The Use of Antiplatelet Therapy in the Outpatient Setting

Canadian Journal of Cardiology 27 (2011) 208–221

Society GuidelinesThe Use of Antiplatelet Therapy in the Outpatient

Setting: Canadian Cardiovascular Society GuidelinesExecutive Summary

Alan D. Bell, MD, CCFP,a André Roussin, MD, FRCPC,b Raymond Cartier, MD,c

Wee Shian Chan, MD, FRCPC,d James D. Douketis, MD, FRCPC,e Anil Gupta, MD, FRCPC,f

Maria E. Kraw, MD, FRCPC,g Thomas F. Lindsay, MD, CM, FRCSC,h

Michael P. Love, MB, ChB, MD, MRCP,i Neesh Pannu, MD, SM, FRCPC,j

Rémi Rabasa-Lhoret, MD, PhD,k Ashfaq Shuaib, MD, FRCPC,l Philip Teal, MD, FRCPC,m

Pierre Théroux, MD,n A. Graham Turpie, MD,o Robert C. Welsh, MD, FRCPC, FACC,p

Jean-François Tanguay, MD, CSPQ, FRCPC, FACC, FAHA, FESCq

a From the Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada;b Internal and Vascular Medicine, Centre Hospitalier Universitaire de Montréal, Montréal, Quebéc, Canada;

c Department of Surgery, Montréal Heart Institute, Montréal, Quebéc, Canada; d Department of Medicine, Women’s College Hospital,Toronto, Ontario, Canada; e Vascular Medicine Institute, St. Joseph’s Healthcare, Hamilton, Ontario, Canada; f Department ofClinical Cardiology, Trillium Health Centre, Mississauga, Ontario, Canada; g Division of Endocrinology, St. Michael’s Hospital,

Toronto, Ontario, Canada; h Department of Vascular and Endovascular Surgery, Toronto General Hospital, Toronto, Ontario, Canada;i Division of Cardiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; j Division of Nephrology, University ofAlberta, Edmonton, Alberta, Canada; k Institut de Recherches Cliniques de Montréal, Département de Nutrition, Université de Montréal,

Montréal, Quebéc, Canada; l Division of Neurology, University of Alberta, Edmonton, Alberta, Canada; m Department of Neurology,University of British Columbia, Vancouver, British Columbia, Canada; n Coronary Care Unit, Montréal Heart Institute, Montréal, Quebéc,

Canada; o Division of Hematology & Thromboembolism (Emeritus), McMaster University, Hamilton, Ontario, Canada; p Department ofq
Interventional Cardiology, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, Montréal Heart Institute,
Université de Montréal, Montréal, Quebéc, Canada

ABSTRACTAntiplatelet agents are a cornerstone of therapy for patients withatherosclerotic vascular disease. There is presently a lack of compre-hensive guidelines focusing on the use of antiplatelet drugs in patientscurrently manifesting or at elevated risk of cardiovascular disease. The
Canadian Antiplatelet Therapy Guidelines Committee reviewed exist
medical literature and the best available evidence and clinical experience. It

0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Publisheddoi:10.1016/j.cjca.2010.12.033

RÉSUMÉLes agents antiplaquettaires sont une des pierres angulaires du traite-ment des patients ayant une maladie vasculaire athérosclérotique.Les lignes directrices qui portent sur l’utilisation des médicamentsantiplaquettaires chez les patients qui manifestent ou qui sont à ris-
que élevé de maladie cardiovasculaire sont à l’heure actuelle incom
The full paper corresponding to this Executive Summary will be publishedas a supplement to the Canadian Journal of Cardiology May/June issue.

Received for publication November 16, 2010. Accepted December 15,2010.

Corresponding author: Dr Jean-François Tanguay, Attention: ChantalSauvé, Montreal Heart Institute, 5000 Belanger Street, #S-2260, Montreal,Québec H1T-1C8, Canada.

