Skip to main content

Advertisement

SpringerLink
Log in

When a Single Antiplatelet Agent for Stroke Prevention Is Not Enough: Current Evidence and Future Applications of Dual Antiplatelet Therapy

  • Cerebrovascular Disease and Stroke (N Rost, Section Editor)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

  • For secondary stroke prevention, long-term dual antiplatelet therapy is not recommended due to increased bleeding risks.

  • There is no specific evidence for using dual antiplatelet therapy for cervical artery dissection or for adding a second antiplatelet agent after a stroke while taking aspirin monotherapy.

  • For patients with atrial fibrillation and stroke/TIA unable to tolerate warfarin, aspirin monotherapy is reasonable. Dual antiplatelet therapy carries a similar risk of major bleeding as warfarin that offsets reductions in stroke risk.

  • Dual antiplatelet therapy is recommended for endovascular cerebrovascular stenting procedures, although the optimal duration of therapy is not well established.

  • Short-term dual antiplatelet therapy when initiated acutely after minor stroke/TIA, particularly in Asian populations or for intracranial atherosclerosis, holds promise though studies to evaluate this approach more generally are ongoing.

  • New antiplatelet agents and additional data on the pharmacogenetics of clopidogrel metabolism have the potential to help to individualize these recommendations moving forward.

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 and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Sandercock PA, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD000029. Recent review of 8 randomized controlled trials evaluating the effect of acute antiplatelet therapy, most significantly showing aspirin started within 48 hours of stroke saved lives and reduced stroke recurrence.

    PubMed  Google Scholar 

  2. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke. 2005;36(4):720–3.

    Article  PubMed  Google Scholar 

  3. Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. Circulation. 2011;123(19):2111–9.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81–106

  5. 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.

  6. Baigent C, Blackwell L, Collins R, 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):1849–60.

    Article  PubMed  Google Scholar 

  7. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236. The 2014 AHA guidelines for secondary stroke prevention with evidence-based recommendations on antiplatelet therapy for different stroke etiologies and safety issues based on thorough review of published data.

    Article  PubMed  Google Scholar 

  8. van Kooten F, Ciabattoni G, Patrono C, Schmitz PI, van Gijn J, Koudstaal PJ. Evidence for episodic platelet activation in acute ischemic stroke. Stroke. 1994;25(2):278–81.

    Article  PubMed  Google Scholar 

  9. Huang DY, Eisert WG. CHANCE trial: early short-term dual antiplatelet treatment for stroke prevention. Stroke. 2013;44(12):3623–4. Important randomized controlled trial showing short-term acute aspirin and clopidogrel therapy is effective for stroke risk reduction in a Chinese population. This trial formed the foundation for several ongoing trials on short-term multiple antiplatelet therapy for acute stroke.

    Article  PubMed  Google Scholar 

  10. Johnston SC, Easton JD, Farrant M, et al. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke. 2013;8(6):479–83.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961–9.

    Article  CAS  PubMed  Google Scholar 

  12. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. NEJM. 1991;325(18):1261–1266.

  13. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group. Lancet. 1991;338(8779):1345–1349.

  14. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54(12):1044–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Johnson ES, Lanes SF, Wentworth 3rd CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose–response effect of aspirin on stroke. Arch Intern Med. 1999;159(11):1248–53.

    Article  CAS  PubMed  Google Scholar 

  16. 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):1329–1339.

  17. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989;1(8649):1215–20.

    Article  CAS  PubMed  Google Scholar 

  18. Hass WK, Easton JD, Adams Jr HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. NEJM. 1989;321(8):501–7.

    Article  CAS  PubMed  Google Scholar 

  19. Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA. 2003;289(22):2947–57.

    Article  CAS  PubMed  Google Scholar 

  20. Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol. 2008;7(6):494–9.

    Article  CAS  PubMed  Google Scholar 

  21. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 2010;9(10):959–68.

    Article  CAS  PubMed  Google Scholar 

  22. Takahashi S, Oida K, Fujiwara R, et al. Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol. 1992;20(6):900–6.

    Article  CAS  PubMed  Google Scholar 

  23. Otsuki M, Saito H, Xu X, et al. Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence. Atherosclerosis. 2001;158(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  24. Xie W, Zheng F, Zhong B, Song X. Long-term antiplatelet mono- and dual therapies after ischemic stroke or transient ischemic attack: network meta-analysis. J Am Heart Assoc. 2015;4(8):e002259. Large meta-analysis showing that long-term dual antiplatelet therapy not only increases risk of major bleeding but also is not superior in reducing ischemic stroke risk compared to antiplatelet monotherapy.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. NEJM. 2015;372(19):1791–800.

    Article  PubMed  Google Scholar 

  26. Husted S, James SK, Bach RG, et al. The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2014;35(23):1541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. NEJM. 2008;359(12):1238–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1–2):1–13.

    Article  CAS  PubMed  Google Scholar 

  29. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367(9523):1665–73.

    Article  CAS  PubMed  Google Scholar 

  30. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. NEJM. 2006;354(16):1706–17.

    Article  CAS  PubMed  Google Scholar 

  31. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331–7.

    Article  CAS  PubMed  Google Scholar 

  32. Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Int Med. 2013;159(7):463–70. Another large review showing aspirin + clopidogrel dual therapy over one year fared no better than clopidogrel alone in preventing stroke while increasing risk of bleeding.

    Article  PubMed  Google Scholar 

  33. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology. 2005;64(5):817–20.

    Article  PubMed  Google Scholar 

  34. Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol. 2007;6(12):1063–72.

