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2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease

A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
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    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
    ,
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    † ACC/AHA Task Force on Clinical Practice Guidelines Liaison.
    Glenn N. Levine
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    † ACC/AHA Task Force on Clinical Practice Guidelines Liaison.
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    ‡ ACC/AHA Representative.
    Eric R. Bates
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    ‡ ACC/AHA Representative.
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    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
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    § Evidence Review Committee Chair.
    John A. Bittl
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    § Evidence Review Committee Chair.
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    ‡ ACC/AHA Representative.
    Ralph G. Brindis
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    Stephan D. Fihn
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    ‡ ACC/AHA Representative.
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    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
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    ‖ American Society of Anesthesiologists/Society of Cardiovascular Anesthesiologists Representative.
    Lee A. Fleisher
    Footnotes
    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
    ‖ American Society of Anesthesiologists/Society of Cardiovascular Anesthesiologists Representative.
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    ‡ ACC/AHA Representative.
    Christopher B. Granger
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    Richard A. Lange
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    ‡ ACC/AHA Representative.
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    ¶ American Association for Thoracic Surgery/Society of Thoracic Surgeons Representative.
    Michael J. Mack
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    ¶ American Association for Thoracic Surgery/Society of Thoracic Surgeons Representative.
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    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
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    ‡ ACC/AHA Representative.
    Laura Mauri
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    ‡ ACC/AHA Representative.
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    # Society for Cardiovascular Angiography and Interventions Representative.
    Roxana Mehran
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    # Society for Cardiovascular Angiography and Interventions Representative.
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    ‡ ACC/AHA Representative.
    Debabrata Mukherjee
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    L. Kristin Newby
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    Patrick T. O'Gara
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    Marc S. Sabatine
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    ‡ ACC/AHA Representative.
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    ‡ ACC/AHA Representative.
    Peter K. Smith
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    ‡ ACC/AHA Representative.
    Sidney C. Smith Jr.
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  • Jonathan L. Halperin
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  • Glenn N. Levine
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  • Sana M. Al-Khatib
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  • Kim K. Birtcher
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  • Biykem Bozkurt
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  • Ralph G. Brindis
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  • Joaquin E. Cigarroa
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  • Federico Gentile
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  • Samuel Gidding
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  • Mark A. Hlatky
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  • John S. Ikonomidis
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  • José A. Joglar
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  • Susan J. Pressler
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  • Duminda N. Wijeysundera
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  • Author Footnotes
    ∗ Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information.
    † ACC/AHA Task Force on Clinical Practice Guidelines Liaison.
    ‡ ACC/AHA Representative.
    § Evidence Review Committee Chair.
    ‖ American Society of Anesthesiologists/Society of Cardiovascular Anesthesiologists Representative.
    ¶ American Association for Thoracic Surgery/Society of Thoracic Surgeons Representative.
    # Society for Cardiovascular Angiography and Interventions Representative.

      Key Words

      Figure thumbnail fx1
      Treatment algorithm for management and duration of P2Y12 inhibitor therapy in patients undergoing CABG.
      See Editorial Commentary page 1276.

      Preamble

      Incorporation of new study results, medications, or devices that merit modification of existing clinical practice guideline recommendations, or the addition of new recommendations, is critical to ensuring that guidelines reflect current knowledge, available treatment options, and optimum medical care. To keep pace with evolving evidence, the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guidelines (“Task Force”) has issued this focused update to revise existing guideline recommendations on the basis of recently published study data. This update has been subject to rigorous, multilevel review and approval, similar to the full guidelines. For specific focused update criteria and additional methodological details, please see the ACC/AHA guideline methodology manual.

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/downloadable/ucm_319826.pdf. American College of Cardiology and American Heart Association. Accessed January 23, 2015.

      Modernization

      Processes have evolved over time in response to published reports from the Institute of Medicine
      Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US)
      Clinical Practice Guidelines We Can Trust.
      Committee on Standards for Systematic Reviews of Comparative Effectiveness Research, Institute of Medicine (US)
      Finding What Works in Health Care: Standards for Systematic Reviews.
      and ACC/AHA mandates,
      • Anderson J.L.
      • Heidenreich P.A.
      • Barnett P.G.
      • et al.
      ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines.
      • Arnett D.K.
      • Goodman R.A.
      • Halperin J.L.
      • et al.
      AHA/ACC/HHS strategies to enhance application of clinical practice guidelines in patients with cardiovascular disease and comorbid conditions: from the American Heart Association, American College of Cardiology, and U.S. Department of Health and Human Services.
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • et al.
      ACCF/AHA clinical practice guideline methodology summit report: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      • Jacobs A.K.
      • Anderson J.L.
      • Halperin J.L.
      The evolution and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      leading to adoption of a “knowledge byte” format. This process entails delineation of a recommendation addressing a specific clinical question, followed by concise text (ideally <250 words per recommendation) and hyperlinked to supportive evidence. This approach better accommodates time constraints on busy clinicians, facilitates easier access to recommendations via electronic search engines and other evolving technology, and supports the evolution of guidelines as “living documents” that can be dynamically updated as needed.

      Class of Recommendation and Level of Evidence

      The Class of Recommendation (COR) and Level of Evidence (LOE) are derived independently of each other according to established criteria. The COR indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit of a clinical action in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1). Recommendations in this focused update reflect the new 2015 COR/LOE system, in which LOE B and C are subcategorized for the purpose of increased granularity.

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/downloadable/ucm_319826.pdf. American College of Cardiology and American Heart Association. Accessed January 23, 2015.

      • Jacobs A.K.
      • Anderson J.L.
      • Halperin J.L.
      The evolution and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Halperin J.L.
      • Levine G.N.
      • Al-Khatib S.M.
      • et al.
      Further Evolution of the ACC/AHA Clinical Practice Guideline Recommendation Classification System: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Table 1Applying class of recommendation and level of evidence to clinical strategies, interventions, treatments, or diagnostic testing in patient care (updated August 2015)

      Relationships With Industry and Other Entities

      The ACC and AHA exclusively sponsor the work of guideline writing committees (GWCs) without commercial support, and members volunteer time for this activity. Selected organizations and professional societies with related interests and expertise are invited to participate as partners or collaborators. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All GWC members and reviewers are required to fully disclose current industry relationships or personal interests, beginning 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced GWC and requires that both the chair and a majority of GWC members have no relevant RWI (see Appendix 1 for the definition of relevance). GWC members are restricted with regard to writing or voting on sections to which RWI apply. Members of the GWC who recused themselves from voting are indicated and specific section recusals are noted in Appendixes 1 and 2. In addition, for transparency, GWC members' comprehensive disclosure information is available as an Online Supplement (http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000404/-/DC1). Comprehensive disclosure information for the Task Force is also available at http://www.acc.org/about-acc/leadership/guidelines-and-documents-task-forces.aspx. The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, genders, ethnicities, intellectual perspectives, and scopes of clinical activities.

      Intended Use

      Guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations may have a broader target. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients' interests. The guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current unless and until it is updated, revised, or superseded by a published addendum.

      Related Issues

      For additional information pertaining to the methodology for grading evidence, assessment of benefit and harm, shared decision making between the patient and clinician, structure of evidence tables and summaries, standardized terminology for articulating recommendations, organizational involvement, peer review, and policies regarding periodic assessment and updating of guideline documents, we encourage readers to consult the ACC/AHA guideline methodology manual.

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/downloadable/ucm_319826.pdf. American College of Cardiology and American Heart Association. Accessed January 23, 2015.