E-mail: [email protected] disclosure information of the authors and reviewers is available from the

CCS on the following websites: www.ccs.ca and www.ccsguidelineprograms.ca.This statement was developed following a thorough consideration of

represents the consensus of a Canadian panel comprised of multidisci-plinary experts on this topic with a mandate to formulate disease-specificrecommendations. These recommendations are aimed to provide a reason-able and practical approach to care for specialists and allied health profes-sionals obliged with the duty of bestowing optimal care to patients andfamilies, and can be subject to change as scientific knowledge and technol-ogy advance and as practice patterns evolve. The statement is not intendedto be a substitute for physicians using their individual judgment in man-aging clinical care in consultation with the patient, with appropriate regardto all the individual circumstances of the patient, diagnostic and treatmentoptions available and available resources. Adherence to these recommen-
dations will not necessarily produce successful outcomes in every case.
by Elsevier Inc. All rights reserved.

mailto:[email protected]

http://www.ccs.ca

http://www.ccsguidelineprograms.ca

Bell et al.Outpatient Antiplatelet Therapy

209

Unlike other vascular preventive strategies, physicians lackclear, easily accessible, evidence-based guidance on which tobase antiplatelet therapy management decisions. Existing doc-uments addressing antiplatelet therapy do so as part of guide-lines and statements encompassing overall treatment recom-mendations for specific disease entities (eg, peripheral arterialdisease [PAD],1 diabetes,2 drug-eluting stent (DES) implanta-tion,3 and stroke4). Therefore, there is no single easily accessi-ble source of antiplatelet therapy recommendations.

To create a concise, therapeutic-based statement on managingantiplatelet therapy in outpatients who have existing, or are at riskof developing, vascular disease, the Canadian Antiplatelet TherapyConsensus Committee was formed by the Canadian Cardiovas-cular Society. As outlined in more detail in the full guideline,5 alsoavailable at http://www.ccs.ca/, the processes used to develop theconsensus recommendations reported herein included (1) a searchfor existing guidelines and new data on topics pertinent to anti-platelet therapy use in the outpatient setting; (2) evaluation of thequality of existing guidelines using the AGREE (Appraisal ofGuidelines for REsearch and Evaluation) instrument;6 (3) devel-opment of recommendations via consideration of existing guide-lines and their associated AGREE score, literature published sub-sequent to existing guidelines, and expert opinion; (4) creation ofgraded recommendations through the 2-tiered system recom-mended by the Canadian Cardiovascular Society (Table 1); and

ing disease-based guidelines and subsequently published literatureand used expert opinion and review to develop guidelines on the use ofantiplatelet therapy in the outpatient setting. This Executive Summaryprovides an abbreviated version of the principal recommendations.Antiplatelet therapy appears to be generally underused, perhaps inpart because of a lack of clear, evidence-based guidance. Here, weprovide specific guidelines for secondary prevention in patients dis-charged from hospital after acute coronary syndromes, percutaneouscoronary intervention, or coronary artery bypass grafting; patients witha history of transient cerebral ischemic events or strokes; and patientswith peripheral arterial disease. Issues related to primary preventionare also addressed, in addition to special clinical contexts such asdiabetes, heart failure, chronic kidney disease, pregnancy or lactation,and perioperative management. Recommendations are provided re-garding pharmacologic interactions that may occur during combina-tion therapy with warfarin, clopidogrel, and proton-pump inhibitors, oraspirin and nonsteroidal anti-inflammatory drugs, as well as for themanagement of bleeding complications. The complete guidelines doc-ument is published as a supplementary issue of the Canadian Journalof Cardiology and is available at http://www.ccs.ca/.

Table 1. Grading system used in the preparation of the Canadian Car

Class of recommendation

I: Evidence and/or general agreement that a given diagnostic procedure/treatmis beneficial, useful, and effective

IIa: Conflicting evidence and/or a divergence of opinion about the usefulnessefficacy of the treatment with the weight of evidence in favour

IIb: Conflicting evidence and/or a divergence of opinion about the usefulnessefficacy of the treatment with the usefulness/efficacy less well established

III: Evidence that the treatment is not useful and in some cases may be harmful

(5) external review by experts in their respective fields who werenot involved in the writing process. (The external reviewers arelisted in Appendix II of the full guideline document.) When nec-essary, individual recommendations were revised after the externalreview process.

In 2 years, the Antiplatelet Consensus Committee in-tends to reconvene to evaluate the need to update the rec-ommendations.

