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Canadian Journal of Cardiology

2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy

Published:December 19, 2017DOI:https://doi.org/10.1016/j.cjca.2017.12.012

      Abstract

      Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence. The present update to the 2011 and 2013 Canadian Cardiovascular Society APT guidelines incorporates new evidence on how to optimize APT use, particularly in situations in which few to no data were previously available. The recommendations update focuses on the following primary topics: (1) the duration of dual APT (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome and non-acute coronary syndrome indications; (2) management of DAPT in patients who undergo noncardiac surgery; (3) management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery; (4) when and how to switch between different oral antiplatelet therapies; and (5) management of antiplatelet and anticoagulant therapy in patients who undergo PCI. For PCI patients, we specifically analyze the particular considerations in patients with atrial fibrillation, mechanical or bioprosthetic valves (including transcatheter aortic valve replacement), venous thromboembolic disease, and established left ventricular thrombus or possible left ventricular thrombus with reduced ejection fraction after ST-segment elevation myocardial infarction. In addition to specific recommendations, we provide values and preferences and practical tips to aid the practicing clinician in the day to day use of these important agents.

      Résumé

      Le traitement antiplaquettaire (TAP) constitue désormais un outil important dans le traitement et la prévention des événements athérosclérotiques, particulièrement ceux qui sont associés à la coronaropathie. Le vaste corpus de données scientifiques a évolué sur la relation entre l’ordonnance de TAP dans les divers contextes cliniques et les rapports bénéfices/risques. Le comité des lignes directrices de la Société canadienne de cardiologie et de l’Association canadienne de cardiologie d’intervention actualise et publie régulièrement ses recommandations en tenant compte des données probantes cliniques les plus récentes. La mise à jour des lignes directrices sur le TAP de la Société canadienne de cardiologie de 2011 et 2013 intègre de nouvelles données probantes sur la façon d’optimiser l’utilisation du TAP, particulièrement dans les situations où il existait peu ou pas de données. La mise à jour des recommandations porte principalement sur les sujets suivants : 1) la durée du double TAP (DTAP) chez les patients qui subissent l’intervention coronarienne percutanée (ICP) en raison d’un syndrome coronarien aigu ou d’un syndrome coronarien non aigu ; 2) la prise en charge du DTAP chez les patients qui subissent une intervention chirurgicale non cardiaque ; 3) la prise en charge du DTAP chez les patients qui subissent un pontage aortocoronarien non urgent ou semi-urgent ; 4) le moment et la façon de passer d’un traitement antiplaquettaire par voie orale à un autre ; 5) la prise en charge du TAP et de l’anticoagulothérapie chez les patients qui subissent une ICP. Chez les patients qui subissent l’ICP, nous analysons notamment les considérations particulières chez les patients qui souffrent de fibrillation auriculaire, qui portent des valves mécaniques ou bioprothétiques (y compris ceux qui ont subi un remplacement valvulaire aortique par cathéter), qui souffrent d’une maladie thrombo-embolique veineuse et dont le diagnostic de thrombus ventriculaire gauche est établi ou dont le diagnostic de thrombus ventriculaire gauche avec fraction d’éjection réduite après l’infarctus du myocarde avec sus-décalage du segment ST est possible. En plus des recommandations particulières, nous donnons des valeurs, des préférences et des conseils pratiques pour aider le clinicien praticien dans l’utilisation quotidienne de ces importants agents.

      Scope of the 2018 Antiplatelet Therapy Guideline Update

      This update to the 2011 and 2013 Canadian Cardiovascular Society (CCS) antiplatelet therapy guidelines incorporates new evidence on how to optimally use antiplatelet therapy, particularly in conditions in which few to no data were previously available.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines.
      • Tanguay J.F.
      • Bell A.D.
      • Ackman M.L.
      • et al.
      Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy.
      The recommendations focused on the following topics:
      • 1.
        The duration of dual antiplatelet therapy (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and non-ACS indications
      • 2.
        Management of DAPT in patients who undergo noncardiac surgery
      • 3.
        Management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery (CABG)
      • 4.
        When and how to switch between oral antiplatelet therapies
      • 5.
        Management of antiplatelet and anticoagulant therapy in patients who undergo PCI with atrial fibrillation (AF), mechanical or bioprosthetic valves (including transcatheter aortic valve replacement [TAVR]), venous thromboembolic disease, and established left ventricular (LV) thrombus (LVT) or possible LVT with reduced ejection fraction after ST-segment elevation myocardial infarction (STEMI).

      Development of the Guidelines

      The CCS appointed co-chairs, a primary panel, and a secondary panel to develop this guideline update. The primary panel developed the scope of the document, identified topics for review, performed the literature review and critical appraisal of the identified literature, drafted the recommendations, and voted on the recommendations. Peer review was provided by the secondary panel and the CCS Guidelines Committee. The final draft was presented and approved by the CCS Executive Committee.
      The committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, which started by defining the question or issue of interest, including the patient population, intervention, comparator, and outcomes.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

      Grade Working Group. The Grading of Recommendations Assessment, Development and Evaluation (GRADE), 2016. Available at: www.gradeworkinggroup.org. Accessed January 26, 2017.

      A systematic search was performed to identify all relevant studies, including systematic reviews and meta-analyses. The committee reviewed the information from the systematic search and evaluated the quality of evidence for each outcome across the studies. Recommendations were then formulated according to the factors outlined in the GRADE approach. Summaries of the literature review are provided online at www.ccs.ca.

      1. Duration of DAPT in Patients Who Undergo PCI

      1.1 Duration of DAPT in patients treated with PCI for ACS

      The recommended duration of DAPT after ACS and PCI was 12 months on the basis of the results of Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), respectively.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines.
      • Tanguay J.F.
      • Bell A.D.
      • Ackman M.L.
      • et al.
      Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy.
      • 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.
      • 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.
      Although a number of recent randomized trials have suggested that DAPT duration may be shortened to 3-6 months after PCI,
      • Schulz-Schupke 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.
      • Gilard M.
      • Barragan P.
      • Noryani A.A.
      • 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.
      • 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.
      • 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.
      • 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).
      • 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.
      particularly with the use of newer generation drug-eluting stents (DESs), most patients enrolled had stable coronary artery disease (CAD) or low-risk ACS with fewer patients having high-risk ACS or STEMI. In one meta-analysis, 67% of ACS patients had biomarker-negative ACS.
      • 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.
      Despite the enrollment of low-risk ACS patients in these trials, shorter durations of DAPT compared with 1 full year of DAPT were still associated with higher rates of myocardial infarction (MI) and stent thrombosis at 1 year.
      • 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.
      This suggests that ACS patients who are not at high risk of bleeding should receive at least 12 months of DAPT (Fig. 1).
      Figure thumbnail gr1
      Figure 1Recommendations for duration of DAPT in patients with ACS (STEMI or NSTEACS) who undergo PCI. ACS, acute coronary syndrome; ASA, acetylsalicylic acid; BID, twice daily; DAPT, dual antiplatelet therapy; NSAID, nonsteroidal anti-inflammatory drug; NSTEACS, non ST-segment elevation acute coronary syndrome; OAC, oral anticoagulant; OD, once daily; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; STEMI, ST-segment elevation myocardial infarction.
      Clopidogrel or prasugrel, in addition to acetylsalicylic acid (ASA), beyond 1 year after PCI was studied in the DAPT trial
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      and the use of ticagrelor long-term after previous MI was studied in the 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 (PEGASUS-TIMI 54) trial.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      In the DAPT trial, 9961 patients with a DES who received PCI (43% for ACS) who did not have a bleeding event within the first year were randomly assigned to continue thienopyridine treatment beyond 1 year or to receive placebo. Continued treatment with thienopyridine, compared with placebo, reduced the rates of stent thrombosis (0.4% vs 1.4%; hazard ratio [HR], 0.29; P < 0.001) and major adverse cardiovascular (CV) and cerebrovascular events (4.3% vs 5.9%; HR, 0.71; P < 0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (HR, 1.36; 95% confidence interval [CI], 1.00-1.85; P = 0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs 1.6%; P = 0.001).
      In the PEGASUS-TIMI 54 trial, 21,162 patients who experienced an MI 1-3 years earlier were randomized in a double-blind fashion to ticagrelor 90 mg twice daily (BID), ticagrelor 60 mg BID, or placebo.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      All the patients were to receive low-dose ASA and were followed for a median of 33 months. The 2 ticagrelor doses each reduced the composite of CV death, MI or stroke (7.85% ticagrelor 90 mg, 7.77% ticagrelor 60 mg, 9.04% placebo; HR 90 mg ticagrelor vs placebo: 0.85; P = 0.008; HR 60 mg ticagrelor vs placebo: 0.84; 95% CI, 0.74-0.95; P = 0.004). Rates of Thrombolysis in Myocardial Infarction (TIMI) major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%; P < 0.001 for each dose vs placebo); the rates of intracranial hemorrhage or fatal bleeding in the 3 groups were 0.63%, 0.71%, and 0.60%, respectively. Because the reduction in ischemic events was offset by an increase in bleeding in DAPT and PEGASUS, patients who have risk factors for recurrent ischemic events might have a more favourable benefit to risk ratio. Clinical and angiographic variables that place a patient at higher risk of ischemia are shown in Table 1.
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
      • Yeh R.W.
      • Secemsky E.A.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
      Table 1High-risk clinical and angiographic features for thrombotic events
      Feature
      Clinical
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
       Before myocardial infarction or troponin-positive acute coronary syndrome
       Diabetes mellitus treated with oral hypoglycemics or insulin
      Net benefit to diabetic patients in the absence of any of other high risk features is unclear.18
       Chronic kidney disease (creatinine clearance ≤ 60 mL/min)
       Previous stent thrombosis
       Current smoker
      Angiographic
       Multiple stents (≥3 stents implanted, ≥ 3 lesions stented)
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
      or use of a biodegradable vascular scaffold
       Long lesion length (>60 mm total stent length)
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
       Complex lesions (bifurcation treated with 2 stents, stenting of chronic occlusion)
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
       Left main or proximal LAD stenting
      • Costa F.
      • Adamo M.
      • Ariotti S.
      • et al.
      Left main or proximal left anterior descending coronary artery disease location identifies high-risk patients deriving potentially greater benefit from prolonged dual antiplatelet therapy duration.
       Multivessel PCI
      • Lee S.Y.
      • Hong M.K.
      • Shin D.H.
      • et al.
      Association between duration of dual antiplatelet therapy and angiographic multivessel disease on outcomes in patients treated with newer-generation drug-eluting stents.
      LAD, left anterior descending artery; PCI, percutaneous coronary intervention.
      Net benefit to diabetic patients in the absence of any of other high risk features is unclear.
      • Bundhun P.K.
      • Yanamala C.M.
      • Huang F.
      Should a prolonged duration of dual anti-platelet therapy be recommended to patients with diabetes mellitus following percutaneous coronary intervention? A systematic review and meta-analysis of 15 studies.
      Factors associated with increased risk of bleeding are shown in Table 2. Other strategies to improve the benefit-risk ratio currently being evaluated in randomized trials include using P2Y12 inhibitor monotherapy without ASA to reduce the risk of bleeding after PCI.
      • Baber U.
      • Dangas G.
      • Cohen D.J.
      • et al.
      Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: rationale and design of the TWILIGHT study.
      ClinicalTrials.gov. GLOBAL LEADERS
      A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation.
      In patients with ACS (STEMI or NSTEMI) who receive PCI:
      • 1.
        We recommend DAPT with ASA 81 mg daily with either ticagrelor 90 mg BID or prasugrel 10 mg once daily over clopidogrel 75 mg once daily for 1 year (Strong Recommendation; High-Quality Evidence).
      • 2.
        We recommend that, in patients who tolerate 1 year of DAPT without a major bleeding event and who are not at high risk of bleeding, DAPT should be extended beyond 1 year (Strong Recommendation; High-Quality Evidence for up to 3 years of treatment). After 1 year, we recommend a DAPT regimen of ASA 81 mg daily plus either ticagrelor 60 mg BID or clopidogrel 75 mg once daily (Strong Recommendation; High-Quality Evidence) or prasugrel 10 mg once daily (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. These recommendations place greater emphasis on reduction of major CV events and stent thrombosis vs an increase in bleeding complications.
      Table 2Factors associated with increased bleeding risk
      Need for OAC in addition to DAPT
      Advanced age (older than 75 years)
      Frailty
      Anemia with hemoglobin < 110 g/L
      Chronic renal failure (creatinine clearance < 40 mL/min)
      Low body weight (<60 kg)
      Hospitalization for bleeding within past year
      Previous stroke/intracranial bleed
      Regular need for NSAIDs or prednisone
      DAPT, dual antiplatelet therapy; NSAIDs, nonsteroidal anti-inflammatory drugs; OAC, oral anticoagulation.
      Practical tip. Recommendations on duration of DAPT apply specifically to duration of P2Y12 inhibitor therapy. ASA should be continued indefinitely in most patients with CAD who are not receiving oral anticoagulant therapy.
      Practical tip. Patients who have clinical or angiographic features for an increased risk of a thrombotic CV event might derive greater absolute benefit from extended DAPT beyond 1 year (Table 1).
      Practical tip. Quantitative risk scores have been developed.
      • Yeh R.W.
      • Secemsky E.A.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
      ClinicalTrials.gov. GLOBAL LEADERS
      A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation.
      • Costa F.
      • van Klaveren D.
      • James S.
      • et al.
      Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
      • Pasea L.
      • Chung S.C.
      • Pujades-Rodriguez M.
      • et al.
      Personalising the decision for prolonged dual antiplatelet therapy: development, validation and potential impact of prognostic models for cardiovascular events and bleeding in myocardial infarction survivors.
      • Baber U.
      • Mehran R.
      • Giustino G.
      • et al.
      Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS.
      These scores might help identify higher-risk patients with greater absolute benefit of extended DAPT (Table 3).
      Table 3Published risk assessment tools for determining duration of DAPT
      Score nameOnline calculatorPatient populationScore descriptionDAPT duration periodsScore variablesValidationComments
      PRECISE-DAPT
      • Costa F.
      • van Klaveren D.
      • James S.
      • et al.
      Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
      www.precisedaptscore.com/predapt/index.htmlPCI with or without ACSEstimates 1-year rates of ischemic and bleeding events for patients treated with PCI.

