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Canadian Journal of Cardiology

The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines

      Abstract

      Antiplatelet agents are a cornerstone of therapy for patients with atherosclerotic vascular disease. There is presently a lack of comprehensive guidelines focusing on the use of antiplatelet drugs in patients currently manifesting or at elevated risk of cardiovascular disease. The Canadian Antiplatelet Therapy Guidelines Committee reviewed existing disease-based guidelines and subsequently published literature and used expert opinion and review to develop guidelines on the use of antiplatelet therapy in the outpatient setting. This full document has been summarized in an Executive Summary published in the Canadian Journal of Cardiology and may be found at http://www.ccs.ca/. Antiplatelet therapy appears to be generally underused, perhaps in part because of a lack of clear, evidence-based guidance. Here, we provide specific guidelines for secondary prevention in patients discharged from hospital following acute coronary syndromes, post–percutaneous coronary intervention, post–coronary artery bypass grafting, patients with a history of transient cerebral ischemic events or strokes, and patients with peripheral arterial disease. Issues related to primary prevention are also addressed, in addition to special clinical contexts such as diabetes, heart failure, chronic kidney disease, pregnancy/lactation, and perioperative management. Recommendations are provided regarding pharmacologic interactions that may occur during combination therapy with warfarin, clopidogrel and proton-pump inhibitors, or acetylsalicylic acid and nonsteroidal anti-inflammatory drugs, as well as for the management of bleeding complications.

      Résumé

      Les agents antiplaquettaires sont une des pierres angulaires du traitement des patients ayant une maladie vasculaire athérosclérotique. Les lignes directrices qui portent sur l'utilisation des médicaments antiplaquettaires chez les patients qui manifestent ou qui sont à risque élevé de maladie cardiovasculaire sont à l'heure actuelle incomplètes. Le comité canadien sur les directives pour le traitement antiplaquettaire a passé en revue les lignes directrices des maladies et, subséquemment la littérature publiée, et les revues et l'opinion des experts pour développer des lignes directrices sur l'utilisation de traitements antiplaquettaires dans la prise en charge externe des patients. Ce document entier a été présenté dans un sommaire exécutif du Journal canadien de cardiologie et peut être consulté au http://www.ccs.ca/. Le traitement antiplaquettaire semble généralement sous-utilisé, peut-être en partie en raison de l'absence de directives claires et prouvées. Ici, nous donnons des lignes directrices spécifiques pour la prévention secondaire chez les patients en soins externes à la suite de syndromes coronariens aigus, d'une intervention coronaire percutanée, d'un pontage aortocoronarien; chez les patients avec une histoire d'ischémies cérébrales transitoires ou d'accidents vasculaires cérébraux et chez les patients avec une maladie artérielle périphérique. Les questions liées à la prévention primaire sont aussi abordées, en plus des contextes cliniques particuliers comme le diabète, l'insuffisance cardiaque, la maladie rénale chronique, la grossesse et l'allaitement, et la gestion périopératoire. Des recommandations sont données tant pour les interactions pharmacologiques qui peuvent survenir durant un traitement combiné avec la warfarine, le clopidogrel et les inhibiteurs de la pompe à protons, ou l'acide acétylsalicylique et les médicaments anti-inflammatoires non stéroïdaux, que pour la gestion des complications hémorragiques.

      Table of Contents

      • Abstract S1
      • Introduction S4
        • Identification of Relevant Clinical Guidelines S5
        • Appraisal of Guidelines Using the AGREE Instrument S5
        • Literature Search S6
        • Preparation of Guidelines S6
        • Regular Updates S6
      • Antiplatelet Therapy for Secondary Prevention in the First Year Following an Acute Coronary Syndrome S6
        • Evidence for Antiplatelet Therapy Post ACS S6
        • Platelet P2Y12 Receptor Antagonists S7
        • Clopidogrel as an Alternative to ASA Post ACS S7
        • Clopidogrel in Addition to ASA Post NSTEACS S7
        • Clopidogrel in Addition to ASA Post STEMI S7
        • Clopidogrel in Addition to ASA Post ACS S8
        • Prasugrel vs Clopidogrel Post ACS S8
        • Ticagrelor vs Clopidogrel Post ACS S8
        • Recommendation S9
      • Antiplatelet Therapy for Secondary Prevention in the First Year Following Percutaneous Coronary Intervention S10
        • ASA in Patients Undergoing PCI S10
        • Dual-Antiplatelet Therapy in Patients With ACS Who Undergo PCI S10
        • Dual-Antiplatelet Therapy in Patients With Stable CAD Who Undergo Nonurgent PCI S11
        • Dual-Antiplatelet Therapy After BMS Implantation S12
        • Dual-Antiplatelet Therapy After DES Implantation S12
        • Recommendation S13
      • Antiplatelet Therapy Beyond 1 Year After Acute Coronary Syndrome or Percutaneous Coronary Intervention S14
        • ASA Therapy Beyond 1 Year Following a Medically Managed ACS S15
        • Clopidogrel vs ASA for Long-Term Management of Patients With ACS S15
        • Antiplatelet Therapy in Addition to ASA Beyond 1 Year for Patients With Medically Managed ACS S15
        • Clopidogrel S15
        • Prasugrel and Ticagrelor S16
        • Post-ACS and Post-PCI Dual-Antiplatelet Therapy Beyond 1 Year S16
        • Recommendation S16
      • Antiplatelet Therapy for Secondary Prevention Following Coronary Artery Bypass Grafting S17
        • Alternative Antithrombotic Therapy for Preventing Saphenous Vein Graft Occlusion S17
        • Optimal Dose of ASA Post CABG S18
        • Optimal Timing of Antiplatelet Therapy Initiation Post CABG S18
        • Clopidogrel in CABG S18
        • ACS, PCI, and CABG S18
        • Recommendation S18
      • Antiplatelet Therapy for Secondary Prevention of Cerebrovascular Disease S18
        • Antithrombotic Therapy for Prevention of Stroke in Patients With a History of TIA or Ischemic Stroke S19
        • ASA Compared With Placebo S19
        • Comparison of Different Doses of ASA S19
        • Other Antiplatelet Agents S19
        • Summary S20
        • Recommendation S21
      • Antiplatelet Therapy for Vascular Prevention in Patients With Peripheral Artery Disease S21
        • PAD: The Asymptomatic and the Symptomatic Patient S21
        • Patients With Asymptomatic PAD S21
        • Patients With Symptomatic PAD, Including Claudication, Critical Limb Ischemia, or Amputation S22
        • Antiplatelet Therapy for Patients With PAD Who Undergo Endovascular Intervention S22
        • Antiplatelet Agents Following Peripheral Surgical Bypass S23
        • Antiplatelet Therapy for the Treatment of AAA S23
        • Recommendation S24
      • Antiplatelet Therapy for Primary Prevention of Vascular Events S24
        • Studies of Primary Prevention in Men S24
        • Studies in Subjects With Risk Factors for Vascular Disease S25
        • The Effect of Sex in Primary Prevention S25
        • Meta-analysis S25
        • Summary S26
        • Recommendation S26
      • Use of Antiplatelet Therapy in Patients With Diabetes S26
        • Primary Prevention S27
        • Observational Cohorts S27
        • Subgroup and Post-Hoc Analyses of Clinical Trials S27
        • Randomized Clinical Trials Conducted in Patients With Diabetes S27
        • Meta-analyses S27
        • Secondary Prevention S28
        • Observational Cohorts S28
        • Subgroup, Post-Hoc, and Meta-analyses of Randomized Trials S28
        • Ongoing Trials S28
        • Specific Subgroups and Situations S28
        • Optimal ASA Dose for Patients With Diabetes S28
        • Other Antiplatelet Therapy S29
        • ASA Resistance in Diabetes S29
        • Summary S29
        • Recommendation S29
      • Use of Antiplatelet Therapy in Patients With Heart Failure S30
        • Randomized Studies Assessing Antiplatelet Therapy With Warfarin or No Therapy S30
        • Nonrandomized Studies S30
        • Adverse Effects of ASA on HF S30
        • Summary S31
        • Recommendation S31
      • Use of Antiplatelet Therapy in Patients With Chronic Kidney Disease S31
        • Primary Prevention S31
        • Secondary Prevention S31
        • ASA S31
        • Clopidogrel S31
        • Prasugrel S32
        • Bleeding Risk S32
        • Summary S32
        • Recommendation S32
      • Use of Antiplatelet Therapy in Women Who Are Pregnant or Breastfeeding S32
        • ASA in Pregnancy S33
        • ASA in Breastfeeding S33
        • Dipyridamole S33
        • Clopidogrel S33
        • Available Recommendations From Existing Guidelines S33
        • Recommendation S33
      • Management of Patients on Antiplatelet Therapy Who Require a Surgical or Other Invasive Procedure S33
        • Patient Profile S34
        • Diagnostic Testing S34
        • Joint Injections S34
        • Minor Dental, Eye, and Skin Procedures S35
        • Noncardiac Surgery S35
        • CABG S35
        • Noncardiac Surgery in Patients With Cardiac Stents S35
        • Recommendation S36
      • Management of Antiplatelet Therapy in Association With Minor Bleeding S36
        • Ecchymosis and Petechiae S36
        • Oral Mucosal Bleeding S37
        • Subconjunctival Bleeding S37
        • Recommendation S37
      • Combination Therapy With Warfarin and Acetylsalicylic Acid: When to Use, When to Consider, When to Avoid S37
        • Evidence for Therapeutic Benefit With Combination Warfarin/ASA Therapy S38
        • When to Consider Combination Warfarin/ASA Therapy S39
        • Patient Groups in Which There Is Good Evidence for Warfarin/ASA Therapy S39
        • Patient Groups in Which There Is Weak Evidence for Warfarin/ASA Therapy S39
        • Patient Groups in Which Warfarin/ASA Therapy Is Reasonable Despite the Lack of Supportive Evidence S39
        • Recommendation S39
      • Interaction Between Clopidogrel and Proton Pump Inhibitors S39
        • Studies S40
        • Observational Studies S40
        • Randomized Controlled Trial S40
        • Post-Hoc Analysis of Randomized Controlled Trials S40
        • Meta-analysis S41
        • Regulatory Guidance S41
        • Current Guidelines S41
        • Genetic Polymorphisms S41
        • Recommendation S41
      • Interaction Between Acetylsalicylic Acid and Nonsteroidal Anti-inflammatory Drugs S41
        • Platelet Function Studies S42
        • Observational and Epidemiologic Studies S42
        • Specific COX-2 Inhibitors, Traditional NSAIDs, and Vascular Events S42
        • Summary S43
        • Recommendation S43
        • Funding Sources S43
      • References S43
      • Appendix I. Composite Domain Scores for Guidelines Assessed Using the AGREE Instrument S55
      • Appendix II. External Expert Reviewers of the Canadian Cardiovascular Society Antiplatelet Therapy Guideline S57
      • Appendix III. Author Relationships With Industry—CCS Antiplatelet Therapy Guideline Committee S58

      Introduction

      Antiplatelet agents are a cornerstone therapy for patients with documented atherosclerotic vascular disease, including those with coronary artery disease (CAD), cerebrovascular disease, and peripheral arterial disease (PAD). The most commonly used antiplatelet agents include acetylsalicylic acid (ASA), ticlopidine, clopidogrel, and dipyridamole. Emerging agents include prasugrel, which was recently approved for marketing, and ticagrelor, which is awaiting approval by Health Canada. Despite clear evidence showing its benefit in preventing adverse cardiovascular events in patients with vascular disease, antiplatelet therapy is underused in clinical practice. In an evaluation of the first and second Canadian Acute Coronary Syndrome (ACS) Registries, discharge use of ASA was reported for 90.4%, 87.9%, and 83.2% of low-, intermediate-, and high-risk patients with non–ST-segment elevation acute coronary syndrome (NSTEACS), respectively.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes.
      Even in the recently published SYNTAX (SYNergy between PCI with TAXus and cardiac surgery) randomized clinical trial, in which ASA was to be used indefinitely in all patients postprocedure, only 91.2% of patients who underwent percutaneous coronary intervention (PCI) and 84.3% of patients who underwent coronary artery bypass grafting (CABG) were taking ASA 12 months after the procedure.
      • Serruys P.W.
      • Morice M.C.
      • Kappetein A.P.
      • et al.
      Percutaneous coronary intervention vs coronary-artery bypass grafting for severe coronary artery disease.
      The underuse of antiplatelet therapy is observed among outpatients treated by both specialists and general practitioners. In the international REACH (REduction of Atherothrombosis for Continued Health) Registry of approximately 68,000 patients who had established, or were at risk for developing, cardiovascular disease, 74.8% of patients treated by general practitioners were receiving ≥ 1 antiplatelet agent, compared with 89.5% of patients treated by cardiologists.
      • Bhatt D.L.
      • Steg P.G.
      • Ohman E.M.
      • et al.
      International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.
      It is important to note that neither the REACH Registry nor the Canadian ACS Registries recorded information on medication contraindications. In an analysis of US outpatients with established cardiovascular disease and no known contraindication, ASA use was reported in only 32.8% of 29.5 million patient visits in 2003.
      • Stafford R.S.
      • Monti V.
      • Ma J.
      Underutilization of aspirin persists in US ambulatory care for the secondary and primary prevention of cardiovascular disease.
      One of the factors that may contribute to the underuse of antiplatelet therapy, particularly among those outside academic hospital or research settings, is the increasing complexity of regimens for the various vascular risk situations. Unlike other vascular preventive strategies, including control of hypertension and hyperlipidaemia, Canadian physicians lack clear, easily accessible, evidence-based guidance on which to base antiplatelet therapy management decisions. Existing Canadian documents addressing antiplatelet therapy do so as part of guidelines and statements encompassing overall treatment recommendations for specific disease entities (eg, PAD,
      • Abramson B.L.
      • Huckell V.
      • Anand S.
      • et al.
      Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease—executive summary.
      diabetes,
      • Bhattacharyya O.K.
      • Shah B.R.
      • Booth G.L.
      Management of cardiovascular disease in patients with diabetes: the 2008 Canadian Diabetes Association guidelines.
      drug-eluting stent [DES] implantation,
      • Love M.P.
      • Schampaert E.
      • Cohen E.A.
      • et al.
      The Canadian Association of Interventional Cardiology and the Canadian Cardiovascular Society joint statement on drug-eluting stents.
      and stroke
      • Lindsay P.
      • Bayley M.
      • McDonald A.
      • et al.
      Toward a more effective approach to stroke: Canadian Best Practice Recommendations for Stroke Care.
      ). Therefore, there is limited discussion on antiplatelet therapy and no easily accessible, single Canadian source of antiplatelet therapy recommendations.
      To create a concise, therapeutic-based statement on managing antiplatelet therapy in Canadian outpatients who have existing, or are at risk of developing, vascular disease, the Canadian Antiplatelet Therapy Consensus Committee was formed. The processes used to develop the guideline recommendations reported herein included the following:
      ∘A search for existing guidelines and new data on the identified topics of interest
      ∘Evaluation of the quality of existing guidelines using the AGREE (Appraisal of Guidelines for REsearch & Evaluation) Instrument
      AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      ∘Development of recommendations via consideration of
      ▪Existing guidelines and their associated AGREE score
      ▪Literature published subsequent to existing guidelines
      ▪Expert opinion
      ∘Creation of graded recommendations using a system set forth by the Canadian Cardiovascular Society (CCS)
      ∘External review by Canadian experts in their respective fields who were not involved in the writing process

      Identification of relevant clinical guidelines

      Based on the conditions for which antiplatelet therapy is used in the outpatient setting, the working group identified the following topics to be addressed in the guideline: post ACS; post PCI; post CABG; long-term secondary prevention in patients with CAD and cerebrovascular disease; vascular prevention in patients with asymptomatic or symptomatic PAD, including those who undergo endovascular or surgical procedures in the peripheral vasculature; patients with abdominal aortic aneurysm (AAA); primary prevention; women who are pregnant or breastfeeding; patients with chronic kidney disease (CKD), heart failure (HF), and diabetes; perioperative setting; patients with a requirement for oral anticoagulation; and potential interactions between ASA and nonsteroidal anti-inflammatory drugs (NSAIDs) and clopidogrel and proton-pump inhibitors (PPIs). Antiplatelet therapy for the management of atrial fibrillation, valvular heart disease, and pediatrics was not addressed.
      The initial search for existing guidelines that might address these topics was performed by searching the National Guidelines Clearinghouse Web site (http://www.guideline.gov). A manual search of the 367 guidelines listed in the “Cardiovascular Diseases” group identified 79 possibly relevant guidelines. A manual search of these individual guidelines identified 67 relevant guidelines published by 24 different associations. To ensure that the most recent guidelines were obtained, the Web sites of the sponsoring associations were searched for updates.

      Appraisal of guidelines using the AGREE instrument

      The AGREE instrument is a generic tool designed to assess the quality of clinical practice guidelines published by local, regional, national, or international groups. Application of the AGREE instrument ensures that recommendations put forth in this guideline are based on a validated, structured, and rigorous development process. The instrument itself is designed to assess 6 factors associated with guideline quality: (1) scope and purpose (assesses the overall aim of the guideline, the specific clinical questions, and the target patient population); (2) stakeholder involvement (focuses on the extent to which the guideline represents the views of its intended users); (3) rigour of development (relates to the process used to gather and synthesize the evidence and the methods used to formulate the recommendations and to update them); (4) clarity and presentation (assesses the language and format of the guidelines); (5) applicability (pertains to the likely organizational, behavioural, and cost implications of applying the guidelines); and (6) editorial independence (assesses the independence of the recommendations and acknowledgement of possible conflict of interest from the guideline development group).
      The writing group applied the AGREE instrument to 63 of the 67 identified guidelines, with most guidelines scored by ≥ 2 members. (The composite domain scores for each of these guidelines are provided in Appendix I.) Overall, most guidelines scored high in the domains of scope and purpose and editorial independence, particularly those published by national societies (eg, those published by the American College of Chest Physicians or European Society of Cardiology). Scores for rigour of development tended to be ∼50% because many guidelines did not include information on items such as identification of relevant data or processes for updating the guidelines. Finally, scores for stakeholder involvement and applicability tended to be ≤ 50%, mainly because most guidelines failed to identify a target audience or consider/consult with patients when formulating recommendations.