Role of the Funding SourceFunding for the preparation of the Canadian Antiplatelet

Therapy Guideline was provided by the Thrombosis Inter-est Group of Canada (TIGC), a registered nonprofit, non-commercial organization dedicated to furthering educationand research in the prevention and treatment of thrombosis.Although several members of the working group are mem-bers of the TIGC, the TIGC as an entity had no input intothe content of the guideline. The funding provided by theTIGC was used to support the creation of a password-pro-tected Web site where group members could upload anddownload references, guidelines, and draft statements; theadministrative services of Sharon O’Doherty of the TIGC;and the editorial assistance of Melanie Leiby, PhD, of in-Science Communications, a Wolters Kluwer business. Au-

plètes. Le comité canadien sur les directives pour le traitement antipla-quettaire a passé en revue les lignes directrices des maladies et, sub-séquemment la littérature publiée, et les revues et l’opinion des expertspour développer des lignes directrices sur l’utilisation de traitements an-tiplaquettaires dans la prise en charge externe des patients. Ce sommaireexécutif fournit une version abrégée des principales recommandations.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 sec-ondaire chez les patients en soins externes à la suite de syndromescoronaires aigus, d’une intervention coronaire percutanée, d’un pontageaortocoronarien; chez les patients avec une histoire d’ischémiescérébrales transitoires ou d’accidents vasculaires cérébraux, et chez lespatients avec une maladie artérielle périphérique. Les questions liées à laprévention primaire sont aussi abordées, en plus des contextes cliniquesparticuliers comme le diabète, l’insuffisance cardiaque, la maladie rénalechronique, la grossesse ou l’allaitement, et la gestion périopératoire.

Des recommandations sont données tant pour les interactions phar-macologiques qui peuvent survenir durant un traitement combiné avec lawarfarine, le clopidogrel et les inhibiteurs de la pompe à protons, oul’aspirine et les médicaments anti-inflammatoires non stéroïdaux, quepour la gestion des complications hémorragiques. Le document entierdes lignes directrices a été publié dans un numéro supplémentaire duJournal canadien de cardiologie et est disponible au http://www.ccs.ca/.

cular Society Antiplatelet Therapy Guideline

Level of evidence

A: Data derived from multiple randomized clinical trials or meta-analyses

B: Data derived from a single randomized clinical trial or largenonrandomized studies

C: Consensus of opinion by experts and/or small studies, retrospectivestudies, and registries

diovas

ent

/

/

http://www.ccs.ca/

http://www.ccs.ca/

http://www.ccs.ca/

210 Canadian Journal of CardiologyVolume 27 2011

thors received no financial or other benefit for their effortsin creating this document.

Antiplatelet Therapy for Secondary Prevention inthe First Year Following an Acute CoronarySyndrome

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

Data from randomized clinical trials demonstrate that com-pared with acetylsalicylic acid (ASA) alone, combination therapywith oral P2Y12 receptor antagonists improves clinical outcomes inpatients with acute coronary syndrome (ACS), although the combi-nation therapy does increase the risk of bleeding.7-11 Evidence fromthe CURE Clopidogrel in Unstable Angina to Prevent RecurrentEvents (CURE) trial supports the use of ASA plus clopidogrel for upto 12 months after non–ST-elevation ACS (NSTEACS), regardlessof the management strategy,7 whereas the Clopidogrel as AdjunctiveReperfusion Therapy–Thrombolysis in Myocardial Infarction 28trial8 and Clopidogrel and Metoprolol in Myocardial Infarction trial9

support up to 30 days of ASA plus clopidogrel after ST-elevationmyocardial infarction (STEMI). In the absence of specific evidencefor long-term dual antiplatelet therapy in STEMI, the findings ofCURE7 and the common underlying pathophysiology of all types ofACSare thebasis forcontinuingtherapy inpatientswithSTEMIafterhospital discharge. The current reality is that an increasing proportionof patients with STEMI undergo in-hospital percutaneous coronaryintervention (PCI), and therefore, continuation of dual antiplatelettherapy after discharge is often mandated by the implantation of oneor more intracoronary stents. Data from the Trial to Assess Improve-ment in Therapeutic Outcomes by Optimizing Platelet Inhibitionwith Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRI-TON-TIMI 38) suggest that combination therapy with ASA and theP2Y12 inhibitor prasugrel provides greater benefit than combinationtherapy with ASA and clopidogrel in patients with NSTEACS andSTEMI, although it is associated with an increased risk of fatal, life-threatening, and major bleeding.10 Results of the Platelet InhibitionandPatientOutcomestrial suggest thatcombinationtherapywiththeP2Y12 inhibitor ticagrelor improves clinical outcomes without in-creasingoverallmajorbleeding,however,nonproceduralmajorbleed-ing was significantly increased.11

