American Journal of Cardiovascular Drugs

, Volume 19, Issue 1, pp 37–47 | Cite as

Efficacy and Safety of the Use of Non-vitamin K Antagonist Oral Anticoagulants in Patients with Ischemic Heart Disease: A Meta-Analysis of Phase III Randomized Trials

  • Linghua Fu
  • Wengen Zhu
  • Lin Huang
  • Jinzhu Hu
  • Jianyong Ma
  • Gregory Y. H. Lip
  • Kui HongEmail author
Systematic Review



There are conflicting published data on non-vitamin K antagonist oral anticoagulants (NOACs), with varying evidence of benefit or harm in acute coronary syndrome (ACS) and non-ACS cohorts. To explore the efficacy and safety of NOAC use in patients with ischemic heart disease (IHD), we conducted a meta-analysis of phase III randomized controlled trials (RCTs).


We systematically searched the Cochrane Library, PubMed, and Embase databases. A random-effect model was selected to pool the effect measurement estimates (hazard ratios [HRs] and 95% confidence intervals [CIs]).


Three RCTs with 39,492 enrolled IHD patients were included. Compared with placebo, NOACs were associated with reduced risks of major adverse cardiac events (MACE) (HR 0.83, 95% CI 0.76–0.90), cardiovascular death (HR 0.82, 95% CI 0.72–0.93), and myocardial infarction (HR 0.87, 95% CI 0.78–0.97) accompanied by increased risks of major bleeding (HR 2.46, 95% CI 1.42–4.26), but not fatal bleeding (HR 1.35, 95% CI 0.76–2.39) or intracranial hemorrhage (HR 2.19, 95% CI 0.91–5.27). Subgroup analysis revealed that NOACs were associated with an increased risk of major bleeding in patients who received dual antiplatelet therapy compared with patients who received single antiplatelet therapy (3.01, 1.82–4.98 vs. 1.66, 1.37–2.03; P for interaction 0.03) and patients with ACS compared with patients with non-ACS (3.27, 2.16–4.95 vs. 1.66, 1.36–2.02; P for interaction 0.004).


In patients with IHD, NOACs confer protection against thrombosis-related complications, but at the cost of an increased hazard of major bleeding. NOACs plus a single antiplatelet drug seem to be a good choice for patients with IHD.


Author Contributions

H-K was responsible for the entire project and revised the draft of the manuscript. F-LH, Z-WG and H-L performed the systematic literature review and drafted the first version of the manuscript with the help of GYHL. All of the authors participated in the interpretation of the results and prepared the final manuscript.

Compliance with Ethical Standards


This study was funded by the National Natural Science Foundation of China (81530013; 81370288; 8153000545) and National Key R&D Program of China (2017YFC1307804).

Conflict of interest

F-LH, Z-WG, H-L, H-JZ, M-JY, GYHL, and H-K declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Supplementary material

40256_2018_299_MOESM1_ESM.docx (309 kb)
Supplementary material 1 (DOCX 303 kb)