      Literature search

      To identify clinical data not included in existing guidelines, the MEDLINE, Embase, and Cochrane databases were searched using the following parameters:
      ∘Timeframe: January 2007 through March 2010 (January 2007 was chosen because most existing guidelines would include data published prior to this)
      ∘Indications: cardiovascular disease, cerebrovascular disease, coronary artery disease, ischemic heart disease, ischemic stroke, peripheral arterial disease, transient ischemic attack
      ∘Agents: aspirin, acetylsalicylic acid, clopidogrel, dipyridamole, prasugrel, ticagrelor, ticlopidine
      ∘Limiters: case-control study, clinical outcome, efficacy, meta-analysis, prospective study, observational study, randomized clinical trial, retrospective study, safety, systematic review
      ∘Keywords: abdominal aortic aneurysm, carotid endarterectomy, carotid stenting, coronary artery bypass grafting, coronary stenting, centesis, chronic kidney disease, congestive heart failure, dental procedure, dermatologic procedure, ecchymosis, epistaxis, joint injection, lactation, peripheral bypass grafting, peripheral stenting, pregnancy, surgery (cardiac and noncardiac)
      Due to the paucity of data on the use of antiplatelet therapy for ischemic event protection among patients with CKD and women who are pregnant or breastfeeding, the searches for these conditions were repeated without use of the limiters just outlined above. This allowed identification of data that provided a safety profile of antiplatelet therapy in these patients.

      Preparation of guidelines

      Individual working groups of ≥ 2 committee members formulated graded summary recommendations for their specific topics. The summary recommendations were based on a synthesis of recommendations from existing guidelines, newly identified clinical data, and, where appropriate, expert clinical opinion and cost-benefit considerations. Whenever possible, the relative, absolute, and net clinical benefits of an intervention were considered when making recommendations. Because of the heterogeneity of the various interventions and the consequences of the events being avoided, no formal cutoffs in terms of numbers needed to treat were established. In situations where absolute benefit is very small, an intervention is not recommended regardless of the relative risk reduction. The grading system used to score the individual recommendations was the 2-tiered system (Class and Level of Evidence) recommended by the CCS (Table 1) .
      Table 1Grading system used in the preparation of the Canadian Cardiovascular Society antiplatelet consensus statement
      Class of RecommendationLevel of Evidence
      I: Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful, and effectiveA: Data derived from multiple randomized clinical trials or meta-analyses
      IIa: Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment with the weight of evidence in favourB: Data derived from a single randomized clinical trial or large nonrandomized studies
      IIb: Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment with the usefulness/efficacy less well establishedC: Consensus of opinion by experts and/or small studies, retrospective studies, and registries
      III: Evidence that the treatment is not useful and in some cases may be harmful
      Upon completion, the summary recommendations for each individual topic were reviewed by the entire working group. Once a group consensus was achieved (ie, two-thirds of the committee as a whole agreed on the recommendations put forth by the individual working groups), the individual sections were sent to external reviewers considered to be experts in the field. All sections were reviewed by ≥ 1 external reviewer with the exception of the section entitled “Use of Antiplatelet Therapy in Patients With Chronic Kidney Disease.” (The external reviewers who provided feedback are listed in Appendix II.) When necessary, individual recommendations were revised following the external review process.

      Regular updates

      The Antiplatelet Consensus Committee intends to reconvene within 2 years to evaluate the need to update the recommendations.

      Antiplatelet Therapy for Secondary Prevention in the First Year Following an Acute Coronary Syndrome

      Working Group: Jean-François Tanguay, MD, CSPQ, FRCPC, FACC, FAHA, FESC, Michael P. Love, MB, ChB, MD, MRCP, and Robert C. Welsh, MD, FRCP, FACC
      Despite major advances in the medical and invasive management of CAD, ACSs continue to cause substantial morbidity. Platelets play a pivotal role in the pathophysiology of ACSs. The triggering event is typically rupture or erosion of an atherosclerotic coronary artery plaque, which results in platelet activation and intracoronary thrombosis.
      • Libby P.
      • Théroux P.
      Pathophysiology of coronary artery disease.
      Therapeutic platelet inhibition is consequently a crucial aspect of ACS management and secondary prevention.
      Contemporary classification of ACS is based on the appearance of the presenting electrocardiogram (ECG) and subsequent measurement of cardiac biomarkers, most commonly troponin.
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine.
      Patients who present with ST-segment elevation on their surface ECG usually have underlying complete occlusion of a coronary artery. The majority of these patients manifest biochemical evidence of myocardial necrosis and are typically labelled as having ST-elevation myocardial infarction (STEMI). Patients who present without ST-segment elevation usually have nonocclusive intracoronary thrombosis. Patients with NSTEACS are usually further subclassified according to their cardiac biomarkers. Those with biochemical evidence of myocardial necrosis are labelled as having non–ST-elevation myocardial infarction (NSTEMI) and those with negative biomarkers are labelled as having unstable angina (UA).

      Evidence for antiplatelet therapy post ACS

      A multitude of large, randomized clinical trials have evaluated the effects of ASA alone and in combination with oral P2Y12 receptor antagonists in patients with ACS. The following section reviews the key evidence supporting antiplatelet therapy in the postdischarge phase of ACS management.
      The Antithrombotic Trialists' Collaboration provides the clearest evidence for the secondary preventive benefits of antiplatelet therapy following an ACS.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      In 19,288 patients treated with antiplatelet therapy during the acute phase of myocardial infarction (MI), most of whom participated in the ISIS-2 (Second International Study of Infarct Survival) trial and received ASA 162 mg once daily,
      ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
      Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
      antiplatelet therapy resulted in large reductions in nonfatal recurrent MI (57% relative and 1.3% absolute risk reductions; P < 0.0001) and vascular death (20% relative and 2.3% absolute risk reductions; P < 0.0001). There was a smaller but still significant reduction in nonfatal stroke (50% relative and 0.3% absolute risk reductions; P = 0.02). Overall, 1 month of antiplatelet therapy resulted in 38 fewer serious events for every 1000 patients treated (number needed to treat [NNT], 26). In the ISIS-2 trial, the benefit of ASA accrued over the first month of therapy and persisted for >10 years.
      ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
      Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
      • Baigent C.
      • Collins R.
      • Appleby P.
      • et al.
      ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
      In the Antiplatelet Trialists' Collaboration meta-analysis of the 18,788 patients with a history of previous MI, treatment with antiplatelet therapy for a mean of 27 months resulted in large reductions in nonfatal recurrent MI (28% relative and 1.8% absolute risk reductions; P < 0.0001) and vascular death (15% relative and 1.4% absolute risk reductions; P = 0.0006).
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      There was again a small but significant reduction in nonfatal stroke (36% relative and 0.5% absolute risk reductions; P = 0.002). Overall, antiplatelet therapy resulted in 36 fewer serious events for every 1000 patients treated (NNT 26).
      Large short- and long-term benefits of ASA have been demonstrated in randomized trials of patients with UA. The Veterans Administration Cooperative Study tested the effect of 12 weeks of ASA 324 mg daily vs placebo in 1266 men with UA.
      • Lewis Jr., H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
      ASA use resulted in 50% relative and 5% absolute risk reductions in death or MI (P = 0.0005). In a multicenter Canadian trial of 555 patients with UA, Cairns and colleagues
      • Cairns J.A.
      • Gent M.
      • Singer J.
      • et al.
      Aspirin, sulfinpyrazone, or both in unstable angina Results of a Canadian multicenter trial.
      showed that ASA 325 mg 4 times daily continued for 2 years resulted in 51% relative and 8.4% absolute risk reductions in cardiac death and nonfatal MI (P = 0.008) after a mean follow-up of 18 months.
      Similarly, the optimal maintenance dose of ASA following ACS has not been definitively established by randomized clinical trials. The Antithrombotic Trialists' Collaboration and other post-hoc trial analyses provide indirect support that lower doses of ASA (ie, 75-100 mg daily) may offer the optimal balance between efficacy and safety.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Campbell C.L.
      • Smyth S.
      • Montalescot G.
      • Steinhubl S.R.
      Aspirin dose for the prevention of cardiovascular disease: a systematic review.
      • 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.
      • Patrono C.García Rodríguez L.A.
      • Landolfi R.
      • Baigent C.
      Low-dose aspirin for the prevention of atherothrombosis.

      Platelet P2Y12 receptor antagonists

      Thienopyridines inhibit platelet aggregation via blockade of platelet P2Y12 adenosine diphosphate (ADP) receptors.
      • Patrono C.
      • Bachmann F.
      • Baigent C.
      • et al.
      Expert consensus document on the use of antiplatelet agents The Task Force on the Use of Antiplatelet Agents in Patients With Atherosclerotic Cardiovascular Disease of the European Society of Cardiology.
      Currently, the oral thienopyridines ticlopidine, clopidogrel, and prasugrel are approved for use in Canada. An application for marketing approval of the novel P2Y12 receptor blocker ticagrelor has been submitted to global regulatory agencies.
      Clopidogrel is preferred over ticlopidine for patients with ACS or undergoing PCI because of the similar efficacy and enhanced safety and tolerability of clopidogrel.
      • Bertrand M.E.
      • Rupprecht H.J.
      • Urban P.
      • Gershlick A.H.
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).
      • Bhatt D.L.
      • Bertrand M.E.
      • Berger P.B.
      • et al.
      Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.
      • Steinhubl S.R.
      • Tan W.A.
      • Foody J.M.
      • Topol E.J.
      Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.
      However, clopidogrel is a prodrug that requires a 2-stage oxidation process mediated by cytochrome P450 to generate its active metabolite,
      • Patrono C.
      • Bachmann F.
      • Baigent C.
      • et al.
      Expert consensus document on the use of antiplatelet agents The Task Force on the Use of Antiplatelet Agents in Patients With Atherosclerotic Cardiovascular Disease of the European Society of Cardiology.
      and varying absorption and reduced metabolism to its active compound secondary to loss-of-function polymorphisms and drug-drug competition for the relevant enzymes of the cytochrome P450 system may decrease and delay the antiplatelet effects of clopidogrel.
      • Momary K.M.
      • Dorsch M.P.
      Factors associated with clopidogrel nonresponsiveness.
      The third-generation agent prasugrel is also a prodrug that requires metabolic conversion, but it is converted to its active form more efficiently and predictably than clopidogrel.
      • Jakubowski J.A.
      • Payne C.D.
      • Brandt J.T.
      • et al.
      The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects.
      As a result, prasugrel has a faster onset of action, is more potent, and demonstrates less interindividual variability compared with clopidogrel. Ticagrelor, the second novel P2Y12 receptor blocker, appears to have a potency and speed of onset similar to those of prasugrel.
      • Storey R.F.
      • Husted S.
      • Harrington R.A.
      • et al.
      Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.
      In contrast with clopidogrel and prasugrel, ticagrelor does not require metabolic activation and is a reversible inhibitor of the platelet P2Y12 receptor. Because of its half-life (7-8.5 hours) and reversibility,
      • Teng R.
      • Butler K.
      Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects.
      ticagrelor requires twice-daily dosing (vs once-daily dosing for clopidogrel and prasugrel).

      Clopidogrel as an alternative to ASA post ACS

      In the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events) trial, 19,185 patients with a history of MI within 35 days of randomization, ischemic stroke at 1 week to 6 months of randomization, or symptomatic PAD were randomized to ASA 325 mg daily or clopidogrel 75 mg daily.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).
      In the overall population and after a mean follow-up period of 1.9 years, clopidogrel reduced the relative risk of the primary composite endpoint of vascular death, MI, or ischemic stroke by 8.7% compared with ASA (5.3% vs 5.8%, absolute risk reduction 0.5%; P = 0.043). Statistical testing for heterogeneity was significant, suggesting that the small benefit of clopidogrel over ASA may not have been equivalent across subgroups. The relative risk reductions in the prespecified subgroups were 7.3% for the 6431 patients with a history of ischemic stroke (95% CI –5.7% to 18.7%; P = 0.26), 23.8% for the 6452 patients with a history of PAD (95% CI 8.9% to 36.2%; P = 0.0028), and –3.7% for the 6302 patients with a history of MI (95% CI –22.1% to 12.0%; P = 0.66).
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).

      Clopidogrel in addition to ASA post NSTEACS

      The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      transformed the global use of clopidogrel and represents the key evidence for thienopyridine therapy in NSTEACS. In the CURE trial, 12,562 patients with either UA (75%) or NSTEMI (25%) given ASA 75-325 mg daily were randomized within 24 hours of presentation to receive clopidogrel (300-mg loading dose followed by 75 mg daily) or placebo for a mean of 9 months (range 3-12 months). The relative risk of the primary composite endpoint of cardiovascular death, nonfatal MI, or stroke was reduced by 20% in patients receiving clopidogrel compared with placebo (9.3% vs 11.4%, absolute risk reduction 2.1%; P < 0.001). Clopidogrel treatment was associated with an increased risk of trial-defined major (3.7% vs 2.7%; P = 0.001) and minor (5.1% vs 2.4%; P < 0.001) bleeding but not life-threatening bleeding (2.2% vs 1.8%; P = 0.13).
      A landmark analysis of the CURE trial showed that the majority of clopidogrel benefit was manifest within the first 30 days of treatment.
      • Yusuf S.
      • Mehta S.R.
      • Zhao F.
      • et al.
      Early and late effects of clopidogrel in patients with acute coronary syndromes.
      Thus, controversy regarding the implications of the CURE trial for the optimal duration of clopidogrel post NSTEACS persists. However, pharmacoeconomic analyses have indicated that clopidogrel plus ASA for 1 year post NSTEACS is highly cost-effective in both Canadian
      • Kolm P.
      • Yuan Y.
      • Veledar E.
      • et al.
      Cost-effectiveness of clopidogrel in acute coronary syndromes in Canada: a long-term analysis based on the CURE trial.
      and global
      • Lyseng-Williamson K.A.
      • Plosker G.L.
      Clopidogrel: a pharmacoeconomic review of its use in patients with non-ST elevation acute coronary syndromes.
      contexts.

      Clopidogrel in addition to ASA post STEMI

      Despite the results of the CURE trial and the similar underlying pathophysiology of all ACSs, clopidogrel was not used widely in patients with STEMI until clinical trials were conducted specifically in this patient population.
      In the CLARITY-TIMI 28 (CLopidogrel as Adjunctive ReperfusIon TherapY–Thrombolysis In Myocardial Infarction 28) trial, 3491 patients aged < 75 years receiving thrombolysis and ASA 162 mg within 12-48 hours of an acute STEMI were randomized to clopidogrel (300-mg loading dose followed by 75 mg daily) or placebo.
      • Sabatine M.S.
      • Cannon C.P.
      • Gibson C.M.
      • et al.
      Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.
      Study drug was continued until coronary angiography; for patients who did not undergo angiography, study drug was continued until day 8 or hospital discharge, whichever came first. For patients who underwent angiography, open-label clopidogrel (300-mg loading dose and 75 mg daily) was recommended. The relative risk of the primary composite endpoint of angiographic occlusion of the infarct-related artery, all-cause death, or recurrent MI at 30 days was reduced by 36% in those receiving clopidogrel vs placebo (15.0% vs 21.7%, absolute risk reduction 6.7%; P < 0.001).
      In COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial), 45,852 patients presenting within 24 hours of suspected acute STEMI were randomized to clopidogrel 75 mg daily (no loading dose) or placebo in addition to ASA 162 mg daily.
      • Chen Z.M.
      • Jiang L.X.
      • Chen Y.P.
      • et al.
      Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.
      Patients undergoing primary PCI were excluded, and ∼50% of those randomized received thrombolytic therapy. The study drug was continued for up to 4 weeks or until death or hospital discharge, whichever came first. After a mean treatment duration of 15 days, the relative risk of the first coprimary endpoint of the composite of death, MI, or stroke was reduced by 9% in clopidogrel vs placebo recipients (9.2% vs 10.1%, absolute risk reduction 0.9%; P = 0.002). The second coprimary endpoint of all-cause mortality was also significantly reduced by clopidogrel (7.5% vs 8.1%, absolute risk reduction 0.6%; P = 0.03). There was no significant increase in trial-defined bleeding associated with clopidogrel.
      • Chen Z.M.
      • Jiang L.X.
      • Chen Y.P.
      • et al.
      Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.
      Although the CLARITY-TIMI 28 trial and COMMIT demonstrated the short-term benefits of acute clopidogrel administration, no randomized trials have specifically evaluated the effects of longer-term clopidogrel administration following STEMI. In the absence of specific evidence for long-term dual-antiplatelet therapy in STEMI, the findings of CURE
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      and the common underlying pathophysiology of all types of ACS are typically cited as the basis for continuing therapy in patients with STEMI after hospital discharge. The current reality is that an increasing proportion of patients with STEMI undergo in-hospital PCI and, therefore, continuation of dual-antiplatelet therapy after discharge is often mandated by the implantation of ≥ 1 intracoronary stents.

      Clopidogrel in addition to ASA post ACS

      In the CURRENT-OASIS (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes) 7 trial, 25,087 patients with ACS (70.8% UA/NSTEMI and 29.2% STEMI) undergoing an early invasive management strategy with intended PCI were randomized in a 2 × 2 factorial fashion to receive double-dose (600-mg loading dose followed by 150 mg daily for 7 days, then 75 mg daily) or standard-dose (300-mg loading dose followed by 75 mg daily) clopidogrel and high-dose (300-325 mg daily) or low-dose (75-100 mg daily) ASA.
      • Mehta S.R.
      • Bassand J.P.
      • Chrolavicius S.
      • et al.
      Dose comparisons of clopidogrel in acute coronary syndromes.
      After 30 days, the primary composite outcome of cardiovascular death, MI, or stroke did not differ between the double-dose and standard-dose clopidogrel recipients (4.2% vs 4.4%, absolute risk reduction 0.2%; P = 0.30). However, a significant interaction associated with PCI was observed such that patients who underwent PCI experienced a significant 0.6% absolute risk reduction (3.9% vs 4.5%; P = 0.039), whereas patients who did not undergo PCI experienced a nonsignificant 0.6% absolute risk increase (4.9% vs 4.3%; P = 0.23). An interaction by ASA dose was also observed such that double-dose clopidogrel significantly reduced the risk of the primary outcome in recipients of high-dose ASA but not in recipients of low-dose ASA. When assessed using the TIMI criteria, double-dose clopidogrel did not significantly increase the risk of major bleeding (1.04% vs 0.95%, absolute risk increase 0.09%; P = 0.50); however, when assessed using trial-defined criteria, the risk of major bleeding was significantly increased by double-dose clopidogrel (2.5% vs 2.0%, absolute risk increase 0.5%; P = 0.01).