RECOMMENDATION

For all patients with ACS who survive to hospital discharge,indefinite therapy with low-dose ASA (75-162 mg daily) isrecommended (Class I, Level A). For patients allergic to orintolerant of ASA, indefinite therapy with clopidogrel 75 mgdaily is recommended (Class IIa, Level B).

For patients presenting with STEMI who are medicallymanaged, clopidogrel 75 mg daily is recommended in ad-dition to ASA 75 to -162 mg daily for at least 14 days (ClassI, Level B) and up to 12 months in the absence of an exces-sive risk of bleeding (Class IIb, Level C).

For patients presenting with STEMI who are managedby PCI, clopidogrel 75 mg daily is recommended in addi-tion to ASA 75 to 162 mg daily for 12 months (Class I, LevelB). Continuation of combined therapy beyond 12 monthsmay be considered in patients with a high risk of thrombosisand a low risk of bleeding (Class IIb, Level C).

For patients presenting with NSTEACS who are medi-cally managed, clopidogrel 75 mg daily is recommended inaddition to ASA 75 to 162 mg daily for at least 1 month(Class I, Level A) and up to 12 months in the absence of anexcessive risk of bleeding (Class I, Level B).

For patients presenting with NSTEACS who are man-aged by PCI, clopidogrel 75 mg daily is recommended inaddition to ASA 75 to 162 mg daily for 12 months (Class I,Level A). Continuation of combined therapy beyond 12months may be considered in patients with a high risk ofthrombosis and a low risk of bleeding (Class IIb, Level C).

For patients presenting with NSTEACS who are managed bycoronary artery bypass grafting (CABG), clopidogrel 75 mg dailyis recommended in addition to ASA 75 to 162 mg daily for aminimum of 1 month and up to 12 months (Class I, Level B).

For patients with ACS who undergo stent implantation andhave an increased risk of stent thrombosis (eg, STEMI, history ofdiabetes mellitus, or prior documented stent thrombosis), prasug-rel 10 mg daily may be considered in addition to ASA 75 to 162mg daily for 12 months (Class IIa, Level B). Prasugrel should beavoided in patients with an increased bleeding risk, likely to un-dergo CABG within 7 days, with a history of stroke or transientischemicattack(TIA),aged�75years,orweighing�60kg(ClassIII, Level B).

For patients with ACS, ticagrelor 90 mg twice daily may beadded toASA75to162mgdaily for12months (Class I,LevelB).(This recommendation assumes that ticagrelor, which is underreview by Health Canada, will be approved as requested in early2011.)

In general, the adenosine diphosphate P2Y12 receptorantagonist added to ASA in the acute setting should bemaintained for the duration of therapy (Class I, Level C).

Antiplatelet Therapy for Secondary Prevention inthe First Year Following PCI

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

Similar to what is observed in ACS, combination therapywith an oral P2Y12 receptor antagonist and ASA is superior toASA alone in patients who undergo PCI. Evidence from thePCI-CURE12 and PCI-Clopidogrel as Adjunctive ReperfusionTherapy13 studies established the efficacy of dual ASA andclopidogrel therapy in patients with NSTEACS and STEMI,respectively, whereas the Clopidogrel for the Reduction ofEvents During Observation study14 established its efficacy inpatients with stable coronary artery disease (CAD) undergoingnonurgent PCI. The combinations of ASA plus prasugrel orticagrelor in patients with ACS undergoing PCI were shownto be superior to ASA plus clopidogrel in the TRITON-TIMI 3810 and Platelet Inhibition and Patient Outcomes-Invasive trials,15 respectively. However, major bleedingrates were noted to be higher. The optimal duration of dualASA/oral P2Y12 receptor antagonist therapy poststenting,particularly among DES recipients, is unknown. Registrydata suggest a protective effect of continuing dual antiplate-let therapy beyond 24 months,16-18 but a recent analysis of 2
randomized clinical trials did not show a benefit for con-


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tinuing ASA plus clopidogrel for 24 months over ASA plusclopidogrel for 12 months followed by ASA alone for anadditional 12 months.19

RECOMMENDATION

Indefinite therapy with ASA 75 to 162 mg dailyshould be used in all patients with acute or chronic isch-emic heart disease without contraindications to its ther-apy (Class I, Level A). This includes patients who haveundergone PCI.