      Jonathan L. Halperin, MD, FACC, FAHA, Chair, ACC/AHA Task Force on Clinical Practice Guidelines

      1. Introduction

      The scope of this focused update is limited to addressing recommendations on duration of dual antiplatelet therapy (DAPT) (aspirin plus a P2Y12 inhibitor) in patients with coronary artery disease (CAD). Recommendations considered are those in 6 guidelines: “2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,”
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      “2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery,”
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
      Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons.
      “2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease,”
      • Fihn S.D.
      • Blankenship J.C.
      • Alexander K.P.
      • et al.
      2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • 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.
      “2013 ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,”
      • O'Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      “2014 ACC/AHA Guideline for NonST-Elevation Acute Coronary Syndromes,”
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and “2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery.”
      • Fleisher L.A.
      • Fleischmann K.E.
      • Auerbach A.D.
      • et al.
      2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      The impetus for this focused update review is 11 studies
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Kim B.-K.
      • Hong M.-K.
      • Shin D.-H.
      • et al.
      A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
      • Feres F.
      • Costa R.A.
      • Abizaid A.
      • et al.
      Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      • Park S.-J.
      • Park D.-W.
      • Kim Y.-H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.L.
      • 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.
      • Lee C.W.
      • Ahn J.-M.
      • Park D.-W.
      • et al.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.
      • Helft G.
      • Steg P.G.
      • Le Feuvre C.
      • et al.
      Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial.
      of patients treated with coronary stent implantation (predominantly with drug-eluting stents [DES]) assessing shorter-duration or longer-duration DAPT, as well as a large, randomized controlled trial (RCT) of patients 1 to 3 years after myocardial infarction (MI) assessing the efficacy of DAPT compared with aspirin monotherapy.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      These studies were published after the formulation of recommendations for duration of DAPT in prior guidelines. The specific mandate of the present writing group is to evaluate, update, harmonize, and, when possible, simplify recommendations on duration of DAPT.
      Although there are several potential combinations of antiplatelet therapy, the term and acronym DAPT has been used to specifically refer to combination antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) and will be used similarly in this focused update. Recommendations in this focused update on duration of DAPT, aspirin dosing in patients treated with DAPT, and timing of elective noncardiac surgery in patients treated with percutaneous coronary intervention (PCI) and DAPT supersede prior corresponding recommendations in the 6 relevant guidelines. These recommendations for duration of DAPT apply to newer-generation stents and, in general, only to those not treated with oral anticoagulant therapy. For the purposes of this focused update, patients with a history of acute coronary syndrome (ACS) >1 year prior who have since remained free of recurrent ACS are considered to have transitioned to stable ischemic heart disease (SIHD) and are addressed in the section on SIHD. Issues and recommendations with regard to P2Y12 inhibitor “pretreatment,” “preloading,” and loading are beyond the scope of this document but are addressed in other guidelines.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Roffi M.
      • Patrono C.
      • Collet J.-P.
      • et al.
      2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      This focused update is designed to function both as a standalone document and to serve as an update to the relevant sections on duration of DAPT in the 6 clinical practice guidelines, replacing relevant text, figures, and recommendations. Thus, by necessity, there is some redundancy in different sections of this document. When possible, the “knowledge byte” format was used for recommendations. In some cases, the complexity of this document required a modification of the knowledge byte format, with several interrelated recommendations grouped together, followed by concise associated text (<250 words of text per recommendation).

      1.1. Methodology and Evidence Review

      Clinical trials published since the 2011 PCI guideline
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      and the 2011 coronary artery bypass graft (CABG) guideline,
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
      Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons.
      published in a peer-reviewed format through December 2015, were reviewed by the Task Force to identify trials and other key data that might affect guideline recommendations. The information considered important enough to prompt updated recommendations is included in evidence tables in the Online Data Supplement.
      In accord with recommendations by the Institute of Medicine
      Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US)
      Clinical Practice Guidelines We Can Trust.
      Committee on Standards for Systematic Reviews of Comparative Effectiveness Research, Institute of Medicine (US)
      Finding What Works in Health Care: Standards for Systematic Reviews.
      and the ACC/AHA Task Force Methodology Summit,

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/downloadable/ucm_319826.pdf. American College of Cardiology and American Heart Association. Accessed January 23, 2015.

      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      • et al.
      ACCF/AHA clinical practice guideline methodology summit report: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      3 critical (PICOTS-formatted; population, intervention, comparison, outcome, timing, setting) questions were developed to address the critical questions related to duration of DAPT. These 3 critical questions were the basis of a formal systematic review and evaluation of the relevant study data by an Evidence Review Committee (ERC).
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Concurrent with this process, writing group members evaluated study data relevant to the numerous current recommendations in the 6 guidelines, including topics not covered in the 3 critical questions (eg, DAPT after CABG). The findings of the ERC and the writing group members were formally presented and discussed, and then modifications to existing recommendations were considered. Recommendations that are based on a body of evidence that includes a systematic review conducted by the ERC are denoted by the superscript SR (eg, LOE B-R SR). See the ERC systematic review report, “Duration of Dual Antiplatelet Therapy: A Systematic Review for the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease,” for the complete evidence review report.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

      1.2. Organization of the Writing Group

      Recommendations on duration of DAPT are currently included in 6 clinical practice guidelines, which are interrelated and overlapping because they address the management of patients with CAD. Therefore, the writing group consisted of the chairs/vice chairs and/or members of all 6 guidelines, representing the fields of cardiovascular medicine, interventional cardiology, cardiac surgery, internal medicine, and cardiovascular anesthesia, as well as expertise in trial design and statistical analysis.

      1.3. Review and Approval

      This focused update was reviewed by the writing committee members from the 6 guidelines; by 5 official reviewers from the ACC and AHA; 2 reviewers each from the American Association for Thoracic Surgery, American College of Emergency Physicians, American Society of Anesthesiologists, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and the Society of Thoracic Surgeons; and by 23 additional content reviewers. Reviewers' RWI information is published in this document (Appendix 2).
      This document was approved for publication by the governing bodies of the ACC and the AHA and was endorsed by the American Association for Thoracic Surgery, American Society of Anesthesiologists, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, Society of Thoracic Surgeons, and Society for Vascular Surgery.

      2. Critical Questions and Systematic Review Findings

      2.1. Critical Questions on Duration of DAPT

      The 3 critical (PICOTS-formatted) questions on DAPT duration are listed in Table 2. Most contemporary studies of DAPT have compared either shorter (3 to 6 months)
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Kim B.-K.
      • Hong M.-K.
      • Shin D.-H.
      • et al.
      A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
      • Feres F.
      • Costa R.A.
      • Abizaid A.
      • et al.
      Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      or longer (18 to 48 months)
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Park S.-J.
      • Park D.-W.
      • Kim Y.-H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.L.
      • 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.
      • Lee C.W.
      • Ahn J.-M.
      • Park D.-W.
      • et al.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.
      duration of therapy with 12 months of DAPT, which is the recommended or minimal duration of therapy for most patients in ACC/AHA
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      • O'Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and European Society of Cardiology
      • Steg P.G.
      • James S.K.
      • Atar D.
      • et al.
      ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation.
      • Wijns W.
      • Kolh P.
      • Danchin N.
      • et al.
      Guidelines on myocardial revascularization.
      • Hamm C.W.
      • Bassand J.-P.
      • Agewall S.
      • et al.
      ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients Presenting Without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      guidelines published between 2011 and 2014. Recommendations based on the findings from the critical question–focused systemic reviews are provided in Sections 4 to 8 of the present document.
      Table 2Critical (PICOTS-formatted) questions on DAPT duration
      Q1: In patients treated with newer (non-first) generation DES for (1) SIHD or (2) ACS, compared with 12 months of DAPT, is 3–6 months of DAPT as effective in preventing stent thrombosis, preventing MACE and/or reducing bleeding complications?
      Q2: In patients treated with newer (non-first) generation DES, compared with 12 months of DAPT, does >12 (18–48) months of DAPT result in differences in mortality rate, decreased MACE, decreased stent thrombosis, and/or increased bleeding?
      Q3: In post-MI (NSTEMI or STEMI) patients who are clinically stable and >12 months past their event, does continued DAPT, compared with aspirin monotherapy, result in differences in mortality rate, decreased nonfatal MI, decreased MACE, and/or increased bleeding?
      SIHD, Stable ischemic heart disease; ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; MACE, major adverse cardiac events; DES, drug-eluting stents; MI, myocardial infarction; NSTEMI, non–ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

      2.2. Studies of Shorter-Duration DAPT After Stent Implantation

      Five RCTs of patients treated with elective DES implantation have compared shorter-duration (3 to 6 months) DAPT with 12 months of DAPT
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Kim B.-K.
      • Hong M.-K.
      • Shin D.-H.
      • et al.
      A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
      • Feres F.
      • Costa R.A.
      • Abizaid A.
      • et al.
      Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      (Data Supplement 1). The trials primarily enrolled low-risk (non-ACS) patients, with only a small proportion having had a recent MI. The main endpoints of these noninferiority trials were composite ischemic events (or net composite events) and stent thrombosis. These studies, as well as several meta-analyses
      • Palmerini T.
      • Sangiorgi D.
      • Valgimigli M.
      • et al.
      Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis.
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      and an analysis by the ERC,
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      did not find any increased risk of stent thrombosis with shorter-duration DAPT. A shorter duration of DAPT results in fewer bleeding complications.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Palmerini T.
      • Sangiorgi D.
      • Valgimigli M.
      • et al.
      Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis.
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      Shorter-duration DAPT may be most reasonable in patients currently being treated with “newer-generation” (eg, everolimus- or zotarolimus-eluting) DES, which are associated with lower stent thrombosis and MI rates than those of “first-generation” (eg, sirolimus- and paclitaxel-eluting) DES, which are rarely, if ever, used in current clinical practice.
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Tandjung K.
      • Claessen B.
      • et al.
      Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis.

