Advertisement
Canadian Journal of Cardiology

Focused 2012 Update of the Canadian Cardiovascular Society Guidelines for the Use of Antiplatelet Therapy

Published:August 26, 2013DOI:https://doi.org/10.1016/j.cjca.2013.07.001

      Abstract

      The initial 2010 Canadian Cardiovascular Society (CCS) Guidelines for the Use of Antiplatelet Therapy in the Outpatient Setting were published in May 2011. As part of a planned re-evaluation within 2 years, we conducted an extensive literature search encompassing all topics included in the 2010 CCS Guidelines, and concluded that there were sufficient new data to merit revisiting the guidance on antiplatelet therapy for secondary prevention in the first year after acute coronary syndrome (ACS), percutaneous coronary intervention, or coronary artery bypass grafting, and the interaction between clopidogrel and proton pump inhibitors. In addition, new clinical trials information about the efficacy and safety of combining novel oral anticoagulants with antiplatelet therapy in ACS justified the addition of a new section of recommendations to the Guidelines. In this focused update, we provide recommendations for the use of clopidogrel, ticagrelor, and prasugrel in non-ST elevation ACS, avoidance of prasugrel in patients with previous stroke/transient ischemic attack, higher doses of clopidogrel (j) /day) for the first 6 days after ACS, and the preferential use of prasugrel or ticagrelor after percutaneous coronary intervention in ACS. For non-ACS stented patients, we recommend acetylsalicylic acid/clopidogrel for 1 year, with at least 1 month of therapy for bare-metal stent patients and 3 months for drug-eluting stent patients unable to tolerate year-long double therapy. We also consider therapy for patients with a history of stent thrombosis, the indications for longer-term treatment, discontinuation timing preoperatively, indications for changing agents, the management of antiplatelet therapy before and after bypass surgery, and use/selection of proton pump inhibitors along with antiplatelet agents.

      Résumé

      Les Lignes directrices de la Société canadienne de cardiologie (SCC) 2010 pour le traitement antiplaquettaire en milieu extrahospitalier furent publiées en mai 2011. Avec une réévaluation planifiée en dedans de 2 ans, nous avons effectué une recherche exhaustive de la littérature couvrant tous les sujets inclus dans les lignes directrices de la SCC 2010 et conclu qu’il y avait suffisamment de nouvelles données probantes publiées qui justifiaient une mise à jour ciblée des lignes directrices pour l'utilisation des thérapies antiplaquettaires pour la prévention secondaire durant la première année après un syndrome coronarien aigu (SCA), une intervention coronarienne percutanée, ou une revascularisation chirurgicale par pontages et les interactions entre le clopidogrel et les inhibiteurs de la pompe à protons (IPP). De plus, le comité a estimé que la publication d’essais cliniques pivots évaluant l’efficacité et la sécurité d’ajouter un nouvel anticoagulant oral à la thérapie antiplaquettaire chez un patient avec SCA exigeait l’addition d’une nouvelle section de recommandations pour ces lignes directrices. Dans cette mise à jour ciblée, nous présentons des recommandations pour l'utilisation du clopidogrel, du ticagrelor et du prasugrel pour les SCA sans élévation du segment ST, d’éviter le prasugrel chez les patients avec antécédents d'accident vasculaire cérébral/ischémie cérébrale transitoire, de doses plus élevées de clopidogrel (150 mg/jour) pour les premiers 6 jours post-SCA, et l'utilisation préférentielle du prasugrel ou du ticagrelor après l’angioplastie lors d'un SCA. Pour les patients stables, nous recommandons acide acétylsalicylique/clopidogrel pour 1 an, avec un minimum d'un mois post-tuteur non médicamenté et 3 mois après tuteur médicamenté chez les patients ne pouvant tolérer la thérapie anti-plaquettaire double pour une année complète. Nous avons considéré le traitement des patients avec thrombose de tuteur, les indications pour le traitement à plus long terme, l'interruption en peri-opératoire, les indications pour changer d'agents, l'utilisation pré et post-pontages, et la sélection des patients pour thérapie concomitante avec les IPP.
      The initial Canadian Cardiovascular Society (CCS) Guidelines on the Use of Antiplatelet Therapy Writing Committee was committed to reconvene within 2 years to evaluate the need for updating the Guidelines.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      After an extensive literature search, this Committee recommended updating the following guidelines: antiplatelet therapy for secondary prevention in the first year after acute coronary syndrome (ACS); percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); and the interaction between clopidogrel and proton pump inhibitors (PPIs). There was additional guidance on the use of novel oral anticoagulants for secondary prevention after an ACS.
      The updated guideline was developed using the same methodology as the original guideline
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      but for this iteration, we adopted the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to evaluate evidence and determine the strength of recommendations.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • et al.
      Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      The primary panel assembled included family physicians, vascular medicine specialists, cardiologists, interventional cardiologists, pharmacists, and cardiovascular surgeons. To maintain continuity, some members of the 2010 panel were retained in the current panel. Additional panelists included individuals without significant conflicts of interest.

      Updated Evidence for Antiplatelet Therapy After ACS in Patients Treated With PCI, CABG, or Medical Therapy Alone

      Optimal acetylsalicylic acid dose after ACS

      An analysis of Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) provides insight into the optimal acetylsalicylic acid (ASA) dose after an ACS.
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      There did not appear to be additional benefit for high-dose ASA in either the ASA alone group (highest dose [≥ 200 mg daily] vs lowest dose [≤ 100 mg daily]) or the ASA plus clopidogrel group.
      • Peters R.J.
      • Mehta S.R.
      • Fox K.A.
      • et al.
      Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
      Conversely, major bleeding increased in a dose-dependent fashion in the ASA alone (1.9% low-dose, 2.8% medium-dose [>100 to < 200 mg daily], 3.7% high-dose) and ASA plus clopidogrel (3.0%, 3.4%, 4.9%, respectively) groups. Analysis of Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE) showed no additional benefit with high- vs low-dose ASA, but high-dose ASA increased bleeding risk. Net adverse clinical events (death, myocardial infarction [MI], stroke, and major bleeding) favoured low-dose ASA in PCI.
      • Jolly S.S.
      • Pogue J.
      • Haladyn K.
      • et al.
      Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study.
      Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Organization to Assess Strategies in Ischemic Syndromes 7 (CURRENT-OASIS 7) was the first large-scale randomized study to assess the optimal ASA dose in patients with ACS scheduled to undergo an early invasive strategy.
      • Mehta S.R.
      • Bassand J.P.
      • Chrolavicius S.
      • et al.
      Dose comparisons of clopidogrel in acute coronary syndromes.
      Overall, there was no significant difference between high-dose (300-325 mg/day) and low-dose (75-100 mg/day) ASA for the primary outcome of cardiovascular death, MI, or stroke at 30 days.
      • Mehta S.R.
      • Bassand J.P.
      • Chrolavicius S.
      • et al.
      Dose comparisons of clopidogrel in acute coronary syndromes.
      In the PCI population, there was no difference between high- and low-dose ASA for the primary outcome or stent thrombosis.
      • Mehta S.R.
      • Tanguay J.F.
      • Eikelboom J.W.
      • et al.
      Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      Major bleeding did not differ between high- and low-dose ASA. There was a nominally significant increase in minor bleeding (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.00-1.26; P = 0.043) and a small excess in major gastrointestinal bleeds (0.4% vs 0.2%; P = 0.039) with high-dose ASA. There were 6 intracranial bleeds in both ASA dose groups.
      Overall, both short-term (CURRENT-OASIS 7) and long-term (CURE) studies suggest that low-dose ASA (81 mg/day in Canada) is the optimal dose after an ACS.

