Skip to main content
SpringerLink
Log in

Rivaroxaban With or Without Aspirin for the Secondary Prevention of Cardiovascular Disease: Clinical Implications of the COMPASS Trial

  • Review Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

The COMPASS trial compared the impact of the selective direct factor Xa inhibitor, rivaroxaban, as monotherapy or in combination with aspirin on major adverse cardiovascular events (MACE) in patients with stable atherosclerotic disease. Patients treated with rivaroxaban 2.5 mg twice daily in combination with aspirin experienced fewer cardiovascular events but more bleeding complications than those who received aspirin monotherapy. In contrast, a higher dose of rivaroxaban (5 mg twice daily) and aspirin produced no clinical benefit and continued to be associated with greater bleeding rates than aspirin. Examining this study in the context of other trials of anticoagulant therapy in atherosclerotic vascular disease, this review attempts to place the role of very low-dose rivaroxaban in clinical context and highlights areas for future research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329–39.

    Article  Google Scholar 

  2. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.

    Article  CAS  PubMed  Google Scholar 

  3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.

    Article  CAS  PubMed  Google Scholar 

  4. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791–800.

    Article  PubMed  Google Scholar 

  5. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371(23):2155–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schulz-Schupke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015;36(20):1252–63.

    Article  CAS  PubMed  Google Scholar 

  7. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423–34.

    Article  CAS  PubMed  Google Scholar 

  8. Fiedler KA, Maeng M, Mehilli J, Schulz-Schupke S, Byrne RA, Sibbing D, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol. 2015;65(16):1619–29.

    Article  PubMed  Google Scholar 

  9. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, 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. 2013;381(9872):1107–15.

    Article  CAS  PubMed  Google Scholar 

  10. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513–24.

    Article  CAS  PubMed  Google Scholar 

  11. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, et al. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005;26(22):2422–34.

    Article  PubMed  Google Scholar 

  12. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992;326(4):242–50.

    Article  CAS  PubMed  Google Scholar 

  13. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368(21):2004–13.

    Article  CAS  PubMed  Google Scholar 

  14. Anonymous. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Lancet. 1997;350(9075):389–96.

    Article  Google Scholar 

  15. Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten HE, Hertzberger DP, et al. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation. 2002;106(6):659–65.

    Article  CAS  PubMed  Google Scholar 

  16. Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P, et al. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation. 2002;105(5):557–63.

    Article  CAS  PubMed  Google Scholar 

  17. Herlitz J, Holm J, Peterson M, Karlson BW, Haglid Evander M, Erhardt L, et al. Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction; the LoWASA study. Eur Heart J. 2004;25(3):232–9.

    Article  CAS  PubMed  Google Scholar 

  18. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969–74.

    Article  CAS  PubMed  Google Scholar 

  19. van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. Antithrombotics in the Secondary Preventionof Events in Coronary Thrombosis-2 Research G. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002;360(9327):109–13.

    Article  PubMed  Google Scholar 

  20. Investigators E, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.

    Article  Google Scholar 

  21. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.

    Article  CAS  PubMed  Google Scholar 

  22. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29–38.

    Article  CAS  PubMed  Google Scholar 

  23. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19.

    Article  CAS  PubMed  Google Scholar 

  24. Krantz MJ, Kaul S. The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). J Am Coll Cardiol. 2013;62(9):777–81.

    Article  PubMed  Google Scholar 

  25. Committee AS, Investigators, Alexander JH, Becker RC, Bhatt DL, Cools F 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. 2009;119(22):2877–85.

  26. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22):2781–9.

    Article  CAS  PubMed  Google Scholar 

  27. Oldgren J, Wallentin L, Alexander JH, James S, Jonelid B, Steg G, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34(22):1670–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, 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. 2017;389(10081):1799–808.

    Article  CAS  PubMed  Google Scholar 

  29. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319–30.

    Article  CAS  PubMed  Google Scholar 

  30. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4.