      2.3. Studies of Longer-Duration DAPT After Stent Implantation

      Six RCTs, consisting predominantly of patients treated with elective DES implantation, compared prolonged DAPT (total therapy duration: 18 to 48 months) with 6 to 12 months of DAPT to determine whether extended therapy reduces late and very late stent thrombosis and prevents ischemic events associated with disease progression and plaque rupture at other nonstented sites
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Park S.-J.
      • Park D.-W.
      • Kim Y.-H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.L.
      • 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.
      • Lee C.W.
      • Ahn J.-M.
      • Park D.-W.
      • et al.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.
      • Helft G.
      • Steg P.G.
      • Le Feuvre C.
      • et al.
      Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial.
      (Data Supplement 2). In the Dual Antiplatelet Therapy study—the largest of these trials—patients who had undergone DES implantation, had been treated with DAPT for 12 months, and were without ischemic or bleeding events during this period were randomized to an additional 18 months of DAPT or to aspirin monotherapy.
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      Extended DAPT resulted in a 0.7% absolute reduction in very late stent thrombosis, a 2.0% absolute reduction in MI, a 1.6% absolute reduction in major adverse cardiac events (MACE), and a 0.9% absolute increase in moderate or severe bleeding. In the subgroup of patients treated with everolimus-eluting stents—currently the most commonly used stent—extended DAPT resulted in a 0.4% absolute reduction in stent thrombosis, a 1.1% absolute reduction in MI, and a 1.2% absolute increase in moderate/severe bleeding.
      • Hermiller J.B.
      • Krucoff M.W.
      • Kereiakes D.J.
      • et al.
      Benefits and risks of extended dual antiplatelet therapy after everolimus-eluting stents.
      Taken as a whole, studies of longer-duration (“prolonged” or “extended”) DAPT
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Park S.-J.
      • Park D.-W.
      • Kim Y.-H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.L.
      • 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.
      • Lee C.W.
      • Ahn J.-M.
      • Park D.-W.
      • et al.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.
      • Helft G.
      • Steg P.G.
      • Le Feuvre C.
      • et al.
      Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial.
      for an additional 18 to 36 months after DES found an absolute decrease in late stent thrombosis and ischemic complications of ≈1% to 2% and an absolute increase in bleeding complications of ≈1% (Data Supplements 2 and 3). A weighted risk-benefit analysis by the ERC of studies of patients treated with DES found 6 fewer MIs and 3 fewer stent thromboses but 5 additional major bleeds per 1000 patients treated with prolonged DAPT per year.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

      2.4. Other Studies Relevant to DAPT >1 Year After MI

      The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial randomized patients with established atherosclerosis or at high risk of clinical atherosclerotic disease to either DAPT (with clopidogrel) or aspirin monotherapy; with DAPT, no significant reduction was found in ischemic effects at a median follow-up of 28 months, but there was a 0.4% absolute increase in severe bleeding.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      A post hoc analysis of patients enrolled in the study with prior MI found a 1.7% absolute decrease in the composite endpoint of cardiovascular death, MI, or stroke events with DAPT, with no benefit in those with CAD without prior MI.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      Patients in the 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) trial were randomized 1 to 3 years after MI with additional high-risk features to either DAPT (with ticagrelor 60 mg or 90 mg twice daily) or continued aspirin monotherapy.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      After a mean of 33 months of therapy, DAPT, when compared with aspirin monotherapy, resulted in a 1.2% to 1.3% absolute reduction in the primary composite endpoint of cardiovascular death, MI, or stroke and a 1.2% to 1.5% absolute increase in major bleeding, with no excess in fatal bleeding or intracranial hemorrhage. In subgroup analysis, the greatest reduction in ischemic events with prolonged DAPT was in patients in whom P2Y12 inhibitor therapy either had not been discontinued or had been discontinued for ≤30 days (absolute reduction in MACE: 1.9% to 2.5%). No benefit was seen in patients in whom P2Y12 inhibitor therapy had been discontinued >1 year before enrollment in the study.
      • Bonaca M.P.
      • Bhatt D.L.
      • Steg P.G.
      • et al.
      Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54.
      In the Dual Antiplatelet Therapy study, the benefit/risk ratio for prolonged DAPT was more favorable for those presenting with MI than those with SIHD.
      • Yeh R.W.
      • Kereiakes D.J.
      • Steg P.G.
      • et al.
      Benefits and risks of extended duration dual antiplatelet therapy after PCI in patients with and without acute myocardial infarction.
      In an analysis of patients with a history of prior MI enrolled in 6 RCTs of extended/prolonged DAPT, extended DAPT significantly decreased the absolute risk of MACE by 1.1% and significantly increased the absolute risk of major bleeding by 0.8%.
      • Udell J.A.
      • Bonaca M.P.
      • Collet J.-P.
      • et al.
      Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials.
      Taken as a whole, trials of prolonged or extended DAPT suggest that the benefit/risk ratio of prolonged DAPT may be more favorable for those with prior MI, with an absolute decrease in ischemic events of ≈1% to 3% at the cost of an absolute increase in bleeding events of ≈1% over the course of several years of prolonged or extended therapy (median durations of therapy: 18 to 33 months) (Data Supplements 3 and 4). This appears biologically plausible because patients with prior MI (usually mediated by plaque rupture) may be at greater risk for future plaque rupture than those without prior MI.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.

      2.5. Prolonged/Extended DAPT and Mortality Rate

      An unexpected finding in the Dual Antiplatelet Therapy study
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      was a borderline-significant increase in overall mortality rate (0.5% absolute increase) with 30 months of DAPT versus 12 months of DAPT in DES-treated patients, which was due to significantly increased deaths from noncardiovascular causes (most commonly cancer), with no increase in cardiovascular deaths, and no significant increase in fatal bleeding.
      • Mauri L.
      • Elmariah S.
      • Yeh R.W.
      • et al.
      Causes of late mortality with dual antiplatelet therapy after coronary stents.
      Five subsequent meta-analyses
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      • Spencer F.A.
      • Prasad M.
      • Vandvik P.O.
      • et al.
      Longer versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis.
      • Montalescot G.
      • Brieger D.
      • Dalby A.J.
      • et al.
      Duration of dual antiplatelet therapy after coronary stenting: a review of the evidence.
      restricted to RCTs of studies enrolling patients treated with predominantly newer generation DES, published prior to the presentation of the OPTIDUAL (Optimal Dual Antiplatelet Therapy) trial, found numerically
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Montalescot G.
      • Brieger D.
      • Dalby A.J.
      • et al.
      Duration of dual antiplatelet therapy after coronary stenting: a review of the evidence.
      or statistically
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      • Spencer F.A.
      • Prasad M.
      • Vandvik P.O.
      • et al.
      Longer versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis.
      significant increased risk of all-cause (though not cardiovascular) death associated with prolonged duration of DAPT (Data Supplements 3 and 4).
      In contrast, a meta-analysis that combined studies of DAPT duration after stent implantation with studies of DAPT duration for other indications
      • Elmariah S.
      • Mauri L.
      • Doros G.
      • et al.
      Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis.
      and an analysis of 6 trials restricted to post-MI patients treated with DAPT
      • Udell J.A.
      • Bonaca M.P.
      • Collet J.-P.
      • et al.
      Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials.
      found no increase in cardiovascular or noncardiovascular mortality rate associated with prolonged DAPT (Data Supplement 3). A US Food and Drug Administration drug safety communication, based on an evaluation of long-term clinical trials of patients with cardiovascular disease or stroke treated with clopidogrel, concluded that long-term clopidogrel treatment did not increase the risk of all-cause death or cancer-related death.

      US Food and Drug Administration. FDA Drug Safety Communication: FDA review finds long-term treatment with blood-thinning medicine Plavix (clopidogrel) does not change risk of death. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm471286.htm. Published November 6, 2015; updated December 9, 2015. Accessed February 17, 2016.