      Platelet P2Y12 receptor antagonists

      Clopidogrel

      Since the initial CCS guidance,
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      limited data on clopidogrel safety and efficacy after ACS have been published. As summarized in the previous guidance, overall results of CURRENT-OASIS 7 showed no significant difference in the 30-day rate of cardiovascular death, MI, or stroke (primary outcome) between double-dose and standard-dose clopidogrel.
      • Mehta S.R.
      • Bassand J.P.
      • Chrolavicius S.
      • et al.
      Dose comparisons of clopidogrel in acute coronary syndromes.
      In the PCI population, a significant 14% relative risk reduction in the primary outcome was observed with the double-dose regimen (3.9% vs 4.5%; HR, 0.86; 95% CI, 0.74-0.99; P = 0.039).
      • Mehta S.R.
      • Tanguay J.F.
      • Eikelboom J.W.
      • et al.
      Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      There was also a 46% relative reduction in definite stent thrombosis (academic research consortium definition
      • Cutlip D.E.
      • Windecker S.
      • Mehran R.
      • et al.
      Clinical end points in coronary stent trials: a case for standardized definitions.
      ) with double-dose clopidogrel (0.7% vs 1.3%; adjusted HR, 0.54; 95% CI, 0.39-0.74). In the PCI population, double-dose clopidogrel increased trial-defined major bleeding (2.5% vs 2.0%; P = 0.01), but not Thrombosis in Myocardial Infarction (TIMI) major or fatal, intracranial, or CABG-related major bleeding.
      • Mehta S.R.
      • Tanguay J.F.
      • Eikelboom J.W.
      • et al.
      Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.

      Prasugrel

      The primary evidence supporting prasugrel in ACS remains the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38).
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      As summarized in the initial CCS guidance,
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      prasugrel significantly reduced the relative risk of the primary end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with clopidogrel; both prasugrel and clopidogrel were given with ASA after confirmation of coronary anatomy without pretreatment.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      Cardiovascular death did not significantly differ between groups. Prasugrel was associated with significant increases in TIMI-defined major, life-threatening, and fatal bleeding in the total population and increased intracranial bleeding in those with a history of cerebrovascular disease. In patients with ST-elevation MI (STEMI) and planned primary or secondary PCI, in whom the study drug could be initiated before angiography, prasugrel significantly reduced the primary end point without increasing risks of major, life-threatening, or fatal bleeding; this benefit with prasugrel was observed for primary and secondary PCI, although it was more pronounced for secondary PCI.
      • Montalescot G.
      • Wiviott S.D.
      • Braunwald E.
      • et al.
      Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial.
      Based on TRITON-TIMI 38, prasugrel is contraindicated in patients with a known history of transient ischemic attack (TIA) or stroke, and the product monograph includes a boxed warning that highlights the bleeding risks and recommends avoidance in patients aged 75 years or older or with body weight < 60 kg.
      • Eli Lilly Canada Inc
      Product monograph for Effient.
      A post hoc analysis of TRITON-TIMI 38 supports the regulatory product label, because net clinical benefit was maximized in patients aged younger than 75 years who weighed ≥ 60 kg without a history of stroke or TIA.
      • Wiviott S.D.
      • Desai N.
      • Murphy S.A.
      • et al.
      Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies.
      The recently completed Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) study of prasugrel vs clopidogrel in patients with non-ST–elevation ACS (NSTEACS) managed medically did not demonstrate added benefit for prasugrel and does not alter our recommendations.
      • Roe M.T.
      • Armstrong P.W.
      • Fox K.A.
      • et al.
      Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.
      However, patients aged 75 years and older or weighing < 60 kg received prasugrel 5 mg/day instead of 10 mg/day and experienced similar rates of bleeding as clopidogrel recipients. Emerging data will provide information on the efficacy and safety of prasugrel in patients pretreated before coronary angiography (A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients With Non-ST-Elevation Myocardial Infarction [ACCOAST] study
      • Montalescot G.
      • Bolognese L.
      • Dudek D.
      • et al.
      A comparison of prasugrel at the time of percutaneous coronary intervention or as pretreatment at the time of diagnosis in patients with non-ST-segment elevation myocardial infarction: design and rationale for the ACCOAST study.
      ), of high vs low body weight (A Pharmacokinetic and Pharmacodynamic Comparison of Prasugrel and Clopidogrel in Low Body Weight vs Higher Body Weight Aspirin-Treated Subjects With Stable Coronary Artery Disease [FEATHER]; NCT01107925), and pretreated with a clopidogrel loading dose (LD) (Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients [TRIPLET]; NCT01115738).

      Ticagrelor

      Ticagrelor is an oral, reversibly binding, direct-acting P2Y12 receptor antagonist. Compared with a 600-mg clopidogrel LD, a 180-mg ticagrelor LD achieves a more rapid, significantly greater antiplatelet effect.
      • Gurbel P.A.
      • Bliden K.P.
      • Butler K.
      • et al.
      Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
      When ticagrelor is discontinued, antiplatelet effect offset is faster than with clopidogrel. However, because ticagrelor achieves a much greater antiplatelet effect, platelet inhibition 24-48 hours after discontinuation of the last dose is similar in ticagrelor- and clopidogrel-treated patients.
      • Gurbel P.A.
      • Bliden K.P.
      • Butler K.
      • et al.
      Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
      As summarized in the initial CCS guidance,
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      Platelet Inhibition and Patient Outcomes (PLATO) compared the efficacy and safety of ticagrelor plus ASA with that of clopidogrel plus ASA, started before cardiac catheterization.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      Compared with clopidogrel, ticagrelor significantly reduced the primary end point of cardiovascular death, MI, or stroke at 12 months, and MI, cardiovascular mortality, and all-cause mortality risks; primary outcome results were similar in patients managed invasively and noninvasively.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      The ticagrelor benefit was not accompanied by an increase in major bleeding, although non–CABG-related bleeding was significantly increased. Data published since the original CCS guidance show that in the 7544 patients undergoing primary PCI for STEMI in PLATO, there was a consistent, but not statistically significant, reduction in the primary end point with ticagrelor (9.4% vs 10.8%; HR, 0.87; 95% CI, 0.75-1.01; P = 0.07) without increased major bleeding risk.
      • Steg P.G.
      • James S.
      • Harrington R.A.
      • et al.
      Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.
      Ticagrelor significantly reduced mortality (9.8% vs 11.3%; HR, 0.87; 95% CI, 0.75-1.00) and reinfarction (4.7% vs 5.8%; HR, 0.80; 95% CI, 0.65-0.98) but significantly increased stroke risk (1.7% vs 1.0%; HR, 1.63; 95% CI, 1.07-2.48). Mahaffey et al. demonstrated that a significant proportion of the regional interaction observed in PLATO was explained by the ASA dose alone and using ASA < 100 mg/day favoured the use of ticagrelor over clopidogrel (HR, 0.77; 95% CI, 0.69-0.86).
      • Mahaffey K.W.
      • Wojdyla D.M.
      • Carroll K.
      • et al.
      Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (PLATO) trial.
      In a more detailed analysis of dyspnoea and ventricular pauses in PLATO, ticagrelor was associated with an increased risk of mild-to-moderate and usually transient dyspnoea (13.8% vs 7.8%; HR, 1.84; 95% CI, 1.68-2.02).
      • Storey R.F.
      • Becker R.C.
      • Harrington R.A.
      • et al.
      Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes.
      Dyspnea rarely resulted in treatment discontinuation (0.9% vs 0.1%). Ventricular pauses ≥ 3 seconds were more common with ticagrelor than clopidogrel in the first week of treatment.
      • Storey R.F.
      • Becker R.C.
      • Harrington R.A.
      • et al.
      Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes.