      Patients with PRECISE-DAPT score > 25 have higher predicted rates of bleeding events and similar rates of ischemic events with shortened DAPT (3-6 months vs 12-24 months)
      3-6 Months vs 12-14 monthsAge, previous bleeding, white blood cell count, hemoglobin, creatinine clearanceValidated in 2 separate cohorts (total patients involved in the development: 29,730);

      c-statistic in the 2 validation cohorts = 0.66 and 0.70
      Discrimination lower for patients receiving prasugrel;

      Angiographic and PCI variables not included;

      Does not provide guidance to support the decision to prolong DAPT over 1 year after PCI
      CALIBER
      • Lee S.Y.
      • Hong M.K.
      • Shin D.H.
      • et al.
      Association between duration of dual antiplatelet therapy and angiographic multivessel disease on outcomes in patients treated with newer-generation drug-eluting stents.
      https://farr-data-lab.shinyapps.io/caliber-prolonged_dapt_benefits_harms_risksPatients surviving 1 year after MI including those treated with or without PCIEstimates ischemic and bleeding events 2-6 years after MI with and without prolonged DAPT12 Months vs > 12 monthsIschemic prediction score includes 20 variables and bleeding prediction score includes 18 variablesValidated in 2 cohorts (total patients involved in the development: 19,784);

      c-statistic in the validation cohort = 0.75 for ischemic end points, and 0.72 for major bleeding
      High number of variables included in the model;

      Angiographic and PCI variables not included;

      Did not include any patients treated with prasugrel
      DAPT
      • Yeh R.W.
      • Secemsky E.A.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
      http://tools.acc.org/DAPTriskapp/#!/content/calculatorPatients 1 year after PCI without bleeding or ischemic eventsEstimates the net benefit between ischemic and bleeding events with prolonged DAPT. Patients with DAPT score ≥ 2 had fewer ischemic and bleeding events with prolonged DAPT (>12 months)12 Months vs >12 monthsAge, cigarette smoking, diabetes mellitus, MI at presentation, previous PCI or MI, paclitaxel-eluting stent, stent diameter < 3 mm, CHF or LVEF < 30%, vein graft stentValidated in a separate retrospective cohort (total patients involved in the development: 19,784);

      c-statistic in the validation cohort = 0.64 in the ischemic as well as bleeding model
      Incorporates angiographic and PCI data;

      < 50% of the patients in the derivation cohort received a second-generation DES;

      Did not include any patients treated with ticagrelor
      ACS, acute coronary syndrome; CALIBER, Cardiovascular Disease Research Using Linked Bespoke Studies and Electronic Health Records; CHF, congestive heart failure; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PRECISE-DAPT, PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.
      Practical tip. An ongoing assessment of bleeding and ischemic risk should be performed at least annually to determine whether DAPT should be continued.
      Practical tip. Prasugrel should be avoided in patients with previous transient ischemic attack or stroke.
      Practical tip. For patients who have a bleeding event during ticagrelor or prasugrel treatment, but for whom continuation of a P2Y12 agent is believed to be warranted, please refer to the de-escalation recommendations in section 2.3.
      Practical tip. In patients with STEMI who receive fibrinolytic therapy, clopidogrel is currently the recommended P2Y12 inhibitor within the first 24 hours. A recent randomized trial showed a higher level of platelet inhibition with ticagrelor compared with clopidogrel.
      • Dehghani P.
      • Lavoie A.
      • Lavi S.
      • et al.
      Effects of ticagrelor versus clopidogrel on platelet function in fibrinolytic-treated STEMI patients undergoing early PCI.
      Ongoing trials are evaluating clinical outcomes with ticagrelor in this setting (ClinicalTrials.gov NCT02298088).

      1.2 Duration of DAPT for patients treated with PCI in non-ACS settings

      1.2.1 Shortened-duration DAPT

      Several recent randomized trials of patients treated with newer-generation DESs, particularly for a non-ACS indication, have evaluated shortening DAPT to less than 1 year (Fig. 2).
      • Schulz-Schupke 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.
      • 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.
      • 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.
      • 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).
      • 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.
      • Han Y.
      • Xu B.
      • Xu K.
      • et al.
      Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimus-eluting stent: randomized substudy of the I-LOVE-IT 2 trial.
      • Hong S.J.
      • Shin D.H.
      • Kim J.S.
      • et al.
      6-Month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial.
      Fifteen published meta-analyses compared 3-6 months vs 12 months of DAPT.
      • Abo-Salem E.
      • Alsidawi S.
      • Jamali H.
      • Effat M.
      • Helmy T.
      Optimal duration of dual antiplatelet therapy after drug-eluting stents: meta-analysis of randomized trials.
      • Liou K.
      • Nagaraja V.
      • Jepson N.
      • Ooi S.Y.
      Optimal duration of dual antiplatelet therapy following drug-eluting stents implantation: a meta-analysis of 7 randomised 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.
      • Tsoi M.F.
      • Cheung C.L.
      • Cheung T.T.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: meta-analysis of large randomised controlled trials.
      • Villablanca P.A.
      • Massera D.
      • Mathew V.
      • et al.
      Outcomes of </=6-month versus 12-month dual antiplatelet therapy after drug-eluting stent implantation: A meta-analysis and meta-regression.
      • Wassef A.W.
      • Khafaji H.
      • Syed I.
      • et al.
      Short duration vs standard duration of dual-antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents - a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials.
      • Yang J.
      • Fan Z.X.
      • Yang C.J.
      • Wang H.B.
      A meta-analysis of randomized clinical trials comparing shorter (less or equal than 6 months) and longer (more or equal than 12 months) dual anti-platelet therapy following drug-eluting coronary stents.
      • Zhang X.L.
      • Zhu Q.Q.
      • Zhu L.
      • et al.
      Optimize the duration of DAPT following DES implantation: an updated system review and meta-analysis of 10 randomized trials.
      • Ziada K.M.
      • Abdel-Latif A.K.
      • Charnigo R.
      • Moliterno D.J.
      Safety of an abbreviated duration of dual antiplatelet therapy (</=6 months) following second-generation drug-eluting stents for coronary artery disease: a systematic review and meta-analysis of randomized trials.
      • Valgimigli M.
      • Ariotti S.
      • Costa F.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: will we ever reach a consensus?.
      • Sheyin O.
      • Perez X.
      • Pierre-Louis B.
      • Kurian D.
      The optimal duration of dual antiplatelet therapy in patients receiving percutaneous coronary intervention with drug-eluting stents.
      • Sharma A.
      • Sharma S.K.
      • Garg A.
      • et al.
      Duration of dual antiplatelet therapy following drug-eluting stent implantation in diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials.
      A consistent finding was that lower rates of bleeding were associated with shorter courses of DAPT.
      • Abo-Salem E.
      • Alsidawi S.
      • Jamali H.
      • Effat M.
      • Helmy T.
      Optimal duration of dual antiplatelet therapy after drug-eluting stents: meta-analysis of randomized trials.
      • Liou K.
      • Nagaraja V.
      • Jepson N.
      • Ooi S.Y.
      Optimal duration of dual antiplatelet therapy following drug-eluting stents implantation: a meta-analysis of 7 randomised 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.
      • Tsoi M.F.
      • Cheung C.L.
      • Cheung T.T.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: meta-analysis of large randomised controlled trials.
      • Villablanca P.A.
      • Massera D.
      • Mathew V.
      • et al.
      Outcomes of </=6-month versus 12-month dual antiplatelet therapy after drug-eluting stent implantation: A meta-analysis and meta-regression.
      • Wassef A.W.
      • Khafaji H.
      • Syed I.
      • et al.
      Short duration vs standard duration of dual-antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents - a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials.
      • Yang J.
      • Fan Z.X.
      • Yang C.J.
      • Wang H.B.
      A meta-analysis of randomized clinical trials comparing shorter (less or equal than 6 months) and longer (more or equal than 12 months) dual anti-platelet therapy following drug-eluting coronary stents.
      • Zhang X.L.
      • Zhu Q.Q.
      • Zhu L.
      • et al.
      Optimize the duration of DAPT following DES implantation: an updated system review and meta-analysis of 10 randomized trials.
      • Sheyin O.
      • Perez X.
      • Pierre-Louis B.
      • Kurian D.
      The optimal duration of dual antiplatelet therapy in patients receiving percutaneous coronary intervention with drug-eluting stents.
      Thirteen meta-analyses showed no difference in ischemic or thrombotic end points with shorter courses of DAPT.
      • Liou K.
      • Nagaraja V.
      • Jepson N.
      • Ooi S.Y.
      Optimal duration of dual antiplatelet therapy following drug-eluting stents implantation: a meta-analysis of 7 randomised controlled trials.
      • Tsoi M.F.
      • Cheung C.L.
      • Cheung T.T.
      • et al.
      Duration of dual antiplatelet therapy after drug-eluting stent implantation: meta-analysis of large randomised controlled trials.
      • Villablanca P.A.
      • Massera D.
      • Mathew V.
      • et al.
      Outcomes of </=6-month versus 12-month dual antiplatelet therapy after drug-eluting stent implantation: A meta-analysis and meta-regression.
      • Wassef A.W.
      • Khafaji H.
      • Syed I.
      • et al.
      Short duration vs standard duration of dual-antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents - a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials.
      • Yang J.
      • Fan Z.X.
      • Yang C.J.
      • Wang H.B.
      A meta-analysis of randomized clinical trials comparing shorter (less or equal than 6 months) and longer (more or equal than 12 months) dual anti-platelet therapy following drug-eluting coronary stents.
      • Zhang X.L.
      • Zhu Q.Q.
      • Zhu L.
      • et al.
      Optimize the duration of DAPT following DES implantation: an updated system review and meta-analysis of 10 randomized trials.
      • Ziada K.M.
      • Abdel-Latif A.K.
      • Charnigo R.
      • Moliterno D.J.
      Safety of an abbreviated duration of dual antiplatelet therapy (</=6 months) following second-generation drug-eluting stents for coronary artery disease: a systematic review and meta-analysis of randomized trials.
      Meta-analyses have also evaluated longer vs shorter durations of DAPT in various patient subgroups, in which a consistent finding was that a shorter duration of DAPT might give rise to an increased risk of ischemic outcomes. These groups include previous ACS,
      • 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.
      multivessel disease,
      • Lee S.Y.
      • Hong M.K.
      • Shin D.H.
      • et al.
      Association between duration of dual antiplatelet therapy and angiographic multivessel disease on outcomes in patients treated with newer-generation drug-eluting stents.
      and complex PCI.
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
      Figure thumbnail gr2
      Figure 2Recommendations for duration of DAPT in patients who undergo elective PCI. ASA, acetylsalicylic acid; BMS, bare-metal stent; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; NSAID, nonsteroidal anti-inflammatory drug; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.

