. & Angiolillo, D. J. Antithrombotic therapy for prevention of cerebral thromboembolic events after transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 10, 1366–1369 (2017).

    PubMed  Google Scholar 

  81. Windecker, S. et al. Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study. Am. Heart J. 184, 81–87 (2017).

    CAS  PubMed  Google Scholar 

  82. Dangas, G. D. et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1911425 (2019).

    Article  PubMed  Google Scholar 

  83. Collet, J.-P. et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: the randomized ATLANTIS trial. Am. Heart J. 200, 44–50 (2018).

    CAS  PubMed  Google Scholar 

  84. Van Mieghem, N. M. et al. Edoxaban versus standard of care and their effects on clinical outcomes in patients having undergone transcatheter aortic valve implantation in atrial fibrillation — rationale and design of the ENVISAGE-TAVI AF trial. Am. Heart J. 205, 63–69 (2018).

    PubMed  Google Scholar 

  85. Capodanno, D., Alfonso, F., Levine, G. N., Valgimigli, M. & Angiolillo, D. J. Dual antiplatelet therapy: appraisal of the ACC/AHA and ESC focused updates. J. Am. Coll. Cardiol. 72, 103–119 (2018).

    Google Scholar 

  86. Zeymer, U., Schrage, B. & Westermann, D. Dual pathway inhibition with low-dose direct factor Xa inhibition after acute coronary syndromes — why is it not used in clinical practice? Thromb. Haemost. 118, 1528–1534 (2018).

    PubMed  Google Scholar 

  87. Angiolillo, D. J. et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention. Circulation 138, 527–536 (2018).

    CAS  PubMed  Google Scholar 

  88. Matsumura-Nakano, Y. et al. Open-label randomized trial comparing oral anticoagulation with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stent implantation. Circulation 139, 604–616 (2019).

    CAS  PubMed  Google Scholar 

  89. Yasuda, S. et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1904143 (2019).

    Article  PubMed  Google Scholar 

  90. van Rein, N. et al. Major bleeding rates in atrial fibrillation patients on single, dual, or triple antithrombotic therapy. Circulation 139, 775–786 (2019).

    PubMed  Google Scholar 

  91. Angiolillo, D. J. et al. Variability in individual responsiveness to clopidogrel. J. Am. Coll. Cardiol. 49, 1505–1516 (2007).

    CAS  PubMed  Google Scholar 

  92. Fox, K. A. A. et al. Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add? Eur. Heart J. https://doi.org/10.1093/eurheartj/ehy347 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Darmon, A. et al. External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry. Eur. Heart J. 39, 750–757a (2018).

    PubMed  Google Scholar 

  94. Hussain, M. A. et al. Antithrombotic therapy for peripheral artery disease: recent advances. J. Am. Coll. Cardiol. 71, 2450–2467 (2018).

    PubMed  Google Scholar 

  95. Boden, W. E. & Bhatt, D. L. Will COMPASS point to a new direction in thrombotic risk reduction in patients with stable cardiovascular disease? Circulation 138, 858–860 (2018).

    PubMed  Google Scholar 

  96. Sumaya, W., Geisler, T., Kristensen, S. D. & Storey, R. F. Dual antiplatelet or dual antithrombotic therapy for secondary prevention in high-risk patients with stable coronary artery disease? Thromb. Haemost. 19, 1583–1589 (2019).

    PubMed  Google Scholar 

  97. Hiatt, W. R. et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N. Engl. J. Med. 376, 32–40 (2017).

    CAS  PubMed  Google Scholar 

  98. Cacoub, P. P. et al. Patients with peripheral arterial disease in the CHARISMA trial. Eur. Heart J. 30, 192–201 (2009).

    CAS  PubMed  Google Scholar 

  99. Bonaca, M. P. et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J. Am. Coll. Cardiol. 67, 2719–2728 (2016).

    CAS  PubMed  Google Scholar 

  100. Bonaca, M. P. et al. Vorapaxar in patients with peripheral artery disease: results from TRA2°P-TIMI 50. Circulation 127, 1522–1529 (2013).

    CAS  PubMed  Google Scholar 

  101. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02504216 (2019).

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D.C. and D.J.A. researched data for the article and wrote the manuscript. All the authors contributed substantially to the discussion of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Dominick J. Angiolillo.