      Updated Data for Antiplatelet Therapy for Secondary Prevention in the First Year After PCI

      Optimal duration of dual antiplatelet therapy after stent implantation

      The optimal dual antiplatelet therapy (DAPT) duration after drug-eluting stent (DES) placement remains controversial. A pooled analysis of randomized trials of patients free of major adverse cardiovascular events (MACEs) and major bleeding for ≥ 12 months after DES placement failed to show a significant benefit for an additional 12 months of DAPT with ASA and clopidogrel over ASA alone.
      • Park S.J.
      • Park D.W.
      • Kim Y.H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      In Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY), 2013 patients undergoing PCI (74% with ACS) were randomized to bare-metal, zotarolimus-eluting (ZES), everolimus-eluting, or paclitaxel-eluting stent implantation. Thirty days later 1970 of these patients underwent a second randomization to either 6 or 24 months of DAPT with ASA 80-160 mg/day and clopidogrel 75 mg/day. At 2 years, there was no significant difference in the risk of the primary end point (death, MI, or cerebrovascular accident) between those who received DAPT for 6 and 24 months or any of the secondary end points, including stent thrombosis, but a 2-fold greater risk of BleedScore type 5, 3, or 2 bleeding (HR, 2.17; 95% CI, 1.44-3.22).
      • Valgimigli M.
      • Campo G.
      • Monti M.
      • et al.
      Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
      A retrospective analysis of 7689 stent recipients in an administrative database (73% with ACS) demonstrated significantly higher bleeding rates but significantly lower MI rates among patients receiving vs not receiving DAPT from 0 to 6 months, 7 to 12 months, and 13 to 18 months after coronary intervention.
      • Tsai T.T.
      • Ho P.M.
      • Xu S.
      • et al.
      Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: insights from the HMO Research Network-Stent Registry (HMORN-stent).
      These findings underscore the need to carefully evaluate and balance ischemic risk reduction with the potential for increased bleeding.
      Newer generation DES might require a shorter DAPT duration, thus minimizing bleeding risk. In a large meta-analysis, the everolimus-eluting stent treatment effect was consistent in patients who received 6 and 12 months of DAPT.
      • Baber U.
      • Mehran R.
      • Sharma S.K.
      • et al.
      Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials.
      In another meta-analysis of 5 clinical trials of ZES recipients, risk-adjusted death, MI, and definite/probable stent thrombosis rates were not significantly different over 3 years between DAPT durations of 6 and ≥ 12 months and 6 and ≥ 24 months.
      • Kandzari D.E.
      • Barker C.S.
      • Leon M.B.
      • et al.
      Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents.
      Similarly, in a prospective, multicentre registry of 823 ZES recipients, DAPT discontinuation at 3 months did not increase the risk of cardiac death, MI, or stent thrombosis at 1 year
      • Hahn J.Y.
      • Song Y.B.
      • Choi J.H.
      • et al.
      Three-month dual antiplatelet therapy after implantation of zotarolimus-eluting stents: the DATE (Duration of Dual Antiplatelet Therapy AfterImplantation of Endeavor Stent) registry.
      ; this registry might have been underpowered because the primary end point rate was only 0.6%, reflecting a low-risk population. The DAPT study, a large, multicentre, randomized trial comparing the efficacy and safety of 1 vs 2 years of DAPT with ASA and either clopidogrel or prasugrel after successful DES placement (NCT00977938),
      • Mauri L.
      • Kereiakes D.J.
      • Normand S.L.
      • et al.
      Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions.
      is expected to provide more information on the optimal duration of DAPT.
      Overall, our recommendations for DAPT duration after stent implantation remain the same as in the initial guidance.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      For patients at increased risk for stent thrombosis or in whom stent thrombosis could be related to dire consequences, DAPT continuation beyond 1 year might be considered after accounting for the perceived bleeding risk, with the ideal duration remaining unknown.
      The following are changed recommendations for NSTEACS (Figs. 1 and 2).
      Recommendation
      • 1.
        We recommend ASA 81 mg daily indefinitely in all patients with NSTEACS (Strong Recommendation, High-Quality Evidence).
      • 2.
        We recommend ticagrelor 90 mg twice daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in patients with moderate to high risk NSTEACS (as defined in PLATO
        • Wallentin L.
        • Becker R.C.
        • Budaj A.
        • et al.
        Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
        : ≥2 or more of (1) ischemic ST changes on electrocardiogram; (2) positive biomarkers; or (3) 1 of the following: 60 years of age or greater, previous MI or CABG, CAD > 50% stenosis in 2 vessels, previous ischemic stroke, diabetes, peripheral arterial disease, or chronic renal dysfunction), managed with either PCI, CABG surgery, or medical therapy alone (Strong Recommendation, High-Quality Evidence).
      • 3.
        We recommend prasugrel 10 mg daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in P2Y12 inhibitor-naive patients with NSTEACS after their coronary anatomy has been defined and PCI planned (Strong Recommendation, High-Quality Evidence).
      • 4.
        We recommend avoiding prasugrel in patients with previous TIA or stroke or in patients who are not treated with PCI. Except in patients with a high probability of undergoing PCI, we recommend avoiding prasugrel before the coronary anatomy has been defined (Strong Recommendation, Moderate-Quality Evidence).
      • 5.
        We recommend clopidogrel 75 mg once daily for 12 months in addition to ASA 81 mg daily in patients with NSTEACS managed with either PCI, CABG, or medical therapy and who are not eligible for ticagrelor or prasugrel (Strong Recommendation, High-Quality Evidence).
      • 6.
        We recommend that in patients in whom clopidogrel is to be used, a higher maintenance dose of 150 mg daily be considered for the first 6 days in patients with NSTEACS treated with PCI (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations place greater emphasis on reduction of major cardiovascular events and stent thrombosis vs an increase in bleeding complications. They also take into account the clinical setting under which each of the antiplatelet drugs were evaluated and the more reliable bioavailability of prasugrel and ticagrelor compared with clopidogrel.
      Figure thumbnail gr1
      Figure 1Recommendations for non-ST–elevation acute coronary syndrome (NSTEACS) 1. ASA, acetylsalicylic acid; CABG, coronary artery bypass grafting; CAD, coronary artery disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes. * Moderate to high-risk NSTEACS as defined in PLATO
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      : ≥ 2 of: (1) ischemic ST changes on electrocardiogram; (2) positive biomarkers; and (3) 1 of the following: 60 years of age or greater, previous MI or CABG, CAD > 50% stenosis in 2 vessels, previous ischemic stroke, diabetes, peripheral arterial disease, or chronic renal dysfunction.
      Figure thumbnail gr2
      Figure 2Recommendations for non-ST–elevation acute coronary syndrome (NSTEACS) 2. ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention; TIA, transient ischemic attack. * Prasugrel should be avoided in patients with previous TIA or stroke. In patients aged 75 years and older, or body weight ≤ 60 kg, prasugrel should be used with caution and a 5-mg dose considered.
      Practical tip. In patients receiving DAPT, we suggest using ASA 81 mg daily.
      Ticagrelor can be used in patients managed with either PCI, CABG, or medical therapy alone, whereas prasugrel should be used only in patients undergoing PCI.
      In patients 75 years of age or older or weight ≤ 60 kg, when available, prasugrel 5 mg daily could be considered.
      The following are changed recommendations for STEMI (Fig. 3).
      Recommendation
      • 1.
        We recommend clopidogrel 75 mg daily for at least 1 month in addition to ASA 81 mg daily in patients with STEMI who were managed with either fibrinolytic therapy or no reperfusion therapy (Strong Recommendation, High-Quality Evidence). We suggest that clopidogrel can be continued for 12 months (Conditional Recommendation, Low-Quality Evidence).
      • 2.
        We recommend either prasugrel 10 mg daily or ticagrelor 90 mg twice daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily after primary PCI (Strong Recommendation, Moderate-Quality Evidence).
      • 3.
        We recommend clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily after primary PCI in patients who are not eligible for prasugrel or ticagrelor (Strong Recommendation, Moderate-Quality Evidence).
      • 4.
        We recommend that in patients in whom clopidogrel is to be used, a higher maintenance dose of 150 mg daily be considered for the first 6 days in patients with STEMI treated with PCI (Strong Recommendation, Moderate-Quality Evidence).
      • 5.
        We recommend avoiding prasugrel in patients with previous TIA or stroke and using a 5-mg dose if required in patients aged years or older or weight ≤ 60 kg (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. These recommendations place greater emphasis on reduction of major cardiovascular events and stent thrombosis vs an increase in bleeding complications. They also take into account the clinical setting under which each of the antiplatelet drugs were evaluated and the more reliable bioavailability of prasugrel and ticagrelor compared with clopidogrel.
      Figure thumbnail gr3
      Figure 3Recommendations for ST-elevation myocardial infarction (STEMI). ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention; TIA, transient ischemic attack. * Prasugrel should be avoided in patients with previous TIA or stroke. In patients aged 75 years and older, or body weight ≤ 60 kg, prasugrel should be used with caution and a 5-mg dose considered.
      The following are changed recommendations for PCI for a non-ACS indication.
      Recommendation
      • 1.
        We recommend that in patients receiving a bare-metal stent who are unable to tolerate clopidogrel for 12 months (eg, increased risk of bleeding or scheduled noncardiac surgery), the minimum duration of therapy should be 1 month (Strong Recommendation, High-Quality Evidence). We suggest in patients at very high risk of bleeding, the minimum duration of treatment may be 2 weeks (Conditional Recommendation, Low-Quality Evidence).
      • 2.
        We suggest that in patients receiving a second-generation DES who are unable to tolerate clopidogrel for 12 months (eg, increased risk of bleeding or scheduled noncardiac surgery), the minimum duration of therapy may be 3 months (Conditional Recommendation, Low-Quality Evidence).
      The following are general recommendations for ACS and PCI.
      Recommendation
      • 1.
        We recommend that for patients who are compliant with clopidogrel and have experienced stent thrombosis, prasugrel 10 mg daily or ticagrelor 90 mg twice daily may be considered in addition to ASA 81 mg daily (Strong Recommendation, Low-Quality Evidence).
      • 2.
        We suggest continuation of a P2Y12 inhibitor with ASA beyond 12 months be considered in patients with a high thrombosis risk and a low bleeding risk (Conditional Recommendation, Low-Quality Evidence).
      • 3.
        We suggest that if patients require surgery (CABG or non-CABG), the P2Y12 inhibitor be withheld, if possible, as follows: clopidogrel 5 days before, ticagrelor 5 days before, and prasugrel 7 days before to the date of surgery (Conditional Recommendation, Low-Quality Evidence).
      • 4.
        We suggest against switching the P2Y12 inhibitor initially selected at discharge unless there is a compelling clinical reason (eg, stent thrombosis, bleeding, or cardiovascular event) (Conditional Recommendation, Very Low-Quality Evidence).