      1.2.2 Extended duration of DAPT after PCI for a non-ACS indication

      Extending DAPT duration beyond 12 months might have benefit in certain patients who receive DES for non-ACS indications.
      • Mauri L.
      • Kereiakes D.J.
      • Yeh R.W.
      • et al.
      Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
      In the DAPT trial, 57% of patients had a non-ACS indication for their index PCI. Three meta-analyses showed consistent results with decreased MI and stent thrombosis, but increased bleeding when DAPT was extended beyond a year after PCI.
      • Bundhun P.K.
      • Yanamala C.M.
      • Huang F.
      Should a prolonged duration of dual anti-platelet therapy be recommended to patients with diabetes mellitus following percutaneous coronary intervention? A systematic review and meta-analysis of 15 studies.
      • Zhang X.L.
      • Zhu Q.Q.
      • Zhu L.
      • et al.
      Optimize the duration of DAPT following DES implantation: an updated system review and meta-analysis of 10 randomized trials.
      • Fei Y.
      • Tsoi M.F.
      • Cheung T.T.
      • Cheung B.M.
      Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: meta-analysis of randomized controlled trials.
      Recently, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      randomized 27,395 patients with stable CAD or peripheral arterial disease to: (1) rivaroxaban 2.5 mg BID with ASA 100 mg daily vs (2) rivaroxaban 5 mg BID vs (3) ASA 100 mg daily. Over a mean follow-up of 23 months, rivaroxaban 2.5 mg with ASA reduced the composite outcome of CV death, MI, or stroke by 24% (4.1% vs 5.4%; HR, 0.76; 95% CI, 0.66-0.86; P < 0.001), reduced all-cause mortality by 18% (3.4% vs 4.1%; HR, 0.82; 95% CI, 0.71-0.96; P = 0.01), increased major bleeding by 70% (3.1% vs 1.9%; HR, 1.70; 95% CI, 1.40-2.05; P < 0.001), but did not significantly increase intracranial or fatal bleeding.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      Rivaroxaban 5 mg BID led to a nonsignificant 10% reduction in the composite outcome. The combination of rivaroxaban 2.5 mg BID and low dose ASA offers another option for secondary prevention in patients with chronic stable CAD.
      In patients undergoing PCI for a non-ACS indication (eg, stable ischemic heart disease):
      • 3.
        We recommend 6 months (and up to 1 year) of DAPT with ASA and clopidogrel (Strong Recommendation; Moderate-Quality Evidence).
      • 4.
        We suggest that in patients who have additional high-risk clinical or angiographic features for thrombotic CV events and who are at low risk of bleeding, it is reasonable to extend the duration of DAPT to >1 year (Weak Recommendation; Moderate-Quality Evidence for up to 3 years of treatment).
      • 5.
        We suggest that in patients who are at high risk of bleeding, the duration of DAPT be shortened to a minimum of 1 month (if a bare-metal stent [BMS] is used) or 3 months (if a DES is used) (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. These recommendations place greater emphasis on reduction of major CV thrombotic events and stent thrombosis vs an increase in bleeding complications. These recommendations presume that patients who experience a clinically significant bleed or at high risk of bleeding would be reassessed for the appropriateness of continuation of DAPT at 1 year.
      Practical tip. A general principle to consider when deciding on the duration of DAPT is a balanced assessment of the risk of thrombotic CV events and bleeding. Patients at lower risk of thrombotic events and higher risk of bleeding can be considered for a shorter duration of DAPT whereas patients at higher risk of thrombotic events and lower risk of bleeding should be considered for a longer duration of DAPT.
      Practical tip. As in the ACS setting, patients who undergo PCI for a non-ACS indication might derive greater absolute benefit of extended DAPT if they have clinical or angiographic features associated with increased risk of thrombotic CV events (Table 1).

      1.3 Risk scores to inform DAPT duration after PCI

      Three risk scores to quantify bleeding and/or ischemic events have been published and retrospectively validated.
      • Yeh R.W.
      • Secemsky E.A.
      • Kereiakes D.J.
      • et al.
      Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
      • Costa F.
      • van Klaveren D.
      • James S.
      • et al.
      Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
      • Pasea L.
      • Chung S.C.
      • Pujades-Rodriguez M.
      • et al.
      Personalising the decision for prolonged dual antiplatelet therapy: development, validation and potential impact of prognostic models for cardiovascular events and bleeding in myocardial infarction survivors.
      To date, no score has been prospectively validated. Table 3 provides a summary of these scores and links to online calculators for each. Scores combining bleeding and ischemic events assume equal clinical importance to each type of event. Risk scores should complement available clinical and angiographic data, and are not a substitute for clinical judgement.

      1.4 Interrupting DAPT for noncardiac surgery

      In patients who are being treated with DAPT after a PCI with a BMS or DES, 2 issues need to be addressed: timing of surgery and perioperative DAPT management.
      The only randomized trial in noncardiac surgery to assess perioperative antiplatelet drug management is Perioperative Ischemic Evaluation (POISE)-2, which showed that perioperative ASA use did not affect the incidence of CV events or mortality but conferred a small but statistically significant increased risk for major bleeding (4.6% vs 3.8%; P = 0.04).
      • Devereaux P.J.
      • Mrkobrada M.
      • Sessler D.I.
      • et al.
      Aspirin in patients undergoing noncardiac surgery.
      However, only 4% of patients had a coronary stent. In a U.S. observational study of 20,590 patients who had noncardiac surgery within 2 years of PCI and 41,180 matched control participants with coronary stents who did not have surgery, there was a clustering of cardiac events within the first 3 months after PCI, with the highest risk if surgery occurred within 4-6 weeks post-PCI.
      • Holcomb C.N.
      • Graham L.A.
      • Richman J.S.
      • et al.
      The incremental risk of noncardiac surgery on adverse cardiac events following coronary stenting.
      Among patients having surgery between 6 weeks and 6 months post-PCI, the absolute risk for cardiac events was higher after complex surgery than for less complex inpatient surgery or outpatient surgery (5.3% vs 3.7% vs 0.1%). A key limitation of this study was that perioperative DAPT management was not specified. In a Danish study of 4031 patients with drug-eluting coronary stents and 20,232 control participants without CAD having noncardiac surgery, the risk for adverse cardiac events appeared highest within the first month post-PCI.
      • Egholm G.
      • Kristensen S.D.
      • Thim T.
      • et al.
      Risk associated with surgery within 12 months after coronary drug-eluting stent implantation.
      Beyond 1 month post-PCI, the risk for cardiac events was not affected by the time interval between PCI and surgery. However, information on perioperative antiplatelet management was lacking. Finally, in a registry of 880 post-PCI patients who had noncardiac surgery, in whom ASA and DAPT was continued in approximately 70% and approximately 10% of patients, respectively, 30-day rates of perioperative adverse cardiac and major bleeding events were 3.5% and 5.6%, respectively.
      • Rossini R.
      • Angiolillo D.J.
      • Musumeci G.
      • et al.
      Antiplatelet therapy and outcome in patients undergoing surgery following coronary stenting: results of the surgery after stenting registry.
      Overall, in post-PCI patients receiving DAPT having noncardiac surgery, the perioperative increased risk of bleeding with ASA continuation appears modest, and until patient management data are available it is reasonable to suggest continuing ASA, whereas in most patients, interrupting P2Y12 therapy.
      • 6.
        In patients undergoing PCI who are treated with a BMS and who require elective noncardiac surgery, we recommend delaying surgery for at least 1 month after PCI (Strong Recommendation; Moderate-Quality Evidence).
      • 7.
        In patients undergoing PCI who are treated with a DES and who require elective noncardiac surgery, we recommend delaying surgery for at least 3 months after PCI (Strong Recommendation; Moderate-Quality Evidence). If there is a need for semiurgent noncardiac surgery, we suggest delaying surgery for at least 1 month after PCI (Weak Recommendation; Low-Quality Evidence).
      • 8.
        In patients undergoing PCI who are treated with either a BMS or DES and who require elective noncardiac surgery, we suggest continuing ASA perioperatively whenever possible (Weak Recommendation; Low-Quality Evidence).
      • 9.
        In patients undergoing PCI who are treated with a BMS or DES and who require elective noncardiac surgery, we suggest withholding clopidogrel and ticagrelor for 5-7 days preoperatively, and prasugrel for 7-10 days preoperatively (Weak Recommendation; Low-Quality Evidence).
      • 10.
        In patients undergoing PCI who are treated with a BMS or DES and who have undergone noncardiac surgery, we suggest restarting maintenance-dose DAPT after surgery, as soon as it is deemed safe by the surgeon (Weak Recommendation; Very Low-Quality Evidence).
      Practical tip. The risk and consequences of perioperative bleeding will vary considerably depending on the type of surgery performed. Some minor surgical procedures carry a low risk of bleeding, whereas others a very high risk of bleeding. For example, some dental, ophthalmological, and endoscopic procedures carry a low risk of bleeding and can be performed without stopping antiplatelet therapy.