  1. 1.
    GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211–59. Scholar
  2. 2.
    Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the global burden of disease 2010 study. Circulation. 2014;129(14):1483–92. Scholar
  3. 3.
    Fox KA, Anderson FA Jr, Goodman SG, Steg PG, Pieper K, Quill A, et al. Time course of events in acute coronary syndromes: implications for clinical practice from the grace registry. Nat Clin Pract Cardiovasc Med. 2008;5(9):580–9. Scholar
  4. 4.
    Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44–164. Scholar
  5. 5.
    Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for Dual Antiplatelet Therapy in Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213–60. Scholar
  6. 6.
    . Authors/Task Force members, Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541–619.
  7. 7.
    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. Scholar
  8. 8.
    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. Scholar
  9. 9.
    Jackson LR 2nd, Ju C, Zettler M, Messenger JC, Cohen DJ, Stone GW, et al. Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the translate-acs study. JACC Cardiovasc Interv. 2015;8(14):1880–9. Scholar
  10. 10.
    Lamberts M, Olesen JB, Ruwald MH, Hansen CM, Karasoy D, Kristensen SL, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185–93. Scholar
  11. 11.
    Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–62. Scholar
  12. 12.
    Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708. Scholar
  13. 13.
    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. Scholar
  14. 14.
    Wallentin LWR, Weaver WD, Emanuelsson H, Goodvin A, Nyström P, Bylock A, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the esteem randomised controlled trial. Lancet. 2003;362(9386):789–97. Scholar
  15. 15.
    APPRAISE Steering Committee and Investigators1, Alexander JH, Becker RC, Bhatt DL, Cools F, Crea 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.
  16. 16.
    Mega JLBE, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, 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. Scholar
  17. 17.
    Oldgren JBA, Granger CB, Khder Y, Roberts J, Siegbahn A, Tijssen JG, 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. Scholar
  18. 18.
    Steg PGMS, Jukema JW, Lip GY, Gibson CM, Kovar F, Kala P, 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. 2011;32(20):2541–4. Scholar
  19. 19.
    Oldgren JWL, Alexander JH, James S, Jönelid B, Steg G, Sundström J. 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. Scholar
  20. 20.
    Komocsi A, Vorobcsuk A, Kehl D, Aradi D. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(20):1537–45. Scholar
  21. 21.
    Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017. (Epub ahead of print).
  22. 22.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. Scholar
  23. 23.
    Verheugt FW. Combined antiplatelet and novel oral anticoagulant therapy after acute coronary syndrome: is three a crowd? Eur Heart J. 2013;34(22):1618–20. Scholar
  24. 24.
    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. Scholar
  25. 25.
    Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ. 2012;345:e7498. Scholar
  26. 26.
    Ogawa H, Goto S, Matsuzaki M, Hiro S. Shima D; APPRAISE-J investigators. Randomized, double-blind trial to evaluate the safety of apixaban with antiplatelet therapy after acute coronary syndrome in Japanese patients (APPRAISE-J). Circ J. 2013;77(9):2341–8.CrossRefGoogle Scholar
  27. 27.
    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. Scholar
  28. 28.
    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. Scholar
  29. 29.
    Khan R, Lopes RD, Neely ML, Stevens SR, Harrington RA, Diaz R, et al. Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome. Heart. 2015;101(18):1475–84. Scholar
  30. 30.
    Hess CN, James S, Lopes RD, Wojdyla DM, Neely ML, Liaw D, et al. Apixaban plus mono versus dual antiplatelet therapy in acute coronary syndromes: insights from the APPRAISE-2 trial. J Am Coll Cardiol. 2015;66(7):777–87. Scholar
  31. 31.
    Cornel JH, Lopes RD, James S, Stevens SR, Neely ML, Liaw D, et al. Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: insights from the APixaban for PRevention of Acute ISchemic Events 2. Am Heart J. 2015;169(4):531–8. Scholar
  32. 32.
    Cavender MA, Gibson CM, Braunwald E, Wiviott SD, Murphy SA, Toda Kato E, et al. The effect of rivaroxaban on myocardial infarction in the ATLAS ACS 2-TIMI 51 trial. Eur Heart J Acute Cardiovasc Care. 2015;4(5):468–74. Scholar
  33. 33.
    Mega JL, Braunwald E, Wiviott SD, Murphy SA, Plotnikov A, Gotcheva N, et al. Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51). Am J Cardiol. 2013;112(4):472–8. Scholar
  34. 34.
    Mega JL, Braunwald E, Murphy SA, Plotnikov AN, Burton P, Kiss RG, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61(18):1853–9. Scholar
  35. 35.
    Gibson CM, Chakrabarti AK, Mega J, Bode C, Bassand JP, Verheugt FW, et al. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J Am Coll Cardiol. 2013;62(4):286–90. Scholar
  36. 36.
    Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012;125(5):669–76. Scholar
  37. 37.
    Bahit MC, Lopes RD, Wojdyla DM, Hohnloser SH, Alexander JH, Lewis BS, et al. Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial. Int J Cardiol. 2013;170(2):215–20. Scholar
  38. 38.
    Mahaffey KW, Stevens SR, White HD, Nessel CC, Goodman SG, Piccini JP, et al. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35(4):233–41. Scholar
  39. 39.
    Gibson CM, Pinto DS, Chi G, Arbetter D, Yee M, Mehran R, 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. Circulation. 2017;135(4):323–33. Scholar
  40. 40.
    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. Scholar
  41. 41.
    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. Scholar
  42. 42.
    Ducrocq G, Amarenco P, Labreuche J, Alberts MJ, Mas JL, Ohman EM, et al. A history of stroke/transient ischemic attack indicates high risks of cardiovascular event and hemorrhagic stroke in patients with coronary artery disease. Circulation. 2013;127(6):730–8. Scholar
  43. 43.
    Palmerini T, Benedetto U, Biondi-Zoccai G, Della Riva D, Bacchi-Reggiani L, Smits PC, et al. Long-term safety of drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol. 2015;65(23):2496–507. Scholar
  44. 44.
    Mahaffey KW, Hager R, Wojdyla D, White HD, Armstrong PW, Alexander JH, et al. Meta-analysis of intracranial hemorrhage in acute coronary syndromes: incidence, predictors, and clinical outcomes. J Am Heart Assoc. 2015;4(6):e001512. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Linghua Fu
    • 1
  • Wengen Zhu
    • 1
  • Lin Huang
    • 1
  • Jinzhu Hu
    • 1
  • Jianyong Ma
    • 1
  • Gregory Y. H. Lip
    • 2
  • Kui Hong
    • 1
    • 3
    Email author
  1. 1.Department of Cardiovascular MedicineThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.University of Birmingham Centre for Cardiovascular Sciences, City HospitalBirminghamUK
  3. 3.Jiangxi Key Laboratory of Molecular MedicineNanchangChina

Personalised recommendations