      What Is the Optimal Antiplatelet Therapy Regimen After CABG?

      Considered the gold standard for preventing saphenous vein graft closure after CABG, ASA is generally continued indefinitely because of its benefit in preventing subsequent clinical events.
      • Chesebro J.H.
      • Clements I.P.
      • Fuster V.
      • et al.
      A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
      • Eagle K.A.
      • Guyton R.A.
      • Davidoff R.
      • et al.
      ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery).
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      However, there is no published evidence suggesting antiplatelet therapy improves arterial graft patency. As summarized in the initial CCS guidance,
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      low-dose ASA initiated 6 hours after surgery appears to maximize prevention of graft occlusion and minimize bleeding risk.
      • Fremes S.E.
      • Levinton C.
      • Naylor C.D.
      • Chen E.
      • Christakis G.T.
      • Goldman B.S.
      Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
      The initial CCS guidance highlighted conflicting evidence on the benefit of DAPT with ASA and clopidogrel on graft-related outcomes after CABG.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
      Observational evidence suggests DAPT might be beneficial in the first month after off-pump CABG but not beyond.
      • Gurbuz A.T.
      • Zia A.A.
      • Vuran A.C.
      • Cui H.
      • Aytac A.
      Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study.
      Results of direct comparisons showed that neither angiographic patency 1 and 12 months after surgery nor intravascular ultrasound-determined intimal hyperplasia differed in stable patients treated with clopidogrel vs DAPT, suggesting no benefit for adding ASA to clopidogrel after CABG.
      • Gao C.
      • Ren C.
      • Li D.
      • Li L.
      Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting.
      • Kulik A.
      • Le May M.R.
      • Voisine P.
      • et al.
      Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogel after surgery for coronary artery disease (CASCADE) trial.
      In another randomized trial, the addition of clopidogrel was superior for preventing graft failure (occlusion and string sign) in radial artery grafts.
      • Sun J.C.
      • Teoh K.H.
      • Lamy A.
      • et al.
      Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study.
      Regardless of its effect on graft-related outcomes, DAPT might reduce overall thrombotic complications in subsets of patients with ACS who undergo CABG.
      • Fitchett D.
      • Eikelboom J.
      • Fremes S.
      • et al.
      Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society.
      Data from the CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) randomized trials provide evidence on the benefits and risks of DAPT with ASA and clopidogrel in CABG.
      • 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.
      • Steinhubl S.R.
      • Berger P.B.
      • Mann 3rd, J.T.
      • et al.
      Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      More recent data provide evidence for DAPT with ASA and prasugrel or ticagrelor in patients with ACS who undergo CABG.
      • Wiviott S.D.
      • Desai N.
      • Murphy S.A.
      • et al.
      Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      • 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.
      • 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.
      In PLATO, 1899 patients underwent CABG.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      • Steinhubl S.R.
      • Berger P.B.
      • Mann 3rd, J.T.
      • et al.
      Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      Preoperatively, ticagrelor and clopidogrel were to be withheld for 1-3 days and 5 days, respectively. In a retrospective analysis, the 1261 patients who underwent CABG and received study treatment in the 7 days before surgery showed a relative risk reduction with ticagrelor similar to that observed in the overall patient population; total mortality was reduced from 9.7% with clopidogrel to 4.7% with ticagrelor (HR, 0.49; 95% CI, 0.32-0.77), cardiovascular death from 7.9% to 4.1% (HR, 0.52; 95% CI, 0.32-0.85), and noncardiovascular death from 2.0% to 0.7%.
      • 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.
      There was no significant difference in CABG-related major bleeding between the treatment arms. Of note, 70% of ticagrelor recipients stopped therapy 3-7 days before surgery, suggesting that the protocol recommendation to stop ticagrelor 1-3 days before surgery was upheld in only a minority of patients. Approximately 2/3 of patients restarted antiplatelet therapy after CABG, of which approximately half restarted within the first 14 days after CABG. In the 422 patients who required CABG after randomization in TRITON-TIMI 38, prasugrel significantly reduced all-cause mortality (2.31% vs 8.67% with clopidogrel; adjusted odds ratio, 0.26; P = 0.025) and increased 12-hour chest tube blood loss (655 ± 580 mL vs 503 ± 378 mL; P = 0.050) without significantly increasing red blood cell transfusion.
      • 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.
      Because of the greater potency of these newer antiplatelet therapies, cardiac surgeons must balance bleeding and efficacy in determining the timing of CABG after ACS. In stable patients with non-life-threatening coronary anatomy, therapy should ideally be withheld for 5 days for clopidogrel or ticagrelor and 7 days for prasugrel. In unstable and emergent patients, surgeons must weigh the potential risk of excess bleeding. Although there is no clear recommendation in the literature, bridging with a glycoprotein IIb/IIIa inhibitor in the 5-7 days before surgery or transfusing platelets at the time of surgery might be considered.
      • Fitchett D.
      • Eikelboom J.
      • Fremes S.
      • et al.
      Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society.
      Considering data suggesting that the rate of stent thrombosis could be as high as 20% in patients undergoing CABG shortly after PCI,
      • Kaluza G.L.
      • Joseph J.
      • Lee J.R.
      • Raizner M.E.
      • Raizner A.E.
      Catastrophic outcomes of noncardiac surgery soon after coronary stenting.
      patients requiring CABG after PCI should continue taking DAPT as recommended in the post-PCI guidelines, particularly if the stented vessel is not bypassed during surgery.
      The following are changed recommendations for antiplatelet therapy (Fig. 4).
      Recommendation
      • 1.
        We recommend that in patients with ACS requiring CABG, the risk of bleeding vs the benefit of continuing DAPT be weighed in deciding the appropriate timing of intervention (Strong Recommendation, Low-Quality Evidence).
      • 2.
        We suggest that, if possible, in patients scheduled for CABG, clopidogrel and ticagrelor be discontinued for 5 days and prasugrel for 7 days before surgery (Conditional Recommendation, Low-Quality Evidence).
      • 3.
        We recommend that DAPT be continued for 12 months in patients with ACS after CABG (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations recognize the importance of the advantage of antiplatelet therapy in patients who have received CABG to prevent early graft occlusion and long-term cardiovascular events, and the importance of weighing the benefits and risks of DAPT when deciding the timing of surgery.
      Figure thumbnail gr4
      Figure 4Recommendations after CABG. ACS, acute coronary syndrome; ASA, acetylsalicylic acid; CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy.
      Practical tip. In stable patients with ACS without critical coronary anatomy who are clinically stable, clopidogrel and ticagrelor should be withheld for 5 days and prasugrel for 7 days before CABG. In patients with ACS, DAPT should be restarted at maintenance dose within 48-72 hours after surgery when deemed safe by the cardiac surgical team.