      Prasugrel vs clopidogrel post ACS

      In TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction 38), 13,608 patients with ACS (74% NSTEACS and 26% STEMI) scheduled to undergo PCI were randomized to receive prasugrel (60-mg loading dose followed by 10 mg daily) or clopidogrel (300-mg loading dose followed by 75 mg daily) following coronary angiography, in addition to ASA 75-162 mg daily.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      After a median 14.5-month follow-up, the relative risk of the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke was reduced by 19% in patients receiving prasugrel vs clopidogrel (9.9% vs 12.1%, absolute risk reduction 2.2%; P < 0.001). Prasugrel significantly reduced the risk of MI, urgent target vessel revascularization, and stent thrombosis, but these benefits occurred at the expense of significant increases in TIMI-defined major, life-threatening, and fatal bleeding. Secondary analysis revealed that the risk-benefit ratio was not favourable for patients aged ≥ 75 years with a low body weight or history of stroke or transient ischemic attack (TIA).
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      A landmark analysis of TRITON-TIMI 38 showed that prasugrel significantly reduced the rate of MI compared with clopidogrel during the first 3 days of treatment (4.27% vs 5.24%, absolute risk reduction 0.97%; P = 0.008) and from day 3 through the end of follow-up (3.40% vs 4.79%, absolute risk reduction 1.39%; P < 0.0001).
      • Antman E.M.
      • Wiviott S.D.
      • Murphy S.A.
      • et al.
      Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.
      In a prespecified analysis of the 3534 patients with STEMI and planned PCI enrolled in TRITON-TIMI 38, prasugrel reduced the relative risk of the primary composite endpoint by 21% compared with clopidogrel (10.0% vs 12.4%, absolute risk reduction 2.4%; P = 0.0221)
      • 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.
      ; notably, the study drug could be initiated before coronary angiography in this subgroup. The risks of major, life-threatening, or fatal bleeding were not significantly increased by prasugrel in the STEMI cohort. Prasugrel has been approved for use in patients with ACS who are to be managed with PCI based on the TRITON-TIMI38 findings. However, the product monographs indicate that prasugrel is contraindicated in patients with a known history of TIA or stroke and include a boxed warning highlighting the bleeding risks and recommending avoidance of prasugrel in patients aged ≥ 75 years or with a body weight < 60 kg.
      Eli Lilly Canada Inc
      Product monograph for Effient.

      Ticagrelor vs clopidogrel post ACS

      In the PLATO (PLATelet inhibition and patient Outcomes) trial, 18,624 patients with ACS (62% NSTEACS and 38% STEMI) were randomized to ticagrelor (180-mg loading dose followed by 90 mg twice daily) or clopidogrel (300- to 600-mg loading dose followed by 75 mg daily) in addition to ASA 75-100 mg daily.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor vs clopidogrel in patients with acute coronary syndromes.
      The relative risk of the primary composite endpoint of vascular death, MI, or stroke at 12 months was reduced by 16% in patients receiving ticagrelor vs clopidogrel (9.8% vs 11.7%, absolute risk reduction 1.9%; P < 0.001). Unexpectedly, ticagrelor was associated with a 21% relative reduction in both cardiovascular (4.0% vs 5.1%, absolute risk reduction 1.1%; P < 0.001) and all-cause (4.5% vs 5.9%, absolute risk reduction 1.4%; P < 0.001) mortality. Ticagrelor did not increase trial-defined major bleeding overall but was associated with a 19% relative increase in non–CABG-related, trial-defined major bleeding (4.5% vs 3.8%, absolute risk increase 0.7%; P = 0.03). Ticagrelor was associated with some unusual side effects, including transient dyspnea and bradycardia, although these rarely required study drug discontinuation.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor vs clopidogrel in patients with acute coronary syndromes.
      Table 2 and Figure 1, Figure 2, Figure 3)
      For all patients with ACS who survive to hospital discharge, indefinite therapy with low-dose ASA (75-162 mg daily) is recommended (Class I, Level A). For patients allergic to or intolerant of ASA, indefinite therapy with clopidogrel 75 mg daily is recommended (Class IIa, Level B).
      For patients presenting with STEMI who are medically managed, clopidogrel 75 mg daily is recommended in addition to ASA 75-162 mg daily for ≥ 14 days (Class I, Level B) and up to 12 months in the absence of an excessive risk of bleeding (Class IIb, Level C).
      For patients presenting with STEMI who are managed by PCI, clopidogrel 75 mg daily is recommended in addition to ASA 75-162 mg daily for 12 months (Class I, Level B). Continuation of combined therapy beyond 12 months may be considered in patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C).
      For patients presenting with NSTEACS who are medically managed, clopidogrel 75 mg daily is recommended in addition to ASA 75-162 mg daily for ≥ 1 month (Class I, Level A) and up to 12 months in the absence of an excessive risk of bleeding (Class I, Level B).
      For patients presenting with NSTEACS who are managed by PCI, clopidogrel 75 mg daily is recommended in addition to ASA 75-162 mg daily for 12 months (Class I, Level A). Continuation of combined therapy beyond 12 months may be considered in patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C).
      For patients presenting with NSTEACS who are managed by CABG, clopidogrel 75 mg daily is recommended in addition to ASA 75-162 mg daily for a minimum of 1 month and up to 12 months (Class I, Level B).
      For patients with ACS who undergo stent implantation and have an increased risk of stent thrombosis (eg, STEMI, history of diabetes mellitus, or prior documented stent thrombosis), prasugrel 10 mg daily may be considered in addition to ASA 75-162 mg daily for 12 months (Class IIa, Level B). Prasugrel should be avoided in patients with an increased bleeding risk, likely to undergo CABG within 7 days, with a history of stroke or TIA, aged ≥ 75 years, or with a weight < 60 kg (Class III, Level B).
      For patients with ACS, ticagrelor 90 mg twice daily may be added to ASA 75-162 mg daily for 12 months (Class I, Level B). (Ticagrelor is currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.)
      In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of therapy (Class I, Level C).
      Figure thumbnail gr1
      Figure 1Postdischarge management of acute coronary syndrome. After an acute coronary syndrome, the outpatient antiplatelet therapy recommendations after ST-elevation myocardial infarction (STEMI) or non–ST-segment elevation acute coronary syndrome (NSTEACS) in medically managed or after percutaneous intervention. In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of therapy (Class I, Level C). ADP, adenosine diphosphate; ASA, acetylsalicylate acid; CABG, coronary artery bypass graft. *Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      Figure thumbnail gr2
      Figure 2Postdischarge management of ST-elevation myocardial infarction (STEMI). The outpatient management after a STEMI is outlined for patients medically managed or after percutaneous intervention. In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of therapy (Class I, Level C). ADP, adenosine diphosphate; ASA, acetylsalicylate acid; CABG, coronary artery bypass graft. *Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      Figure thumbnail gr3
      Figure 3Postdischarge management of non-ST-segment elevation acute coronary syndrome (NSTEACS). The outpatient management after a NSTEACS is outlined for patients medically managed or after percutaneous intervention. In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of therapy (Class I, Level C). ADP, adenosine diphosphate; ASA, acetylsalicylate acid; CABG, coronary artery bypass graft. *Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      Table 2Recommendations for antiplatelet therapy following hospital discharge for acute coronary syndrome
      AgentRecommended Dose and Duration of TherapyClass (Level of Evidence)
      ASAUse 75-162 mg/d indefinitelyI (A)
      75-162 mg/d is recommended to minimize bleeding complicationsIIa (B)
      Clopidogrel75 mg/d indefinitely in ASA allergy or intoleranceIIa (B)
      ASA + clopidogrelPost STEMI
      Medically managed
       ASA 75-162 mg/d and clopidogrel 75 mg/d for a minimum of 14 dI (B)
       Clopidogrel 75 mg/d may be continued for 12 mo in the absence of excess bleeding riskIIa (C)
      Post PCI
       ASA 75-162 mg/d and clopidogrel 75 mg/d for 12 moI (B)
       ASA 75-162 mg/d and clopidogrel 75 mg/d may be continued beyond 12 mo in patients with a high risk of thrombosis and a low risk of bleedingIIa (C)
      Post NSTEACS
      Medically managed
       ASA 75-162 mg/d and clopidogrel 75 mg/d for a minimum of 1 moI (A)
       Clopidogrel 75 mg/d may be continued for 12 mo in the absence of excessive bleeding riskI (B)
      Post PCI
       ASA 75-162 mg/d and clopidogrel 75 mg/d for 12 moI (A)
       ASA 75-162 mg/d and clopidogrel 75 mg/d may be continued beyond 12 mo in patients with a high risk of thrombosis and a low risk of bleedingIIb (C)
      Post CABG
       ASA 75-162 mg/d and clopidogrel 75 mg/d for a minimum of 1 mo and up to 12 moI (B)
      ASA + prasugrel ASA 75-162 mg/d and prasugrel 10 mg/d for 12 mo in patients who undergo stent implantation and have an increased risk of thrombosis (eg, STEMI, history of diabetes mellitus, prior documented stent thrombosis)IIa (B)
       ASA 75-162 mg/d plus prasugrel 10 mg/d should be avoided in patients at a high risk of bleeding, likely to undergo CABG within 7 d, with a history of stroke or TIA, aged ≥75 y, or weight <60 kgIII (B)
      ASA + ticagrelor
      Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
       ASA 75-162 mg/d plus ticagrelor
      Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      90 mg twice daily for 12 mo
      I (B)
      ASA, acetylsalicylic acid; CABG, coronary artery bypass grafting; NSTEACS, non–ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack.
      low asterisk Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.

      Antiplatelet Therapy for Secondary Prevention in the First Year Following Percutaneous Coronary Intervention

      Working Group: Jean-François Tanguay, MD, CSPQ, FRCPC, FACC, FAHA, FESC, Michael P. Love, MB, ChB, MD, MRCP, and Robert C. Welsh, MD, FRCP, FACC
      During PCI, mechanically induced plaque rupture and vessel injury, combined with the implantation of a metallic stent scaffolding, require effective antiplatelet therapy to prevent thrombosis. Dual-antiplatelet therapy with ASA and either ticlopidine, clopidogrel, prasugrel, or ticagrelor is critical at the time of the procedure, as well as in the month following BMS implantation and the 6-12 months after DES implantation, because it allows time for vessel healing, plaque stabilization, and reendothelialization.
      • Libby P.
      • Théroux P.
      Pathophysiology of coronary artery disease.
      Importantly, premature discontinuation of dual-antiplatelet therapy post PCI is associated with increased risks of subacute (1-30 days) and late (30 days to 1 year) stent thrombosis. The optimal duration of long-term dual-antiplatelet therapy (ie, > 1 year) post PCI remains an area of current investigation.

      ASA in patients undergoing PCI

      ASA was the first antiplatelet agent used after coronary stenting. The initial studies exploring single antiplatelet therapy with ASA in combination with oral anticoagulation with warfarin reported a very high rate of stent thrombosis that ranged from 15% to 20%.
      • de Feyter P.J.
      • DeScheerder I.
      • van den Brand M.
      • et al.
      Emergency stenting for refractory acute coronary artery occlusion during coronary angioplasty.
      • Serruys P.W.
      • Strauss B.H.
      • Beatt K.J.
      • et al.
      Angiographic follow-up after placement of a self-expanding coronary-artery stent.
      • Sigwart U.
      • Puel J.
      • Mirkovitch V.
      • Joffre F.
      • Kappenberger L.
      Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty.
      Despite these shortcomings, ASA remains the cornerstone of antiplatelet therapy post-coronary stenting. Based on the results of a meta-analysis of > 200 trials, low-dose ASA (75-150 mg daily) provides a benefit similar to that of higher ASA doses (160-325 mg daily) but is associated with a lower incidence of bleeding.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.

      Dual-Antiplatelet therapy in patients with ACS who undergo PCI

      The efficacy and safety of dual-antiplatelet therapy with ASA and an ADP P2Y12 antagonist in patients with ACS who undergo PCI have been assessed in prespecified analyses of large ACS trials. For patients with NSTEACS who undergo PCI, the benefit of dual ASA and clopidogrel therapy was demonstrated in the PCI-CURE trial (N = 2658), in which ASA plus clopidogrel reduced the relative risk of the primary composite endpoint by 30% vs ASA alone (4.5% vs 6.4%, absolute risk reduction 1.9%; P = 0.03).
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      Similarly, the PCI-CLARITY study (N = 1863) demonstrated benefit for ASA and clopidogrel in patients with STEMI (relative risk reduction 46%, 3.6% vs 6.2%, absolute risk reduction 2.6%; P = 0.008).
      • Sabatine M.S.
      • Cannon C.P.
      • Gibson C.M.
      • et al.
      Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study.
      The benefit of adding the ADP P2Y12 receptor blockers prasugrel and ticagrelor to ASA in patients with ACS undergoing PCI has also been shown. Among the 10,074 patients with NSTEACS in TRITON-TIMI 38, all of whom were randomized after coronary angiography and underwent PCI, prasugrel plus ASA reduced the relative risk of the primary composite endpoint by 19% vs clopidogrel plus ASA (9.9% vs 12.1%, absolute risk reduction 2.2%; P < 0.05).
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      Similar reductions were observed for the 3534 patients with STEMI (relative risk reduction 21%, 10.0% vs 12.4%, absolute risk reduction 2.4%; P < 0.05).
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      In the PLATO invasive study of 13,408 patients scheduled to undergo an invasive management strategy, ASA plus the reversible, direct-acting ADP receptor antagonist ticagrelor reduced the risk in patients with STEMI (N = 6575; relative risk reduction 14%, 8.1% vs 9.5%, absolute risk reduction 1.4%; P = ns) and NSTEACS (N = 6805; relative risk reduction 17%, 9.7% vs 11.8%, absolute risk reduction 2.1%; P < 0.05).
      • Cannon C.P.
      • Harrington R.A.
      • James S.
      • et al.
      Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study.
      Importantly, a reduction in cardiovascular mortality was also demonstrated in the overall PLATO invasive population (relative risk reduction 18%, 3.4% vs 4.3%, absolute risk reduction 0.9%; P = 0.0250).

      Dual-Antiplatelet therapy in patients with stable CAD who undergo nonurgent PCI

      Only 1 randomized study, the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, has examined the benefit of dual-antiplatelet therapy in 2116 patients with stable CAD who underwent nonurgent PCI with bare-metal stent (BMS) placement.
      • 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.
      In addition to ASA 325 mg daily, patients were randomly assigned to receive a 300-mg clopidogrel loading dose or no loading dose before PCI. Thereafter, all patients received clopidogrel 75 mg daily until day 28. From day 29 to 12 months, patients in the loading-dose group continued to receive clopidogrel 75 mg daily, whereas those in the control group received placebo. At 12 months, the relative risk of the primary composite endpoint of death, MI, or stroke was reduced by 26.9% in the group that received a clopidogrel loading dose and long-term treatment (8.5% vs 11.5%, absolute risk reduction 3.0%; P = 0.02). Although it is not possible to separate the benefit of clopidogrel preloading from the prolonged duration of dual-antiplatelet therapy, a sustained benefit of the prolonged dual-antiplatelet strategy was observed after nonurgent PCI.
      • 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.

      Dual-Antiplatelet therapy after BMS implantation

      In several studies, dual-antiplatelet therapy with ASA and ticlopidine significantly reduced cardiac events after implantation of a BMS compared with either ASA alone or ASA plus oral anticoagulation.
      • Schomig A.
      • Neumann F.J.
      • Kastrati A.
      • et al.
      A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.
      • Leon M.B.
      • Baim D.S.
      • Popma J.J.
      • et al.
      A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting Stent Anticoagulation Restenosis Study Investigators.
      • Bertrand M.E.
      • Legrand V.
      • Boland J.
      • et al.
      Randomized multicenter comparison of conventional anticoagulation vs antiplatelet therapy in unplanned and elective coronary stenting The full anticoagulation vs aspirin and ticlopidine (FANTASTIC) study.
      • Urban P.
      • Macaya C.
      • Rupprecht H.J.
      • et al.
      Randomized evaluation of anticoagulation vs antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin And Ticlopidine Trial after Intracoronary Stenting (MATTIS).
      This protective effect mainly resulted from a reduction of acute and subacute stent thrombosis, which had an incidence of < 1%. Moreover, most studies showed a dramatic reduction of hemorrhagic complications with ASA plus ticlopidine compared with combined ASA and oral anticoagulant therapy. In the FANTASTIC (Full ANTicoagulation vs ASpirin and TIClopidine) study, hemorrhagic events occurred in 13.5% of ASA-plus-ticlopidine recipients and 21% of ASA–plus–vitamin K antagonist recipients.
      • Bertrand M.E.
      • Legrand V.
      • Boland J.
      • et al.
      Randomized multicenter comparison of conventional anticoagulation vs antiplatelet therapy in unplanned and elective coronary stenting The full anticoagulation vs aspirin and ticlopidine (FANTASTIC) study.
      Despite its superiority to ASA and oral anticoagulation, the clinical use of ticlopidine was limited due to its hematologic toxicity,
      • Love B.B.
      • Biller J.
      • Gent M.
      Adverse haematological effects of ticlopidine Prevention, recognition and management.
      which subsequently led to substitution with clopidogrel. Indeed, 3 randomized studies
      • Bertrand M.E.
      • Rupprecht H.J.
      • Urban P.
      • Gershlick A.H.
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).
      • Moussa I.
      • Oetgen M.
      • Roubin G.
      • et al.
      Effectiveness of clopidogrel and aspirin vs ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation.
      • Müller C.
      • Büttner H.J.
      • Petersen J.
      • Roskamm H.
      A randomized comparison of clopidogrel and aspirin vs ticlopidine and aspirin after the placement of coronary-artery stents.
      and a meta-analysis
      • Bhatt D.L.
      • Bertrand M.E.
      • Berger P.B.
      • et al.
      Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.
      showed that clopidogrel was at least as effective as ticlopidine and was a well-tolerated, much safer antiplatelet therapy choice.