All patients who have undergone PCI with bare-metalstent (BMS) implantation should be given clopidogrel 75mg daily in addition to ASA 75 to 162 mg daily for at least1 month (Class I, Level B) and up to 12 months in theabsence of an excessive risk of bleeding (Class I, Level B)after stent implantation.

For patients with recent bleeding or at increased risk forbleeding, a BMS should be implanted, and clopidogrel 75mg daily should be added to ASA 75 to 162 mg daily for aminimum of 2 weeks (Class I, Level B).

All patients who have undergone PCI with DES implan-tation should be given clopidogrel 75 mg daily in additionto ASA 75 to 162 mg daily for 12 months (Class I, Level A).

Continuation of dual antiplatelet therapy with ASA 75to 162 mg daily and clopidogrel 75 mg daily beyond 1 yearmay be considered in patients with an increased risk of stentthrombosis as long as the perceived risk of bleeding isdeemed acceptable (Class IIb, Level C).

For patients with ACS who undergo stent implantationand have an increased risk of stent thrombosis (eg, STEMI,history of diabetes mellitus, or prior documented stentthrombosis), prasugrel 10 mg daily may be considered inaddition to ASA 75 to 162 mg daily for 12 months (ClassIIa, Level B). Prasugrel should be avoided in patients withan increased bleeding risk, likely to undergo CABG within7 days, with a history of stroke or TIA, aged �75 years, orweighing �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 to 162mg daily for 12 months (Class I, Level B). (This recommen-dation assumes that ticagrelor, which is under review byHealth Canada, will be approved as requested in early2011.)

Antiplatelet Therapy for Secondary PreventionBeyond 1 Year Following ACS or PCI

Working Group: Anil Gupta, MD, FRCPC, and PierreThéroux, MD

As shown in the post-ACS and post-PCI sections of the guide-line, combination therapy with an oral P2Y12 antagonist and ASAis recommended for up to 1 year following the event. Beyond thistimeframe, the most studied, commonly used antiplatelet therapyis ASA monotherapy,20-22 with the evidence suggesting that dosesgreater than 75 to 81 mg once daily do not provide additionalclinical benefit but increase the risk of bleeding.21 Clopidogrelmonotherapy is another treatment option for long-term manage-ment of patients with CAD.23 The overall results of the Clopi-
dogrel for High Atherothrombotic Risk and Ischemic Stabiliza-
tion, Management, and Avoidance trial do not support the long-term use of combined ASA-clopidogrel therapy in patients with,or at risk of, ischemic vascular events.24 However, use in the pre-defined subgroup of stable patients with prior atherothromboticevents, reduced the relative risk of the primary endpoint.

RECOMMENDATION

For all patients with ACS who survive to hospital dis-charge, indefinite therapy with low-dose ASA (75-162 mgdaily) is recommended (Class I, Level A).

For patients allergic to or intolerant of ASA, indefinitetherapy with clopidogrel 75 mg daily is recommended(Class IIa, Level B).

Dual antiplatelet therapy with ASA 75 to 162 mgdaily and clopidogrel 75 mg daily may be consideredbeyond 1 year in patients with ACS (see the recommen-dations in the section titled Antiplatelet Therapy for Sec-ondary Prevention in the First Year Following an AcuteCoronary Syndrome) who are medically managed, pro-vided the risk of bleeding is low (Class IIb, Level C).

For all post-PCI patients, indefinite therapy with ASA75 to 162 mg daily is recommended, regardless of type ofstent (Class I, Level A).

Dual antiplatelet therapy with ASA 75 to 162 mg dailyand clopidogrel 75 mg daily may be considered beyond 1year in patients with ACS who receive a BMS or DES,provided their risk of bleeding is low (Class IIb, Level C).