      Should Novel Oral Anticoagulants Be Used With Antiplatelet Agents for Secondary Prevention After ACS?

      Patients with ACS remain at high risk for recurrent ischemic events despite significant advances in management. Considering the key role of platelet and coagulation factors in atherothrombosis, modern ACS treatment algorithms combine antithrombin and antiplatelet agents. Although an abundance of evidence demonstrates that prolonged antiplatelet therapy reduces recurrent events after ACS, data supporting long-term antiplatelet plus anticoagulant combination therapy are less convincing. Prolonged subcutaneous dalteparin use reduces recurrent events among troponin T-positive patients,
      • Lindahl B.
      • Venge P.
      • Wallentin L.
      Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group.
      and warfarin alone and in combination with antiplatelet agents reduces the risk of post-ACS events.
      • Rothberg M.B.
      • Celestin C.
      • Fiore L.D.
      • Lawler E.
      • Cook J.R.
      Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.
      • Hurlen M.
      • Abdelnoor M.
      • Smith P.
      • Erikssen J.
      • Arnesen H.
      Warfarin, aspirin, or both after myocardial infarction.
      However, the most recent guidelines from the American College of Cardiology Foundation/American Heart Association and the Focused 2012 Update of the CCS Atrial Fibrillation Guidelines note that concomitant use of warfarin with ASA or DAPT is associated with a greater bleeding risk and should be monitored closely.
      • Wright R.S.
      • Anderson J.L.
      • Adams C.D.
      • et al.
      2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      • Skane A.C.
      • Healy J.S.
      • Cairns J.A.
      • et al.
      Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.
      Although a recent meta-analysis
      • Andrade J.G.
      • Deyell M.W.
      • Khoo C.
      • et al.
      Risk of bleeding on triple antithrombotic therapy following percutaneous coronary intervention/stenting: a systematic review and meta-analysis.
      suggested a significant increase in major bleeding with triple therapy, the stroke and bleeding risks assessment might help select which PCI patient should continue taking triple therapy.
      • Ho K.W.
      • Ivanov J.
      • Frixa X.
      • et al.
      Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.
      • Healey J.S.
      Trifecta or triple threat? The challenge of post-PCI management in patients receiving chronic oral anticoagulant therapy.
      Novel oral anticoagulants targeting factors IIa and Xa are now available for preventing venous thromboembolism and strokes in atrial fibrillation. In the phase III Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS2-TIMI 51) trial, 15,526 patients were randomized within 7 days of ACS to rivaroxaban 2.5 mg or 5 mg twice daily or placebo for a mean of 13 months.
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46).
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      Background therapy included a thienopyridine, mainly clopidogrel and ASA in more than 90% of patients. Rivaroxaban at either dose significantly reduced the primary end point of cardiovascular death, MI, or stroke vs placebo (8.9% vs 10.7%; HR, 0.84; 95% CI, 0.74-0.96). Rivaroxaban 2.5 mg twice daily significantly reduced death from cardiovascular (2.7% vs 4.1%) and any (2.9% vs 4.5%) cause, benefits not seen with 5 mg twice daily. Rivaroxaban increased rates of non-CABG-related TIMI major bleeding (2.1% vs 0.6%; P < 0.001) and intracranial hemorrhage (0.6% vs 0.2%; P = 0.009) Rivaroxaban 2.5 mg twice daily resulted in fewer fatal bleeding events than 5 mg twice-daily (0.1% vs 0.4%; P = 0.04).
      In the phase III Apixaban for Prevention of Acute Ischemic Safety Events (APPRAISE-2) trial, subjects with ACS in the previous 7 days were randomized to apixaban 5 mg twice daily or placebo.
      • Alexander J.H.
      • Becker R.C.
      • Bhatt D.L.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary ayndrome.
      Among enroled patients, 97% and 81% were taking ASA, and a P2Y12 inhibitor, predominantly clopidogrel, respectively. APPRAISE-2 was terminated prematurely after the recruitment of 7392 patients because of increased major bleeding with apixaban without a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, MI, or ischemic stroke occurred in 7.5% of apixaban and 7.9% of placebo recipients (HR, 0.95; 95% CI, 0.80-1.11). Major TIMI bleeding occurred in 1.3% of patients who received ≥ 1 apixaban dose and 0.5% of patients who received ≥ 1 placebo dose (HR, 2.59; 95% CI, 1.50-4.46). A greater number of intracranial and fatal bleeding events occurred with apixaban.
      The phase II Randomized Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multi-centre, Prospective, Placebo Controlled, Cohort Dose Escalation Study (RE-DEEM) trial randomized 1861 subjects within 14 days of ACS, who were receiving treatment with ASA and clopidogrel, to placebo or dabigatran 50 mg, 75 mg, 110 mg, or 150 mg twice daily.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      Compared with placebo, a dose-dependent increase in the primary outcome of major or clinically relevant minor bleeding during the 6-month treatment period was observed with dabigatran: HR, 1.77 (95% CI, 0.70-4.50) for 50 mg; HR, 2.17 (95% CI, 0.88-5.31) for 75 mg; HR, 3.92 (95% CI, 1.72-8.95) for 110 mg; and HR, 4.27 (95% CI, 1.86-9.81) for 150 mg. A phase III trial of dabigatran in patients with ACS has, to date, not been conducted.
      Recommendation
      We suggest against the use of triple therapy with rivaroxaban, clopidogrel, and ASA over the use of dual therapy with ticagrelor or prasugrel plus ASA for secondary prevention of ACS (Conditional Recommendation, Very Low-Quality Evidence).
      Values and preferences. This recommendation recognizes the significant absolute benefit of triple therapy with rivaroxaban, clopidogrel, and ASA over dual therapy with clopidogrel and ASA for the composite outcome of cardiovascular death, MI, or stroke, and total mortality. However, we remain concerned about the 4-fold increased risk of major bleeding and > 3-fold increase in intracranial hemorrhage. The recommendation further acknowledges the loss to follow-up of a significant number of patients in ATLAS ACS2-TIMI 51, which has precluded approval of this combination by the US Food and Drug Administration pending additional supporting documentation.
      A similar ischemic benefit has been observed over clopidogrel plus ASA by using DAPT with ASA plus ticagrelor
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      or prasugrel
      • Wiviott S.D.
      • Desai N.
      • Murphy S.A.
      • et al.
      Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies.
      with an apparent lesser increased risk of bleeding over triple therapy with rivaroxaban, clopidogrel, and ASA. Our recommendation further recognizes the increased complexity and cost of taking 3 medications over 2. However, significant differences exist in the design of studies examining these strategies, and the lack of validity in cross-study comparisons is acknowledged by the very low level of evidence assigned to this recommendation.
      Practical tip. There might be patients in whom combining an oral anticoagulant with DAPT is warranted, such as patients with atrial fibrillation or a mechanical heart valve who develop ACS. Attention is needed to monitor and minimize the duration of “triple antithrombotic therapy” considering the high risk for bleeding associated with such treatment.
      Recommendation
      We recommend against the use of dabigatran and apixaban at any dose in combination with antiplatelet therapy for secondary prevention of ACS (Strong Recommendation, High-Quality Evidence).
      Values and preferences. This recommendation recognizes that existing evidence does not demonstrate benefit for the use of apixaban and suggests harm associated with the use of dabigatran in the setting of ACS treated with DAPT.