      Dual-Antiplatelet therapy after DES implantation

      DESs have diminished the need for repeat revascularization secondary to in-stent restenosis, the main limitation associated with BMS implantation.
      • Brodie B.R.
      • Stuckey T.
      • Downey W.
      • et al.
      Outcomes with drug-eluting stents vs bare metal stents in acute ST-elevation myocardial infarction: results from the Strategic Transcatheter Evaluation of New Therapies (STENT) Group.
      Currently, DES usage varies across regions, but their use is predicted to increase with the availability of later-generation DES that are associated with decreased costs, improved deliverability, and enhanced clinical outcomes.
      • Sheiban I.
      • Villata G.
      • Bollati M.
      • et al.
      Next-generation drug-eluting stents in coronary artery disease: focus on everolimus-eluting stent (Xience V).
      Although stent thrombosis occurs following only 0.5%-2% of stent placements,
      • Moussa I.D.
      • Colombo A.
      Antiplatelet therapy discontinuation following drug-eluting stent placement: dangers, reasons, and management recommendations.
      it is a major safety concern and limits the efficacy of PCI. Stent thrombosis occurs most frequently in the first month after stent implantation (subacute), but numerous cases of late (30 days to 1 year) and very late (> 1 year) stent thrombosis have been described, particularly in DES recipients.
      • Roukoz H.
      • Bavry A.A.
      • Sarkees M.L.
      • et al.
      Comprehensive meta-analysis on drug-eluting stents vs bare-metal stents during extended follow-up.
      • Bavry A.A.
      • Kumbhani D.J.
      • Helton T.J.
      • et al.
      Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials.
      • Stettler C.
      • Wandel S.
      • Allemann S.
      • et al.
      Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis.
      • Pfisterer M.Brunner-La Rocca H.P.
      • Buser P.T.
      • et al.
      Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs bare-metal stents.
      Furthermore, stent thrombosis is associated with rates of mortality as high as 45%.
      • Pfisterer M.Brunner-La Rocca H.P.
      • Buser P.T.
      • et al.
      Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs bare-metal stents.
      • Eisenstein E.L.
      • Anstrom K.J.
      • Kong D.F.
      • et al.
      Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation.
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • et al.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      Predictors of late stent thrombosis include stenting of small vessels, presence of multiple lesions, long segments implanted with overlapping stents, stenting of ostial bifurcation lesions, suboptimal stent deployment, decreased left ventricular function, advanced age, diabetes mellitus, renal failure, and ACS.
      • Moussa I.D.
      • Colombo A.
      Antiplatelet therapy discontinuation following drug-eluting stent placement: dangers, reasons, and management recommendations.
      Premature discontinuation of dual-antiplatelet therapy is associated with a marked increased risk of stent thrombosis, and in multivariate analysis, premature discontinuation of dual-antiplatelet therapy is an independent predictor of stent thrombosis.
      • Moussa I.D.
      • Colombo A.
      Antiplatelet therapy discontinuation following drug-eluting stent placement: dangers, reasons, and management recommendations.
      However, the optimal duration of dual-antiplatelet therapy post stenting is unknown. Registry data derived from DES recipients have demonstrated a protective effect of continuing dual-antiplatelet therapy beyond 24 months.
      • Pfisterer M.Brunner-La Rocca H.P.
      • Buser P.T.
      • et al.
      Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs bare-metal stents.
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • et al.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      • Tanzilli G.
      • Greco C.
      • Pelliccia F.
      • et al.
      Effectiveness of two-year clopidogrel + aspirin in abolishing the risk of very late thrombosis after drug-eluting stent implantation (from the TYCOON [two-year ClOpidOgrel need] study).
      In a recent analysis of 2 randomized clinical trials, 2701 patients who had received a DES and were free of major adverse cardiac or cerebrovascular events and major bleeding for a period of ≥ 12 months were randomized to receive clopidogrel 75 mg daily plus ASA 100-200 mg daily or ASA 100-200 mg daily alone.
      • Park S.J.
      • Park D.W.
      • Kim Y.H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      In this study, the use of dual-antiplatelet therapy for a period > 12 months post stenting was not significantly more effective than ASA monotherapy in reducing the rate of the primary composite endpoint of MI or death from cardiac causes (hazard ratio [HR] 1.65, 95% CI 0.80-3.36; P = 0.17). The Dual AntiPlatelet Therapy (DAPT) study, a large multicenter, randomized controlled trial comparing the efficacy and safety of 1 vs 2 years of dual-antiplatelet therapy with ASA and either clopidogrel or prasugrel with ASA following successful DES placement (ClinicalTrials.gov Identifier NCT00977938), is under way and may provide more information on the optimal duration of dual-antiplatelet therapy in this setting.
      Thus, in patients perceived to be at increased risk for stent thrombosis or in whom stent thrombosis could be related to dire consequences, continuation of dual-antiplatelet therapy beyond 1 year may be considered with the ideal duration remaining unknown. The individual patient decision to continue beyond 1 year must also take into account perceived bleeding risks of such an individual.
      Table 3 and Fig. 4)
      Indefinite therapy with ASA 75-162 mg daily should be used in all patients with acute or chronic ischemic heart disease without contraindications to its therapy (Class I, Level A). This includes patients who have undergone PCI.
      All patients who have undergone PCI with BMS implantation should be given clopidogrel 75 mg daily in addition to ASA 75-162 mg daily for ≥ 1 month (Class I, Level B) and up to 12 months in the absence of an excessive risk of bleeding (Class I, Level B) after stent implantation.
      For patients with recent bleeding or at increased risk for bleeding, a BMS should be implanted and clopidogrel 75 mg daily should be added to ASA 75-162 mg daily for a minimum of 2 weeks (Class I, Level B).
      All patients who have undergone PCI with DES implantation should be given clopidogrel 75 mg daily in addition to ASA 75-162 mg daily for 12 months (Class I, Level A).
      Continuation of dual-antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg daily beyond 1 year may be considered in patients with an increased risk of stent thrombosis as long as the perceived risk of bleeding is deemed acceptable (Class IIb, Level C).
      For patients with ACS who undergo stent implantation and have an increased risk of stent thrombosis (eg, STEMI, history of diabetes mellitus, or prior documented stent thrombosis), prasugrel 10 mg daily may be considered in addition to ASA 75-162 mg daily for 12 months (Class IIa, Level B). Prasugrel should be avoided in patients with an increased bleeding risk, likely to undergo CABG within 7 days, with a history of stroke or TIA, aged ≥ 75 years, or of weight < 60 kg (Class III, Level B).
      For patients with ACS who undergo stent implantation, ticagrelor 90 mg twice daily may be added to ASA 75-162 mg daily for 12 months (Class I, Level B). (Ticagrelor is currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.)
      Table 3Recommendations for antiplatelet therapy following hospital discharge for Percutaneous Coronary Intervention (PCI)
      AgentRecommended dose and duration of therapyClass (level of evidence)
      ASA75-162 mg/d indefinitelyI (A)
      Clopidogrel75 mg/d indefinitely in ASA allergy or intoleranceIIa (C)
      ASA + clopidogrelPost-BMS
       ASA 75-162 mg/d and clopidogrel 75 mg/d for ≥ 1 moI (B)
       ASA 75-162 mg/d and clopidogrel 75 mg/d for up to 12 mo in the absence of an excessive risk of bleedingI (B)
       For patients with a high risk of bleeding, a BMS should be implanted and ASA 75-162 mg/d and clopidogrel 75 mg/d continued for a minimum of 2 wkI (B)
       ASA 75-162 mg/d and clopidogrel 75 mg/d beyond 1 y may be considered if the risk of stent thrombosis is high and the risk of bleeding is lowIIb (C)
      Post-DES
       ASA 75-162 mg/d and clopidogrel 75 mg/d for 12 moI (A)
       ASA 75-162 mg/d and clopidogrel 75 mg/d beyond 1 y may be considered if the risk of stent thrombosis is high and the risk of bleeding is lowIIb (C)
      ASA + prasugrelPost-ACS
       ASA 75-162 mg/d and prasugrel 10 mg/d may be considered in patients with increased risk of stent thrombosis (eg, STEMI, history of diabetes mellitus, or prior documented stent thrombosis)IIa (B)
       ASA 75-162 mg/d plus prasugrel 10 mg/d should be avoided in patients with an increased bleeding risk, likely to undergo CABG within 7 d, with a history of stroke or TIA, aged ≥ 75 y, or weight < 60 kgIII (B)
      ASA + ticagrelor
      Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      • Post-ACS
      •  ASA 75-162 mg/d and ticagrelor
        Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
        90 mg twice daily for 12 mo
      I (B)
      The clinical reason for PCI must be taken into consideration. Specifically, if there is a discrepancy in the suggested duration of therapy, the longer duration of dual antiplatelet therapy is preferred.
      ACS, acute coronary syndrome; ASA, acetylsalicylic acid; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack.
      low asterisk Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.
      Figure thumbnail gr4
      Figure 4Postdischarge management of patients undergoing percutaneous coronary intervention (PCI). The outpatient management after a PCI is outlined for patients receiving a bare-metal stent or drug-eluting stent. ASA, acetylsalicylate acid; CABG, coronary artery bypass graft. *Currently under review by Health Canada. All recommendations concerning ticagrelor are conditional on approval by Health Canada.

      Antiplatelet Therapy Beyond 1 Year After Acute Coronary Syndrome or Percutaneous Coronary Intervention

      Working Group: Anil Gupta, MD, FRCPC, and Pierre Théroux, MD, CM, FACC, FAHA
      Antiplatelet therapy is a mainstay in the management of patients with CAD, whether acute or chronic. Other sections of this document clearly define the evidence and recommendations for the use of antiplatelet agents in the short-term management of patients with ACS or those who undergo PCI or CABG. In this section, the available data supporting long-term antiplatelet therapy in patients with stable CAD will be presented and consensus recommendations provided. However, before presenting the evidence for long-term antiplatelet therapy, it is important to note that no clinical trial can truly provide sufficient data to recommend indefinite use of medical therapy. Many of the studies quoted are indeed longer-term extensions of studies initiated during or very shortly after the acute phase and are discussed in the previous sections. Thus, “indefinite” recommendations are based on extrapolations from trials based on the data available and a contemporary understanding of CAD pathophysiology. Accordingly, therapy with certain agents (eg, lipid-lowering agents, renin-angiotensin-aldosterone system [RAAS] inhibitors) is generally accepted as life-long treatments despite the finite duration of clinical trials. Additionally, the optimal balance among efficacy, safety, cost-effectiveness, and affordability must be individualized.

      ASA therapy beyond 1 year following a medically managed ACS

      Some of the initial evidence suggesting a benefit for long-term ASA therapy is from a multicenter Canadian trial conducted by Cairns and colleagues. In this randomized trial of 555 patients with UA, those treated with ASA 325 mg 4 times daily (alone or with sulfinpyrazone 200 mg 4 times daily) for a mean of 18 months experienced a 51% reduction in the relative risk of the primary composite endpoint of cardiac death or nonfatal MI compared with patients who received sulfinpyrazone alone or placebo (8.6% vs 17.0%, absolute risk reduction 8.4%; P = 0.008).
      • Cairns J.A.
      • Gent M.
      • Singer J.
      • et al.
      Aspirin, sulfinpyrazone, or both in unstable angina Results of a Canadian multicenter trial.
      The most comprehensive data supporting the long-term benefit of ASA following ACS come from the Antithrombotic Trialists' Collaboration 2002 update.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      Among 18,788 patients with a history of previous MI, treatment with ASA vs control for a mean of 27 months prevented 36 vascular events (vascular death, MI, or stroke) per 1000 patients treated (13.5% vs 17.0%; P < 0.0001). Specifically, treatment with ASA prevented 18 nonfatal MIs (P < 0.0001), 5 nonfatal strokes (P = 0.002), and 14 vascular deaths (P = 0.0006) per 1000 patients treated.
      A more recent update of the Antithrombotic Trialists' Collaboration that reported results by an intention-to-treat analysis for ASA recipients only shed new light on the role of ASA in the secondary prevention of CAD.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      This meta-analysis included 16 secondary prevention trials and a total of 17,000 individuals, 43,000 person-years, and 3306 serious vascular events. The trials were highly variable regarding the dose of ASA used (50 mg once daily to 500 mg 3 times daily) and length of follow-up (averages ranged from 1 year to > 3 years). ASA appeared to reduce vascular mortality (rate ratio [RR] 0.91, 95% CI 0.82-1.00; P = 0.06) but had no significant effect on other mortality (RR 0.85, 95% CI 0.66-1.08; P = 0.2), leading to a 10% reduction in total mortality (RR 0.90, 95% CI 0.82-0.99; P = 0.02). A nonsignificant increase in hemorrhagic stroke was observed in the secondary prevention trials, but reductions of about one-fifth in total stroke (2.08% vs 2.54% per year; P = 0.002) and coronary events (4.3% vs 5.3% per year; P < 0.0001) were observed. No heterogeneity of effect between men and women was observed for any of the secondary prevention outcomes. Despite the potential for an increased risk of hemorrhagic stroke, hypothetical calculations of the absolute effects of ASA allocation on 5-year outcomes suggest a substantial net benefit of ASA in reducing nonfatal vascular events that is irrespective of age or sex.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      The optimal ASA dose has not been definitively established by directly comparing different dosing regimens in large, randomized clinical trials. However, most evidence suggests that low-dose ASA is preferable to higher doses for long-term secondary prevention of CAD. In the 2002 Antithrombotic Trialists' Collaboration update, an analysis of 3 trials (n = 3570) that directly compared ASA ≥ 75 mg daily with ASA < 75 mg daily failed to demonstrate a significant difference in vascular events between the dose regimens.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      Considering both direct and indirect comparisons of ASA dose, the odds of a vascular event were reduced by 19% with ASA 500 mg to 1500 mg daily, by 26% with ASA 160 mg to 325 mg daily, and by 32% with ASA 75 mg to 150 mg daily. Authors of another meta-analysis specifically addressing the optimal ASA dose concluded that there is little evidence supporting increased efficacy of ASA doses > 75-81 mg daily but much evidence to suggest that larger doses significantly increase the risk of gastrointestinal bleeding.
      • Campbell C.L.
      • Smyth S.
      • Montalescot G.
      • Steinhubl S.R.
      Aspirin dose for the prevention of cardiovascular disease: a systematic review.

      Clopidogrel vs ASA for long-term management of patients with ACS

      The CAPRIE study compared clopidogrel 75 mg daily with ASA 325 mg daily in 19,185 patients with MI experienced within 35 days, ischemic stroke experienced between 1 week and 6 months of enrollment, or symptomatic PAD.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).
      After a mean follow-up of 1.91 years, clopidogrel reduced the relative risk of the primary composite endpoint of vascular death, MI, or ischemic stroke by 8.7% vs ASA (5.32% vs 5.83% per year, absolute risk reduction 0.51% per year; P = 0.043). No major differences in safety between the 2 groups were observed. However, heterogeneity by enrolling condition was observed such that patients with a history of symptomatic PAD had improved outcomes with clopidogrel but patients with a history of stroke had only a marginal benefit and patients with a history of MI had none (relative risk increase 3.7%, 5.03% vs 4.84% per year, absolute risk increase 0.19% per year; P = 0.66).

      Antiplatelet therapy in addition to ASA beyond 1 year for patients with medically managed ACS

      Clopidogrel

      Overall, there is a paucity of a priori data evaluating the long-term (ie, > 1 year) use of clopidogrel in addition to ASA. Much of the evidence supporting its long-term use comes from the CURE trial of patients with NSTEACS.
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      In analysis of outcomes by treatment strategy (medical management, PCI, or CABG), medically managed patients (n = 7985) experienced a significant 20% relative reduction in the risk of the primary composite endpoint of cardiovascular death, nonfatal MI, or stroke at 12 months, the same benefit observed in the overall patient population.
      • 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.
      However, the optimal duration of clopidogrel therapy within 1 year of the event remains controversial given that most of the benefit associated with clopidogrel in the CURE trial was observed within the first month, although it persisted for the entire 12-month follow-up.
      • Yusuf S.
      • Mehta S.R.
      • Zhao F.
      • et al.
      Early and late effects of clopidogrel in patients with acute coronary syndromes.
      Additional data on the relative benefits of long-term dual-antiplatelet therapy with ASA and clopidogrel in patients with CAD come from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial. The CHARISMA trial was a prospective, randomized, blinded, placebo-controlled study that compared the efficacy and safety of clopidogrel 75 mg once daily plus ASA 75-162 mg once daily vs ASA 75-162 mg once daily alone in patients with clinically evident cardiovascular disease or multiple cardiovascular risk factors.
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.
      In the overall trial of 15,603 patients, there was no statistical difference in the primary composite endpoint of cardiovascular death, MI, or all-cause stroke in the group treated with clopidogrel and ASA vs ASA alone after a median 28 months of follow-up (RR 0.93, 95% CI 0.83-1.05; P = 0.22). However, in the predefined subgroup of patients with established cardiovascular disease (n = 12,153), the relative risk of the primary endpoint was reduced by 12% (6.9% vs 7.9%, RR 0.88, 95% CI 0.77-0.998; P = 0.046) with no excess of GUSTO (Global Utilization of Strategies to prevent ThrOmbosis)-defined severe bleeding.
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.
      Conversely, no benefit was observed for the 3284 patients with multiple risk factors only (RR 1.20, 95% CI 0.91-1.59; P = 0.20), and a higher rate of GUSTO-defined severe bleeding was observed for clopidogrel-plus-ASA recipients. In a post-hoc analysis of the more narrowly defined “CAPRIE-like” subgroup of 9478 patients with documented prior MI (median time from event 23.6 months), ischemic stroke (median time from event 3.5 months), or symptomatic PAD (median time from diagnosis 23.6 months), the relative risk of the primary composite endpoint was significantly lower for clopidogrel plus ASA vs ASA alone after a median 27.6-month follow-up (HR 0.83, 95% CI 0.72-0.96; P = 0.02).
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      A slightly larger benefit was observed for the 3846 patients who had a prior MI (HR 0.77, 95% CI 0.61-0.98; P = 0.031).
      • Bhatt D.L.
      • Flather M.D.
      • Hacke W.
      • et al.
      Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.
      In neither the CAPRIE-like subgroup nor the prior MI subgroups was the risk of GUSTO-defined severe bleeding significantly increased.