      The primary analysis by the ERC of 11 RCTs (including OPTIDUAL) compared use of DAPT for 18 to 48 months with use of DAPT for 6 to 12 months in patients who had received predominantly newer-generation DES and found no statistically significant difference in all-cause mortality rate.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      A majority of writing group members believe the data as a whole do not seem to suggest prolonged DAPT results in increased mortality.

      3. Overriding Concepts and Recommendations for DAPT and Duration of Therapy

      3.1. General Overriding Concepts

      Overriding concepts and relevant recommendations for DAPT and duration of therapy are summarized in Table 3. Intensification of antiplatelet therapy, with the addition of a P2Y12 inhibitor to aspirin monotherapy, necessitates a fundamental tradeoff between decreasing ischemic risk and increasing bleeding risk.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      • Steinhubl S.R.
      • Berger P.B.
      • Mann 3rd, J.T.
      • et al.
      Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      Similarly, longer compared with shorter duration of DAPT generally results in decreased ischemic risk at the expense of increased bleeding risk.
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Spencer F.A.
      • Prasad M.
      • Vandvik P.O.
      • et al.
      Longer versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis.
      Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischemic risk and increased bleeding risk.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      • Montalescot G.
      • Wiviott S.D.
      • Braunwald E.
      • et al.
      Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial.
      Table 3Overriding concepts and updated recommendations for DAPT and duration
      Intensification of antiplatelet therapy, with the addition of a P2Y12 inhibitor to aspirin monotherapy, as well as prolongation of DAPT, necessitates a fundamental tradeoff between decreasing ischemic risk and increasing bleeding risk. Decisions about treatment with and duration of DAPT require a thoughtful assessment of the benefit/risk ratio, integration of study data, and consideration of patient preference.
      In general, shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk, whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk.
      Prior recommendations for duration of DAPT for patients treated with DES were based on data from “first-generation” DES, which are rarely if ever used in current clinical practice. Compared with first-generation stents, newer-generation stents have an improved safety profile and lower risk of stent thrombosis. Recommendations in this focused update apply to newer-generation stents.
      Updated recommendations for duration of DAPT are now similar for patients with NSTE-ACS and STEMI, as both are part of the spectrum of acute coronary syndrome.
      A Class I recommendation (“should be given”) in most clinical settings is made for at least 6–12 months of DAPT (depending on the setting), and a Class IIb recommendation (“may be reasonable”) is made for prolonged DAPT beyond this initial 6- to 12-month period.
      In studies of prolonged DAPT after DES implantation or after MI, duration of therapy was limited to several years (akin to many other studied therapies). Thus, in patients for whom the benefit/risk ratio seemingly favors prolonged therapy, the true optimal duration of therapy is unknown.
      Recommendations in the document apply specifically to duration of P2Y12 inhibitor therapy in patients with CAD treated with DAPT. Aspirin therapy should almost always be continued indefinitely in patients with CAD.
      Lower daily doses of aspirin, including in patients treated with DAPT, are associated with lower bleeding complications and comparable ischemic protection
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Patrono C.
      • Baigent C.
      • Hirsh J.
      • et al.
      Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      • Peters R.J.G.
      • Mehta S.R.
      • Fox K.A.A.
      • et al.
      Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
      • Steinhubl S.R.
      • Bhatt D.L.
      • Brennan D.M.
      • et al.
      Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding.
      • Mehta S.R.
      • Tanguay J.-F.
      • Eikelboom J.W.
      • et al.
      Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      than are higher doses of aspirin. The recommended daily dose of aspirin in patients treated with DAPT is 81 mg (range, 75 mg to 100 mg).
      DAPT, Dual antiplatelet therapy; DES, drug-eluting stent; NSTE-ACS, non–ST-elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction; MI, myocardial infarction; CAD, coronary artery disease.
      In general, recommendations for duration of DAPT in the present focused update consist of a Class I recommendation (“should be given”) for a minimum period of time (in most cases 6 to 12 months) and a Class IIb recommendation (“may be considered”) for continuation of DAPT beyond that period of time. Shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk, whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk. These recommendations do not generally apply to patients treated with oral anticoagulant therapy, who were excluded from almost all studies of DAPT duration and who are at significantly increased bleeding risk (as discussed in Section 3.4). Decisions about duration of DAPT are best made on an individual basis and should integrate clinical judgment, assessment of the benefit/risk ratio, and patient preference. Aspirin therapy is almost always continued indefinitely in patients with CAD, and recommendations on duration of DAPT should be taken to mean the recommended duration of P2Y12 inhibitor therapy (in addition to aspirin therapy). Figure 1 summarizes recommendations for duration of DAPT according to clinical status.
      Figure thumbnail gr1
      Figure 1Master treatment algorithm for duration of P2Y12 inhibitor therapy in patients with CAD treated with DAPT. Colors correspond to Class of Recommendation in . Clopidogrel is the only currently used P2Y12 inhibitor studied in patients with SIHD undergoing PCI. Aspirin therapy is almost always continued indefinitely in patients with CAD. Patients with a history of ACS >1 year prior who have since remained free of recurrent ACS are considered to have transitioned to SIHD. In patients treated with DAPT after DES implantation who develop a high risk of bleeding (eg, treatment with oral anticoagulant therapy), are at high risk of severe bleeding complication (eg, major intracranial surgery), or develop significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 3 months for SIHD or after 6 months for ACS may be reasonable. Arrows at the bottom of the figure denote that the optimal duration of prolonged DAPT is not established. CAD, Coronary artery disease; SIHD, stable ischemic heart disease; ACS, acute coronary syndrome; NSTE-ACS, non–ST-elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction; Hx, history; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; Lytic, fibrinolytic therapy; S/P, status post; BMS, bare metal stent; DES, drug-eluting stent; DAPT, dual antiplatelet therapy.

      3.2. Factors Associated With Increased Ischemic and Bleeding Risk

      Factors that have been associated with increased ischemic risk (including increased risk of stent thrombosis) and increased bleeding risk are listed in Table 4. Individual patients may have factors for both increased ischemic and bleeding risk, and some factors are associated with both increased ischemic and bleeding risk, making it difficult in many patients to assess the benefit/risk ratio of prolonged DAPT.
      Table 4Clinical and procedural factors associated with increased ischemic risk (including stent thrombosis) or increased bleeding risk
      • Califf R.M.
      • Armstrong P.W.
      • Carver J.R.
      • et al.
      27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 5. Stratification of patients into high, medium and low risk subgroups for purposes of risk factor management.
      • Sachdev M.
      • Sun J.L.
      • Tsiatis A.A.
      • et al.
      The prognostic importance of comorbidity for mortality in patients with stable coronary artery disease.
      • Binder R.K.
      • Lüscher T.F.
      • O'Connor S.A.
      Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischaemia and bleeding?.
      • Subherwal S.
      • Bach R.G.
      • Chen A.Y.
      • et al.
      Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score.
      • Moscucci M.
      • Fox K.A.
      • Cannon C.P.
      • et al.
      Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE).
      • Mehran R.
      • Pocock S.J.
      • Nikolsky E.
      • et al.
      A risk score to predict bleeding in patients with acute coronary syndromes.
      • Baber U.
      • Mehran R.
      • Sharma S.K.
      • et al.
      Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials.
      • Cayla G.
      • Hulot J.-S.
      • O'Connor S.A.
      • et al.
      Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis.
      • Campo G.
      • Tebaldi M.
      • Vranckx P.
      • et al.
      Short- versus long-term duration of dual antiplatelet therapy in patients treated for in-stent restenosis: a PRODIGY trial substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia).
      Increased ischemic risk/risk of stent thrombosis (may favor longer-duration DAPT)Increased bleeding risk (may favor shorter-duration DAPT)
      Increased ischemic riskHistory of prior bleeding
       Advanced ageOral anticoagulant therapy
       ACS presentationFemale sex
       Multiple prior MIsAdvanced age
       Extensive CADLow body weight
       Diabetes mellitusCKD
       CKDDiabetes mellitus
      Increased risk of stent thrombosisAnemia
       ACS presentationChronic steroid or NSAID therapy
       Diabetes mellitus
       Left ventricular ejection fraction <40%
       First-generation drug-eluting stent
       Stent undersizing
       Stent underdeployment
       Small stent diameter
       Greater stent length
       Bifurcation stents
       In-stent restenosis
      DAPT, Dual antiplatelet therapy; ACS, acute coronary syndrome; MI, myocardial infarction; CAD, coronary artery disease; CKD, chronic kidney disease; NSAID, nonsteroidal anti-inflammatory drug.
      A new risk score (the “DAPT score”), derived from the Dual Antiplatelet Therapy study, may be useful for decisions about whether to continue (prolong or extend) DAPT in patients treated with coronary stent implantation. Analysis of study data suggests that in patients treated for 1 year with DAPT without significant bleeding or ischemic events, the benefit/risk ratio with prolonged DAPT may be favorable for those with a high DAPT score (≥2) because prolonged DAPT reduces net (ischemic plus bleeding) events when compared with nonprolonged DAPT.
      • Yeh R.W.
      • Secemsky E.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond one year after percutaneous coronary intervention: an analysis from the randomized Dual Antiplatelet Therapy Study.
      Conversely, in those with a low DAPT score (<2), the benefit/risk ratio with prolonged DAPT is not favorable (increased bleeding without a reduction in ischemic events). Factors that contribute to a high DAPT score include diabetes mellitus, current cigarette use, prior PCI or prior MI, congestive heart failure or left ventricular ejection fraction <30%, MI at presentation, vein graft PCI, and stent diameter <3 mm; older age contributes to a low (less favorable) DAPT score. Factors and their weighting used to calculate a DAPT score are provided in Table 5.
      Table 5Factors used to calculate a “DAPT score”
      VariablePoints
      Age ≥75 y−2
      Age 65 to <75 y−1
      Age <65 y0
      Current cigarette smoker1
      Diabetes mellitus1
      MI at presentation1
      Prior PCI or prior MI1
      Stent diameter <3 mm1
      Paclitaxel-eluting stent1
      CHF or LVEF <30%2
      Saphenous vein graft PCI2
      A score of ≥2 is associated with a favorable benefit/risk ratio for prolonged DAPT while a score of <2 is associated with an unfavorable benefit/risk ratio. MI, Myocardial infarction; PCI, percutaneous coronary intervention; CHF, congestive heart failure; LVEF, left ventricular ejection fraction. Adapted with permission from Yeh et al.
      • Yeh R.W.
      • Secemsky E.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond one year after percutaneous coronary intervention: an analysis from the randomized Dual Antiplatelet Therapy Study.