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Competing interests

D.C. has received speakers’ honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer, and consulting fees from Abbott Vascular, Bayer and Daiichi Sankyo. D.L.B. is on the Advisory Board of Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio and Regado Biosciences; is on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care and TobeSoft; is Chair of the AHA Quality Oversight Committee; is on the Data Monitoring Committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo) and Population Health Research Institute; has received honoraria from the ACC (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer) and WebMD (CME steering committees); he is involved in Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair) and VA CART Research and Publications Committee (Chair); he has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic and The Medicines Company; receives Royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a site co-investigator at Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; is a trustee for ACC; and has performed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma and Takeda. J.W.E. holds a mid-career award from the Heart and Stroke Foundation of Ontario, Canada, and the Jack Hirsh/Population Health Research Institute Chair in Thrombosis and Atherosclerosis; and has received honoraria and research support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer and Servier. K.A.A.F. has received grants from AstraZeneca, Bayer and Janssen; and speaker engagements and consulting fees from Bayer, Janssen, Regeneron, Sanofi and Vereseon. T.G. has received speaker fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer and Daiichi Sankyo; and has received institutional research grants from Bayer AG, Bristol-Myers Squibb/Pfizer and Daiichi Sankyo; is a recipient of funding from the DFG (German Research Foundation) Klinische Forschergruppe 274 (Platelets — Molecular Mechanisms and Translational Implications and the Collaborative Research Center Transregio 240). C.M.G. is chief executive officer of the Baim Institute for Clinical Research, and has received research grant funding from Angel Medical Corp., Bayer Corp., CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson and Portola Pharmaceuticals; consultant fees from Amarin Pharama, Amgen, Bayer Corp., Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Cardiovascular Research Foundation, CSL Behring, Chiesi, Duke Clinical Research Institute, Eli Lilly and Company, Gilead Sciences, Inc., Impact Bio Ltd., Janssen Pharmaceuticals, Johnson & Johnson Corp., The Medicines Company, MedImmune, Medtelligence, Merck & Co., Inc., Microport, Novo Nordisk, PERT Consortium, Pharma Mar, Portola Pharmaceuticals, Sanofi, Somahlution, Vereseon Corporation and WebMD; and royalties as a contributor from UpToDate in Cardiovascular Medicine. J.R.G.-J. has received institutional research funding from Angem, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ferrer International, Medtronic, MDS, Novartis, Pfizer, Sanofi and Servier; and is a consultant to Bayer, Boehringer-Ingelheim and Amgen. S.J. has received institutional research grants and speaker honoraria from Abbot Vascular, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer-Ingelheim, Boston Scientific, Jensen, The Medicines Company and Novo Nordisk. R.D.L has received consulting fees from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and Sanofi; and has received institutional grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and Sanofi. R.M. has received institutional research funding from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi Sankyo, Medtronic, Novartis and OrbusNeich; is a consultant to Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Regeneron Pharmaceuticals Inc. (no fees), Roivant Sciences Inc. and Sanofi; is an institutional consultant (payment to institution) with Abbott Vascular and Spectranetics/Phillips/Volcano Corporation; is on the executive committee for Bristol-Myers Squibb and Janssen Pharmaceuticals; and receives institutional (payment to institution) advisory board funding from Bristol-Myers Squibb, Novartis and Data Safety Monitoring Board membership funding to institution from Watermark Research; has <1% equity with Claret Medical and Elixir Medical. G.M. reports research grants to the Institution or consulting/or lecture fees from Abbott, ACC Foundation, Actelion, Amgen, AstraZeneca, Axis-Santé, Bayer, Beth Israel Deaconess Medical, Boston-Scientific, Boehringer Ingelheim, Brigham Women’s Hospital, Bristol-Myers Squibb, China heart House, Daiichi Sankyo, Idorsia, Elsevier, Europa, Fédération Française de Cardiologie, ICAN, Lead-Up, Medtronic, Menarini, MSD, Novo Nordisk, Partners, Pfizer, Quantum Genomics, Sanofi, Servier and WebMD. M.P. reports research grants to the Institution from AstraZeneca, Bayer, Heartflow, Janssen, NIH, Procyrion and Medtronic; and consulting or advisory board fees from Bayer, Janssen, Medscape and Amgen. P.G.S. reports research grants from Amarin, Bayer, Merck, Sanofi and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi and Servier. R.F.S. reports research grants to the institution from AstraZeneca and PlaqueTec; consultancy fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, GlyCardial, Haemonetics, Idorsia, Novartis, PlaqueTec and Thromboserin; and speaker fees or honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer and Medscape. P.V. has received personal fees from AstraZeneca, Bayer HealthCare, CLS Behring and Daiichi Sankyo. J.I.W. has received institutional research funding from Bayer and Boehringer-Ingelheim and consultant fees and honoraria from Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis Pharmaceuticals, Pfizer, Portola, Janssen, Servier and Tetherex. R.W. reports research grants and honoraria from AstraZeneca, Bayer and Boehringer-Ingelheim; and honoraria from Amgen, Bristol-Myers Squibb/Pfizer and Eli Lilly. U.Z. reports research grants from AstraZeneca, Bristol-Myers Squibb, Novartis and Eli Lilly; and speakers fees or honoraria from Abiomed, AstraZeneca, B. Braun, Bayer, Biotronik, Boehringer-Ingelheim, Bristol-Myers Squibb, Correvio, Daiichi Sankyo, Eli Lilly, Ferrer, Medtronic, Medicines Company, MSD, Novartis, Pfizer, Sanofi and Trommsdorf. D.J.A. has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi and The Medicines Company; has received payments for participation in review activities from CeloNova and St Jude Medical; his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical and Renal Guard Solutions.

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Nature Reviews Cardiology thanks D. Mukherjee, F. J. Neumann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Capodanno, D., Bhatt, D.L., Eikelboom, J.W. et al. Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease. Nat Rev Cardiol 17, 242–257 (2020). https://doi.org/10.1038/s41569-019-0314-y

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