      Prasugrel and ticagrelor

      There is even less clinical evidence to support the long-term use of prasugrel and ticagrelor in patients with stable CAD. TRITON-TIMI 38 compared the effect of prasugrel (60-mg loading dose, 10 mg daily), another thienopyridine, with clopidogrel (300-mg loading dose, 75 mg daily) in 13,608 patients with moderate- to high-risk ACS scheduled to undergo PCI.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      All patients also received ASA 75-162 mg daily. After a median 14.5 months of follow-up, prasugrel was associated with a 19% relative reduction and a 2.2% absolute reduction in the risk of the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.81, 95% CI 0.73-0.90; P < 0.001), mainly due to a reduction of nonfatal MI (HR 0.76, 95% CI 0.67-0.85; P < 0.001). However, an increase in TIMI-defined major (HR 1.32, 95% CI 1.03-1.68; P = 0.03) and fatal (0.4% vs 0.1%; P = 0.002) bleeding was observed with prasugrel. A landmark analysis of TRITON-TIMI 38 showed that the benefit of prasugrel over clopidogrel emerged within the first 3 days of therapy and was maintained over the median 15-month follow-up period.
      • Antman E.M.
      • Wiviott S.D.
      • Murphy S.A.
      • et al.
      Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.
      Notably, the significant increase in TIMI-defined major bleeding associated with prasugrel in the primary analysis
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel vs clopidogrel in patients with acute coronary syndromes.
      emerged only on the third day of treatment but continued throughout the study.
      • Antman E.M.
      • Wiviott S.D.
      • Murphy S.A.
      • et al.
      Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.
      The PLATO trial examined, in addition to ASA 75-100 mg daily, the effect of ticagrelor (180-mg loading dose, 90 mg twice daily), an oral, reversible P2Y12 antagonist, vs that of clopidogrel (300- to 600-mg loading dose, 75 mg once daily) in 18,624 patients admitted to the hospital with ACS.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor vs clopidogrel in patients with acute coronary syndromes.
      A 16% relative reduction and 1.9% absolute reduction in the risk of the primary composite endpoint of vascular death, MI, or stroke were demonstrated at 12 months (HR 0.84, 95% CI 0.77-0.92; P < 0.001). All individual components of the primary endpoint were significantly reduced, including vascular death. In contrast with TRITON-TIMI 38, the bleeding risks observed in the PLATO trial appeared similar throughout the study duration, although ticagrelor was associated with a higher rate of non–CABG-related, trial-defined major bleeding (4.5% vs 3.8%; P = 0.03). In a landmark analysis of the PLATO trial, significant benefits for ticagrelor over clopidogrel emerged within the first 30 days and appeared to diverge in further favour of ticagrelor as treatment continued through the 1-year follow-up.
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor vs clopidogrel in patients with acute coronary syndromes.

      Post-ACS and post-PCI dual-antiplatelet therapy beyond 1 year

      The evidence derived from large clinical trials that support the use of dual-antiplatelet therapy beyond 1 year post stenting is limited. Anecdotal pathophysiological reports, various DES trial meta-analyses,
      • Roukoz H.
      • Bavry A.A.
      • Sarkees M.L.
      • et al.
      Comprehensive meta-analysis on drug-eluting stents vs bare-metal stents during extended follow-up.
      • Bavry A.A.
      • Kumbhani D.J.
      • Helton T.J.
      • et al.
      Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials.
      • Stettler C.
      • Wandel S.
      • Allemann S.
      • et al.
      Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis.
      and BASKET-LATE (Basel Stent Kosten Effektivitäts Trial–LAte Thrombotic Events)
      • Pfisterer M.Brunner-La Rocca H.P.
      • Buser P.T.
      • et al.
      Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs bare-metal stents.
      raised concern about an increase in late and very late stent thrombosis in DES recipients. A recent report from South Korea combined the results of 2 very similar randomized clinical trials in which 2701 patients who had received a DES and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of ≥ 12 months were randomized to receive clopidogrel 75 mg daily plus ASA 100-200 mg daily or ASA 100-200 mg daily alone.
      • Park S.J.
      • Park D.W.
      • Kim Y.H.
      • et al.
      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      The 2 studies were open-label, but excellent study drug adherence was reported. In this analysis, the use of dual-antiplatelet therapy for a period > 12 months was not significantly more effective than ASA monotherapy in reducing the rate of MI or death from cardiac causes as an opposite trend toward higher event rates was observed (HR 1.65, 95% CI 0.80-3.36; P = 0.17). It should be noted that due to a lower than expected rate of the primary endpoint, the study was underpowered to detect a clinically significant difference in outcomes.
      The US Food and Drug Administration (FDA) confirmed a significant reduction of long-term restenosis when DESs are used as recommended (ie, “on-label”), whereas “off-label” use of DES may be associated with an increased risk of very late stent thrombosis, MI, and death.
      • Pinto Slottow T.L.
      • Waksman R.
      Overview of the 2006 Food and Drug Administration Circulatory System Devices Panel meeting on drug-eluting stent thrombosis.
      However, more recent data suggest that off-label use of DES does not incur a greater risk than on- or off-label use of BMS.
      • Ko D.T.
      • Chiu M.
      • Guo H.
      • et al.
      Safety and effectiveness of drug-eluting and bare-metal stents for patients with off- and on-label indications.
      • Roy P.
      • Buch A.N.
      • Javaid A.
      • et al.
      Impact of “off-label” utilization of drug-eluting stents on clinical outcomes in patients undergoing percutaneous coronary intervention.
      • Carlsson J.
      • James S.K.
      • Lindbäck J.
      • et al.
      Outcome of drug-eluting vs bare-metal stenting used according to on- and off-label criteria.
      Based on the preponderance of evidence, the Canadian Association of Interventional Cardiology recommends that all patients treated with DES should remain on ASA and clopidogrel for ≥ 12 months.
      • Love M.P.
      • Schampaert E.
      • Cohen E.A.
      • et al.
      The Canadian Association of Interventional Cardiology and the Canadian Cardiovascular Society joint statement on drug-eluting stents.
      They further suggest that dual-antiplatelet therapy of a longer duration should be considered in patients treated with DES or in those whom stent thrombosis is likely to have fatal consequences (eg, recipients of multiple stents or stents for bifurcation lesions, or left main disease). Because this statement was published in 2007, no new, compelling data have led to any need to deviate from these recommendations.
      Fig. 5)
      For all patients with ACS who survive to hospital discharge, indefinite therapy with low-dose ASA (75-162 mg daily) is recommended (Class I, Level A).
      For patients allergic to or intolerant of ASA, indefinite therapy with clopidogrel 75 mg daily is recommended (Class IIa, Level B).
      Dual-antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg daily may be considered beyond 1 year in patients with ACS (see post-ACS recommendations) who are medically managed provided the risk of bleeding is low (Class IIb, Level C).
      For all post-PCI patients, indefinite therapy with ASA 75-162 mg daily is recommended, regardless of type of stent (Class I, Level A).
      Dual-antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg daily may be considered beyond 1 year in patients with ACS who receive a BMS or DES provided their risk of bleeding is low (Class IIb, Level C).
      Figure thumbnail gr5
      Figure 5Management of stable coronary artery disease. The outpatient management of patients with stable coronary artery disease or more than one year after an acute coronary syndrome may consider dual-antiplatelet therapy if high risk of thrombosis and low risk of bleeding. ACS, acute coronary syndrome: ASA, acetylsalicylate acid.

      Antiplatelet Therapy for Secondary Prevention Following Coronary Artery Bypass Grafting

      Working Group: Raymond Cartier, MD, FRCPC
      For 30 years, antiplatelet therapy has been the gold standard for preventing saphenous vein graft closure after CABG.
      • 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.
      ASA is recognized as the standard of care and is generally continued indefinitely given its benefit in preventing subsequent clinical events,
      • 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).
      although there is no evidence in the literature that antiplatelet therapy improves arterial graft patency.

      Alternative antithrombotic therapy for preventing saphenous vein graft occlusion

      Although ASA is the standard of care in preventing venous graft occlusion post CABG, other antiplatelet agents have been shown to be effective. Prospective randomized trials have shown ticlopidine 250 mg twice daily to be an effective means of preventing graft closure,
      • Chevigné M.
      • David J.L.
      • Rigo P.
      • Limet R.
      Effect of ticlopidine on saphenous vein bypass patency rates: a double-blind study.
      • Limet R.
      • David J.L.
      • Magotteaux P.
      • Larock M.P.
      • Rigo P.
      Prevention of aorta-coronary bypass graft occlusion Beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass grafts: a double-blind study.
      with a benefit that on indirect comparison appears to be similar to that of ASA. In contemporary clinical practice, clopidogrel is recommended instead of ticlopidine for patients allergic to or intolerant of ASA because clopidogrel is safer.
      • 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).
      If ticlopidine is used, white cell count monitoring is mandatory after 1 to 2 weeks and monthly thereafter.
      • Love B.B.
      • Biller J.
      • Gent M.
      Adverse haematological effects of ticlopidine Prevention, recognition and management.
      Note, however, that no randomized trial has specifically studied the efficacy of clopidogrel in prevention of post-CABG vein graft closure. Indobufen, a reversible inhibitor of platelet cyclooxygenase, and the combination of ASA and dipyridamole were once used to prevent early graft failure at 1 year
      • Rajah S.M.
      • Nair U.
      • Rees M.
      • et al.
      Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting.
      but are no longer used due to side effects and a lack of documented efficacy.
      • Goldman S.
      • Copeland J.
      • Moritz T.
      • et al.
      Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study.
      • Sethi G.K.
      • Copeland J.G.
      • Goldman S.
      • et al.
      Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy.
      Warfarin appears to be as effective as antiplatelet therapy in preventing saphenous graft closure post CABG, but it is associated with a higher risk of bleeding complications.
      • Fremes S.E.
      • Levinton C.
      • Naylor C.D.
      • et al.
      Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
      However, there is clinical evidence that reduced-intensity anticoagulation could maintain the antithrombotic effect with less anticoagulant-related bleeding.
      • Hull R.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      The combination of warfarin and ASA 330 mg 3 times daily plus dipyridamole 75 mg 3 times daily was shown to be superior to warfarin alone,
      • Brooks N.
      • Wright J.
      • Sturridge M.
      • et al.
      Randomised placebo controlled trial of aspirin and dipyridamole in the prevention of coronary vein graft occlusion.
      • Rajah S.M.
      • Salter M.C.
      • Donaldson D.R.
      • et al.
      Acetylsalicylic acid and dipyridamole improve the early patency of aorta-coronary bypass grafts A double-blind, placebo-controlled, randomized trial.
      but no trial has directly compared ASA plus warfarin with ASA alone. (Further information on the long-term use of warfarin and ASA is available in “Combination Therapy With Warfarin and ASA: When to Use, When to Consider, When to Avoid.”)

      Optimal dose of ASA post CABG

      The optimal dose of ASA after CABG has been a topic of debate. Following their extensive review of 114 manuscripts, Dunning and Das
      • Dunning J.
      • Das S.
      What is the optimal dose of aspirin after discharge following coronary bypass surgery.
      suggested that ASA 325 mg daily was the optimal dose for providing the best balance among saphenous vein graft patency, patient survival, and adverse events. In a meta-analysis of 17 studies, Fremes and colleagues
      • Fremes S.E.
      • Levinton C.
      • Naylor C.D.
      • et al.
      Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
      concluded that low (∼100 mg) and medium (∼325 mg) daily doses of ASA were more effective than high-dose (∼975 mg) ASA in preventing saphenous vein graft occlusion and caused less gastrointestinal side effects.

      Optimal timing of antiplatelet therapy initiation post CABG

      In their meta-analysis, Fremes and colleagues
      • Fremes S.E.
      • Levinton C.
      • Naylor C.D.
      • et al.
      Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
      established that to be effective, ASA had to be initiated within the first 24 hours after surgery. There was evidence that the greatest benefit was obtained when ASA was initiated in the hour immediately following surgery, although increased postoperative bleeding was reported. They concluded that the optimal benefit of ASA administration was observed when it was started 6 hours after surgery completion. They found no advantage for starting ASA prior to surgery in regard to graft occlusion prevention.

      Clopidogrel in CABG

      To date, no prospective, randomized trial has shown that adding clopidogrel to ASA after CABG improves saphenous vein graft closure prevention. There is observational evidence that dual-antiplatelet therapy may be helpful 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.
      For conventional on-pump surgery, the ongoing CASCADE (Clopidogrel After Surgery for Coronary Artery Disease) trial was recently published.
      • Kulik A.
      • Le May M.
      • Wells G.A.
      • Mesana T.G.
      • Ruel M.
      The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin vs aspirin alone after coronary bypass surgery [NCT00228423].
      Approximately 100 post-CABG patients were randomized to receive either ASA 162 mg daily plus placebo or ASA 162 mg daily plus clopidogrel 75 mg daily for 1 year, after which intravascular ultrasound and angiography was performed to assess graft patency. No difference in the primary outcome of graft intimal hyperplasia was noted for dual-antiplatelet therapy over ASA alone. No statistical differences were noted in the secondary vascular or graft patency outcomes, nor were differences noted in major bleeding.
      • Kulik A.
      • Le May M.R.
      • Voisine P.
      • et al.
      Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) Trial.
      In a direct comparison of clopidogrel 75 mg daily vs clopidogrel 75 mg plus ASA 100 mg daily conducted among 197 patients, angiographic patency at 1 and 12 months post surgery was similar in the 2 groups, suggesting the absence of benefit for adding clopidogrel to ASA following CABG.
      • Gao C.
      • Ren C.
      • Li D.
      • Li L.
      Clopidogrel and aspirin vs clopidogrel alone on graft patency after coronary artery bypass grafting.

      ACS, PCI, and CABG

      Although there is no proven benefit for the postoperative use of clopidogrel plus ASA in improving graft patency, dual-antiplatelet therapy might benefit specific subsets of patients in regard to general thrombotic complications. Several randomized clinical trials, including the CURE and CREDO trials, have provided randomized data to clinicians. In the CURE trial of patients with NSTEACS, the majority of benefit observed for clopidogrel (300-mg loading dose, 75 mg daily) plus ASA (75 mg to 325 mg daily) in the overall population was maintained in the 2072 patients who underwent CABG as part of their revascularization strategy (relative risk reduction in the composite endpoint of cardiovascular death, nonfatal MI, or stroke, 11%; 14.5% with clopidogrel vs 16.2% with ASA; absolute risk reduction 1.7%).
      • 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.
      Most of this benefit was derived from those patients who underwent CABG during the initial hospitalization period (relative risk reduction 19%, 13.4% vs 16.4%, absolute risk reduction 3.0%). The significant benefit of clopidogrel was limited to the period prior to CABG. In the CREDO trial of patients undergoing nonurgent PCI, the subgroup of patients who underwent CABG instead of PCI showed some reduction in the risk of sudden death, new MI, or stroke over the following 12 months.
      • 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.
      However, the cohort of surgical patients was small (n = 83) and the results were not significant.
      There is some evidence that the in-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.
      Therefore, patients requiring CABG after PCI should remain on clopidogrel and ASA for 9 to 12 months as recommended per the post-PCI guidelines, particularly if the stented vessel is not bypassed during surgery.
      • Popma J.J.
      • Berger P.
      • Ohman E.M.
      • et al.
      Antithrombotic therapy during percutaneous coronary intervention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      Clopidogrel can be suspended if the stented vessel is bypassed unless other preoperative conditions that suggest its use are
      Fig. 6)
      For all patients who undergo saphenous vein CABG, ASA 75-162 mg daily is recommended as lifelong therapy unless contraindicated (Class I, Level A). ASA should be initiated within 24 hours of surgery completion (Class IIa, Level B).
      For all patients who undergo saphenous vein CABG and have a contraindication to ASA, clopidogrel 75 mg daily is preferred over ticlopidine 250 mg twice daily due to the superior safety profile of clopidogrel (Class IIa, Level C).
      In patients undergoing CABG after PCI, dual-antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg daily may be maintained for 9-12 months unless the stented vessel is adequately bypassed (Class IIb, Level C).
      Figure thumbnail gr6
      Figure 6Management of post-coronary artery bypass graft. The outpatient management of patients after coronary artery bypass graft is outlined in this figure and may include dual-antiplatelet therapy when a recently stented vessel is not adequately bypassed. ASA, acetylsalicylate acid; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

      Antiplatelet Therapy for Secondary Prevention of Cerebrovascular Disease

      Working Group: Ashfaq Shuaib, MD, FRCP, and Philip Teal, MD, FRCP
      Patients who present with TIA or ischemic stroke are at an increased risk of recurrent stroke and other vascular events. The risk is highest in the initial 2 days after the event and may remain high for the subsequent 90 days.
      • Giles M.F.
      • Rothwell P.M.
      Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis.
      Overall, the risk of stroke at 90 days is ∼17% (95% CI 9%-25%) when the outcome is actively ascertained,
      • Wu C.M.
      • McLaughlin K.
      • Lorenzetti D.L.
      • et al.
      Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis.
      and the risk of combined vascular complications (ie, MI, stroke, and vascular death) is ∼44% (95% CI 42%-46%) at 10 years.
      • van Wijk I.
      • Kappelle L.J.
      • van Gijn J.
      • et al.
      Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study.
      The ABCD2 score is often used to classify the risk of subsequent stroke.
      • Giles M.F.
      • Rothwell P.M.
      Systematic review and pooled analysis of published and unpublished validations of the ABCD and ABCD2 transient ischemic attack risk scores.
      Clinical features that should be considered when assessing the risk of ischemic stroke recurrence include age, the type of symptoms (eg, patients presenting with motor and speech impairment are at a high risk of early recurrence), the presence of diabetes or hypertension, and the duration of symptoms. Notably, expedited evaluation and early treatment may lower the risk of recurrence.
      • Rothwell P.M.
      • Giles M.F.
      • Chandratheva A.
      • et al.
      Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.
      Recently updated consensus statements from the Canadian Stroke Network,
      • Lindsay P.
      • Bayley M.
      • McDonald A.
      • et al.
      Toward a more effective approach to stroke: Canadian Best Practice Recommendations for Stroke Care.
      the American Heart Association (AHA)/American Stroke Association,
      • Adams R.J.
      • Albers G.
      • Alberts M.J.
      • et al.
      Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack.
      and the American College of Chest Physicians
      • Albers G.W.
      • Amarenco P.
      • Easton J.D.
      • Sacco R.L.
      • Teal P.
      Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      incorporate newer data on the use of antiplatelet agents in secondary ischemic stroke prevention.