      Should PPIs Be Used in Patients Taking DAPT That Includes Clopidogrel?

      Patients receiving clopidogrel, particularly as part of DAPT, are often prescribed PPIs for gastroprotection or acid suppression. Results from 2 meta-analyses and a large randomized clinical trial show that PPIs reduce the risk of upper gastrointestinal bleeding by ≥ 50% in this population.
      • Siller-Matula J.M.
      • Jilma B.
      • Schrör K.
      • Christ G.
      • Huber K.
      Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.
      • Kwok C.S.
      • Nijjar R.S.
      • Loke Y.K.
      Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis.
      • Bhatt D.L.
      • Cryer B.L.
      • Contant C.F.
      • et al.
      Clopidogrel with or without omeprazole in coronary artery disease.
      The effect of PPI and clopidogrel coadministration on ischemic events is less clear. Reports from several observational studies suggest concomitant PPI use might mitigate the beneficial effect of clopidogrel.
      • Juurlink D.N.
      • Gomes T.
      • Ko D.T.
      • et al.
      A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
      • van Boxel O.S.
      • van Oijen M.G.
      • Hagenaars M.P.
      • Smout A.J.
      • Siersema P.D.
      Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study.
      In a large Canadian case-control study of patients prescribed clopidogrel after an acute MI, current PPI users had an increased risk of reinfarction compared with nonusers (odds ratio, 1.27; 95% CI, 1.03-1.57).
      • Juurlink D.N.
      • Gomes T.
      • Ko D.T.
      • et al.
      A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
      The biological plausibility for a clopidogrel/PPI interaction stems from the 2-step metabolism of clopidogrel mediated by the hepatic cytochrome system, specifically CYP2C19. CYP2C19 is known to be inhibited by certain PPIs, including omeprazole. Of note, in the Canadian case-control study, pantoprazole, a PPI with minimal inhibitory effect on CYP2C19, was not associated with increased reinfarction risk.
      • van Boxel O.S.
      • van Oijen M.G.
      • Hagenaars M.P.
      • Smout A.J.
      • Siersema P.D.
      Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study.
      The potentially significant drug-drug interaction between clopidogrel and PPIs, mainly omeprazole, is supported by platelet function studies.
      • Wiviott S.D.
      • Trenk D.
      • Frelinger A.L.
      • et al.
      Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial.
      • Angiolillo D.J.
      • Gibson C.M.
      • Cheng S.
      • et al.
      Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.
      Several cohort studies have been recently published in this area.
      • Burkard T.
      • Kaiser C.A.
      • Brunner-La Rocca H.
      • et al.
      Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial.
      • Simon T.
      • Steg P.G.
      • Gilard M.
      • et al.
      Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry.
      • Schmidt M.
      • Johansen M.B.
      • Robertson D.J.
      • et al.
      Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation.
      • Charlot M.
      • Grove E.L.
      • Hansen P.R.
      • et al.
      Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study.
      • Charlot M.
      • Ahlehoff O.
      • Norgaard M.L.
      • et al.
      Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.
      • Harjai K.J.
      • Shenoy C.
      • Orshaw P.
      • Usmani S.
      • Boura J.
      • Mehta R.H.
      Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators.
      One of these studies suggests PPI and clopidogrel coadministration is associated with an increased MACE risk,
      • Burkard T.
      • Kaiser C.A.
      • Brunner-La Rocca H.
      • et al.
      Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial.
      while another does not.
      • Simon T.
      • Steg P.G.
      • Gilard M.
      • et al.
      Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry.
      Emerging evidence from other studies suggests that “channeling bias” (a tendency of clinicians to prescribe treatment based on prognosis, ie, a patient who is perceived to be more “high risk” with multiple comorbidities would be more likely to be prescribed PPIs) plays a major role in the observed MACE risk observed with PPI and clopidogrel coadministration.
      • Schmidt M.
      • Johansen M.B.
      • Robertson D.J.
      • et al.
      Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation.
      • Charlot M.
      • Grove E.L.
      • Hansen P.R.
      • et al.
      Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study.
      • Charlot M.
      • Ahlehoff O.
      • Norgaard M.L.
      • et al.
      Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.
      • Harjai K.J.
      • Shenoy C.
      • Orshaw P.
      • Usmani S.
      • Boura J.
      • Mehta R.H.
      Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators.
      A reanalysis of PLATO demonstrated that PPI use was independently associated with a higher rate of cardiovascular death, MI, and stroke at 12 months in clopidogrel and ticagrelor recipients even though ticagrelor is not dependent on CYP2C19 conversion.
      • Goodman S.G.
      • Clare R.
      • Pieper K.S.
      • et al.
      Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial.
      A higher rate of cardiovascular events was also observed with non-PPI gastrointestinal treatments. In a Danish cohort study of 13,001 patients who underwent coronary stenting, there was a nonsignificant interaction effect for the use of PPIs modifying the cardioprotective effect of clopidogrel (HR, 1.20; 95% CI, 0.91-1.58).
      • Schmidt M.
      • Johansen M.B.
      • Robertson D.J.
      • et al.
      Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation.
      Interestingly, before PCI and independent of clopidogrel use, PPI users had a 25% increased MACE compared with PPI nonusers. In another study using a Danish administrative registry, MACE risk was increased in patients receiving PPIs with ASA alone and without clopidogrel (HR, 1.46; 95% CI, 1.33-1.61; P < 0.001).
      • Charlot M.
      • Grove E.L.
      • Hansen P.R.
      • et al.
      Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study.
      In a separate study, the authors further confirmed that PPI use itself was associated with an increased MACE risk independent of clopidogrel.
      • Charlot M.
      • Ahlehoff O.
      • Norgaard M.L.
      • et al.
      Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.
      In a retrospective analysis of a randomized clinical trial that compared 2 types of DES, all patients who underwent PCI and received clopidogrel were analyzed for PPI use.
      • Burkard T.
      • Kaiser C.A.
      • Brunner-La Rocca H.
      • et al.
      Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial.
      Compared with PPI nonusers, users had a higher risk of MACE (30.3% vs 20.8%; P = 0.027) and MI (14.7% vs 7.4%; P = 0.01). After regression analysis, PPI use remained an independent predictor of MACE. Results from the French Registry of Acute ST-Elevation and Non-ST–Elevation Myocardial Infarction (FAST-MI) registry of 3670 patients with MI revealed that cardiovascular events were not increased in patients who received both clopidogrel and PPIs.
      • Simon T.
      • Steg P.G.
      • Gilard M.
      • et al.
      Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry.
      In another cohort study that investigated post-PCI clinical outcomes, the authors reported that with propensity-adjusted analyses, MACEs were not increased with PPI and DAPT coadministration even though PPI users were older and had more comorbidities than nonusers.
      • Harjai K.J.
      • Shenoy C.
      • Orshaw P.
      • Usmani S.
      • Boura J.
      • Mehta R.H.
      Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators.
      Notably, results from 2 randomized clinical trials do not support a clinically significant interaction between PPIs and clopidogrel.
      • Bhatt D.L.
      • Cryer B.L.
      • Contant C.F.
      • et al.
      Clopidogrel with or without omeprazole in coronary artery disease.
      • Hsu P.I.
      • Lai K.H.
      • Liu C.P.
      Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis.
      The Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) showed no difference in the MACE risk between patients who received DAPT with or without omeprazole (4.9% vs 5.7%), whereas the risk of upper gastrointestinal bleeding was reduced by > 50% in the PPI-treated group.
      • Bhatt D.L.
      • Cryer B.L.
      • Contant C.F.
      • et al.
      Clopidogrel with or without omeprazole in coronary artery disease.
      However, the COGENT population was at low MACE risk: < 50% of patients had a history of ACS. In a small study, 165 patients with atherosclerotic disease and increased risk of peptic ulcer disease were randomized to esomeprazole plus clopidogrel or clopidogrel alone.
      • Hsu P.I.
      • Lai K.H.
      • Liu C.P.
      Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis.
      There was no observed increase in platelet activity in esomeprazole recipients. Both of these trials are limited by potential type II error. Since our initial guidance, several meta-analyses have been published.
      • Siller-Matula J.M.
      • Jilma B.
      • Schrör K.
      • Christ G.
      • Huber K.
      Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.
      • Kwok C.S.
      • Nijjar R.S.
      • Loke Y.K.
      Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis.
      • Gerson L.B.
      • McMahon D.
      • Olkin I.
      • Stave C.
      • Rockson S.G.
      Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature.
      • Huang B.
      • Huang Y.
      • Li Y.
      • et al.
      Adverse cardiovascular effects of concomitant use of proton pump inhibitors and clopidogrel in patients with coronary artery disease: a systematic review and meta-analysis.
      These meta-analyses found significant heterogeneity among studies. When results of these, mostly observational studies, were pooled, increased MACE risk was noted with PPI/clopidogrel coadministration.
      Recommendation
      We recommend selective use of PPIs in patients receiving DAPT at high risk of upper gastrointestinal bleeding (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. This recommendation recognizes the risk and consequences of gastrointestinal bleeding and the benefit demonstrated to prevent these events in this population.
      This recommendation recognizes that CYP2C19 inhibition significantly reduces the pharmacologic action of clopidogrel on platelet inhibition. We also recognize that although the physiological effect has not been clearly demonstrated to have a clinical effect on thrombotic events, it has also not been eliminated. Because PPIs with minimal effect on CYP2C19 are widely available, use of such agents might be most prudent. Specific PPIs that inhibit CYP2C19 can interact with clopidogrel, resulting in reduced efficacy and consequently, increased risk of cardiovascular events; this might be particularly undesirable in patients deemed at “high risk” of rethrombosis. Point-of-care genotyping might provide an alternative approach when broader experience has been achieved.
      • Roberts J.D.
      • Wells G.A.
      • Le May M.R.
      • et al.
      Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.
      Practical tip. PPIs should not be used routinely in all patients taking DAPT but should be considered in patients at higher risk of gastrointestinal bleeding.