      1.5 Elective or semiurgent CABG surgery after ACS

      Patients who are receiving DAPT and require elective or semiurgent CABG surgery pose a special challenge, especially after an ACS because of the high bleeding risk associated with CABG and the potentially serious consequences of bleeding (eg, pericardial tamponade). The only randomized trial to assess perioperative use of ASA before CABG is Antithrombotic Therapy in Acute Coronary Syndromes (ATACAS), which reported that preoperative use of ASA was not associated with an increased risk for bleeding or transfusion requirements but also did not mitigate the risk for ACS or mortality.
      • Myles P.S.
      • Smith J.A.
      • Painter T.
      Aspirin before coronary artery surgery.
      The neutral findings of this trial might have arisen from the study design whereby ASA was initiated 1-2 hours before CABG, after a ≥ 4-day interruption period, which is not done in clinical practice. The findings suggest, in concert with older studies,
      • Mangano D.T.
      Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery.
      • Dacey L.J.
      • Munoz J.J.
      • Johnson E.R.
      • et al.
      Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients.
      • Bybee K.A.
      • Powell B.D.
      • Valeti U.
      • et al.
      Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting.
      that it is reasonable to continue ASA in patients with or without an ACS who require CABG. In a registry of ASA-treated patients with an ACS who required CABG surgery, of whom 1266 were receiving ticagrelor and 978 receiving clopidogrel, it appeared that stopping ticagrelor for at least 3 days and stopping clopidogrel for 5 days before CABG was needed to mitigate the risk for perioperative bleeding, compared with a shorter interruption interval.
      • Hansson E.C.
      • Jideus L.
      • Aberg B.
      • et al.
      Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study.
      Additional observational studies support these interruption intervals for ticagrelor and clopidogrel, with a longer interval for prasugrel.
      • 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.
      • Biancari F.
      • Airaksinen K.E.
      • Lip G.Y.
      Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies.
      • Gherli R.
      • Mariscalco G.
      • Dalen M.
      • et al.
      Safety of preoperative use of ticagrelor with or without aspirin compared with aspirin alone in patients with acute coronary syndromes undergoing coronary artery bypass grafting.
      • Mehta R.H.
      • Roe M.T.
      • Mulgund J.
      • et al.
      Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery.
      • Fox K.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.
      • 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.
      • 11.
        We recommend continuation of ASA in all patients with ACS who require CABG surgery (Strong Recommendation; Moderate-Quality Evidence).
      • 12.
        To minimize the risk of bleeding, for patients with an ACS who are receiving ticagrelor and need semi-urgent CABG, we suggest a minimum interruption of ticagrelor for 48-72 hours before CABG (Weak Recommendation; Low-Quality Evidence) and recommend an ideal interruption period of 5 days before elective CABG (Strong Recommendation; Moderate-Quality Evidence).
      • 13.
        To minimize the risk of bleeding, for patients with an ACS who are receiving clopidogrel and need semiurgent CABG, we suggest a minimum interruption of clopidogrel for 48-72 hours before CABG (Weak Recommendation; Low-Quality Evidence) and recommend an ideal interruption period of 5 days before elective CABG (Strong Recommendation; Moderate-Quality Evidence).
      • 14.
        To minimize the risk of bleeding, for patients with an ACS who are receiving prasugrel and need semiurgent CABG, we suggest a minimum interruption of prasugrel for 5 days before CABG (Weak Recommendation; Very Low-Quality Evidence) and recommend an ideal interruption period of 7 days before elective CABG (Strong Recommendation; Moderate-Quality Evidence).
      Practical tip. Antiplatelet therapy management in the perioperative period should be based on a balanced assessment of the risks of coronary thrombotic complications vs the risk of perioperative bleeding in discussion with the surgeon, interventional cardiologist, attending physician/cardiologist, and the patient.

      2. Switching Therapy

      No large randomized trial with definitive clinical outcomes data has been performed to support switching between P2Y12 inhibitors.
      In large international registries, intensification of therapy from clopidogrel to a more potent P2Y12 inhibitor has been reported in 5%-50% of patients, whereas de-escalation from a more potent agent to clopidogrel was undertaken in up to 11% of patients.
      • Alexopoulos D.
      • Xanthopoulou I.
      • Deftereos S.
      • et al.
      In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prevalence, predictors and short-term outcome.
      • Clemmensen P.
      • Grieco N.
      • Ince H.
      • et al.
      MULTInational non-interventional study of patients with ST-segment elevation myocardial infarction treated with PRimary Angioplasty and Concomitant use of upstream antiplatelet therapy with prasugrel or clopidogrel–the European MULTIPRAC Registry.
      • Bagai A.
      • Peterson E.D.
      • Honeycutt E.
      • et al.
      In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study.
      • De Luca L.
      • Leonardi S.
      • Cavallini C.
      • et al.
      Contemporary antithrombotic strategies in patients with acute coronary syndrome admitted to cardiac care units in Italy: the EYESHOT Study.
      • Bagai A.
      • Wang Y.
      • Wang T.Y.
      • et al.
      In-hospital switching between clopidogrel and prasugrel among patients with acute myocardial infarction treated with percutaneous coronary intervention: insights into contemporary practice from the national cardiovascular data registry.
      • De Luca G.
      • Verdoia M.
      • Schaffer A.
      • et al.
      Switching from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center experience.
      • Loh J.P.
      • Pendyala L.K.
      • Kitabata H.
      • et al.
      Safety of reloading prasugrel in addition to clopidogrel loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
      • Almendro-Delia M.
      • Blanco Ponce E.
      • Gomez-Dominguez R.
      • et al.
      Safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with acute coronary syndrome. An analysis from the ‘real world’.
      • Pourdjabbar A.
      • Hibbert B.
      • Chong A.Y.
      • et al.
      A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL OPTI-CROSS Study.
      Common reasons for switching are outlined in Supplemental Table S1.
      The predominant evidence for switching between P2Y12 inhibitors is on the basis of pharmacodynamic data from small, randomized studies, which lack power to definitively assess ischemic or bleeding outcomes. Registry data consisting of > 4000 patients with switching did not show a signal for increased major bleeding complications.
      • Alexopoulos D.
      • Xanthopoulou I.
      • Deftereos S.
      • et al.
      In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prevalence, predictors and short-term outcome.
      • Clemmensen P.
      • Grieco N.
      • Ince H.
      • et al.
      MULTInational non-interventional study of patients with ST-segment elevation myocardial infarction treated with PRimary Angioplasty and Concomitant use of upstream antiplatelet therapy with prasugrel or clopidogrel–the European MULTIPRAC Registry.
      • Bagai A.
      • Peterson E.D.
      • Honeycutt E.
      • et al.
      In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study.
      • De Luca L.
      • Leonardi S.
      • Cavallini C.
      • et al.
      Contemporary antithrombotic strategies in patients with acute coronary syndrome admitted to cardiac care units in Italy: the EYESHOT Study.
      • Bagai A.
      • Wang Y.
      • Wang T.Y.
      • et al.
      In-hospital switching between clopidogrel and prasugrel among patients with acute myocardial infarction treated with percutaneous coronary intervention: insights into contemporary practice from the national cardiovascular data registry.
      • De Luca G.
      • Verdoia M.
      • Schaffer A.
      • et al.
      Switching from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center experience.
      • Loh J.P.
      • Pendyala L.K.
      • Kitabata H.
      • et al.
      Safety of reloading prasugrel in addition to clopidogrel loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
      • Almendro-Delia M.
      • Blanco Ponce E.
      • Gomez-Dominguez R.
      • et al.
      Safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with acute coronary syndrome. An analysis from the ‘real world’.
      • Rollini F.
      • Franchi F.
      • Angiolillo D.J.
      Switching P2Y12-receptor inhibitors in patients with coronary artery disease.
      • 15.
        We suggest against switching the P2Y12 inhibitor initially selected at hospital discharge unless there is a compelling clinical reason to do so (eg, stent thrombosis, CV event, bleeding, or significant side effects/intolerance) (Weak Recommendation; Low-Quality Evidence).

      2.1 Intensification strategies

      2.1.1 Switching from clopidogrel to ticagrelor

      In the Platelet Inhibition and Patient Outcomes (PLATO) trial, 47.1% (n = 4396) of patients randomized to ticagrelor received clopidogrel in the 24 hours preceding randomization (Supplemental Table S1).
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      From pharmacodynamic studies, a ticagrelor 180 mg loading dose resulted in early improvement in platelet inhibition compared with 90 mg, among patients receiving clopidogrel; this effect was abrogated by 72 hours.
      • Caiazzo G.
      • De Rosa S.
      • Torella D.
      • et al.
      Administration of a loading dose has no additive effect on platelet aggregation during the switch from ongoing clopidogrel treatment to ticagrelor in patients with acute coronary syndrome.
      • Lhermusier T.
      • Voisin S.
      • Murat G.
      • et al.
      Switching patients from clopidogrel to novel P2Y12 receptor inhibitors in acute coronary syndrome: comparative effects of prasugrel and ticagrelor on platelet reactivity.
      No increase in bleeding was observed using the loading dose of 180 mg.
      • 16.
        For patients requiring a switch from clopidogrel to ticagrelor, we recommend a ticagrelor loading dose of 180 mg followed by 90 mg BID, regardless of the timing of the last clopidogrel dose (Strong Recommendation; Moderate-Quality Evidence).