      Antithrombotic therapy for prevention of stroke in patients with a history of TIA or ischemic stroke

      A number of trials have looked at the efficacy and safety of antithrombotic medications in the prevention of recurrence in patients with TIA and ischemic stroke. The best evidence is for antiplatelet agents, of which ASA has been studied most extensively. Overall, ASA reduces the risk of vascular events by ∼13% (95% CI 6%-19%) compared with controls.
      • Algra A.
      • van Gijn J.
      Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin.
      In the second Antithrombotic Trialists' Collaboration meta-analysis published in 2002, the protective effects of ASA were observed for both young and old subjects and men and women and in patients with and without hypertension or diabetes.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      In the Algra and van Gijn mini–meta-analysis of trials specifically looking at stroke recurrence in patients with a previous history of TIA or ischemic stroke, the incidence of recurrent stroke was no different in patients taking high-dose (> 1000 mg daily) or low-dose (< 100 mg daily) ASA.
      • Algra A.
      • van Gijn J.
      Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia.

      ASA compared with placebo

      The Canadian Aspirin Trial was the first major study to evaluate the efficacy of ASA for reducing stroke recurrence. In total, 585 patients with TIA were enrolled in a randomized, blinded study comparing ASA 1300 mg daily (alone or in combination with sulfinpyrazone) with placebo.
      The Canadian Cooperative Study Group
      A randomized trial of aspirin and sulfinpyrazone in threatened stroke.
      There was a significant 31% reduction in the relative risk of stroke or death in the ASA-treated group. The effect was sex-dependent (48% risk reduction in men vs no effect in women). The absence of an effect in women was likely due to an insufficient number of women enrolled in the trial.
      In SALT (Swedish Aspirin Low-dose Trial), ASA 75 mg daily was compared with placebo in 1360 patients with TIA or minor ischemic stroke.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      There was a significant 18% reduction in the relative risk of recurrent stroke or death, as well as a significant 17% relative reduction in the risk of MI or other vascular death, in the ASA-treated group.

      Comparison of different doses of ASA

      The Dutch TIA Trial compared ASA 30 mg daily with ASA 283 mg daily in 3131 patients with TIA or minor ischemic stroke.
      The Dutch TIA Trial Study Group
      A comparison of two doses of aspirin (30 mg versus. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke.
      The lower ASA dose was as effective as the higher dose in preventing the primary outcome of recurrent stroke, MI, or vascular death. Furthermore, fewer bleeding events were observed in the low-dose groups. The UK-TIA (United Kingdom Transient Ischaemic Attack) trial treated 2435 patients with TIA or minor ischemic stroke with ASA 600 mg twice daily (n = 815), ASA 300 mg once daily (n = 806), or placebo (n = 814) in a prospective, randomized, and double-blinded fashion.
      • Farrell B.
      • Godwin J.
      • Richards S.
      • Warlow C.
      The United Kingdom Transient Ischaemic Attack (UK-TIA) aspirin trial: final results.
      There were no differences in stroke recurrence between the 2 doses of ASA, but the lower dose resulted in significantly fewer gastrointestinal complications. The odds of reaching the primary composite endpoint of stroke, MI, or vascular death were significantly lower (15%) in the 2 actively treated groups compared with the control group.

      Other antiplatelet agents

      Ticlopidine is a thienopyridine antiplatelet agent that blocks the platelet P2Y12 ADP receptor, resulting in an inhibition of fibrinogen binding to platelets. Two large trials evaluated the efficacy of ticlopidine in preventing recurrent stroke in patients with previous cerebrovascular disease. CATS (Canadian American Ticlopidine Study) enrolled 1072 patients who had sustained a thromboembolic stroke.
      • Gent M.
      • Blakely J.A.
      • Easton J.D.
      • et al.
      The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.
      In this study, ticlopidine 250 mg twice daily was compared with placebo. The risk of the primary composite endpoint of stroke, MI, or vascular death was 15.3% per year in the placebo group and 10.8% per year in the ticlopidine group (relative risk reduction 30.2%, 95% CI 7.5%-48.3%). In TASS (Ticlopidine ASpirin Stroke trial), 3069 subjects who experienced cerebral or retinal ischemia or TIA within the previous 3 months were randomized to ticlopidine 250 mg twice daily or ASA 650 mg twice daily.
      • Hass W.K.
      • Easton J.D.
      • Adams Jr, H.P.
      • et al.
      A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients Ticlopidine Aspirin Stroke Study Group.
      Compared with ASA, ticlopidine reduced the relative risk of the primary endpoint, recurrent stroke, by 21% (95% CI 4%-38%) at 3 years. A 12% (95% CI –2% to 26%) decrease in the relative risk of nonfatal stroke or death was also evident in the ticlopidine-treated patients compared with those who were treated with ASA.
      Clopidogrel, another thienopyridine antiplatelet agent, was initially evaluated in stroke prevention in the CAPRIE study.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).
      The CAPRIE study enrolled 19,185 patients with a history of MI within 35 days of randomization (n = 6302), ischemic stroke between 1 week or 6 months of randomization (n = 6431), or symptomatic PAD (n = 6452) and randomized them to clopidogrel 75 mg daily or ASA 325 mg daily. In the total population, the risk of the primary composite endpoint of ischemic stroke, MI, or vascular death was significantly reduced from 5.83% per year in the ASA group to 5.32% per year in the clopidogrel group (relative risk reduction 8.7%, 95% CI 0.3%-16.5%; P = 0.043). In the subgroup of patients with a history of ischemic stroke, clopidogrel reduced the event rate from 7.71% per year to 7.15% per year, although this difference was not significant (relative risk reduction 7.3%; P = 0.26). However, the CAPRIE trial was not designed to examine treatment effects in individual patient subgroups.
      There are additional studies that have compared the efficacy and safety of clopidogrel with other antiplatelet therapy regimens. These include the MATCH (Management of ATherothrombosis for Continued Health) and PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) trials. In the MATCH trial, 7599 patients with ischemic stroke or TIA were treated with clopidogrel 75 mg daily or clopidogrel 75 mg daily plus ASA 75 mg daily for 18 months.
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial.
      The primary composite endpoint of ischemic stroke, MI, vascular death, or rehospitalization for an acute ischemic event was evident in 15.7% of patients receiving combination therapy and 16.7% of patients on clopidogrel-alone treatment. The 6.4% relative risk reduction associated with combination therapy was not significantly better than clopidogrel monotherapy (P = 0.244). Additionally, there was a significantly higher risk of trial-defined life-threatening bleeds in the combination therapy group (2.6% vs 1.3%; P < 0.0001). The PRoFESS trial was a comparison between clopidogrel 75 mg once daily and the combination of extended-release (ER) dipyridamole 200 mg twice daily and ASA 25 mg twice daily in 20,332 patients with ischemic stroke.
      • Sacco R.L.
      • Diener H.C.
      • Yusuf S.
      • et al.
      Aspirin and extended-release dipyridamole vs clopidogrel for recurrent stroke.
      After a mean duration of 2.5 years, no difference in the risk of the primary endpoint, stroke recurrence of any type, was observed (8.8% on clopidogrel vs 9.0% on ASA plus ER dipyridamole; HR 1.01; 95% CI 0.92-1.11). The rate of the secondary composite endpoint of stroke of any type, MI, or vascular death was 13.1% in each treatment group.
      The combination of ASA and clopidogrel is recommended for patients post ACS and post PCI (see sections on ACS and PCI for specific recommendations). However, there are limited data on the use of this combination for stroke prevention. As evidenced in the MATCH trial, the long-term combination of ASA and clopidogrel is not superior to the use of clopidogrel alone and may increase the risk of systemic and intracranial hemorrhage (2.6% on combination and 1.3% on clopidogrel alone).
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial.
      The FASTER (Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence) trial, a small pilot study (N = 392) on the use of the combination initiated within 24 hours of TIA or minor ischemic stroke onset, suggested a trend toward better 90-day outcomes in the combination group compared with ASA 81 mg once daily alone.
      • Kennedy J.
      • Hill M.D.
      • Ryckborst K.J.
      • et al.
      Fast Assessment of Stroke and Transient ischaemic attack to prevent Early Recurrence (FASTER): a randomised controlled pilot trial.
      Six patients treated with clopidogrel and ASA experienced an intracranial or extracranial hemorrhage, whereas none treated with ASA alone did so. A larger study of 633 patients with minor ischemic stroke or TIA noted significantly increased rates of major and life-threatening bleeding in patients treated acutely with ASA plus clopidogrel vs ASA alone.
      • Geraghty O.C.
      • Kennedy J.
      • Chandratheva A.
      • et al.
      Preliminary evidence of a high risk of bleeding on aspirin plus clopidogrel in aspirin-naive patients in the acute phase after TIA or minor ischaemic stroke.
      Similar to the FASTER study, this effect was only noted in ASA-naive subjects.
      The combination of ER dipyridamole and ASA is considerably better than ASA alone in preventing recurrent stroke in patients with TIA or previous stroke. In ESPS-2 (European Stroke Prevention Study 2), the safety and efficacy of ER dipyridamole 200 mg twice daily plus ASA 25 mg twice daily were compared with ER dipyridamole 200 mg twice daily, ASA 25 mg twice daily, or placebo in 6602 patients with a history of ischemic stroke or TIA.
      • Diener H.C.
      • Cunha L.
      • Forbes C.
      • et al.
      European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.
      After 2 years of follow-up, both ER dipyridamole (16% relative reduction) and ASA (18% relative reduction) were significantly better than placebo in reducing the risk of fatal or nonfatal recurrent stroke. The combination of ER dipyridamole and ASA was significantly better than placebo (37% relative risk reduction) and ASA (23% relative risk reduction). A second trial comparing ASA plus dipyridamole with ASA was ESPRIT (European/Australasian Stroke Prevention in Reversible Ischemia Trial). In ESPRIT, 2739 patients with a history of ischemic stroke or TIA in the previous 6 months were randomized to ASA 30-325 mg per day with or without dipyridamole 200 mg twice daily.
      • Halkes P.H.
      • van Gijn J.
      • Kappelle L.J.
      • Koudstaal P.J.
      • Algra A.
      Aspirin plus dipyridamole vs aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.
      Notably, not all patients received ER preparations of dipyridamole, and the study was not blinded, although event adjudication was. After a mean follow-up of 3.5 years, ASA plus dipyridamole reduced the relative risk of the primary composite outcome of nonfatal stroke, nonfatal MI, vascular death, or nonfatal, trial-defined major bleeding by 20% compared with ASA alone (13% vs 16%, absolute risk reduction 3%). When major bleeding was excluded from the composite endpoint, the relative risk reduction was 22% (11% vs 14%, absolute risk reduction 3%). However, patients in the combination group more often discontinued study medication due to side effects, mainly headache. The most recent trial studying the efficacy and safety of ASA plus ER dipyridamole was the previously described PRoFESS trial.
      • Sacco R.L.
      • Diener H.C.
      • Yusuf S.
      • et al.
      Aspirin and extended-release dipyridamole vs clopidogrel for recurrent stroke.

      Summary

      Ischemic stroke comprises multiple mechanisms that include artery-to-artery emboli, cardioembolism, occlusion/damage of small vessels by localized mechanisms (ie, lacunar stroke), and a number of other uncommon conditions. Patients presenting with TIAs have similar underlying pathophysiology but recover earlier than patients who experience an ischemic stroke, likely due to faster reestablishment of blood flow to the ischemic region. The majority of studies examining the use of antiplatelet therapy in secondary stroke prevention enrolled patients with TIA or mild ischemic strokes and excluded patients with a cardioembolic mechanism or a rare cause of ischemic stroke. Treatment algorithms and published guidelines do not generally differentiate between patients with TIA or ischemic noncardioembolic stroke. Early treatment with antiplatelet agents and the appropriate management of associated risk factors remain the best means to prevent recurrent stroke and other vascular complications in patients with TIA or ischemic stroke.
      Fig. 7)
      Patients who sustain a TIA or ischemic stroke of noncardiac origin should be treated with an antiplatelet agent (Class I, Level A). Initial therapy should be ASA 75-162 mg once daily, clopidogrel 75 mg once daily, or ER dipyridamole 200 mg twice daily plus ASA 25 mg twice daily (Class I, Level A). The choice of antiplatelet therapy regimen is determined by consideration of cost, tolerance, and other associated vascular conditions. Available data do not allow for differentiation of antiplatelet regimen by specific stroke subtype (Class IIb, Level C).
      The combination of ASA 75-162 mg daily plus clopidogrel 75 mg daily in the first month after TIA or minor ischemic stroke may be superior to ASA alone in patients not at a high risk of bleeding (Class IIb, Level C).
      The combination of ASA 75-162 mg daily plus clopidogrel 75 mg daily should not be used for secondary stroke prevention beyond 1 month unless otherwise indicated and the risk of bleeding is low (Class III, Level B).
      Figure thumbnail gr7
      Figure 7Management of transient ischemic attack (TIA) and ischemic stroke. The outpatient management of TIA or ischemic stroke of noncardiac origin can include dual-antiplatelet therapy for the first month. ASA, acetylsalicylate acid; ER, extended-release; TIA, transient ischemic attack.

      Antiplatelet Therapy for Vascular Prevention in Patients With Peripheral Artery Disease

      Working Group: André Roussin, MD, FRCP, and Thomas F. Lindsay, MD, CM, FRCSC
      Compared with coronary and cerebrovascular disease, antiplatelet therapy in PAD has a disadvantage of much smaller studies in which agents other than ASA are frequently grouped. This leads to recommendations that differ somewhat between scientific societies. For example, the Canadian Consensus recommends antiplatelet therapy, namely ASA or clopidogrel, for all patients with PAD at a grade IA level of recommendation.
      • Abramson B.L.
      • Huckell V.
      • Anand S.
      • et al.
      Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease—executive summary.
      This recommendation is based on the Antithrombotic Trialists' Collaboration meta-analysis, which concluded that antiplatelet agents as a class are effective in preventing vascular endpoints in patients with PAD.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      In contrast, the Trans-Atlantic Inter-Society Consensus (TASC II),
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • et al.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      the AHA/ACC,
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • et al.
      ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
      the Scottish Intercollegiate Guidelines Network,
      Scottish Intercollegiate Guidelines Network, Diagnosis and management of peripheral arterial disease
      a national clinical guideline.
      and the American College of Chest Physicians
      • Sobel M.
      • Verhaeghe R.
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      recommend antiplatelet therapy with varying grade levels of recommendation depending on whether the patient is symptomatic or has associated coronary or cerebrovascular disease. The present recommendations are based on a review of all existing guidelines and publications, taking into account Canadian expertise.

      PAD: The asymptomatic and the symptomatic patient

      Patients with asymptomatic PAD

      In the clinical setting, patients are said to have asymptomatic PAD whenever a bruit is found along major vessels or when peripheral pulsations are reduced or absent. Finding an abnormally enlarged artery, leading to suspicion of an aneurysm, is also evidence of asymptomatic PAD. The formal definition of asymptomatic PAD is usually described in the literature as an ankle-brachial index (ABI) ≤ 0.9.
      • Hiatt W.R.
      Medical treatment of peripheral arterial disease and claudication.
      • Doobay A.V.
      • Anand S.S.
      Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review.
      Patients with asymptomatic PAD usually harbour traditional risk factors; however, patients with asymptomatic PAD and diabetes or coexisting CAD or cerebrovascular disease are a subclass of patients who have different antiplatelet therapy indications. Patients with asymptomatic PAD with an ABI < 0.9 have been shown in many studies to present with a cardiovascular morbidity and mortality rate approximately halfway between that of a patient with a normal ABI and that of a patient with claudication.
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      There is only 1 randomized clinical trial assessing the use of antiplatelet agents specifically in asymptomatic PAD.
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      This study enrolled 3350 patients with an ABI ≤ 0.95 and randomized them to ASA 100 mg daily or placebo. No reduction in stroke, MI, revascularization, or mortality was demonstrated. A modest, nonsignificant increase in bleeding was observed in the ASA group. Similarly, a 2 × 2 factorial randomized clinical trial conducted in 1276 patients with diabetes and asymptomatic PAD (defined as ABI < 1.0) revealed an absence of benefit of ASA 100 mg once daily or antioxidant combined or alone compared with placebo after a mean follow-up of 6.7 years.
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention Of Progression of Arterial Disease And diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      The trial was powered to show an efficacy of 25%, and a higher than usual ABI was selected because of the notion that patients with diabetes have harder arteries. It is striking, however, that the median ABI of all patients in the study was ∼0.9, which is the standard cutoff point for normality. A subgroup analysis of the 314 patients with an ABI ≤ 0.9 (roughly as many as > 0.9) showed an odds ratio of 0.81 (0.58-1.14) for the primary endpoint that did not reach statistical significance (P = 0.089).