      Acknowledgements

      The authors thank Sharon O'Doherty of the Thrombosis Interest Group of Canada and Kevin McKenzie of Lucid Consultancy for administrative assistance and Melanie Leiby, PhD, for editorial assistance.
      Secondary Reviewers: Paul W. Armstrong, MD, FRCPC (University of Alberta, Edmonton, Alberta), David Fitchett, BChir, MD, MRCP, FRCP, FACC, FESC (University of Toronto and St. Michael's Hospital, Toronto, Ontario), Michael P. Love, MB, ChB, MD, MRCP (Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia), Pierre Théroux, MD, CSPQ, FRCPC, FACC, FAHA, FESC (Montréal Heart Institute, Université de Montréal, Québec), and Robert C. Welsh, MD, FRCPC, FACC (University of Alberta, Edmonton, Alberta).

      Funding Sources

      Funding of this guideline update was provided at arms length by the Thrombosis Interest Group of Canada (http://www.tigc.org/), a registered nonprofit, noncommercial organization dedicated to furthering education and research in the prevention and treatment of thrombosis. The authors received no financial or other benefit for creating this document.

      References

        • Bell A.D.
        • Roussin A.
        • Cartier R.
        • et al.
        The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines.
        Can J Cardiol. 2011; 27: S1-59
        • Guyatt G.H.
        • Oxman A.D.
        • Vist G.
        • et al.
        Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
        BMJ. 2008; 336: 924-926
        • Yusuf S.
        • Zhao F.
        • Mehta S.R.
        • Chrolavicius S.
        • Tognoni G.
        • Fox K.K.
        Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
        N Engl J Med. 2001; 345: 494-502
        • Peters R.J.
        • Mehta S.R.
        • Fox K.A.
        • et al.
        Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
        Circulation. 2003; 108: 1682-1687
        • Jolly S.S.
        • Pogue J.
        • Haladyn K.
        • et al.
        Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study.
        Eur Heart J. 2009; 30: 900-907
        • Mehta S.R.
        • Bassand J.P.
        • Chrolavicius S.
        • et al.
        Dose comparisons of clopidogrel in acute coronary syndromes.
        N Engl J Med. 2010; 363: 930-942
        • Mehta S.R.
        • Tanguay J.F.
        • Eikelboom J.W.
        • et al.
        Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
        Lancet. 2010; 376: 1233-1243
        • Cutlip D.E.
        • Windecker S.
        • Mehran R.
        • et al.
        Clinical end points in coronary stent trials: a case for standardized definitions.
        Circulation. 2007; 115: 2344-2351
        • Wiviott S.D.
        • Braunwald E.
        • McCabe C.H.
        • et al.
        Prasugrel versus clopidogrel in patients with acute coronary syndromes.
        N Engl J Med. 2007; 357: 2001-2015
        • Montalescot G.
        • Wiviott S.D.
        • Braunwald E.
        • et al.
        Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial.
        Lancet. 2009; 373: 723-731
        • Eli Lilly Canada Inc
        Product monograph for Effient.
        Eli Lilly Canada Inc, Toronto2011
        • Wiviott S.D.
        • Desai N.
        • Murphy S.A.
        • et al.
        Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies.
        Am J Cardiol. 2011; 108: 905-911
        • Roe M.T.
        • Armstrong P.W.
        • Fox K.A.
        • et al.
        Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.
        N Engl J Med. 2012; 367: 1297-1309
        • Montalescot G.
        • Bolognese L.
        • Dudek D.
        • et al.
        A comparison of prasugrel at the time of percutaneous coronary intervention or as pretreatment at the time of diagnosis in patients with non-ST-segment elevation myocardial infarction: design and rationale for the ACCOAST study.
        Am Heart J. 2011; 161: 650-656.e1
        • Gurbel P.A.
        • Bliden K.P.
        • Butler K.
        • et al.
        Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
        Circulation. 2009; 120: 2577-2585
        • Wallentin L.
        • Becker R.C.
        • Budaj A.
        • et al.
        Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
        N Engl J Med. 2009; 361: 1045-1057
        • Steg P.G.
        • James S.
        • Harrington R.A.
        • et al.
        Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.
        Circualtion. 2010; 122: 2131-2141
        • Mahaffey K.W.
        • Wojdyla D.M.
        • Carroll K.
        • et al.
        Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (PLATO) trial.
        Circulation. 2011; 124: 544-554
        • Storey R.F.
        • Becker R.C.
        • Harrington R.A.
        • et al.
        Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes.
        Eur Heart J. 2011; 32: 2945-2953
        • Park S.J.
        • Park D.W.
        • Kim Y.H.
        • et al.
        Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
        N Engl J Med. 2010; 362: 1374-1382
        • Valgimigli M.
        • Campo G.
        • Monti M.
        • et al.
        Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
        Circulation. 2012; 125: 2015-2026
        • Tsai T.T.
        • Ho P.M.
        • Xu S.
        • et al.
        Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: insights from the HMO Research Network-Stent Registry (HMORN-stent).
        Circ Cardiovasc Interv. 2010; 3: 230-235
        • Baber U.
        • Mehran R.
        • Sharma S.K.
        • et al.
        Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials.
        J Am Coll Cardiol. 2011; 58: 1569-1577
        • Kandzari D.E.
        • Barker C.S.
        • Leon M.B.
        • et al.
        Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents.
        JACC Cardiovasc Interv. 2011; 4: 1119-1128
        • Hahn J.Y.
        • Song Y.B.
        • Choi J.H.
        • et al.
        Three-month dual antiplatelet therapy after implantation of zotarolimus-eluting stents: the DATE (Duration of Dual Antiplatelet Therapy AfterImplantation of Endeavor Stent) registry.
        Circ J. 2010; 74: 2314-2321
        • Mauri L.
        • Kereiakes D.J.
        • Normand S.L.
        • et al.
        Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions.
        Am Heart J. 2010; 160 (1035-1041, 1041.e1)
        • Chesebro J.H.
        • Clements I.P.
        • Fuster V.
        • et al.
        A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
        N Engl J Med. 1982; 307: 73-78
        • Eagle K.A.
        • Guyton R.A.
        • Davidoff R.
        • et al.
        ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery).
        Circulation. 2004; 110: e340-e437
        • Becker R.C.
        • Meade T.W.
        • Berger P.B.
        • et al.
        The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 776S-814S
        • Fremes S.E.
        • Levinton C.
        • Naylor C.D.
        • Chen E.
        • Christakis G.T.
        • Goldman B.S.
        Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
        Eur J Cardiothorac Surg. 1993; 7: 169-180
        • Gurbuz A.T.
        • Zia A.A.
        • Vuran A.C.
        • Cui H.
        • Aytac A.
        Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study.
        Eur J Cardiothorac Surg. 2006; 29: 190-195
        • Gao C.
        • Ren C.
        • Li D.
        • Li L.
        Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting.
        Ann Thorac Surg. 2009; 88: 59-62