      2.1.2 Switching from clopidogrel to prasugrel

      In Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON), pretreatment with clopidogrel before randomization led to exclusion.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      Consequently, clinical data from a large trial is lacking for a switch from clopidogrel to prasugrel. Accordingly, decision-making must be on the basis of smaller pharmacodynamic studies consisting of > 3000 patients (Supplemental Fig. S1).
      • Loh J.P.
      • Pendyala L.K.
      • Kitabata H.
      • et al.
      Safety of reloading prasugrel in addition to clopidogrel loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
      • Angiolillo D.J.
      • Saucedo J.F.
      • Deraad R.
      • et al.
      Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study.
      • Payne C.D.
      • Li Y.G.
      • Brandt J.T.
      • et al.
      Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects.
      • Diodati J.G.
      • Saucedo J.F.
      • French J.K.
      • et al.
      Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial.
      • Lhermusier T.
      • Lipinski M.J.
      • Drenning D.
      • et al.
      Switching patients from clopidogrel to prasugrel in acute coronary syndrome: impact of the clopidogrel loading dose on platelet reactivity.
      • Raber L.
      • Klingenberg R.
      • Heg D.
      • et al.
      Safety of prasugrel loading doses in patients pre-loaded with clopidogrel in the setting of primary percutaneous coronary intervention: results of a nonrandomized observational study.
      Two randomized studies, Switching Anti Platelet Study (SWAP; n = 139) and Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET; n = 282), evaluated the effects of a loading dose of prasugrel.
      • Angiolillo D.J.
      • Saucedo J.F.
      • Deraad R.
      • et al.
      Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study.
      • Diodati J.G.
      • Saucedo J.F.
      • French J.K.
      • et al.
      Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial.
      The 60-mg loading dose provided a significant increase in platelet inhibition by 2 hours compared with the 10-mg maintenance dose alone. No increase in bleeding outcomes was observed.
      • 17.
        For patients requiring a switch from clopidogrel to prasugrel, we recommend a prasugrel loading dose of 60 mg followed by 10 mg daily, regardless of the timing of the last clopidogrel dose (Strong Recommendation; Moderate-Quality Evidence).

      2.2 Switching between prasugrel and ticagrelor

      Switching to another potent P2Y12 receptor inhibitor rather than de-escalation to clopidogrel would be preferred for patients deemed at higher risk for ischemic events (Supplemental Fig. S2).

      2.2.1 Switching from prasugrel to ticagrelor

      SWAP-3 was the only randomized study to evaluate the switch from prasugrel to ticagrelor.
      • Franchi F.
      • Faz G.T.
      • Rollini F.
      • et al.
      Pharmacodynamic effects of switching from prasugrel to ticagrelor: results of the prospective, randomized SWAP-3 study.
      In 82 ACS patients initially treated with prasugrel, a loading dose of 180 mg of ticagrelor followed by 90 mg BID vs direct initiation of a 90-mg BID dose was compared with a control arm of patients who continued to receive prasugrel. Both switching groups, irrespective of the use of the 180-mg loading dose, showed an early, but transient greater platelet inhibition present by 2 hours and maintained up to 48 hours. At 1 week, both arms were noninferior compared with patients maintained with prasugrel. There was no major or minor bleeding observed in either switching strategy.
      • 18.
        For patients requiring a switch from prasugrel to ticagrelor, we suggest ticagrelor 90 mg BID, without a loading dose, to be initiated at the time of the next scheduled prasugrel dose (Weak Recommendation; Very Low-Quality Evidence).

      2.2.2 Switching from ticagrelor to prasugrel

      The SWAP-2 study randomized 110 patients with stable CAD initially treated with ticagrelor to receive a 60-mg loading dose of prasugrel vs direct initiation of a 10-mg daily dose and compared with a control arm of patients maintained with ticagrelor.
      • Angiolillo D.J.
      • Curzen N.
      • Gurbel P.
      • et al.
      Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease: results of the SWAP-2 study (Switching Anti Platelet-2).
      In both switching strategies, a transient increase in platelet reactivity was observed in the first 48 hours, an effect that was diminished in patients receiving a 60-mg loading dose of prasugrel. By 7 days, the 2 strategies had comparable platelet inhibition, with no significant bleeding outcomes observed.
      • 19.
        For patients requiring a switch from ticagrelor to prasugrel, we suggest a prasugrel loading dose of 60 mg followed by 10 mg daily, to be initiated at the timing of the next scheduled ticagrelor dose (Weak Recommendation; Very Low-Quality Evidence).

      2.3 De-escalation strategies

      When de-escalating from ticagrelor or prasugrel to clopidogrel, it is important to consider the rationale for switching to balance bleeding vs thrombotic risks (Supplemental Fig. S3). In patients who have suffered major bleeding during treatment with potent P2Y12 inhibitors, there might concerns for further bleeding, which might outweigh ischemic risks and in this context discontinuation might be considered. For patients with high-risk features (Table 1), de-escalation to clopidogrel should be considered to complete the recommended duration of DAPT.
      • 20.
        For patients receiving ticagrelor or prasugrel who experience a clinically significant bleeding complication that has resolved, we suggest de-escalating to clopidogrel 75 mg daily (Weak Recommendation; Very Low-Quality Evidence).
      Patients may be switched because of side effects with prasugrel or ticagrelor treatment, in which case thrombotic risks might override concerns of bleeding. In the absence of features associated with high risk for thrombotic events (Table 1), de-escalation to clopidogrel can also be considered (in lieu of switching between potent agents in high-risk patients). Among prasugrel- or ticagrelor-treated patients, who subsequently develop a new indication for requiring concurrent treatment with an oral anticoagulant, de-escalation to clopidogrel should also be considered (refer to Section 3).

      2.3.1 Switching from ticagrelor to clopidogrel

      The Optimizing Crossover from Ticagrelor to Clopidogrel in Patients with Acute Coronary Syndrome (OPTI-CROSS) study evaluated strategies for switching from ticagrelor to clopidogrel.
      • Pourdjabbar A.
      • Hibbert B.
      • Chong A.Y.
      • et al.
      A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL OPTI-CROSS Study.
      Sixty patients were randomized to receive either a 600 mg loading dose followed by 75 mg daily vs directly starting 75 mg daily. At 48 hours after randomization, a loading dose provided improved platelet inhibition compared with the maintenance dose alone; however, this difference was no longer present by 72 hours, thus suggesting an early protective effect with loading.
      • 21.
        For patients receiving ticagrelor who are experiencing significant side effects (excluding bleeding) or who are unable to tolerate the drug (and where prasugrel is not an option), we suggest de-escalating to clopidogrel with a loading dose of 600 mg followed by 75 mg daily, to be initiated at the time of the next scheduled ticagrelor dose (Weak Recommendation; Very Low-Quality Evidence).
      Practical tip. The loading dose of 600 mg conveys a short-term (48 hours) pharmacodynamic advantage after the switch to clopidogrel that might be relevant in the early post-ACS/PCI period. In patients who are stable, a loading dose of 300 mg or switching directly to 75 mg daily with no loading dose are also reasonable options, especially for patients believed to be at high risk for bleeding. Timing of Platelet Inhibition after Acute Coronary Syndrome (TOPIC) study, switching from ticagrelor directly to clopidogrel 75 mg daily 1 month after ACS
      • Cuisset T.
      • Deharo P.
      • Quilici J.
      • et al.
      Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
      was reported to decrease bleeding without an increase in ischemic events, with the caveat that the study was not powered for ischemic outcomes.
      • Cuisset T.
      • Deharo P.
      • Quilici J.
      • et al.
      Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
      Practical tip. The optimal time for the initiation of clopidogrel has not been extensively studied. In OPTI-CROSS, the switch was made at the next scheduled ticagrelor dose; extending to the following morning (ie, 24 hours after the last ticagrelor dose) might also be reasonable on the basis of pharmacodynamics data from the Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies (RESPOND) study.
      • Gurbel P.A.
      • Bliden K.P.
      • Butler K.
      • et al.
      Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.

      2.3.2 Switching from prasugrel to clopidogrel

      Switching from prasugrel to clopidogrel 75 mg daily, without additional loading, was evaluated in the TOPIC study (in patients without adverse events by 1 month after ACS) and in the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) trial (initiated 1 week after ACS and then guided on the basis of platelet function testing).
      • Cuisset T.
      • Deharo P.
      • Quilici J.
      • et al.
      Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
      • Sibbing D.
      • Aradi D.
      • Jacobshagen C.
      • et al.
      Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial.
      There was lower bleeding with no signal for increased ischemic outcomes in the de-escalation groups, but it should be noted that both trials were underpowered to assess ischemic end points.
      • 22.
        For patients receiving prasugrel who are experiencing significant side effects (excluding bleeding) or who are unable to tolerate the drug (and for whom ticagrelor is not an option), we suggest de-escalating to clopidogrel directly at 75 mg daily (without a loading dose) at the time of the next scheduled prasugrel dose (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. The suggested strategies are formulated on the basis of a systematic review of the literature evaluating pharmacodynamic evidence for optimal platelet inhibition, balanced with an absence of significant bleeding complications. Studies in which patients were identified as nonresponders using platelet function testing before randomization were excluded because of generalizability concerns.