      Patients with symptomatic PAD, including claudication, critical limb ischemia, or amputation

      In the clinical setting, symptomatic PAD refers to patients with claudication, rest pain, or ischemic lesions. Other symptoms are less reliable. Most of these patients will have an ABI ≤ 0.9, with a minority showing PAD only by Doppler criteria during a treadmill evaluation. Symptomatic PAD has been shown in many settings to harbour a high risk of cardiovascular events and total mortality, even after multivariate analysis that takes into account the usual risk factors.
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      A systematic review of 24 randomized clinical trials of antiplatelet therapy for the prevention of MI, stroke, or vascular death in patients with PAD published between 1990 and 1999 found the number of events to be 6.5% for the antiplatelet therapy treatment group, compared with 8.1% for the placebo group (odds ratio [OR] 0.78, 95% CI 0.63-0.96).
      • Robless P.
      • Mikhailidis D.P.
      • Stansby G.
      Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease.
      This analysis included ASA, other cyclooxygenase inhibitors, ticlopidine, and clopidogrel, as well as 2 agents not available in Canada (suloctidil and picotamide).
      The Antithrombotic Trialists' Collaboration reviewed the efficacy of antiplatelet therapy in PAD, including ASA, dipyridamole, ticlopidine, clopidogrel, and picotamide. By including all 42 trials of 9214 patients with claudication or peripheral grafting or angioplasty, there was a 23% odds reduction of vascular events (P = 0.004).
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      The same reduction was observed with a nonsignificant heterogeneity test in the 26 trials including 6263 patients with claudication only. Low-dose ASA (75-150 mg daily) was as effective as higher doses. Based largely on this meta-analysis, the Canadian Consensus group arrived at a grade 1A recommendation for the use of ASA or clopidogrel therapy for patients with symptomatic PAD.
      • Abramson B.L.
      • Huckell V.
      • Anand S.
      • et al.
      Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease—executive summary.
      Recently, a new meta-analysis focusing specifically on randomized clinical trials comparing ASA, with or without dipyridamole, with placebo in patients with PAD included 18 studies comprising 5269 patients.
      • Berger J.S.
      • Krantz M.J.
      • Kittelson J.M.
      • Hiatt W.R.
      Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials.
      For the primary endpoint of cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death), the analysis had 88% power to detect a 25% reduction in cardiovascular events and 70% power to detect a 20% reduction in the ASA group compared with the control group. Cardiovascular events were experienced by 251 of 2823 (8.9%) patients taking ASA alone or with dipyridamole and by 269 of 2446 (11.0%) in the control group (pooled RR 0.88, 95% CI 0.76-1.04). ASA therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2823 [1.8%] vs 76 of 2446 [3.1%], RR 0.66, 95% CI 0.47-0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3019 participants taking ASA alone vs control, ASA was associated with a nonsignificant reduction in cardiovascular events (125 of 1516 [8.2%] vs 144 of 1503 [9.6%], RR 0.75, 95% CI 0.48-1.18), a significant reduction in nonfatal stroke (32 of 1516 [2.1%] vs 51 of 1503 [3.4%], RR 0.64, 95% CI 0.42-0.99) but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. As stated by the authors,
      • Berger J.S.
      • Krantz M.J.
      • Kittelson J.M.
      • Hiatt W.R.
      Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials.
      results for the primary endpoint may reflect limited statistical power due to the small size and scope of the majority of studies.
      The largest single study of antiplatelet drugs comprising patients with PAD is the CAPRIE trial, which compared clopidogrel 75 mg once daily with ASA 325 mg once daily in 19,185 patients with MI within 35 days of randomization, ischemic stroke within 1 week to 6 months of randomization, or symptomatic PAD.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).
      The primary outcome was the composite of MI, ischemic stroke, or vascular death, and patients were followed for a mean of 1.9 years. The results demonstrated that clopidogrel was slightly more effective than ASA in reducing the combined outcome of MI, ischemic stroke, or vascular death (8.7% relative risk reduction, P = 0.043) with a similar safety profile. In the subgroup of 6452 patients with PAD, there was a highly significant reduction in major vascular outcomes of clopidogrel over ASA (23.8% relative risk reduction, P = 0.0028).
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE).
      The addition of dipyridamole to ASA produced no significant further reduction in vascular events compared with ASA alone.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      The combined use of low-doses ASA 75-162 mg once daily with clopidogrel 75 mg once daily was not shown to be superior to ASA alone in the CHARISMA trial, which followed 15,603 patients for a median of 28 months.
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.
      The rate of the primary efficacy endpoint of MI, all-cause stroke, or cardiovascular death was 6.8% with clopidogrel plus ASA and 7.3% with placebo plus ASA (RR 0.93, 95% CI 0.83-1.05; P = 0.22). The inclusion criteria led to 21% of patients having risk factors without overt atherosclerotic disease and 78% having documented vascular disease, of whom 23% had symptomatic PAD. In the much larger subgroup of symptomatic patients, the rate of events was 6.9% with clopidogrel and 7.9% with placebo (RR 0.88, 95% CI 0.77-0.998; P = 0.046).
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.
      The possible role of oral anticoagulants, mostly warfarin or acenocoumarol adjusted to an international normalized ratio (INR) of 2.0-3.0, in addition to antiplatelet therapy, namely mostly with ASA 81-325 mg once daily, ticlopidine, or clopidogrel, compared with antiplatelet therapy alone was resolved in the WAVE (Warfarin and Antiplatelet Vascular Evaluation) trial.
      • Anand S.
      • Yusuf S.
      • Xie C.
      • et al.
      Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.
      This multicenter, open-label, randomized controlled trial of 2161 patients with PAD (82% with lower limb PAD, others with carotid or subclavian disease) followed for a mean of 35 months demonstrated that in patients with PAD, the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications. Life-threatening bleeding occurred in 4.0% of patients of receiving combination therapy compared with 1.2% of patients receiving antiplatelet therapy alone (RR 3.41, 95% CI 1.84-6.35; P < 0.001).

      Antiplatelet therapy for patients with PAD who undergo endovascular intervention

      Angioplasty with or without stent placement is a cornerstone of therapy for treating patients with claudication and increasingly, patients with limb-threatening ischemia. Because ASA is already recommended for all patients with symptomatic PAD, the question is whether the addition of a second agent can improve patency following angioplasty given the data on dual-antiplatelet agents in the coronary circulation.
      For patients undergoing lower extremity balloon angioplasty (with or without stenting) for chronic symptomatic PAD, the American College of Chest Physicians recommends long-term ASA 75-100 mg daily (Grade 1C) but recommends against anticoagulation with heparin or vitamin K antagonists (Grade 1A).
      • Sobel M.
      • Verhaeghe R.
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      At present, there is no randomized evidence that dual-antiplatelet therapy improves patency for primary angioplasty in the peripheral circulation. This area is in evolution as angioplasty and recanalization of superficial femoral, popliteal, and tibial vessels are increasing in frequency. Dual-antiplatelet therapy may be beneficial under these conditions; however, this has yet to be subjected to randomized trial comparisons.

      Antiplatelet agents following peripheral surgical bypass

      Antiplatelet agents have been studied most often in those who have undergone infrainguinal bypass surgery. However, low-dose ASA is recommended by the American College of Chest Physicians for all patients who undergo arterial reconstruction, including aortobifemoral reconstructions, axillofemoral or bifemoral bypass, iliofemoral bypass, common femoral repair, and profundaplasty.
      • Sobel M.
      • Verhaeghe R.
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      For those undergoing infrainguinal reconstruction with venous conduits or prosthetic grafts, low-dose ASA is recommended (Grade 1A). Anticoagulation with vitamin K antagonists is not recommended for routine postoperative use (Grade 2A). The recommendation against anticoagulation with vitamin K antagonists (target INR 3.0-4.5) or low-molecular-weight heparins in patients with prosthetic grafts is because these agents have not been associated with improved patency compared with ASA and they significantly increase the risk of bleeding.
      The BOA Study Group
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial.
      However, in those with infrainguinal grafts with a high risk of thrombosis and limb loss, combination vitamin K antagonist and ASA therapy may be of benefit in select cases (Grade 2B).
      • Sobel M.
      • Verhaeghe R.
      Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

      Antiplatelet therapy for the treatment of AAA

      There are no randomized trials that have examined the role of antiplatelet agents in the prevention of MI, stroke, or cardiovascular death in patients with AAA. Aortic aneurysms are associated with increasing age, male sex, hypertension, and smoking,
      • Zankl A.R.
      • Schumacher H.
      • Krumsdorf U.
      • et al.
      Pathology, natural history and treatment of abdominal aortic aneurysms.
      • Grootenboer N.
      • Bosch J.L.
      • Hendriks J.M.
      • van Sambeek M.R.
      Epidemiology, aetiology, risk of rupture and treatment of abdominal aortic aneurysms: does sex matter?.
      suggesting that atherosclerosis may be a component of AAA pathophysiology. In a study in which coronary angiography was performed in 1000 consecutive preoperative vascular surgery patients, 26% of patients had AAA.
      • Hertzer N.R.
      • Beven E.G.
      • Young J.R.
      • et al.
      Coronary artery disease in peripheral vascular patients A classification of 1000 coronary angiograms and results of surgical management.
      Of these individuals, 35% had normal coronary arteries (6%) or mild to moderate disease (29%), a further 29% had advanced but compensated CAD, and 31% had correctable CAD. Thus, AAA etiology is likely a spectrum that ranges from pure atherosclerosis to a pure degenerative disease.
      It is not a surprise to vascular specialists that a recent study suggested that the presence of an AAA is a measure of subclinical atherosclerosis.
      • Freiberg M.S.
      • Arnold A.M.
      • Newman A.B.
      • et al.
      Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study.
      An analysis of the REACH Registry, which enrolled outpatients with either established atherosclerosis or a high risk thereof, prospectively noted that there was an established diagnosis of AAA in 2.5% of that cohort.
      • Baumgartner I.
      • Hirsch A.T.
      • Abola M.T.
      • et al.
      Cardiovascular risk profile and outcome of patients with abdominal aortic aneurysm in out-patients with atherothrombosis: data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry.
      The prevalence of an AAA was 2.8% in those with symptomatic atherothrombosis compared with 1.2% in those with ≥ 3 atherosclerotic risk factors. When 1-year outcomes were compared between those with and without AAA, rates of fatal and nonfatal coronary and cerebrovascular events did not differ between the cohorts. However, significantly increased rates of cardiovascular deaths and hospitalizations for atherothrombotic events, including coronary, carotid, and peripheral vascular interventions and surgical revascularizations, were observed in patients with AAA. The REACH data support the concept that those with a diagnosis of AAA are at increased risk of adverse atherosclerotic events and that prophylactic use of ASA in this patient population would likely be of benefit. Preliminary evidence for the prophylactic use of antiplatelet therapy comes from a prospective study in which low-dose ASA was associated with a reduced expansion rate and a reduced risk of AAA surgery in patients whose aortic size was 40-49 mm.
      • Lindholt J.S.
      • Sorensen H.T.
      • Michel J.B.
      • Thomsen H.F.
      • Henneberg E.W.
      Low-dose aspirin may prevent growth and later surgical repair of medium-sized abdominal aortic aneurysms.
      Low-dose ASA is recommended for those with an AAA, with the evidence stronger for those with clinical or subclinical PAD.
      Figure 8, Figure 9)
      For patients with asymptomatic PAD with an ABI < 0.9, low-dose ASA (75-162 mg daily) may be considered for those at high risk because of associated atherosclerotic risk factors in the absence of risk factors for bleeding (Class IIb, Level C).
      For patients with symptomatic PAD without overt CAD or cerebrovascular disease, low-dose ASA (75-162 mg daily) or clopidogrel 75 mg daily is recommended, providing the risk for bleeding is low (Class IIb, Level B). The choice of drug may depend on patient preference and cost considerations.
      For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B).
      For patients with intermittent claudication, dipyridamole should not be used in addition to ASA (Class III, Level C).
      For patients with intermittent claudication, using clopidogrel 75 mg daily in addition to ASA 75-162 mg daily is not recommended unless the patient is judged to be at high vascular risk along with a low risk of bleeding (Class IIb, Level B).
      For patients with symptomatic PAD with overt CAD or cerebrovascular disease, antiplatelet therapy as indicated for the CAD and/or cerebrovascular status is recommended (Class I, Level A).
      For patients with symptomatic PAD without compelling indications for oral anticoagulation such as atrial fibrillation or venous thromboembolism, oral anticoagulation should not be added to antiplatelet therapy (Class III, Level B).
      For patients with symptomatic PAD with an indication for oral anticoagulation such as atrial fibrillation, venous thromboembolism, heart failure, or mechanical valves, antiplatelet therapy should not be added to oral anticoagulation (Class III, Level A).
      Long-term antiplatelet therapy with ASA 75-162 mg daily should be given to patients who undergo lower-extremity balloon angioplasty with or without stenting for chronic symptomatic PAD (Class IIa, Level C). Anticoagulation with heparin or vitamin K antagonists should be avoided in this setting (Class III, Level B).
      For all infrainguinal reconstructions, low-dose ASA (75-162 mg daily) should be given (Class IIa, Level B). In those with infrainguinal grafts and a high risk of thrombosis or limb loss, combination therapy with a vitamin K antagonist and ASA may be of benefit (Class IIb, Level C).
      Low-dose ASA (75-162 mg daily) may be considered for all patients with an AAA, particularly those with clinical or subclinical PAD (Class IIb, Level C).
      Figure thumbnail gr8
      Figure 8Management of peripheral arterial disease (PAD). The outpatient management of patients with symptomatic or asymptomatic PAD is outlined. ASA, acetylsalicylate acid; CAD, coronary artery disease. *Asymptomatic PAD is defined by ankle-brachial index < 0.9 in the absence of claudication or other manifestations of obstructive vascular disease in the extremities. For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B). For patients with PAD with an indication for oral anticoagulation such as atrial fibrillation, venous thromboembolism, heart failure, or mechanical valves, antiplatelet therapy should not be added to oral anticoagulation (Class III, Level A).
      Figure thumbnail gr9
      Figure 9Management of post peripheral artery surgery. The outpatient management of patients after peripheral artery surgery or percutaneous revascularization or presenting an abdominal aortic aneurysm (AAA). ASA, acetylsalicylate acid; PAD, peripheral arterial disease. *For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B).

      Antiplatelet Therapy for Primary Prevention of Vascular Events

      Working Group: Alan D. Bell, MD, CCFP, and James D. Douketis, MD, FRCP
      For the purpose of these guidelines, “primary prevention” is defined as antiplatelet strategies, administered to individuals free of any evidence of manifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof. These include, but are not limited to, syndromes of angina pectoris, MI, ischemic stroke, TIA, intermittent claudication, and critical limb ischemia. Over the past 2 decades, an abundance of well-designed clinical trials and meta-analyses examining the role of ASA and other antiplatelet agents for primary prevention of vascular events have been published or are ongoing.

      Studies of primary prevention in men

      The British Doctors' Study randomized, in a 2:1 allocation, 5139 male physicians aged < 79 years to open-label ASA 500 mg daily or ASA avoidance.
      • Peto R.
      • Gray R.
      • Collins R.
      • et al.
      Randomised trial of prophylactic daily aspirin in British male doctors.
      Subjects with a history of MI or stroke were excluded. A history of other ischemic vascular manifestations, including angina pectoris or TIA, was allowed. After a mean of 5.6 years, no statistically significant between-group differences were noted for nonfatal MI, nonfatal stroke, vascular death, or bleeding. A trend for an increased rate of disabling stroke was noted in the ASA group.
      As part of a 2 × 2 factorial study examining the role of ASA in primary vascular protection and β-carotene in cancer prevention, the Physicians' Health Study randomized, in a double-blind fashion, 22,071 US male physicians aged 40-84 years with no history of MI, stroke, or TIA to receive ASA 325 mg every second day or placebo.
      Steering Committee of the Physicians' Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians' Health Study.
      The study was stopped early after a mean follow-up of 60.2 months due to an observed benefit in the ASA group. The relative risk of MI in ASA recipients was 0.56 (95% CI 0.45-0.70; P < 0.00001), although benefit was observed only in those aged > 50 years. With regard to other risk factors, elevated levels of cholesterol reduced the benefit of ASA, while smoking, blood pressure, diabetes mellitus, body mass index, and family history had no effect. A trend toward an increased stroke risk was observed and driven by hemorrhagic stroke (RR 2.14, 95% CI 0.96-4.77; P = 0.06). No difference was noted for cardiovascular mortality (RR 0.96, 95% CI 0.60-1.54). Bleeding events requiring transfusion were increased in the ASA group (RR 1.71, 95% CI 1.09-2.69; P = 0.02). Although the relative benefit associated with ASA for the prevention of MI was substantial, the absolute risk benefit was only 0.18% per year (NNT of 556 persons for 1 year) due to the low absolute event rate and attenuation by the increased bleeding risk. A subsequent nested case-control study of the Physicians' Health Study demonstrated that the MI benefit derived from ASA appeared to be related to the baseline level of C-reactive protein (CRP).
      • Ridker P.M.
      • Cushman M.
      • Stampfer M.J.
      • Tracy R.P.
      • Hennekens C.H.
      Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
      In men in the highest quartile of CRP levels, ASA conferred a 55.7% reduction in the risk of MI (P = 0.02), whereas those in the lowest CRP quartile had a nonsignificant 13.9% reduction (P = 0.77). Further trials are warranted to assess the potential beneficial effects of ASA in selected patient subgroups, such as those with elevated CRP.