      3.3. Specific P2Y12 Inhibitors: Recommendations

      In the PLATO (Platelet Inhibition and Patient Outcomes) trial,
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      patients with ACS were treated with either medical therapy alone or medical therapy plus PCI. Treatment with ticagrelor 90 mg twice daily, compared with clopidogrel 75 mg once daily, resulted in fewer ischemic complications and stent thromboses but more frequent non–CABG-related bleeding (Data Supplement 5). In the TRITON-TIMI 38 (Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38)
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      study, patients with ACS undergoing planned PCI were treated with prasugrel 10 mg daily, compared with clopidogrel 75 mg daily. Prasugrel treatment resulted in fewer ischemic complications and stent thromboses but more frequent bleeding, including life-threatening and fatal bleeding. Because of increased rates of major bleeding with prasugrel (compared with clopidogrel), there was no net benefit of prasugrel therapy in those ≥75 years of age and those <60 kg, and there was net harm (including increased risk of intracranial hemorrhage) in those with prior stroke or transient ischemic attack (TIA). The Class IIa preferential recommendations for ticagrelor 90 mg twice daily and for prasugrel 10 mg once daily (compared with clopidogrel) in the 2014 NonST-Elevation Acute Coronary Syndromes (NSTE-ACS) guideline are continued in this focused update and are now included in relevant PCI and ST-Elevation Myocardial Infarction (STEMI) recommendations, as well.
      In the PEGASUS-TIMI 54 study of post-MI patients, both 60-mg and 90-mg twice-daily doses of ticagrelor were evaluated.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      The benefit/risk ratio appears to be numerically more favorable for the 60-mg dose, although no formal statistical comparison was made between results of the 2 dosing regimens. The 60-mg twice-daily dose has now been approved by the US Food and Drug Administration for reduction in ischemic events in patients with ACS or a history of MI.

      US Food and Drug Administration. Medical Device Reporting (MDR). Available at: http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm. Updated July 16, 2015; accessed February 17, 2016.

      3.4. Platelet Function Testing, Genetic Testing, and Switching of P2Y12 Inhibitors

      The role of platelet function testing and genetic testing in patients treated with DAPT is addressed in the 2011 ACCF/AHA/SCAI PCI guideline and the 2014 ACC/AHA NSTE-ACS guideline.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      To date, no RCT has demonstrated that routine platelet function testing or genetic testing to guide P2Y12 inhibitor therapy improves outcome; thus, the routine use of platelet function and genetic testing is not recommended (Class III: No Benefit).
      No randomized data are available on the long-term safety or efficacy of “switching” patients treated for weeks or months with a P2Y12 inhibitor to a different P2Y12 inhibitor.

      3.5. Proton Pump Inhibitors and DAPT

      The use of proton pump inhibitors (PPIs) in patients treated with DAPT is discussed in a 2010 ACCF/ACG/AHA expert consensus document.
      • Abraham N.S.
      • Hlatky M.A.
      • Antman E.M.
      • et al.
      ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents.
      Recommendations on the use of PPIs are given in the 2011 ACCF/AHA/SCAI PCI guideline.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      PPIs should be used in patients with a history of prior gastrointestinal bleeding treated with DAPT (Class I). In patients with increased risk of gastrointestinal bleeding, including those with advanced age and those with concomitant use of warfarin, steroids, or nonsteroidal anti-inflammatory drugs, use of PPIs is reasonable (Class IIa). Routine use of PPIs is not recommended for patients at low risk of gastrointestinal bleeding (Class III: No Benefit).

      3.6. Aspirin Dosing in Patients Treated With DAPT: Recommendation

      Because aspirin dosing recommendations across ACC/AHA clinical practice guidelines are not consistent with regard to dose or class of recommendation, and because aspirin is a component of DAPT, a comprehensive review of these issues was undertaken. Large overviews, including studies of nearly 200,000 persons, have consistently shown that lower aspirin doses (≤100 mg daily) are associated with less major and total bleeding than are higher doses, either when used as monotherapy or when combined with the P2Y12 inhibitor clopidogrel.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Peters R.J.G.
      • Mehta S.R.
      • Fox K.A.A.
      • et al.
      Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials.
      • Jolly S.S.
      • Pogue J.
      • Haladyn K.
      • et al.
      Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study.
      • Xian Y.
      • Wang T.Y.
      • McCoy L.A.
      • et al.
      Association of discharge aspirin dose with outcomes after acute myocardial infarction: insights from the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.
      Daily aspirin doses as low as 30 mg to 50 mg inactivate the platelet cyclo-oxygenase-1 enzyme and inhibit thromboxane production.
      • Montalescot G.
      • Drobinski G.
      • Maclouf J.
      • et al.
      Evaluation of thromboxane production and complement activation during myocardial ischemia in patients with angina pectoris.
      • Patrono C.
      • Ciabattoni G.
      • Patrignani P.
      • et al.
      Clinical pharmacology of platelet cyclooxygenase inhibition.
      • Steinhubl S.R.
      • Berger P.B.
      Aspirin following PCI: too much of a good thing?.
      Studies comparing lower (75 mg to 150 mg) with higher aspirin doses have consistently found comparable ischemic event rates with either dose when used as monotherapy or when combined with the P2Y12 inhibitor clopidogrel.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Patrono C.
      • Baigent C.
      • Hirsh J.
      • et al.
      Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      • Peters R.J.G.
      • Mehta S.R.
      • Fox K.A.A.
      • et al.
      Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
      • Steinhubl S.R.
      • Bhatt D.L.
      • Brennan D.M.
      • et al.
      Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding.
      • Mehta S.R.
      • Tanguay J.-F.
      • Eikelboom J.W.
      • et al.
      Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      • Xian Y.
      • Wang T.Y.
      • McCoy L.A.
      • et al.
      Association of discharge aspirin dose with outcomes after acute myocardial infarction: insights from the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.
      The efficacy of ticagrelor seems to be decreased in patients treated with higher aspirin doses (≥300 mg daily) versus lower aspirin doses (≤100 mg daily).
      • Mahaffey K.W.
      • Wojdyla D.M.
      • Carroll K.
      • et al.
      Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial.
      On the basis of available data, the optimal range of aspirin dose in patients treated with DAPT that provides maximal protection from ischemic events and minimizes bleeding risk appears to be 75 mg to 100 mg (Data Supplement 6). For practical purposes, because the relevant aspirin dose available in the United States is 81 mg, this maintenance dose is recommended in patients with CAD treated with DAPT. The ongoing ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effective ness) trial, which the present writing group endorses, is expected to yield additional information on optimal aspirin dosing in patients with atherosclerotic cardiovascular disease.