      3. Patients With AF Who Undergo PCI

      Approximately 20% of patients with AF will require PCI at some time.
      • Kralev S.
      • Schneider K.
      • Lang S.
      • Suselbeck T.
      • Borggrefe M.
      Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography.
      Up to 21% of ACS patients will have new or established AF.
      • Schmitt J.
      • Duray G.
      • Gersh B.J.
      • Hohnloser S.H.
      Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications.
      In the absence of clear evidence for the optimal pharmacologic strategy to balance the risks of ischemic stroke and stent thrombosis, the use of “triple therapy” with 2 antiplatelet agents and an oral anticoagulant is commonly used. With PCI alone, DAPT is more effective than warfarin with ASA in reducing coronary events.
      • Mehta S.R.
      • Yusuf S.
      Clopidogrel in Unstable angina to prevent Recurrent Events Study Investigators
      The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.
      In ACS, DAPT reduces clinical events.
      • 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.
      • 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.
      • 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.
      • Chen Z.M.
      • Jiang L.X.
      • Chen Y.P.
      • et al.
      Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.
      In patients with nonvalvular AF, oral anticoagulation (OAC) with warfarin reduces the risk of stroke
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      and is more effective than DAPT in preventing thrombotic complications.
      • Connolly S.
      • Pogue J.
      • et al.
      ACTIVE Writing Group of the ACTIVE Investigators
      Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.
      Non-vitamin K-dependent oral anticoagulants (NOACs) are preferred to warfarin in AF because of their greater convenience and, with some agents, the lower risks of bleeding events and mortality.
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      • Verma A.
      • Cairns J.A.
      • Mitchell L.B.
      • et al.
      2014 Focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation.
      • Macle L.
      • Cairns J.
      • Leblanc K.
      • et al.
      2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation.
      Although the rationale for “triple therapy” seems reasonable, the risk of bleeding events is concerning. Analyses from the NOAC AF trials suggest a 30%-60% increased bleeding risk in patients receiving a NOAC plus an antiplatelet agent.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      • 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.
      • Xu H.
      • Ruff C.T.
      • Giugliano R.P.
      • et al.
      Concomitant use of single antiplatelet therapy with edoxaban or warfarin in patients with atrial fibrillation: analysis from the ENGAGE AF-TIMI48 trial.
      • Goodman S.G.
      • Wojdyla D.M.
      • Piccini J.P.
      • et al.
      Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).
      In a large Danish registry of AF patients, greater nonfatal and fatal bleeds were observed with the combination of warfarin with ASA. Warfarin with clopidogrel as well as triple therapy conferred more than a threefold higher risk of bleeding compared with warfarin alone.
      • Hansen M.L.
      • Sorensen 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.
      In a large meta-analysis (mostly observational studies), a combination of clopidogrel and OAC (a so-called “dual pathway”) reduced the risk of bleeding compared with triple therapy with no difference in major adverse cardiac events.
      • D’Ascenzo F.
      • Taha S.
      • Moretti C.
      • et al.
      Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention.
      The What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST) trial (n = 573) compared clopidogrel and warfarin (dual pathway) with ASA and clopidogrel with warfarin (triple therapy) in patients with a need for anticoagulation who underwent PCI.
      • Dewilde W.J.
      • Oirbans T.
      • Verheugt F.W.
      • 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.
      In this open-label trial, a reduction in bleeding (most of which was minor bleeding) was observed with the dual pathway approach. The trial was not powered for efficacy. The Intracoronary Stenting and Antithrombotic Regimen-Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting (ISAR-TRIPLE) trial (n = 614) randomized patients receiving OAC and PCI during concomitant warfarin and ASA treatment to either 6 weeks of clopidogrel (shorter triple therapy) or 6 months of clopidogrel (longer triple therapy). The trial showed no differences in bleeding or efficacy but was notably underpowered for these outcomes. In a post hoc landmark analysis after 6 weeks (with both arms of the study receiving triple therapy at 6 weeks), the 6-month group seemed to experience more major bleeding events.
      • 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.
      The An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial (n = 2124) evaluated 2 recent concepts in antithrombotic therapy: the use of a NOAC in place of warfarin and the dual pathway with elimination of ASA as an alternative to a traditional triple therapy regimen. In this open-label study of AF patients receiving PCI, patients were randomized to a P2Y12 inhibitor (94.4% received clopidogrel and only 4.3% ticagrelor and 1.3% prasugrel) with rivaroxaban 15 mg daily (dual pathway) for 12 months, DAPT with rivaroxaban 2.5 mg BID (reduced-dose triple therapy) for 1, 6, or 12 months, or DAPT with warfarin (traditional triple therapy) for 1, 6, or 12 months. The dual pathway as well as the reduced-dose triple therapy strategies reduced clinically significant bleeding compared with traditional triple therapy with warfarin. The main limitation of this trial was that it was not powered to detect moderate differences in efficacy, including stroke or stent thrombosis.
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      In a post hoc analysis, there was a reduction in the composite of all-cause death and rehospitalizations (CV hospitalizations as well as bleeding hospitalizations) with rivaroxaban-based strategies compared with traditional triple therapy with warfarin.
      • Gibson C.M.
      • Pinto D.S.
      • Chi G.
      • et al.
      Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy.
      The Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI)
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      trial (n = 2725) evaluated 2 doses of dabigatran in patients with AF who underwent PCI. Patients were randomized to dual pathway with dabigatran (110 mg or 150 mg BID) with a P2Y12 inhibitor (88% received clopidogrel and 12% received ticagrelor) vs traditional triple therapy with warfarin with a P2Y12 inhibitor (clopidogrel or ticagrelor) and ASA. Both dual pathway approaches reduced clinically significant bleeding compared with warfarin triple therapy and was noninferior with respect to risk of thromboembolic events—recognizing this study was also underpowered to detect differences in these events. The trials that evaluated a dual pathway regimen are summarized in Supplemental Table S2. Ongoing studies include AUGUSTUS (NCT02415400), which is evaluating apixaban, and EdoxabanTreatment Versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI) (NCT02866175), which is evaluating edoxaban.
      • 23.
        We recommend that patients who have concomitant AF and symptomatic CAD receive a regimen of antithrombotic therapy based on a balanced assessment of their risk of: (1) ischemic stroke; (2) future coronary event(s); and (3) clinically significant bleeding associated with the use of antithrombotic agents (Strong Recommendation; High-Quality Evidence).
      In patients with AF without high-risk features who undergo elective PCI we make the following recommendation (Fig. 3).
      In patients with AF undergoing elective PCI without high-risk features:
      • 24.
        If age is < 65 years and Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) = 0, we recommend DAPT alone with ASA 81 mg daily with clopidogrel 75 mg daily for 6 months (and up to 1 year; Strong Recommendation; High-Quality Evidence).
      Values and preferences. The risk of stroke varies from approximately 0.7% per year in patients younger than 65 years of age and CHADS2 score of 0, to approximately 2.1% per year in patients 65-74 years of age. The risk of stent thrombosis is greatest in the first month after PCI and declines thereafter. In patients with AF at lower risk of stroke, this recommendation gives greater weight to the prevention of future coronary events and less major bleeding with DAPT than with OAC, and less weight to the greater risk of stroke with DAPT than with OAC.
      Figure thumbnail gr3
      Figure 3Recommendations for patients with AF without high-risk features who undergo elective PCI. ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, acetylsalicylic acid; BID, twice daily; BMS, bare-metal stent; CCS, Canadian Cardiovascular Society; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; DES, drug-eluting stent; INR, international normalized ratio; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.
      Practical tip. In patients who are at high risk of bleeding, the duration of DAPT should be shortened to a minimum of 1 month (if a BMS was used) or 3 months (if a DES was used) as per recommendation 5.
      In patients with AF who undergo elective PCI without high-risk features, we make the following recommendation (Fig. 3).
      In patients with AF undergoing elective PCI without high-risk features:
      • 25.
        If age ≥ 65 years or CHADS2 ≥ 1, we suggest OAC plus clopidogrel 75 mg daily for at least 1 month (and up to 12 months) after BMS implantation and for at least 3 months (and up to 12 months) after DES implantation (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. The risk of stroke is increased to 2.1% per year in 65- to 74-year-old patients and even higher in patients older than 75 years, providing a rationale for the inclusion of OAC in the regimen. The suggestion for OAC and clopidogrel (and omission of ASA) is on the basis of randomized trials that showed a lower risk of bleeding with this regimen vs warfarin with clopidogrel and ASA (traditional triple therapy). Although the evidence suggests a major compromise in efficacy is unlikely by omitting ASA, it is acknowledged that none of the randomized trials were individually powered to detect moderate differences in thrombotic events. Doses of OAC evaluated in randomized trials of patients with AF who undergo PCI are shown in Table 4. Rivaroxaban 15 mg daily (10 mg daily in patients with renal dysfunction) with clopidogrel and dabigatran 110 or 150 mg BID and clopidogrel have been evaluated in randomized trials vs traditional warfarin-based triple therapy. At the time this document was written, randomized trials evaluating apixaban- and edoxaban-based regimens in patients with AF who undergo PCI were in progress, so no dose recommendations with these agents are provided.
      Table 4Dual pathway and triple therapy regimens evaluated in clinical trials
      Dual pathway
       1. Rivaroxaban 15 mg OD with clopidogrel 75 mg OD
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
       2. Dabigatran 110
      In the RE-DUAL PCI trial, the 110 mg BID dabigatran dose was associated with a trend to a higher risk of death or thrombotic events (11% vs 8.5%; hazard ratio, 1.30; 95% confidence interval, 0.98-1.73; P = 0.07). This risk was not observed with the 150 mg BID dose (7.9% vs 7.9%; hazard ratio, 0.97; 95% confidence interval, 0.68-1.39; P = 0.44). Therefore, in patients who are not at high risk of bleeding, the dabigatran 150 mg BID dose, when used in combination with clopidogrel 75 mg daily (ASA omitted), might be preferable.
      or 150 mg BID with clopidogrel 75 mg OD
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
       3. Warfarin with clopidogrel 75 mg OD
      • Dewilde W.J.
      • Oirbans T.
      • Verheugt F.W.
      • 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.
      Triple therapy
       1. Rivaroxaban 2.5 mg BID with ASA 81 mg OD and clopidogrel 75 mg OD
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
       2. Warfarin (INR, 2.0-2.5) with ASA 81 mg OD and clopidogrel 75 mg OD
      • 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.
      ASA, acetylsalicylic acid; BID, twice daily; INR, international normalized ratio; OD, every day.
      In the RE-DUAL PCI trial, the 110 mg BID dabigatran dose was associated with a trend to a higher risk of death or thrombotic events (11% vs 8.5%; hazard ratio, 1.30; 95% confidence interval, 0.98-1.73; P = 0.07). This risk was not observed with the 150 mg BID dose (7.9% vs 7.9%; hazard ratio, 0.97; 95% confidence interval, 0.68-1.39; P = 0.44). Therefore, in patients who are not at high risk of bleeding, the dabigatran 150 mg BID dose, when used in combination with clopidogrel 75 mg daily (ASA omitted), might be preferable.
      After the initial period of antithrombotic therapy, we make the following recommendations for patients with AF who undergo elective PCI without high-risk features (Fig. 3).
      Following the initial period of antithrombotic therapy for patients with AF undergoing elective PCI without high-risk features:
      • 26.
        If age is < 65 and CHADS2 = 0, we recommend long-term therapy with either ASA alone or, if high-risk clinical or angiographic features of ischemic events develop and low risk of bleeding, ASA plus a P2Y12 inhibitor (Strong Recommendation, High Quality Evidence); or
      After the initial period of antithrombotic therapy for patients with AF without high-risk features who undergo elective PCI, if age is 65 years or older or CHADS2 ≥ 1 we recommend long-term therapy with either OAC alone (Strong Recommendation; High-Quality Evidence) or, if high-risk clinical or angiographic features for ischemic events develop and low risk of bleeding, OAC and single antiplatelet therapy with aspirin or a P2Y12 inhibitor (Weak Recommendation; Low-Quality Evidence).
      Practical tip. All patients should receive ASA 81 mg (or a minimum of 160 mg if ASA-naive) on the day of the PCI procedure.
      In patients with AF who undergo PCI for ACS or elective PCI with high risk features (Fig. 4) we make the following recommendation.
      In patients with AF undergoing PCI for ACS or high-risk elective PCI:
      • 27.
        If age < 65 years and CHADS2 = 0, we recommend DAPT alone with ASA 81 mg daily plus a P2Y12 inhibitor (ticagrelor or prasugrel recommended for patients with ACS and clopidogrel recommended for patients who undergo elective PCI) for up to 12 months (Strong Recommendation; High-Quality Evidence).
      Values and preferences. Patients with AF who are younger than 65 years and CHADS2 = 0 who undergo PCI require DAPT to reduce thrombotic coronary events. OAC is not recommended in these patients with low risk of stroke.
      Practical tip. The duration of treatment with DAPT in patients with ACS (or those who undergo high-risk PCI) who also have AF with a low risk of stroke should depend on a balanced assessment of the risk of coronary thrombotic events (Table 1) and bleeding (Table 2). Patients at lower risk of coronary thrombotic events and higher risk of bleeding can be considered for shorter-duration DAPT and patients at higher risk of coronary thrombotic events and lower risk of bleeding should be considered for longer duration of DAPT.
      In patients with AF undergoing PCI for ACS or high-risk elective PCI:
      • 28.
        If age ≥ 65 years or CHADS2 ≥ 1∗, we recommend an initial regimen of triple therapy with ASA 81 mg daily plus clopidogrel 75 mg daily plus reduced intensity/dose OAC. ASA may be discontinued as early as the day following PCI or it can be continued for up to 6 months of treatment, depending on the risk of recurrent coronary thrombotic events versus major bleeding (Strong Recommendation, Moderate Quality Evidence). Following ASA discontinuation, we suggest that OAC plus clopidogrel 75 mg daily be continued for up to 12 months after the initial PCI (Weak Recommendation, Moderate Evidence).
        If CHADS2 = 1 and Age < 65 another option for initial treatment (especially if high-risk for ischemic events) is DAPT alone using ASA + ticagrelor or prasugrel, similar to the recommendation for the CHADS2 = 0 patient.
      Values and preferences. In patients 65-74 years of age, the risk of stroke is approximately 2.1% per year and still higher beyond age 75 years, whereas the risk of coronary events is approximately 6%-10% per year after ACS (STEMI or non-STEMI), providing a rationale for the inclusion of OAC in the post-PCI antithrombotic regimen. Because the risk of bleeding is higher with triple therapy, a reduced intensity/dose of OAC is suggested when it is used in this context. The duration of triple therapy will vary depending on an individual patient's risk of ischemic (Table 1) vs bleeding events (Table 2). In patients with a low risk of thrombotic events and a high risk of bleeding, the duration of triple therapy can be short, with omission of ASA as early as the day after PCI. In patients with a very high risk of thrombotic events and low bleeding risk, ASA could be continued longer, for up to 6 months of treatment. For patients at intermediate risk of ischemic and bleeding events the duration of aspirin will be somewhere in between (for example 1 month or 3 months).
      Practical tip. All patients should receive ASA 81 mg (or 160 mg if ASA-naive) on the day of the PCI procedure. Thereafter, ASA can be discontinued as early as the day after PCI.
      Practical tip. Factors associated with an increased risk of ischemic and bleeding events are shown in Tables 1 and 2.
      Practical tip. When combining OAC with antiplatelet therapy, consider reducing the dose of OAC (or intensity of warfarin), with possible omission of ASA the day after PCI, because of the higher risk of bleeding in this context.
      OAC regimens evaluated in the context of a triple therapy regimen include (Table 4):
      • Rivaroxaban 2.5 mg BID with ASA and clopidogrel
      • Warfarin (the recommended international normalized ratio target is 2.0-2.5)
      The OAC regimens that have been evaluated in the context of a dual pathway regimen include (Table 4):
      • Rivaroxaban 15 mg daily (10 mg in patients with renal dysfunction) and clopidogrel 75 mg daily
      • Dabigatran 110 mg or 150 mg BID and clopidogrel 75 mg daily. Note that in the RE-DUAL PCI trial, which evaluated dabigatran in patients with AF who underwent PCI, the dabigatran 110 mg BID was associated with a trend to a higher risk of death or thrombotic events (11% vs 8.5%; HR, 1.30, 95% CI, 0.98-1.73; P = 0.07). This risk was not observed with the dabigatran 150 mg BID dose (7.9% vs 7.9%; HR, 0.97; 95% CI, 0.68-1.39; P = 0.44). Therefore, in patients who are not at high risk of bleeding, the dabigatran 150 mg BID dose, when used in combination with clopidogrel 75 mg daily (ASA omitted), might be preferable
      • Trials evaluating apixaban and edoxaban in patients with AF who undergo PCI are ongoing
      Practical tip. Consider using a proton pump inhibitor for protection against gastrointestinal bleeding while patients are receiving a triple therapy regimen.
      Practical tip. When a P2Y12 inhibitor is to be combined with OAC as part of a dual pathway or triple therapy regimen, then clopidogrel is suggested over ticagrelor or prasugrel because of its lower risk of bleeding complications and the lack of data on ticagrelor or prasugrel in combination with OAC.
      Practical tip. Several risk scores have been formulated to quantitate ischemic risk (Table 3). Although none of these scores have been validated in a population of patients with AF who undergo PCI, they might still be helpful to the clinician in estimating risk.
      After the initial period of antithrombotic therapy for patients with AF with high-risk features who undergo PCI for ACS or high-risk elective PCI the following recommendations are made (Fig. 4):
      Following the initial period of antithrombotic therapy for patients with AF undergoing PCI for ACS or high-risk elective PCI:
      • 29.
        If age < 65 years and CHADS2 = 0, we recommend long-term therapy with either ASA alone or, if high-risk clinical or angiographic features of ischemic events and low risk of bleeding, ASA with P2Y12 inhibitor (Strong Recommendation; High-Quality Evidence); or
      If age is 65 years or older or CHADS2 ≥ 1 we recommend long-term therapy with either OAC alone (Strong Recommendation; Moderate- and High-Quality Evidence) or, if high-risk clinical or angiographic features of ischemic events persist and low risk of bleeding, OAC with single antiplatelet therapy with ASA or a P2Y12 inhibitor (Weak Recommendation; Low-Quality Evidence).
      Figure thumbnail gr4
      Figure 4Recommendations for patients with AF who undergo PCI for ACS or high-risk elective PCI. ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, acetylsalicylic acid; BID, twice daily; CCS, Canadian Cardiovascular Society; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; DAPT, dual antiplatelet therapy; INR, international normalized ratio; OAC, oral anticoagulant; PCI, percutaneous coronary intervention.
      Practical tip. The COMPASS trial
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      showed that, in patients with stable CAD or peripheral arterial disease who did not have AF, ASA used in addition to very low dose OAC (rivaroxaban 2.5 mg BID) reduced major CV events. It is important to note that rivaroxaban 2.5 mg BID has not been evaluated for long-term stroke prevention in patients with AF. The standard stroke prevention dose of rivaroxaban in patients with AF is 15 mg or 20 mg daily. Consideration could be given to extending treatment long-term with OAC (at a standard AF stroke prevention dose) and single antiplatelet therapy (clopidogrel or ASA) in selected patients at low risk of bleeding who have high-risk clinical or angiographic features for ischemic events.

