Efficacy and Safety of Extended Antithrombotic Therapy in Stable Coronary Artery Disease: Systematic Review of the Literature

Main Article Content

Gustavo Alexis Lemus-Barrios Jesus Beltrán España Luisa Fernanda Rincón Benavides Edward Andrés Cáceres Méndez Angel Alberto García Peña


Extended dual antithrombotic therapy, which entails the concurrent administration of acetylsalicylic acid and a P2Y12 inhibitor or anticoagulant beyond the initial 12 months of presenting with acute coronary syndrome, has been the subject of considerable research in recent years. The objective of this study was to evaluate the impact of dual antithrombotic therapy in stable coronary artery disease. We conducted a registered (PROSPERO CRD42023394771) assessing the safety and efficacy of antithrombotic therapy published over the past 20 years up to May 2021 in four databases (PubMed, EMBASE, BVSalud /LILACS, Cochrane Reviews). Using the RoB2 tool, we evaluated the risk of bias. We performed a literature search using keywords and identified 95 eligible articles, of which 23 were excluded as duplicates. After applying the inclusion and exclusion criteria, we found 29 articles for a detailed review and assessment of bias by applying the ROB2 toll, and we found that five articles had a low risk of bias. Our analysis found that extended dual antithrombotic therapy reduces ischemic cardiovascular outcomes, but it comes at the cost of an increased risk of bleeding when compared with acetylsalicylic acid monotherapy.

Article Details

How to Cite
LEMUS-BARRIOS, Gustavo Alexis et al. Efficacy and Safety of Extended Antithrombotic Therapy in Stable Coronary Artery Disease: Systematic Review of the Literature. Medical Research Archives, [S.l.], v. 12, n. 3, mar. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5107>. Date accessed: 13 apr. 2024. doi: https://doi.org/10.18103/mra.v12i3.5107.
Review Articles


1. Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study [published correction appears in J Am Coll Cardiol. 2021 Apr 20;77(15):1958-1959]. J Am Coll Cardiol. 2020;76(25):2982-3021. doi:10.1016/j.jacc.2020.11.010.
2. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA.2010;304(12):1350-1357. doi:10.1001/jama.2010.1322
3. Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36(19):1163-1170. doi:10.1093/eurheartj/ehu505
4. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477. doi:10.1093/eurheartj/ehz425
5. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice [published correction appears in Eur Heart J. 2022 Nov 7;43(42):4468]. Eur Heart J. 2021;42(34):3227-3337. doi:10.1093/eurheartj/ehab484.
6. Mortensen MB, Blaha MJ, Nordestgaard BG. Eligibility and Preventive Potential for New Evidence-Based Cardiovascular Drugs in Secondary Prevention. JAMA Cardiol. 2020;5(2):209-215. doi:10.1001/jamacardio.2019.4759
7. Chan Pin Yin DRPP, Ten Berg JM. Long-term residual cardiovascular risk after acute coronary syndrome: antithrombotic treatment options. Neth Heart J. 2022;30(1):38-46. doi:10.1007/s12471-021-01604-4
8. Sumaya W, Geisler T, Kristensen SD, Storey RF. Dual Antiplatelet or Dual Antithrombotic Therapy for Secondary Prevention in High-Risk Patients with Stable Coronary Artery Disease? [published correction appears in Thromb Haemost. 2019 Oct;119(10):e1]. Thromb Haemost. 2019;119(10):1583-1589. doi:10.1055/s-0039-1679903.
9. Baigent C, Blackwell L, et al. 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. doi:10.1016/S0140-6736(09)60503-1.
10. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation . Eur Heart J. 2021;42(14):1289-1367. doi:10.1093/eurheartj/ehaa575
11. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med.2014;371(23):2155-2166. doi:10.1056/NEJMoa1409312.
12. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med.2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118
13. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800. doi:10.1056/NEJMoa1500857.
14. Greenhalgh T, Peacock R. Effectiveness and efficiency of search methods in systematic reviews of complex evidence: audit of primary sources. BMJ. 2005;331(7524):1064-1065. doi:10.1136/bmj.38636.593461.68.
15. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/bmj.l4898.
16. 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(1):14-23. doi:10.1016/j.jacc.2021.04.083.
17. Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease. N Engl J Med. 2018;379(14):1332-1342. doi:10.1056/NEJMoa1808848.
18. Branch KR, Probstfield JL, Eikelboom JW, et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease. Circulation. 2019;140(7):529-537. doi:10.1161/CIRCULATIONAHA.119.039609.
19. Bhatt DL, Eikelboom JW, Connolly SJ, et al. Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial. Circulation. 2020;141(23):1841-1854. doi:10.1161/CIRCULATIONAHA.120.046448.
20. Guzik TJ, Ramasundarahettige C, Pogosova N, et al. Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial. J Am Coll Cardiol. 2021;77(5):511-525. doi:10.1016/j.jacc.2020.11.061.
21. Fox KAA, Eikelboom JW, Shestakovska O, Connolly SJ, Metsarinne KP, Yusuf S. Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial. J Am Coll Cardiol. 2019;73(18):2243-2250. doi:10.1016/j.jacc.2019.02.048.
22. Vanassche T, Verhamme P, Anand SS, et al. Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial. Eur J Prev Cardiol. 2020;27(3):296-307. doi:10.1177/2047487319882154.
23. Greenberg B, Neaton JD, Anker SD, 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. 2019;4(6):515-523. doi:10.1001/jamacardio.2019.1049.
24. Eikelboom JW, Bosch JJ, Connolly SJ, et al. Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin. J Am Coll Cardiol. 2019;74(12):1519-1528. doi:10.1016/j.jacc.2019.07.065
25. Mehra MR, Vaduganathan M, Fu M, et al. A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial. Eur Heart J. 2019;40(44):3593-3602. doi:10.1093/eurheartj/ehz427.
26. Liang Y, Zhu J, Liu L, et al. Efficacy and safety of rivaroxaban plus aspirin in women and men with chronic coronary or peripheral artery disease [published correction appears in Cardiovasc Res. 2021 May 25;117(6):1577]. Cardiovasc Res. 2021;117(3):942-949. doi:10.1093/cvr/cvaa100.
27. Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA. The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease [published correction appears in Circulation. 2020 Jul 7;142(1):e23]. Circulation. 2020;142(1):40-48.
28. Sharma M, Hart RG, Connolly SJ, et al. Stroke Outcomes in the COMPASS Trial. Circulation. 2019;139(9):1134-1145. doi:10.1161/CIRCULATIONAHA.118.035864.
29. Magnani G, Ardissino D, Im K, et al. Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long-Term Ticagrelor in Stable Patients With Prior Myocardial Infarction. J Am Heart Assoc. 2021;10(4):e017008. doi:10.1161/JAHA.120.017008
30. Bonaca MP, Goto S, Bhatt DL, et al. Prevention of Stroke with Ticagrelor in Patients with Prior Myocardial Infarction: Insights from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54). Circulation. 2016;134(12):861-871. doi:10.1161/CIRCULATIONAHA.116.024637.
31. Bansilal S, Bonaca MP, Cornel JH, et al. Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. J Am Coll Cardiol. 2018;71(5):489-496. doi:10.1016/j.jacc.2017.11.050.
32. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med. 2019;381(14):1309-1320. doi:10.1056/NEJMoa1908077.
33. Eikelboom JW, Bosch J, Connolly SJ, et al. Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial. Eur Heart J Cardiovasc Pharmacother. 2022;8(8):786-795. doi:10.1093/ehjcvp/pvac023
34. Vanassche T, Verhamme P, Anand SS, et al. Low-dose rivaroxaban plus aspirin in patients with polypharmacy and multimorbidity: an analysis from the COMPASS trial. Eur Heart J Cardiovasc Pharmacother. 2022;8(5):462-473. doi:10.1093/ehjcvp/pvab050.
35. Perera KS, Ng KKH, Nayar S, et al. Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial. JAMA Neurol. 2020;77(1):43-48. doi:10.1001/jamaneurol.2019.2984.
36. Bainey KR, Welsh RC, Connolly SJ, et al. Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI)]. Circulation.2020;141(14):1141-1151. doi:10.1161/CIRCULATIONAHA.119.044598
37. Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J.2016;37(4):365-374. doi:10.1093/eurheartj/ehv481
38. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129(3):304-312. doi:10.1161/CIRCULATIONAHA.113.003303.
39. Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014;384(9954):1577-1585. doi:10.1016/S0140-6736(14)60612-7.
40. Gilard M, Barragan P, Noryani AAL, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65(8):777-786. doi:10.1016/j.jacc.2014.11.008.
41. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125(16):2015-2026. doi:10.1161/CIRCULATIONAHA.111.071589
42. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76(6):908-916. doi:10.1111/bcp.12114
43. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi:10.1111/j.1538-7836.2005.01204.x
44. Valdivielso JM, Rodríguez-Puyol D, Pascual J, et al. Atherosclerosis in Chronic Kidney Disease: More, Less, or Just Different?. Arterioscler Thromb Vasc Biol. 2019;39(10):1938-1966. doi:10.1161/ATVBAHA.119.312705
45. Adams MJ, Irish AB, Watts GF, Oostryck R, Dogra GK. Hypercoagulability in chronic kidney disease is associated with coagulation activation but not endothelial function. Thromb Res. 2008;123(2):374-380. doi:10.1016/j.thromres.2008.03.024
46. Molnar AO, Bota SE, Garg AX, et al. The Risk of Major Hemorrhage with CKD. J Am Soc Nephrol. 2016;27(9):2825-2832. doi:10.1681/ASN.2015050535.
47. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13):1482-1487. doi:10.1161/CIRCULATIONAHA.107.696906
48. Zannad F, Stough WG, Regnault V, et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol. 2013;167(5):1772-1782. doi:10.1016/j.ijcard.2012.12.018
49. Jafri SM, Ozawa T, Mammen E, Levine TB, Johnson C, Goldstein S. Platelet function, thrombin and fibrinolytic activity in patients with heart failure. Eur Heart J. 1993;14(2):205-212. doi:10.1093/eurheartj/14.2.205
50. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes [published correction appears in Eur Heart J. 2020 Nov 21;41(44):4242]. Eur Heart J. 2020;41(3):407-477. doi:10.1093/eurheartj/ehz425.
51. Yeh RW, Secemsky EA, Kereiakes 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 [published correction appears in JAMA. 2016 Jul 19;316(3):350] [published correction appears in JAMA. 2016 Jul 19;316(3):350]. JAMA. 2016;315(16):1735-1749. doi:10.1001/jama.2016.3775
52. Dagenais GR, Dyal L, Bosch JJ, et al. Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease. Heart. 2021;107(14):1130-1137. doi:10.1136/heartjnl-2020-318758.