      National Patient-Centered Clinical Research Network. ADAPTABLE, the Aspirin Study - A Patient-Centered Trial. Available at: http://theaspirinstudy.org. Accessed February 17, 2016.

      3.7. Triple Therapy (Aspirin, P2Y12 Inhibitor, and Oral Anticoagulant)

      The recommended management of patients on “triple therapy” (aspirin, P2Y12 inhibitor, and oral anticoagulant) is beyond the scope of this focused update. However, a brief discussion of the topic is included for the purposes of completeness and end-user education.
      Compared with oral anticoagulation therapy alone, the addition of DAPT to oral anticoagulant therapy results in at least a 2- to 3-fold increase in bleeding complications.
      • Dans A.L.
      • Connolly S.J.
      • Wallentin L.
      • et al.
      Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.
      • Faxon D.P.
      • Eikelboom J.W.
      • Berger P.B.
      • et al.
      Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North-American perspective.
      • Hansen M.L.
      • Srensen R.
      • Clausen M.T.
      • et al.
      Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.
      • Sørensen R.
      • Hansen M.L.
      • Abildstrom S.Z.
      • et al.
      Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data.
      Discussion and recommendations on triple therapy are provided in the 2014 ACC/AHA NSTE-ACS guideline,
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      a 2014 European joint consensus document,
      • Lip G.Y.H.
      • Windecker S.
      • Huber K.
      • et al.
      Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA).
      a North American consensus document,
      • Faxon D.P.
      • Eikelboom J.W.
      • Berger P.B.
      • et al.
      Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North-American perspective.
      and several comprehensive state-of-the-art papers and reviews. A partial summary and synthesis of these recommendations are given in Table 6.
      Table 6Summary and synthesis of guideline, expert consensus documents, and comprehensive review article recommendations on the management of patients treated with triple therapy
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Lip G.Y.H.
      • Windecker S.
      • Huber K.
      • et al.
      Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA).
      • Dewilde W.J.M.
      • Janssen P.W.A.
      • Verheugt F.W.A.
      • et al.
      Triple therapy for atrial fibrillation and percutaneous coronary intervention: a contemporary review.
      • Moser M.
      • Olivier C.B.
      • Bode C.
      Triple antithrombotic therapy in cardiac patients: more questions than answers.
      • Capodanno D.
      • Angiolillo D.J.
      Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in the setting of acute coronary syndromes or percutaneous coronary interventions.
      Assess ischemic and bleeding risks using validated risk predictors (eg, CHA2DS2-VASc, HAS-BLED)
      Keep triple therapy duration as short as possible; dual therapy only (oral anticoagulant and clopidogrel) may be considered in select patients
      Consider a target INR of 2.0–2.5 when warfarin is used
      Clopidogrel is the P2Y12 inhibitor of choice
      Use low-dose (≤100 mg daily) aspirin
      PPIs should be used in patients with a history of gastrointestinal bleeding and are reasonable to use in patients with increased risk of gastrointestinal bleeding
      CHA2DS2-VASc, Congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65–74 years, sex category; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly; INR, international normalized ratio; PPIs, proton pump inhibitors.
      One trial comparing “double therapy” (oral anticoagulant plus clopidogrel) with triple therapy (oral anticoagulant plus aspirin and clopidogrel)
      • Dewilde W.J.M.
      • Oirbans T.
      • Verheugt F.W.A.
      • 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.
      and 1 trial comparing differing durations of triple therapy have been published.
      • Fiedler K.A.
      • Maeng M.
      • Mehilli J.
      • et al.
      Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE Trial.
      Several more similar trials comparing oral anticoagulant therapy plus P2Y12 inhibitor with triple therapy are ongoing.

      4. Percutaneous Coronary Intervention

      4.1. Duration of DAPT in Patients With SIHD Treated With PCI: Recommendations

      Tabled 1
      SR, Systematic review.

      4.2. Duration of DAPT in Patients With ACS Treated With PCI: Recommendations

      Tabled 1
      SR, Systematic review.