      4. Other Reasons for Anticoagulation

      • 30.
        We recommend that patients who have concomitant symptomatic CAD and another condition requiring OAC receive a regimen of antithrombotic therapy that is based on a balanced assessment of their risk of: (1) systemic embolism; (2) future coronary event(s); and (3) clinically significant bleeding associated with the use of antithrombotic agents (Strong Recommendation; High-Quality Evidence).

      4.1 Prosthetic heart valves

      Anticoagulation with vitamin K antagonist (VKA) and/or antiplatelet therapy is indicated to prevent thrombotic complications of a surgically implanted prosthetic heart valve (PHV). A careful assessment of the potential risks of valve thrombosis and systemic bleeding is required when considering a given antithrombotic regimen. As such the optimal combination of agents, duration of antithrombotic therapy, and optimal therapeutic international normalized ratio levels all differ for specific types of valves and are influenced by valvular as well as patient-level characteristics.
      • Bourguignon T.
      • Bergoend E.
      • Mirza A.
      • et al.
      Risk factors for valve-related complications after mechanical heart valve replacement in 505 patients with long-term follow up.
      • Edmunds Jr., L.H.
      Thrombotic and bleeding complications of prosthetic heart valves.
      Studies of patients with mechanical
      • Eikelboom J.W.
      • Connolly S.J.
      • Brueckmann M.
      • et al.
      Dabigatran versus warfarin in patients with mechanical heart valves.
      • Lin S.S.
      • Tiong I.Y.
      • Asher C.R.
      • et al.
      Prediction of thrombus-related mechanical prosthetic valve dysfunction using transesophageal echocardiography.
      as well as bioprosthetic heart valves
      • Laplace G.
      • Lafitte S.
      • Labeque J.N.
      • et al.
      Clinical significance of early thrombosis after prosthetic mitral valve replacement: a postoperative monocentric study of 680 patients.
      • Sundt T.M.
      • Zehr K.J.
      • Dearani J.A.
      • et al.
      Is early anticoagulation with warfarin necessary after bioprosthetic aortic valve replacement?.
      have shown an increased risk of valve thrombosis early in the postoperative period, highlighting the importance of adequate antithrombotic regimens early after surgical valve replacement.
      Currently the combination of a VKA and low dose ASA (75-100 mg daily) is recommended for patients with a mechanical heart valve; a truncated dose of VKA followed by continuous use of low-dose ASA is recommended for patients with surgically implanted bioprosthetic valves, although it is reasonable to also consider use of antiplatelet therapy alone without OAC.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      NOACs are contraindicated among patients with mechanical PHVs.
      Approximately 10% of patients in WOEST (49 of 563) and approximately 7% of patients in ISAR-TRIPLE (45 of 614) had a PHV as their indication for OAC
      • Dewilde W.J.
      • Oirbans T.
      • Verheugt F.W.
      • 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.
      • 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.
      ; the subgroup of patients in WOEST with PHV appeared to derive a similar benefit from double therapy as opposed to traditional triple therapy compared with the main WOEST population (P for interaction = 0.116). Retrospective cohort studies that compared traditional triple therapy to double that have included patients with PHV have not reported separate events among PHV patients because of small numbers (2%-11% of total cohort population).
      • Gilard M.
      • Blanchard D.
      • Helft G.
      • et al.
      Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral antiCOagulants [STENTICO]).
      • Karjalainen P.P.
      • Porela P.
      • Ylitalo A.
      • et al.
      Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting.
      • Rubboli A.
      • Colletta M.
      • Valencia J.
      • et al.
      Periprocedural management and in-hospital outcome of patients with indication for oral anticoagulation undergoing coronary artery stenting.
      • Rubboli A.
      • Sciahbasi A.
      • Briguori C.
      • et al.
      In-hospital management and outcome of patients on warfarin undergoing coronary stent implantation: results of the multicenter, prospective WARfarin and coronary STENTing (WAR-STENT) registry.
      • Sambola A.
      • Ferreira-Gonzalez I.
      • Angel J.
      • et al.
      Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study.
      • Sarafoff N.
      • Martischnig A.
      • Wealer J.
      • et al.
      Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation.
      • Sarafoff N.
      • Ndrepepa G.
      • Mehilli J.
      • et al.
      Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation.
      • Uchida Y.
      • Mori F.
      • Ogawa H.
      • Takagi A.
      • Hagiwara N.
      Impact of anticoagulant therapy with dual antiplatelet therapy on prognosis after treatment with drug-eluting coronary stents.
      Randomized trials of TAVR compared with traditional surgical aortic valve replacement have used DAPT for at least 1 month postprocedure.
      • Adams D.H.
      • Popma J.J.
      • Reardon M.J.
      • et al.
      Transcatheter aortic-valve replacement with a self-expanding prosthesis.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      • Leon M.B.
      • Smith C.R.
      • Mack M.J.
      • et al.
      Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.
      However, these regimens have not been on the basis of randomized data and as such the use of DAPT after TAVR is given a relatively weak recommendation.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      In patients with a previous valve replacement who undergo PCI for an ACS or non-ACS indication the following recommendations are made.
      In patients with a previous valve replacement who undergo PCI for an ACS or non-ACS indication:
      • 31.
        For patients with a mechanical valve replacement, we suggest an initial regimen of ASA 81 mg daily plus clopidogrel 75 mg daily plus a VKA (triple therapy). ASA may be discontinued as early as the day after PCI or it can be continued up to 6 months of treatment, depending on the risk of recurrent thrombotic events vs major bleeding (Weak Recommendation; Very Low-Quality Evidence).
      • 32.
        For patients with a mechanical valve replacement, we recommend against the use of a NOAC regardless of whether it is in combination with antiplatelet therapy or used alone (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. After PCI, the uninterrupted use of a VKA (warfarin) is critical to minimize the risk of valve thrombosis in patients with a mechanical valve. A NOAC should not be used in this setting. The duration of triple therapy will vary depending on an individual patient's risk of thrombotic vs bleeding events. In patients with low risk of thrombotic events and high risk of bleeding, the duration of triple therapy can be short, with omission of ASA as early as the day after PCI. In patients with high risk of thrombotic events and low bleeding risk, the duration of triple therapy can be longer, for up to 6 months of treatment. Patients at intermediate risk of thrombotic and bleeding events the duration of triple therapy will be somewhere in between.
      Practical tip. In patients with a mechanical heart valve, warfarin is specifically indicated. Other OACs are not recommended.
      In patients with a previous valve replacement who undergo PCI for an ACS or non-ACS indication, note the following recommendations.
      • 33.
        For patients with a surgical bioprosthetic valve replacement, (implanted < 6 months), we suggest DAPT with ASA 81 mg daily and clopidogrel 75 mg daily for at least 6 months (and up to 12 months) (Weak Recommendation; Very Low-Quality Evidence).
      • 34.
        For patients with a TAVR (implanted < 6 months), we suggest DAPT with ASA 81 mg daily and clopidogrel 75 mg daily for 3-6 months (Weak Recommendation; Very Low-Quality Evidence).