  31. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114(8):774–82.

    Article  PubMed  Google Scholar 

  32. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111(16):2042–9.

    Article  CAS  PubMed  Google Scholar 

  33. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, 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. 2018;391(10117):219–29.

    Article  CAS  PubMed  Google Scholar 

  34. Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004;24(6):1015–22.

    Article  CAS  PubMed  Google Scholar 

  35. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–84.

    Article  CAS  PubMed  Google Scholar 

  36. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297(5):499–508.

    Article  CAS  PubMed  Google Scholar 

  37. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556–65.

    Article  CAS  PubMed  Google Scholar 

  38. Puri R, Nissen SE, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, et al. Factors underlying regression of coronary atheroma with potent statin therapy. Eur Heart J. 2013;34(24):1818–25.

    Article  CAS  PubMed  Google Scholar 

  39. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.

    Article  CAS  PubMed  Google Scholar 

  40. Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. Circulation. 2016;134(24):1931–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22.

    Article  CAS  PubMed  Google Scholar 

  42. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.

    Article  CAS  PubMed  Google Scholar 

  43. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.

    Article  CAS  Google Scholar 

  45. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    Article  CAS  PubMed  Google Scholar 

  46. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304(12):1350–7.

    Article  CAS  PubMed  Google Scholar 

  47. Hussain MA, Al-Omran M, Mamdani M, Eisenberg N, Premji A, Saldanha L, et al. Efficacy of a guideline-recommended risk-reduction program to improve cardiovascular and limb outcomes in patients with peripheral arterial disease. JAMA Surg. 2016;151(8):742–50.

    Article  PubMed  Google Scholar 

  48. Subherwal S, Patel MR, Kober L, Peterson ED, Bhatt DL, Gislason GH, et al. Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study. Eur J Prev Cardiol. 2015;22(3):317–25.

    Article  PubMed  Google Scholar 

  49. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2018;137(4):338–50.

    Article  CAS  PubMed  Google Scholar 

  50. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706–17.

    Article  CAS  PubMed  Google Scholar 

  51. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, et al. Ticagrelor versus Clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  52. Bonaca MP, Gutierrez JA, Creager MA, Scirica BM, Olin J, Murphy SA, et al. Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery disease: results from the trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosis-thrombolysis in myocardial infarction 50 (TRA2 degrees P-TIMI 50). Circulation. 2016;133(10):997–1005.

    Article  CAS  PubMed  Google Scholar 

  53. Yeh RW, Secemsky EA, Kereiakes DJ, Normand SL, Gershlick AH, Cohen DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA. 2016;315(16):1735–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ademi Z, Zomer E, Tonkin A, Liew D. Cost-effectiveness of rivaroxaban and aspirin compared to aspirin alone in patients with stable cardiovascular disease: an Australian perspective. Int J Cardiol. 2018;270:54–9.

    Article  PubMed  Google Scholar 

  55. Begum N, Stephens S, Schoeman O, Fraschke A, Kirsch B, Briere JB, et al. Cost-effectiveness analysis of rivaroxaban in the secondary prevention of acute coronary syndromes in Sweden. Cardiol Ther. 2015;4(2):131–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia

    Stephen J. Nicholls & Adam J. Nelson

  2. Monash Cardiovascular Research Centre, Monash University, Clayton, Melbourne, VIC, Australia

    Stephen J. Nicholls

Authors
  1. Stephen J. Nicholls
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam J. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen J. Nicholls.

Ethics declarations

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

SJN has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, and Novo Nordisk. AJN has no conflicts of interest that are directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nicholls, S.J., Nelson, A.J. Rivaroxaban With or Without Aspirin for the Secondary Prevention of Cardiovascular Disease: Clinical Implications of the COMPASS Trial. Am J Cardiovasc Drugs 19, 343–348 (2019). https://doi.org/10.1007/s40256-018-00322-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-018-00322-4

Search

Navigation