      4.3. Duration of DAPT in Patients With SIHD and ACS Treated With PCI

      DAPT in patients treated with coronary stent implantation reduces the risk of stent thrombosis and ischemic events
      • Steinhubl S.R.
      • Berger P.B.
      • Mann 3rd, J.T.
      • et al.
      Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Leon M.B.
      • Baim D.S.
      • Popma J.J.
      • et al.
      A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators.
      • Schömig A.
      • Neumann F.J.
      • Kastrati A.
      • et al.
      A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.
      • Cutlip D.E.
      • Baim D.S.
      • Ho K.K.
      • et al.
      Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials.
      (Data Supplement 7). The risk of stent thrombosis in patients treated with a bare metal stent (BMS) is greatest in the first days to weeks after implantation.
      • Cutlip D.E.
      • Baim D.S.
      • Ho K.K.
      • et al.
      Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials.
      • Wilson S.H.
      • Rihal C.S.
      • Bell M.R.
      • et al.
      Timing of coronary stent thrombosis in patients treated with ticlopidine and aspirin.
      Cessation of DAPT during this period, particularly in cases of patients undergoing surgery, is associated with an unacceptable rate of often catastrophic stent thrombosis.
      • Kaluza G.L.
      • Joseph J.
      • Lee J.R.
      • et al.
      Catastrophic outcomes of noncardiac surgery soon after coronary stenting.
      • Wilson S.H.
      • Fasseas P.
      • Orford J.L.
      • et al.
      Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting.
      • Nuttall G.A.
      • Brown M.J.
      • Stombaugh J.W.
      • et al.
      Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention.
      Thus, a minimum duration of DAPT of 1 month is generally recommended for patients treated with BMS. In current practice, BMS are generally reserved for patients who cannot receive DAPT for more than ≈1 month for reasons of active bleeding, nonadherence to medical therapy, or planned surgery.
      The recommended minimum duration of DAPT in patients treated with first-generation DES, based primarily on observational data and one subgroup analysis, has been 12 months.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Eisenstein E.L.
      • Anstrom K.J.
      • Kong D.F.
      • et al.
      Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation.
      • Grines C.L.
      • Bonow R.O.
      • Casey D.E.
      • et al.
      Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians.
      • Pfisterer M.
      • Brunner-La Rocca H.P.
      • Buser P.T.
      • et al.
      Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents.
      Compared with first-generation DES, currently used newer-generation DES have a lower risk of stent thrombosis and appear to require a shorter minimum duration of DAPT.
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      • Navarese E.P.
      • Tandjung K.
      • Claessen B.
      • et al.
      Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis.
      • Brar S.S.
      • Kim J.
      • Brar S.K.
      • et al.
      Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions.
      • Eisenstein E.L.
      • Anstrom K.J.
      • Kong D.F.
      • et al.
      Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation.
      Five RCTs
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Kim B.-K.
      • Hong M.-K.
      • Shin D.-H.
      • et al.
      A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
      • Feres F.
      • Costa R.A.
      • Abizaid A.
      • et al.
      Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      of primarily low-risk (non-ACS) patients treated with DES comparing shorter-duration (3 to 6 months) DAPT with 12 months of DAPT, as well as several meta-analyses
      • Palmerini T.
      • Sangiorgi D.
      • Valgimigli M.
      • et al.
      Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis.
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      and an analysis by the ERC,
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      did not find an increased risk of stent thrombosis with shorter-duration DAPT, although the individual trials were underpowered to detect such a difference (Data Supplements 1 and 3). Therefore, in patients with SIHD treated with DES, the minimum recommended duration of DAPT has been decreased from 12 to 6 months.
      The PCI-CURE analysis
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      of patients in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      demonstrated that treatment with DAPT for up to 12 months in patients with NSTE-ACS treated with BMS reduced ischemic events compared with aspirin monotherapy (Data Supplement 4). Based primarily on the CURE trial and PCI-CURE analyses, the prior recommendation that patients with NSTE-ACS treated with coronary stent implantation be treated with DAPT for at least 12 months is continued in this update and has been extrapolated to patients with STEMI treated with PCI as well, on the basis of the consideration that NSTE-ACS and STEMI are part of the spectrum of ACS.
      As detailed in Section 2, treatment with prolonged (or “extended”) DAPT beyond a minimum recommended duration of therapy necessitates a fundamental tradeoff between decreasing ischemic risk (eg, MI and stent thrombosis) and increasing bleeding risk.
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Palmerini T.
      • Sangiorgi D.
      • Valgimigli M.
      • et al.
      Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      • Spencer F.A.
      • Prasad M.
      • Vandvik P.O.
      • et al.
      Longer versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis.
      Prolonged or extended DAPT for an additional 18 to 36 months (after an initial 6 to 12 months of DAPT) in patients treated with DES implantation results in an absolute decrease in stent thrombosis and ischemic complications of ≈1% to 2% and an absolute increase in bleeding complications of ≈1% (Data Supplements 1, 2, and 3).
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      • Park S.-J.
      • Park D.-W.
      • Kim Y.-H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      • Collet J.-P.
      • Silvain J.
      • Barthélémy O.
      • et al.
      Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.L.
      • 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.
      • Lee C.W.
      • Ahn J.-M.
      • Park D.-W.
      • et al.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.
      • Helft G.
      • Steg P.G.
      • Le Feuvre C.
      • et al.
      Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial.
      • Bittl J.A.
      • Baber U.
      • Bradley S.M.
      • et al.
      Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Palmerini T.
      • Benedetto U.
      • Bacchi-Reggiani L.
      • et al.
      Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      • Navarese E.P.
      • Andreotti F.
      • Schulze V.
      • et al.
      Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
      • Spencer F.A.
      • Prasad M.
      • Vandvik P.O.
      • et al.
      Longer versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis.
      Newer-generation stents, particularly everolimus-eluting stents, are associated with lower rates of stent thrombosis, and the absolute reduction in the rate of stent thrombosis with prolonged DAPT in patients treated with everolimus-eluting stents is modest.
      • Hermiller J.B.
      • Krucoff M.W.
      • Kereiakes D.J.
      • et al.
      Benefits and risks of extended dual antiplatelet therapy after everolimus-eluting stents.
      • Navarese E.P.
      • Kowalewski M.
      • Kandzari D.
      • et al.
      First-generation versus second-generation drug-eluting stents in current clinical practice: updated evidence from a comprehensive meta-analysis of randomised clinical trials comprising 31 379 patients.
      • Palmerini T.
      • Kirtane A.J.
      • Serruys P.W.
      • et al.
      Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials.
      • Räber L.
      • Magro M.
      • Stefanini G.G.
      • et al.
      Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study.
      • Sarno G.
      • Lagerqvist B.
      • Nilsson J.
      • et al.
      Stent thrombosis in new-generation drug-eluting stents in patients with STEMI undergoing primary PCI: a report from SCAAR.
      The benefit/risk ratio of prolonged DAPT in patients treated with PCI may be more favorable for those with prior MI (or ACS) than for those with SIHD.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      • Yeh R.W.
      • Kereiakes D.J.
      • Steg P.G.
      • et al.
      Benefits and risks of extended duration dual antiplatelet therapy after PCI in patients with and without acute myocardial infarction.
      Preliminary data suggest that in patients with a high DAPT score the benefit/risk ratio with prolonged DAPT may be favorable and that in those with a low DAPT score the benefit/risk ratio with prolonged DAPT is not favorable.
      • Yeh R.W.
      • Secemsky E.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond one year after percutaneous coronary intervention: an analysis from the randomized Dual Antiplatelet Therapy Study.
      In patients treated with coronary stent implantation who have increased bleeding risk (eg, oral anticoagulation), increased risk of severe bleeding complications (eg, major intracranial surgery), or significant overt bleeding, the benefit/risk ratio may favor shorter-than-recommended duration of DAPT.
      • Colombo A.
      • Chieffo A.
      • Frasheri A.
      • et al.
      Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial.
      • Gwon H.-C.
      • Hahn J.-Y.
      • Park K.W.
      • et al.
      Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
      • Kim B.-K.
      • Hong M.-K.
      • Shin D.-H.
      • et al.
      A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
      • Feres F.
      • Costa R.A.
      • Abizaid A.
      • et al.
      Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
      • Schulz-Schüpke S.
      • Byrne R.A.
      • Ten Berg J.M.
      • et al.
      ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
      • Palmerini T.
      • Sangiorgi D.
      • Valgimigli M.
      • et al.
      Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis.
      • Giustino G.
      • Baber U.
      • Sartori S.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
      Decisions about treatment with and duration of DAPT require a thoughtful assessment of the benefit/risk ratio, integration of current and future study data, and consideration of patient preference.
      In studies of drug-eluting bioabsorbable polymer stents and bioabsorbable stents (third- and fourth-generation stents), by study protocol, DAPT was continued for at least 6 to 12 months.
      • Kočka V.
      • Malý M.
      • Toušek P.
      • et al.
      Bioresorbable vascular scaffolds in acute ST-segment elevation myocardial infarction: a prospective multicentre study “Prague 19”.
      • Kereiakes D.J.
      • Meredith I.T.
      • Windecker S.
      • et al.
      Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.
      • Puricel S.
      • Arroyo D.
      • Corpataux N.
      • et al.
      Comparison of everolimus- and biolimus-eluting coronary stents with everolimus-eluting bioresorbable vascular scaffolds.
      • Gao R.
      • Yang Y.
      • Han Y.
      • et al.
      Bioresorbable vascular scaffolds versus metallic stents in patients with coronary artery disease: ABSORB China Trial.
      • Windecker S.
      • Serruys P.W.
      • Wandel S.
      • et al.
      Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial.
      • Meredith I.T.
      • Verheye S.
      • Dubois C.L.
      • et al.
      Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent.
      • Ellis S.G.
      • Kereiakes D.J.
      • Metzger D.C.
      • et al.
      Everolimus-eluting bioresorbable scaffolds for coronary artery disease.
      In a study of a novel polymer-free and carrier-free drug-coated stent in patients at high risk of bleeding complications, by study protocol, DAPT was continued for only 1 month.
      • Urban P.
      • Meredith I.T.
      • Abizaid A.
      • et al.
      Polymer-free drug-coated coronary stents in patients at high bleeding risk.
      These stents have not been included in the studies of shorter- or longer-duration (prolonged/extended) DAPT discussed in this focused update. Because none of these stents (except one biodegradable polymer DES) was approved by the US Food and Drug Administration at the time this focused update was written, recommendations for duration of DAPT for such stents are not included.
      Recommendations for duration of DAPT in patients treated with PCI are summarized in Figure 2.
      Figure thumbnail gr2
      Figure 2Treatment algorithm for duration of P2Y12 inhibitor therapy in patients treated with PCI. Colors correspond to Class of Recommendation in . Arrows at the bottom of the figure denote that the optimal duration of prolonged DAPT is not established. Clopidogrel is the only currently used P2Y12 inhibitor studied in patients with SIHD undergoing PCI. Aspirin therapy is almost always continued indefinitely in patients with coronary artery disease. *High bleeding risk denotes those who have or develop a high risk of bleeding (eg, treatment with oral anticoagulant therapy) or are at increased risk of severe bleeding complication (eg, major intracranial surgery). PCI, Percutaneous coronary intervention; SIHD, stable ischemic heart disease; ACS, acute coronary syndrome; DES, drug-eluting stent; BMS, bare metal stent; DAPT, dual antiplatelet therapy.