        • Kulik A.
        • Le May M.R.
        • Voisine P.
        • et al.
        Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogel after surgery for coronary artery disease (CASCADE) trial.
        Circulation. 2010; 122: 2680-2687
        • Sun J.C.
        • Teoh K.H.
        • Lamy A.
        • et al.
        Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study.
        Am Heart J. 2010; 160: 1178-1184
        • Fitchett D.
        • Eikelboom J.
        • Fremes S.
        • et al.
        Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society.
        Can J Cardiol. 2009; 25: 683-689
        • 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.
        Circulation. 2004; 110: 1202-1208
        • Steinhubl S.R.
        • Berger P.B.
        • Mann 3rd, J.T.
        • et al.
        Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
        JAMA. 2002; 228: 2411-2420
        • 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.
        J Am Coll Cardiol. 2011; 57: 672-684
        • 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.
        J Am Coll Cardiol. 2012; 60: 388-396
        • Kaluza G.L.
        • Joseph J.
        • Lee J.R.
        • Raizner M.E.
        • Raizner A.E.
        Catastrophic outcomes of noncardiac surgery soon after coronary stenting.
        J Am Coll Cardiol. 2000; 35: 1288-1294
        • Lindahl B.
        • Venge P.
        • Wallentin L.
        Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group.
        J Am Coll Cardiol. 1997; 29: 43-48
        • Rothberg M.B.
        • Celestin C.
        • Fiore L.D.
        • Lawler E.
        • Cook J.R.
        Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.
        Ann Intern Med. 2005; 143: 241-250
        • Hurlen M.
        • Abdelnoor M.
        • Smith P.
        • Erikssen J.
        • Arnesen H.
        Warfarin, aspirin, or both after myocardial infarction.
        N Engl J Med. 2002; 347: 969-974
        • Wright R.S.
        • Anderson J.L.
        • Adams C.D.
        • et al.
        2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
        J Am Coll Cardiol. 2011; 57: 1920-1959
        • Skane A.C.
        • Healy J.S.
        • Cairns J.A.
        • et al.
        Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.
        Can J Cardiol. 2012; 28: 125-136
        • Andrade J.G.
        • Deyell M.W.
        • Khoo C.
        • et al.
        Risk of bleeding on triple antithrombotic therapy following percutaneous coronary intervention/stenting: a systematic review and meta-analysis.
        Can J Cardiol. 2013; 29: 204-212
        • Ho K.W.
        • Ivanov J.
        • Frixa X.
        • et al.
        Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.
        Can J Cardiol. 2013; 29: 213-218
        • Healey J.S.
        Trifecta or triple threat? The challenge of post-PCI management in patients receiving chronic oral anticoagulant therapy.
        Can J Cardiol. 2013; 29: 136-138
        • Mega J.L.
        • Braunwald E.
        • Mohanavelu S.
        • et al.
        Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46).
        Lancet. 2009; 374: 29-38
        • Mega J.L.
        • Braunwald E.
        • Wiviott S.D.
        • et al.
        Rivaroxaban in patients with a recent acute coronary syndrome.
        N Engl J Med. 2012; 366: 9-19
        • Alexander J.H.
        • Becker R.C.
        • Bhatt D.L.
        • et al.
        Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
        Circulation. 2009; 119: 2877-2885
        • Alexander J.H.
        • Lopes R.D.
        • James S.
        • et al.
        Apixaban with antiplatelet therapy after acute coronary ayndrome.
        N Engl J Med. 2011; 365: 699-708
        • Oldgren J.
        • Budaj A.
        • Granger C.B.
        • et al.
        Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
        Eur Heart J. 2011; 32: 2781-2789
        • Siller-Matula J.M.
        • Jilma B.
        • Schrör K.
        • Christ G.
        • Huber K.
        Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.
        J Thromb Haemost. 2010; 8: 2624-2641
        • Kwok C.S.
        • Nijjar R.S.
        • Loke Y.K.
        Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis.
        Drug Saf. 2011; 34: 47-57
        • Bhatt D.L.
        • Cryer B.L.
        • Contant C.F.
        • et al.
        Clopidogrel with or without omeprazole in coronary artery disease.
        N Engl J Med. 2010; 363: 1909-1917
        • Juurlink D.N.
        • Gomes T.
        • Ko D.T.
        • et al.
        A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
        CMAJ. 2009; 180: 713-718
        • van Boxel O.S.
        • van Oijen M.G.
        • Hagenaars M.P.
        • Smout A.J.
        • Siersema P.D.
        Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study.
        Am J Gastroenterol. 2010; 105: 2430-2436
        • Wiviott S.D.
        • Trenk D.
        • Frelinger A.L.
        • et al.
        Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial.
        Circulation. 2007; 11: 2923-2932
        • Angiolillo D.J.
        • Gibson C.M.
        • Cheng S.
        • et al.
        Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.
        Clin Pharmacol Ther. 2011; 89: 65-74
        • Burkard T.
        • Kaiser C.A.
        • Brunner-La Rocca H.
        • et al.
        Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial.
        J Intern Med. 2012; 271: 257-263
        • Simon T.
        • Steg P.G.
        • Gilard M.
        • et al.
        Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry.
        Circulation. 2011; 123: 474-482
        • Schmidt M.
        • Johansen M.B.
        • Robertson D.J.
        • et al.
        Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation.
        Aliment Pharmacol Ther. 2012; 35: 165-174
        • Charlot M.
        • Grove E.L.
        • Hansen P.R.
        • et al.
        Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study.
        BMJ. 2011; 342: d2690
        • Charlot M.
        • Ahlehoff O.
        • Norgaard M.L.
        • et al.
        Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.
        Ann Intern Med. 2010; 153: 378-386
        • Harjai K.J.
        • Shenoy C.
        • Orshaw P.
        • Usmani S.
        • Boura J.
        • Mehta R.H.
        Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators.
        Circ Cardiovasc Interv. 2011; 4: 162-170
        • Goodman S.G.
        • Clare R.
        • Pieper K.S.
        • et al.
        Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial.
        Circulation. 2012; 125: 978-986
        • Hsu P.I.
        • Lai K.H.
        • Liu C.P.
        Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis.
        Gastroenterology. 2011; 140 ([erratum in 2011;141:778]): 791-798
        • Gerson L.B.
        • McMahon D.
        • Olkin I.
        • Stave C.
        • Rockson S.G.
        Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature.
        Dig Dis Sci. 2012; 57: 1304-1313
        • Huang B.
        • Huang Y.
        • Li Y.
        • et al.
        Adverse cardiovascular effects of concomitant use of proton pump inhibitors and clopidogrel in patients with coronary artery disease: a systematic review and meta-analysis.
        Arch Med Res. 2012; 43: 212-224
        • Roberts J.D.
        • Wells G.A.
        • Le May M.R.
        • et al.
        Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.
        Lancet. 2012; 379: 1705-1711