      Studies in subjects with risk factors for vascular disease

      Aside from studies that examined primary prevention in patients with diabetes, which are covered in the section of this guideline entitled “Use of Antiplatelet Therapy in Patients with Diabetes,” 3 studies examined primary prevention of vascular events in high-risk patients. The Thrombosis Prevention Trial randomized 5085 men in the top quintile of ischemic heart disease risk (based on a score derived from the Northwick Park Heart Study
      • Meade T.W.
      • Mellows S.
      • Brozovic M.
      • et al.
      Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.
      ) to low-intensity oral anticoagulation with warfarin (target INR 1.5), controlled-release ASA 75 mg daily, combined ASA plus warfarin, or placebo.
      The Medical Research Council's General Practice Research Framework
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.
      Subjects with a history of MI or stroke were excluded. Compared with placebo and over a median follow-up of 6.8 years, ASA was associated with nonsignificant relative reductions of 23% in the risk of ischemic heart disease (absolute risk reduction 0.31%, NNT 322 for 1 year) and 36% in the risk of nonfatal ischemic cardiac events (absolute risk reduction 0.32%, NNT 312 for 1 year). No differences in rates of stroke or major bleeding were observed in the ASA-only group. The Primary Prevention Project enrolled 4495 men and women with a mean age of 64.4 years and ≥ 1 major risk factor (age ≥ 65 years, hypertension, diabetes mellitus, hypercholesterolemia, obesity, or history of MI before age 55 in a first-degree relative).
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      Patients with a history of ischemic vascular events or disease were excluded. Subjects were randomized in an open-label, 2 × 2 factorial design to ASA 100 mg daily, vitamin E 300 mg daily, and placebo. The study was stopped after a mean follow-up of 3.6 years when the interim results were consistent with other primary prevention trials that demonstrated a benefit for ASA treatment. ASA reduced the relative risk of cardiovascular death by 44% (RR 0.56, 95% CI 0.31-0.99, NNT 597 for 1 year) and any cardiovascular event by 23% (RR 0.77, 95% CI 0.62-0.95, NNT 189 for 1 year). Nonsignificant relative risk reductions were observed for the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (RR 0.71, 95% CI 0.48-1.04, NNT 450 for 1 year), MI (RR 0.69, 95% CI 0.38-1.23, NNT 900 for 1 year) and all stroke (RR 0.67, 95% CI 0.36-1.27, NNT 900 for 1 year). Severe bleeding was increased by 3.67-fold in ASA recipients (P = 0.0008; number needed to harm [NNH] 450 for 1 year). No differences were noted in the rate of hemorrhagic stroke. The CHARISMA trial randomized 15,603 men and women with manifest, stable vascular disease or multiple risk factors but no manifest disease to treatment with ASA 75-162 mg daily with or without clopidogrel 75 mg daily.
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.
      Patients were followed for a mean of 28 months. The primary prevention population did not benefit from dual-antiplatelet therapy as a nonsignificant increased risk of the primary composite endpoint of MI, all-cause stroke, or cardiovascular death was noted (RR 1.20, 95% CI 0.91 to 1.59; P = 0.20). Rates of GUSTO-defined severe and moderate bleeding were also increased by clopidogrel (RR 1.67 and 1.57; P = 0.07 and P = 0.08, respectively).
      The value of low-dose ASA in the management of patients with hypertension was examined in the HOT (Hypertension Optimal Treatment) study of 18,790 hypertensive subjects aged 50-80 years.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
      In the HOT study, patients were randomized in a double-blind fashion to ASA 75 mg daily or placebo and followed for a mean of 3.8 years. At study entry, ∼16% of subjects had ischemic heart disease. During the study, blood pressure was aggressively managed to diastolic targets of ≤ 90, ≤ 85, or ≤ 80 mm Hg. The use of ASA was associated with significant reductions in major cardiovascular events excluding silent MI (RR 0.85, 95% CI 0.73-0.99, absolute risk reduction 0.16%, NNT 625 for 1 year) and nonsilent MI (RR 0.64, 95% CI 0.49-0.85, absolute risk reduction 0.13%, NNT 769 for 1 year). No significant benefit was noted for stroke, cardiovascular or total mortality, or silent MI. No hazard for cerebral or fatal bleeding was noted, although nonfatal major bleeding was significantly increased (RR 1.84, absolute risk 0.63%; P < 0.001; NNH 606 for 1 year).
      Although the studies in patients with risk factors for vascular events indicate, in some cases, a significant relative benefit for ASA in primary prevention, the absolute benefits are small and further attenuated by bleeding events. Despite a lack of requisite evidence, a net therapeutic benefit as primary prevention against cardiovascular events in select patients, particularly those with a low baseline risk for bleeding, cannot be excluded. At the population level, such high-risk asymptomatic patients have not been clearly defined, but they may include patients with multiple cardiovascular risk factors, those with evidence of vascular disease on imaging, and, possibly, patients with elevated levels of inflammatory markers (eg, CRP). At an individual level, clinicians may identify patients who may be at high vascular risk in whom ASA may provide a net therapeutic benefit. Although the risk factors for bleeding tend to mimic those for ischemic events, bleeding risk is greater in women, those with prior bleeds or bleeding diatheses, and with the use of concomitant medications such as NSAIDs.
      • Alexander K.P.
      • Peterson E.D.
      Minimizing the risks of anticoagulants and platelet inhibitors.

      The effect of sex in primary prevention

      To examine the effects of ASA in women in primary vascular prevention, the Women's Health Study randomized 39,876 women aged ≥ 45 years in a double-blind fashion to ASA 100 mg on alternate days or placebo.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      All participants were free of any manifestation of ischemic vascular disease. After a mean follow-up of 10.1 years, the relative risk of the primary composite endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was reduced by a nonsignificant 9% (RR 0.91, 95% CI 0.80-1.03; P = 0.13). However, a significant 17% reduction was seen in the relative risk of all strokes (RR 0.83, 95% CI 0.69-0.99; P = 0.04), driven by a 24% reduction in the relative risk of ischemic stroke (RR 0.76, 95% CI 0.63-0.93; P = 0.009). ASA had no effect on the relative risk of MI (RR 1.02, 95% CI 0.84-1.25; P = 0.83) or death from cardiovascular causes (RR 0.95, 95% CI 0.74-1.22; P = 0.68). A nonsignificant increase in the risk of hemorrhagic stroke was observed with ASA (RR 1.24, 95% CI 0.82-1.87; P = 0.31), whereas a significant increase of 40% in the relative risk of gastrointestinal bleeding requiring transfusion was noted in ASA recipients (RR 1.40, 95% CI 1.07-1.83; P = 0.02). In women aged ≥ 65 years, ASA significantly reduced the relative risks of the primary composite endpoint, ischemic stroke, and MI (by 26%, 30%, and 34%, respectively). As in all of the previously described primary prevention studies, the absolute risk reduction observed with ASA was small. For example, the absolute risk reduction for ischemic stroke was 0.255%, resulting in an NNT to prevent 1 event over 10.1 years of 392. Stated another way, treating 1000 women with ASA for 10 years would prevent ∼2.5 ischemic strokes and cause ∼1 gastrointestinal bleed requiring transfusion.

      Meta-analysis

      A meta-analysis by Berger and colleagues
      • Berger J.S.
      • Roncaglioni M.C.
      • Avanzini F.
      • et al.
      Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.
      examined the sex differences associated with primary prevention by combining the results from 6 of the aforementioned studies. Results of this meta-analysis showed that use of ASA in women was associated with a 17% reduction in the relative risk of ischemic stroke (RR 0.83, 95% CI 0.70-0.97; P = 0.02) but no significant effect on MI. In contrast, men saw a 32% reduction in the relative risk of MI (RR 0.68, 95% CI 0.54-0.86; P = 0.001) but no effect on stroke. Both sexes saw a significant reduction in the relative risk of total vascular events: 12% in women (RR 0.88, 95% CI 0.79-0.99; P = 0.03) and 14% in men (RR 0.86, 95% CI 0.78-0.94; P = 0.01). Major bleeding was significantly increased in women and men (RR of 1.68 in women [95% CI, 1.13-2.52; P = 0.01] and 1.72 in men [95% CI, 1.35-2.20; P < 0.001]). Of note is the low absolute benefit of ASA in both sexes. Based on this analysis, treatment of 1000 men and 1000 women for a mean of 6.4 years would be required to prevent 8 MIs in men and 3 strokes in women, at a cost of 3 major bleeding events in men and 2.5 such events in women.
      A recent Antithrombotic Trialists' Collaboration meta-analysis of individual participant data from randomized trials of primary and secondary vascular prevention with ASA included > 95,000 individuals and 3554 serious vascular events in the primary prevention analysis.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      In this analysis, ASA was associated with a 12% relative reduction in the risk of serious vascular events (RR 0.88, 95% CI 0.82-0.94; P = 0.0001). This effect was not altered in any of the prespecified subgroups, including those of individual risk factors and the calculated 5-year risk of CAD. Similar results were noted for coronary events (RR 0.82, 95% CI 0.75-0.90; P = 0.0002) and ischemic stroke (RR 0.86, 95% CI 0.74-1.00; P = 0.05). No mortality benefit was noted. Although the proportional reductions in nonfatal events offered by ASA were similar in the primary and secondary prevention trials, the absolute risk reductions differed by an order of magnitude. Absolute annual risk reductions for vascular events, MI, and ischemic stroke in primary prevention trials were 0.07% (NNT for 1 year 1428), 0.06% (NNT for 1 year 1667), and 0.02% (NNT for 1 year 5000), respectively. ASA was associated with a 32% increase in the relative risk of hemorrhagic stroke (RR 1.32, 95% CI 1.00-1.75; P = 0.05; absolute risk increase 0.01%) and a 54% increase in the relative risk of major extracranial bleeding (RR 1.54, 95% CI 1.30-1.82; P < 0.0001; absolute risk increase 0.03%). The same factors that increased vascular risk were also noted to increase bleeding risk. Bleeding risk did not differ significantly in the primary and secondary prevention analyses, but the very low absolute vascular benefit of ASA in primary prevention was significantly attenuated by bleeding. In contrast, in secondary prevention, the vascular benefit far outweighed the bleeding risk.

      Summary

      The absolute net benefit of any intervention is dictated by the treatment effect, associated adverse events, and absolute event rates. Although the proportional treatment effect of ASA is similar in primary and secondary prevention, the low event rate in primary prevention diminishes or possibly nullifies the absolute net benefit. Further, most of the studies considered were conducted prior to the widespread use of other primary risk reduction therapies, including statins and inhibitors of the RAAS, which would likely further reduce the absolute event rates and net benefit of ASA. Although vascular events are likely to have a greater impact on disability and mortality than bleeding and the cost of ASA is low, a clear margin of benefit must apply before recommending a therapy to a vast, healthy population. Although many guidelines have recommended ASA for primary prevention based on age or calculated vascular risk,
      • 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).
      Joint British Societies
      JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice.
      • Pearson T.A.
      • Blair S.N.
      • Daniels S.R.
      • et al.
      AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases American Heart Association Science Advisory and Coordinating Committee.
      U.S. Preventive Services Task Force
      Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement.
      the benefit in such populations has not been demonstrated. With regard to individual risk factors, studies of ASA for risk prevention in patients with diabetes have been disappointing.
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention Of Progression of Arterial Disease And diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      ETDRS Investigators
      Aspirin effects on mortality and morbidity in patients with diabetes mellitus Early Treatment Diabetic Retinopathy Study report 14.
      For example, compared with the benefit observed in the entire Primary Prevention Project population, lesser benefits were noted in the diabetic cohort.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      Further, an earlier meta-analysis conducted by the Antithrombotic Trialists' Collaboration
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      failed to demonstrate any benefit for ASA in subjects with diabetes, whereas a 22% relative risk reduction was observed overall. Similarly, smoking, which is used in most risk stratification methods, attenuated the benefit of ASA observed in the Women's Health Study
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      and the Physician's Health Study,
      Steering Committee of the Physicians' Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians' Health Study.
      consistent with data indicating that smoking increases ASA resistance.
      • Cambria-Kiely J.A.
      • Gandhi P.J.
      Possible mechanisms of aspirin resistance.
      An Antithrombotic Trialists' Collaboration prediction model of high-risk subjects (ie, those with a 10-year event rate > 20%) receiving statin therapy suggests that the absolute benefit of ASA in primary vascular protection is small and approximately equivalent to the risk of major bleeding.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      Fig. 10)
      For men and women without evidence of manifest vascular disease, the use of ASA at any dose is not recommended for routine use to prevent ischemic vascular events (Class III, Level A).
      For men and women without evidence of manifest vascular disease, the use of clopidogrel 75 mg daily plus ASA at any dose is not recommended to prevent ischemic vascular events (Class III, Level B).
      In special circumstances in men and women without evidence of manifest vascular disease in whom vascular risk is considered high and bleeding risk is low, ASA 75-162 mg daily may be considered (Class IIb, Level C).
      Figure thumbnail gr10
      Figure 10Primary prevention in patients without evidence of manifest vascular disease. For the purpose of this guideline, primary prevention is defined as antiplatelet strategies, administered to individuals free of any evidence of manifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof. These include, but are not limited to, syndromes of angina pectoris, MI, ischemic stroke, TIA, intermittent claudication, and critical limb ischemia. ASA, acetylsalicylate acid; TIA, transient ischemic attack.

      Use of Antiplatelet Therapy in Patients With Diabetes

      Working Group: Maria E. Kraw, MD, FRCP, and Rémi Rabasa-Lhoret, MD, PhD
      Cardiovascular disease is a major cause of mortality and morbidity for patients with diabetes.
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      In addition to traditional risk factors such as smoking, systemic hypertension, dyslipidemia, and dysglycaemia, atherosclerosis in patients with diabetes can be associated with a procoagulant state, which plays a key role in atherogenesis and its thrombotic complications. Individuals with diabetes have a variety of alterations in platelet function that can predispose them to increased platelet activation and thrombosis. These alterations include increased platelet turnover,
      • DiMinno G.
      • Silver M.J.
      • Cerbone A.M.
      • Murphy S.
      Trial of repeated low-dose aspirin in diabetic angiopathy.
      enhanced platelet aggregation,
      • Halushka P.V.
      • Rogers R.C.
      • Loadholt C.B.
      • Colwell J.A.
      Increased platelet thromboxane synthesis in diabetes mellitus.
      and increased thromboxane synthesis.
      • Davì G.
      • Catalano I.
      • Averna M.
      • et al.
      Thromboxane biosynthesis and platelet function in type II diabetes mellitus.
      Based on these observations and benefits extrapolated from large trials conducted in high-risk populations, antiplatelet therapy has been widely recommended for primary and secondary prevention in patients with diabetes. However, based on a critical appraisal of new and existing data,
      • Sirois C.
      • Poirier P.
      • Moisan J.
      • Grégoire J.P.
      The benefit of aspirin therapy in type 2 diabetes: what is the evidence?.
      various professional organizations, including the Canadian Diabetes Association,
      • Bhattacharyya O.K.
      • Shah B.R.
      • Booth G.L.
      Management of cardiovascular disease in patients with diabetes: the 2008 Canadian Diabetes Association guidelines.
      have recently reduced the level of evidence supporting use of antiplatelet therapy in patients with diabetes. ASA is the antiplatelet agent most commonly studied in the prevention of cardiovascular events in persons with diabetes. While many trials with subgroups of patients with diabetes are available, surprisingly, only a few trials of mixed primary and secondary prevention were designed to investigate antiplatelet therapy specifically in the diabetic population.

      Primary prevention

      Observational cohorts

      The recently published Fremantle Diabetes study provides one of the largest prospective, observational cohorts assessing the impact of ASA for primary prevention in patients with type 2 diabetes.
      • Ong G.
      • Davis T.M.
      • Davis W.A.
      Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting: the Fremantle Diabetes study.
      In this cohort of 651 patients followed for a mean of 11.6 years, regular use of ASA ≥ 75 mg daily at baseline was associated with reduced risks of cardiovascular and all-cause mortality (HR 0.30 [95% CI 0.09-0.95] and 0.53 [95% CI 0.28-0.98], respectively). Conversely, a prospective study of 5731 Chinese patients with type 2 diabetes and no cardiovascular disease, of whom 1034 (18%) were using ASA, showed that ASA use was associated with an increased risk of vascular death, nonfatal MI, or nonfatal stroke (HR 2.07, 95% CI 1.66-2.59; P < 0.001).
      • Leung W.Y.
      • So W.Y.
      • Stewart D.
      • et al.
      Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients—a longitudinal observational study.
      Because these observational studies are accompanied by many potential biases introduced by the failure to account for changes in antiplatelet therapy throughout the study duration, their results should be interpreted with caution.

      Subgroup and post-hoc analysis of clinical trials

      Several large studies of primary prevention included subgroups of patients with diabetes. The US Physicians' Health Study was a primary prevention trial that assessed the efficacy and safety of ASA 325 mg taken every 2 days in 22,071 male physicians.
      Steering Committee of the Physicians' Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians' Health Study.
      In the subgroup of 533 men with diabetes, ASA use reduced the risk of MI, although the result was not significant, possibly due to the small number of events (11 events in the ASA group [4.0%] vs 26 events [10.1%) in the placebo group; P = 0.22). The Women's Health Study was designed to study whether low-dose ASA (100 mg every second day) was beneficial in 39,876 initially health women aged > 45 years.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      Data from the subgroup of 1027 women with diabetes (only 2.6% of the total population) showed no significant benefit for ASA in preventing the primary endpoint of major cardiovascular events (RR 0.90, 95% CI 0.63-1.29; P = 0.57). However, a significant reduction in the risk of stroke (RR 0.46, 95% CI 0.25-0.85; P = 0.01) was observed. Notably, this reduction was much larger than the stroke risk reduction observed for the total population (RR 0.83, 95% CI 0.69-0.99; P = 0.04). The Primary Prevention Project studied the effect of low-dose ASA (100 mg daily) and/or vitamin E in 4495 people with one or more cardiovascular risk factors for a median of 3.7 years.
      • de Gaetano G.
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
      Whereas a clear benefit for subjects without diabetes was observed (41% reduction in major cardiovascular events), in the 1031 patients with diabetes, the decrease in major cardiovascular events was not significant (RR 0.90, 95% CI 0.50-1.62), nor was the 23% increase in cardiovascular deaths.
      • Sacco M.
      • Pellegrini F.
      • Roncaglioni M.C.
      • et al.
      Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.
      The adherence to therapy in the Primary Prevention Project was low, with 28.2% of persons assigned to ASA stopping therapy before the end of the trial. This low adherence might have affected the statistical power of this trial.

      Randomized clinical trials conducted in patients with diabetes

      Two randomized controlled trials evaluated the efficacy of ASA for primary prevention specifically in patients with diabetes. Using an open-label design, the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) trial randomized 2539 patients with type 2 diabetes and no history of atherosclerotic disease to low-dose ASA (81 or 100 mg daily) or no ASA.
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      After a mean follow-up of 4.37 years, there was no significant difference in the primary endpoint of atherosclerotic events (13.6 per 1000 person-years in the ASA-treated group vs 17.0 per 1000 person years in the nontreated group; HR 0.80, 95% CI 0.58-1.10; P = 0.16). Among the 1363 patients aged >65 years, secondary endpoint analyses indicated a favourable 32% reduction in the primary endpoint (6.3% vs 9.2%; P = 0.047), as well as a significant reduction in the incidence of fatal coronary and cerebrovascular events (0.08% vs 0.8%; P = 0.0037) in the total population.
      The POPADAD (Prevention Of Progression of Arterial Disease And Diabetes) trial studied ASA 100 mg daily with or without antioxidant therapy in 1276 patients with type 1 or 2 diabetes and asymptomatic PAD (defined as ABI ≤ 0.99) but no symptomatic cardiovascular disease.
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The Prevention Of Progression of Arterial Disease And diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      Thus, the POPADAD trial can be viewed as a mixed primary and secondary prevention intervention. After a median of 6.7 years of follow-up, there was no difference in primary events among ASA recipients compared with the non–ASA-treated persons (18.2% vs 18.3%, HR 0.98, 95% CI 0.76-1.26). The antioxidant intervention also failed to provide benefit. It should be noted that the number of events in both the JPAD and POPAPAD trials was lower than expected, leading to limited statistical power.

      Meta-analyses

      To overcome the aforementioned limitations, 3 recent meta-analyses have examined the use of low-dose ASA in the primary prevention of cardiovascular events. However, none of these meta-analyses have shown a clear benefit for ASA in cardiovascular risk reduction in patients with diabetes. Subgroup analysis of the 5126 patients with diabetes included in the 2009 Antithrombotic Trialists' Collaboration meta-analysis indicated a nonsignificant trend toward a benefit for prevention of vascular events in patients exposed to ASA (RR 0.88, 95% CI 0.67-1.15).
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.