      5. Recommendations for Duration of DAPT in Patients Undergoing CABG

      Aspirin therapy after CABG improves vein graft patency, particularly during the first postoperative year, and reduces MACE.
      • Farooq V.
      • Serruys P.W.
      • Bourantas C.
      • et al.
      Incidence and multivariable correlates of long-term mortality in patients treated with surgical or percutaneous revascularization in the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial.
      • Johnson W.D.
      • Kayser K.L.
      • Hartz A.J.
      • et al.
      Aspirin use and survival after coronary bypass surgery.
      • Chesebro J.H.
      • Clements I.P.
      • Fuster V.
      • et al.
      A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
      • Chesebro J.H.
      • Fuster V.
      • Elveback L.R.
      • et al.
      Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations.
      • Goldman S.
      • Copeland J.
      • Moritz T.
      • et al.
      Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study.
      In the CURE study,
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      the reduction in ischemic events in patients treated with aspirin plus clopidogrel who underwent CABG was consistent with the study population as a whole, although benefit was primarily observed mainly before the procedure.
      • Fox K.A.A.
      • Mehta S.R.
      • Peters R.
      • et al.
      Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial.
      A propensity score analysis of a Danish administrative database
      • Sørensen R.
      • Abildstrøm S.Z.
      • Hansen P.R.
      • et al.
      Efficacy of post-operative clopidogrel treatment in patients revascularized with coronary artery bypass grafting after myocardial infarction.
      demonstrated during a mean follow-up of 466 ± 144 days significantly fewer deaths in patients treated with aspirin plus clopidogrel than in those treated with aspirin alone, although there was no reduction in the incidence of recurrent MI.
      The impact of clopidogrel on graft occlusion after on-pump CABG has been evaluated in 5 studies (Data Supplement 10). Several randomized and nonrandomized trials and a post hoc substudy analysis of patients predominantly undergoing on-pump CABG did not demonstrate any differences in graft patency between antiplatelet monotherapy and DAPT when assessed at follow-up ranging from 1 month to 1 year after CABG.
      • Ebrahimi R.
      • Bakaeen F.G.
      • Uberoi A.
      • et al.
      Effect of clopidogrel use post coronary artery bypass surgery on graft patency.
      • Kulik A.
      • Le May M.R.
      • Voisine P.
      • et al.
      Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial.
      • Gao C.
      • Ren C.
      • Li D.
      • et al.
      Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting.
      • Sun J.C.J.
      • Teoh K.H.T.
      • Lamy A.
      • et al.
      Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study.
      In the only RCT to demonstrate a benefit of DAPT, vein graft patency 3 months after CABG was significantly higher in patients treated with clopidogrel and aspirin (100 mg) than in those receiving aspirin monotherapy.
      • Gao G.
      • Zheng Z.
      • Pi Y.
      • et al.
      Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.
      Two meta-analyses and 1 systematic overview assessed the potential benefits of DAPT after CABG and reported mixed results
      • Deo S.V.
      • Dunlay S.M.
      • Shah I.K.
      • et al.
      Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis.
      • Nocerino A.G.
      • Achenbach S.
      • Taylor A.J.
      Meta-analysis of effect of single versus dual antiplatelet therapy on early patency of bypass conduits after coronary artery bypass grafting.
      • de Leon N.
      • Jackevicius C.A.
      Use of aspirin and clopidogrel after coronary artery bypass graft surgery.
      (Data Supplement 10). In the largest meta-analysis of patients pooled from 5 RCTs and 6 observational studies,
      • Deo S.V.
      • Dunlay S.M.
      • Shah I.K.
      • et al.
      Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis.
      DAPT was associated with reduced vein graft occlusion and 30-day mortality rate as compared with aspirin monotherapy. A meta-analysis of only the 5 RCTs
      • Nocerino A.G.
      • Achenbach S.
      • Taylor A.J.
      Meta-analysis of effect of single versus dual antiplatelet therapy on early patency of bypass conduits after coronary artery bypass grafting.
      showed that DAPT was associated with a significantly lower vein graft occlusion at 1 year versus antiplatelet monotherapy but with no improvement in arterial graft patency. Major bleeding after surgery was more frequent with DAPT.
      • Deo S.V.
      • Dunlay S.M.
      • Shah I.K.
      • et al.
      Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis.
      • Nocerino A.G.
      • Achenbach S.
      • Taylor A.J.
      Meta-analysis of effect of single versus dual antiplatelet therapy on early patency of bypass conduits after coronary artery bypass grafting.
      • de Leon N.
      • Jackevicius C.A.
      Use of aspirin and clopidogrel after coronary artery bypass graft surgery.
      The benefits of DAPT in off-pump CABG patients were noted in terms of improved graft patency
      • Ibrahim K.
      • Tjomsland O.
      • Halvorsen D.
      • et al.
      Effect of clopidogrel on midterm graft patency following off-pump coronary revascularization surgery.
      • Mannacio V.A.
      • Di Tommaso L.
      • Antignan A.
      • et al.
      Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study.
      and clinical outcome
      • Gurbuz A.T.
      • Zia A.A.
      • Vuran A.C.
      • et al.
      Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study.
      in single-center observational studies
      • Ibrahim K.
      • Tjomsland O.
      • Halvorsen D.
      • et al.
      Effect of clopidogrel on midterm graft patency following off-pump coronary revascularization surgery.
      • Gurbuz A.T.
      • Zia A.A.
      • Vuran A.C.
      • et al.
      Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study.
      and an RCT
      • Mannacio V.A.
      • Di Tommaso L.
      • Antignan A.
      • et al.
      Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study.
      (Data Supplement 10).
      Only data from post hoc analyses are available on the utility of newer P2Y12 inhibitors in patients with ACS who undergo CABG. In a retrospective analysis of patients in the TRITON-TIMI 38 study
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      who underwent CABG,
      • Smith P.K.
      • Goodnough L.T.
      • Levy J.H.
      • et al.
      Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis.
      prasugrel treatment was associated with a significantly lower 30-day mortality rate than that of clopidogrel and more postoperative blood loss. A post hoc analysis of patients who underwent CABG in the PLATO study
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      showed that the primary endpoint at 1 year was similar for both treatments, but a significant reduction in cardiovascular mortality was noted with ticagrelor compared with clopidogrel.
      • Held C.
      • Asenblad N.
      • Bassand J.P.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial.
      • Varenhorst C.
      • Alstrom U.
      • Scirica B.M.
      • et al.
      Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery.
      Issues related to the timing of discontinuation of DAPT before CABG are beyond the scope of this update but are addressed in the 2011 CABG guideline.
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
      Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons.
      Figure 3 summarizes recommendations for the management and duration of P2Y12 inhibitor therapy in patients undergoing CABG.
      Figure thumbnail gr3
      Figure 3Treatment algorithm for management and duration of P2Y12 inhibitor therapy in patients undergoing CABG. Colors correspond to Class of Recommendation in . Aspirin therapy is almost always continued indefinitely in patients with coronary artery disease. *Duration of DAPT therapy can vary from as little as 4 weeks to >12 months, depending on the clinical setting and bleeding risk. CABG, Coronary artery bypass graft surgery; SIHD, stable ischemic heart disease; S/P, status post; ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; post-op, postoperatively; DAPT, dual antiplatelet therapy.

      6. Recommendations for Duration of DAPT in Patients with SIHD

      Tabled 1
      SR, Systematic review.
      For the purposes of this update, patients with a history of ACS >1 year prior who have remained free of recurrent ACS are considered to have transitioned to SIHD.
      In the CHARISMA trial, which randomized patients with established atherosclerosis or at high risk of clinical atherosclerotic disease to either DAPT (with clopidogrel) or aspirin monotherapy, no significant reduction was found in ischemic effects at a median follow-up of 28 months with DAPT, but a 0.4% absolute increase was seen in severe bleeding.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      In a post hoc analysis of patients enrolled in the study with prior MI, a 1.7% absolute decrease in the composite endpoint of cardiovascular death, MI, or stroke events was observed with DAPT, but no benefit was seen in those with CAD without prior MI (Data Supplement 4).
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      In the PEGASUS-TIMI 54 trial, in which stable patients 1 to 3 years after MI with additional high-risk features were randomized to either DAPT (with ticagrelor 60 mg or 90 mg twice daily) or continued aspirin monotherapy, a mean of 33 months of DAPT led to a 1.2% to 1.3% absolute reduction in ischemic events and a 1.2% to 1.5% increase in major bleeding.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      In subgroup analysis, the greatest reduction in ischemic events was in patients in whom P2Y12 inhibitor therapy either had not been discontinued or had been discontinued ≤30 days before enrollment in the study (absolute reduction in MACE: 1.9% to 2.5%), and no benefit was seen in patients in whom P2Y12 inhibitor therapy had been discontinued >1 year before enrollment in the study.
      • Bonaca M.P.
      • Bhatt D.L.
      • Steg P.G.
      • et al.
      Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54.
      On the basis of all studies of DAPT in post-MI patients, extended DAPT for approximately 18 to 36 months leads to an absolute decrease in ischemic complications of ≈1% to 3% and an absolute increase in bleeding complications of ≈1% (Data Supplement 4).
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      • Bhatt D.L.
      • Fox K.A.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.