      4.2 Venous thromboembolic disease

      Venous thromboembolic disease (VTE), comprising deep venous thrombosis and pulmonary embolism, carries a significant risk of short- and long-term mortality if left untreated.
      • Kearon C.
      Natural history of venous thromboembolism.
      In addition, up to 50% of untreated patients with symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) will have recurrent thrombosis within 3 months of the index event.
      • Hull R.
      • Delmore T.
      • Genton E.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      • Nielsen H.K.
      • Husted S.E.
      • Krusell L.R.
      • et al.
      Anticoagulant therapy in deep venous thrombosis. A randomized controlled study.
      Therefore, oral and parenteral anticoagulants are necessary to prevent as well as treat VTE.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.
      Although antiplatelet therapy is not indicated for the initial treatment of VTE, the extended use of ASA is given a weak recommendation for the prevention of recurrent VTE after the initial period of anticoagulant therapy.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.
      Approximately 7.5% of patients in the ISAR TRIPLE trial had VTE as their indication for OAC; no separate outcomes were reported for this subgroup of patients
      • 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.
      ; the WOEST trial did not report the numbers of enrolled patients who had VTE. Relatively few patients with VTE are described among retrospective cohort studies that compared traditional triple therapy with double therapy among patients who require OAC as well as DAPT.
      • Gilard M.
      • Blanchard D.
      • Helft G.
      • et al.
      Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral antiCOagulants [STENTICO]).
      • Karjalainen P.P.
      • Porela P.
      • Ylitalo A.
      • et al.
      Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting.
      • Rubboli A.
      • Colletta M.
      • Valencia J.
      • et al.
      Periprocedural management and in-hospital outcome of patients with indication for oral anticoagulation undergoing coronary artery stenting.
      • Rubboli A.
      • Sciahbasi A.
      • Briguori C.
      • et al.
      In-hospital management and outcome of patients on warfarin undergoing coronary stent implantation: results of the multicenter, prospective WARfarin and coronary STENTing (WAR-STENT) registry.
      • Sambola A.
      • Ferreira-Gonzalez I.
      • Angel J.
      • et al.
      Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study.
      • Sarafoff N.
      • Martischnig A.
      • Wealer J.
      • et al.
      Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation.
      • Sarafoff N.
      • Ndrepepa G.
      • Mehilli J.
      • et al.
      Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation.
      • Uchida Y.
      • Mori F.
      • Ogawa H.
      • Takagi A.
      • Hagiwara N.
      Impact of anticoagulant therapy with dual antiplatelet therapy on prognosis after treatment with drug-eluting coronary stents.
      The following recommendations are made for patients with venous thromboembolism who undergo PCI for an ACS or non-ACS indication (in selected patients who require extended VTE prophylaxis (ie, orthopaedic surgery or surgical oncology), the same recommendations can be followed as for VTE therapy. When VTE prophylaxis is discontinued, DAPT can be resumed if minimum duration has not been completed as per other clinical risk profile).
      In patients with venous thromboembolism undergoing PCI for an ACS or non-ACS indication:
      • 35.
        We suggest an initial regimen of ASA 81 mg daily plus clopidogrel 75 mg daily with either parenteral or OAC (in accordance with DVT/PE recommendations). ASA may be discontinued as early as the day after PCI or it can be continued up to 6 months of treatment, depending on the risk of recurrent ischemic events vs major bleeding. After ASA discontinuation, we suggest that OAC plus clopidogrel 75 mg daily be continued for up to 12 months after the initial PCI (Weak Recommendation; Very Low-Quality Evidence).
      • 36.
        For patients requiring an elective PCI, we recommend delaying PCI if appropriate until the completion of parenteral or OAC for VTE (Strong Recommendation; Very Low-Quality Evidence).
      Values and preferences. This recommendation places emphasis on optimizing the prevention and treatment of DVT and PE with either a parenteral or oral anticoagulant.

      4.3 LVT formation after MI

      LVT formation is a feared complication after acute STEMI, with the risk being highest in the first 3 months after an index event.
      • Delewi R.
      • Zijlstra F.
      • Piek J.J.
      Left ventricular thrombus formation after acute myocardial infarction.
      The risk of LVT formation has remained significant even in the era of primary PCI and DAPT,
      • Solheim S.
      • Seljeflot I.
      • Lunde K.
      • et al.
      Frequency of left ventricular thrombus in patients with anterior wall acute myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy.
      leading to a class IIa recommendation for anticoagulant therapy for STEMI patients with asymptomatic LVT and a class IIb recommendation for those with anterior/apical akinesis or dyskinesis.
      • 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.
      However, several studies have failed to show a clear benefit of routine anticoagulation in addition to DAPT after anterior STEMI. A substudy of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial showed no benefit of triple therapy among STEMI patients treated with primary PCI for the reduction short- or long-term ischemic outcomes but did show significant increases in major bleeding.
      • Nikolsky E.
      • Mehran R.
      • Dangas G.D.
      • et al.
      Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial).
      Udell et al. showed no benefit of warfarin use for up to 3 months among a cohort of elderly patients after acute MI, and furthermore showed no difference in the risk of stroke between patients who presented with an anterior MI compared with those with a nonanterior MI.
      • Udell J.A.
      • Wang J.T.
      • Gladstone D.J.
      • Tu J.V.
      Anticoagulation after anterior myocardial infarction and the risk of stroke.
      Le May et al. identified 460 patients with anterior STEMI who had undergone primary PCI and received DAPT with (n = 131) and without (n = 329) warfarin.
      • Le May M.R.
      • Acharya S.
      • Wells G.A.
      • et al.
      Prophylactic warfarin therapy after primary percutaneous coronary intervention for anterior ST-segment elevation myocardial infarction.
      Patients in the warfarin group had a higher rate of net adverse clinical events (all-cause mortality, stroke, reinfarction, and major bleeding) at 180 days compared with those in the no-warfarin group (14.7% vs 4.6%; P = 0.001). Use of warfarin therapy was an independent predictor of net adverse clinical events after propensity scoring analysis (odds ratio, 4.01; 95% CI, 2.15-7.5). Shavadia et al. recently reported similar results with no benefit for triple therapy in a series of consecutive STEMI patients with anterior LV dysfunction.
      • Shavadia J.S.
      • Youngson E.
      • Bainey K.R.
      • Bakal J.
      • Welsh R.C.
      Outcomes and prognostic impact of prophylactic oral anticoagulation in anterior ST-segment elevation myocardial infarction patients with left ventricular dysfunction.
      In patients with established LVT who undergo PCI for an ACS or non-ACS indication we make the following recommendation.
      In patients with established left ventricular thrombus who undergo PCI for an ACS or non-ACS indication:
      • 37.
        We suggest an initial regimen of triple therapy with ASA 81 mg daily with clopidogrel 75 mg daily plus OAC. ASA may be discontinued as early as the day after PCI or it can be continued up to 6 months of treatment, depending on the risk of recurrent coronary ischemic events vs major bleeding. After ASA discontinuation, we suggest treatment with OAC plus clopidogrel 75 mg daily for up to 1 year. If there is evidence of LV thrombus resolution ≥ 3 months after PCI, we suggest discontinuation of OAC and treatment with ASA 81 mg daily plus a P2Y12 inhibitor for up to 1 year after PCI (Weak Recommendation; Very Low-Quality Evidence).
      Practical tip. Warfarin is the only anticoagulant evaluated for the treatment of established LVT. Although NOACS are generally safer than warfarin, they have not been evaluated specifically in this context.
      We make the following recommendations for patients who undergo PCI for an ACS indication who are at high risk of developing LV thrombus.
      In patients who undergo PCI for an ACS indication who are at high risk of developing LV thrombus:
      • 38.
        We recommend DAPT with ASA 81 mg daily plus either ticagrelor 90 mg BID or prasugrel 10 mg once daily for up to 1 year (Strong Recommendation; Moderate-Quality Evidence).
      • 39.
        We suggest routine use of triple therapy should be avoided because of the weak evidence for prevention of LV thrombus and higher risk of bleeding events (Weak Recommendation; Moderate-Quality Evidence).

      Acknowledgements

      The primary panel is indebted to Ms Christianna Brooks of the CCS for her hard work and dedication in coordinating this guideline committee.

      Appendix

      Members of the Secondary Panel that contributed to this work are as follows:
      Paul W. Armstrong, MD, Canadian VIGOUR Centre, Department of Medicine (Cardiology), University of Alberta, Edmonton, Alberta, Canada; Akshay Bagai, MD, MHS, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Claudia Bucci, PharmD, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; Jean-Pierre Déry, MD, Quebec Heart and Lung Institute, Quebec, Canada; Jean G. Diodati, MD, Hopital du Sacré-Coeur Montréal, Université de Montréal, Montréal, Québec, Canada; Jocelyn Dupuis, MD, PhD, Université de Montréal, Institut de Cardiologie de Montréal, Montréal, Québec, Canada; David Fitchett, MD, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Michael P. Love, MB, ChB, MRCP, MD, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada; and Robert Welsh, MD, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

      Supplementary Material

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