    Article  PubMed  Google Scholar 

  35. Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology. 2006;66(5):641–6.

    Article  CAS  PubMed  Google Scholar 

  36. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284(22):2901–6.

    Article  CAS  PubMed  Google Scholar 

  37. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283–92.

    Article  PubMed  Google Scholar 

  38. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9(2):159–66.

    Article  CAS  PubMed  Google Scholar 

  39. Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet. 2014;383(9921):984–98.

    Article  PubMed  Google Scholar 

  40. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. NEJM. 2009;360(4):354–62.

    Article  CAS  PubMed  Google Scholar 

  41. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke. 2008;39(8):2396–9.

    Article  PubMed  Google Scholar 

  42. Kwon SU, Cho YJ, Koo JS, et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005;36(4):782–6.

    Article  CAS  PubMed  Google Scholar 

  43. Kwon SU, Hong KS, Kang DW, et al. Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis. Stroke. 2011;42(10):2883–90.

    Article  CAS  PubMed  Google Scholar 

  44. Wang X, Lin WH, Zhao YD, et al. The effectiveness of dual antiplatelet treatment in acute ischemic stroke patients with intracranial arterial stenosis: a subgroup analysis of CLAIR study. Int J Stroke. 2013;8(8):663–8.

    Article  PubMed  Google Scholar 

  45. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. NEJM. 2011;365(11):993–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Derdeyn CP, Chimowitz MI, Lynn MJ, et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet. 2014;383(9914):333–41.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zaidat OO, Klucznik R, Alexander MJ, et al. The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis. Neurology. 2008;70(17):1518–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. NEJM. 2012;367(9):817–25.

    Article  PubMed  Google Scholar 

  49. Cote R, Zhang Y, Hart RG, et al. ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection? Neurology. 2014;82(5):382–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol. 2009;8(7):668–78.

    Article  PubMed  Google Scholar 

  51. Markus HS, Hayter E, Levi C, Feldman A, Venables G, Norris J. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14(4):361–7.

    Article  CAS  PubMed  Google Scholar 

  52. Gawaz M, Neumann FJ, Ott I, May A, Rudiger S, Schomig A. Changes in membrane glycoproteins of circulating platelets after coronary stent implantation. Heart. 1996;76(2):166–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Parsson H, Cwikiel W, Johansson K, Swartbol P, Norgren L. Deposition of platelets and neutrophils in porcine iliac arteries after angioplasty and Wallstent placement compared with angioplasty alone. Cardiovasc Intervent Radiol. 1994;17(4):190–6.

    Article  CAS  PubMed  Google Scholar 

  54. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol. 2000;35(1):157–63.

    Article  CAS  PubMed  Google Scholar 

  55. McKevitt FM, Randall MS, Cleveland TJ, Gaines PA, Tan KT, Venables GS. The benefits of combined anti-platelet treatment in carotid artery stenting. Eur J Vasc Endovasc Surg. 2005;29(5):522–7.

    Article  CAS  PubMed  Google Scholar 

  56. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 Suppl):546s–92.

    Article  CAS  PubMed  Google Scholar 

  57. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. NEJM. 2009;360(20):2066–78.

    Article  PubMed  Google Scholar 

  58. Connolly SJ, Eikelboom JW, Ng J, et al. Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable. Ann Intern Med. 2011;155(9):579–86.

    Article  PubMed  Google Scholar 

  59. Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med. 2002;162(19):2197–202.

    Article  CAS  PubMed  Google Scholar 

  60. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998;280(22):1930–5.

    Article  CAS  PubMed  Google Scholar 

  61. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. NEJM. 2001;345(7):494–502.

    Article  CAS  PubMed  Google Scholar 

  62. Zakarija A, Kwaan HC, Moake JL, et al. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008). Kidney Int Suppl. 2009;112:S20–4.

    Article  CAS  PubMed  Google Scholar 

  63. Xian Y, Federspiel JJ, Grau-Sepulveda M, et al. Risks and benefits associated with prestroke antiplatelet therapy among patients with acute ischemic stroke treated with intravenous tissue plasminogen activator. JAMA Neurology. 2015:1–10.

  64. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51(3):256–60.

    Article  CAS  PubMed  Google Scholar 

  65. Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153(6):378–86.

    Article  PubMed  Google Scholar 

  66. Drepper MD, Spahr L, Frossard JL. Clopidogrel and proton pump inhibitors—where do we stand in 2012? World J Gastroenterol. 2012;18(18):2161–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Depta JP, Fowler J, Novak E, et al. Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack. Stroke. 2012;43(9):2376–81.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, University of California, 675 Nelson Rising Lane, Room 411B, Box 0663, San Francisco, CA, 94143, USA

    Kristy Yuan MD & Anthony S. Kim MD MAS

Authors
  1. Kristy Yuan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony S. Kim MD MAS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony S. Kim MD MAS.

Ethics declarations

Conflict of Interest

Kristy Yuan declares no potential conflicts of interest.

Anthony S. Kim reports research grants from SanBio and BioGen and funding for a government sponsored clinical trial in which clopidogrel was provided by Sanofi.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Cerebrovascular Disease and Stroke

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, K., Kim, A.S. When a Single Antiplatelet Agent for Stroke Prevention Is Not Enough: Current Evidence and Future Applications of Dual Antiplatelet Therapy. Curr Treat Options Cardio Med 18, 26 (2016). https://doi.org/10.1007/s11936-016-0449-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11936-016-0449-7

Keywords

Search

Navigation