Antiplatelet Therapy for Secondary PreventionFollowing CABG

Working Group: Raymond Cartier, MDASAis recognizedas the standardof care forpreventing saphenous

vein graft closure after CABG and is generally continued indefinitely,given its benefit in preventing subsequent clinical events.25 A largemeta-analysis showed that low (approximately 100 mg) and medium(approximately 325 mg) daily doses of ASA were more effective thanhigh-dose(approximately975mg)ASAinpreventingsaphenousveingraftocclusionandcaused less gastrointestinal sideeffects.26 Althoughticlopidineprovidesabenefit similar to thatofASAinpreventinggraftclosure,27,28 it is not recommended for use because of its relativelypoor safety and tolerability profile. Despite a lack of direct clinical trialevidence, clopidogrel is recommended for patients who have under-gone CABG and who are allergic to or intolerant of ASA. Evidencefrom the CURE and Clopidogrel for the Reduction of IschemicEvents During Observation clinical trials suggests that although com-bination ASA-clopidogrel therapy may decrease the risk of cardiovas-cular events in patients who undergo CABG, it also significantly in-creases the risk of bleeding.13,29 There is no evidence in the literaturethat antiplatelet therapy, including combination ASA-clopidogrel,30

improves arterial graft patency.

RECOMMENDATION

For all patients who undergo saphenous vein CABG sur-gery, ASA 75 to 162 mg daily is recommended as lifelongtherapy 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 sur-gery and have a contraindication to ASA, clopidogrel 75 mgdaily is preferred over ticlopidine 250 mg twice daily because ofthe superior safety profile of clopidogrel (Class IIa, Level C).

In patients undergoing CABG after PCI, dual antiplate-let therapy with ASA 75 to 162 mg daily and clopidogrel 75mg daily may be maintained for 9 to 12 months unless thestented vessel is adequately bypassed (Class IIb, Level C).

Antiplatelet Therapy for the SecondaryPrevention of Cerebrovascular Disease

Working Group: Ashfaq Shuaib, MD, FRCP, and PhilipTeal, MD, FRCP

For secondary prevention in patients with TIA or ischemicstroke, antiplatelet therapy regimens with proven efficacy in-clude ASA monotherapy,31 ticlopidine monotherapy,32,33

clopidogrel monotherapy,23,24 and the combination of ASAand dipyridamole.34-36 As demonstrated in both the Manage-ment of Atherothrombosis for Continued Health and theClopidogrel for High Atherothrombotic Risk and IschemicStabilization, Management, and Avoidance studies, combinedASA-clopidogrel therapy should not be used for long-term sec-ondary prevention following stroke or TIA because it does notsignificantly improve ischemic event prevention but signifi-cantly increases the risk of bleeding.37-38 Some evidence sug-gests that combination therapy may provide benefit in the pe-riod immediately following stroke or TIA.39,40

RECOMMENDATION

Patients who suffer a TIA or ischemic stroke of noncar-diac origin should be treated with an antiplatelet agent(Class I, Level A). Initial therapy should be ASA 75 to 162mg once daily, clopidogrel 75 mg once daily, or ER dipyr-idamole 200 mg twice daily plus ASA 25 mg twice daily(Class I, Level A). The choice of antiplatelet therapy regi-men is determined by consideration of cost, tolerance, andother associated vascular conditions. Available data do notallow for differentiation of antiplatelet regimen by specificstroke subtype (Class IIb, Level C).

The combination of ASA 75 to 162 mg daily plus clopi-dogrel 75 mg daily in the first month after TIA or minorischemic stroke may be superior to ASA alone in patientsnot at a high risk of bleeding (Class IIb, Level C).

The combination of ASA 75 to 162 mg daily plus clopidogrel75 mg daily should not be used for secondary stroke preventionbeyond 1 month unless otherwise indicated and the risk of

Antiplatelet Therapy for Vascular Prevention inPatients With PAD

Working Group: André Roussin, MD, FRCPC, andThomas F. Lindsay, MD, CM, FRCSC

For patients with asymptomatic PAD (ie, patients with a bruitalong major vessels or reduced or absent peripheral pulsations, an
abnormally enlarged artery leading to suspicion of an aneurysm, or
an ankle-brachial index � 0.9), the limited evidence does notsupport a benefit for antiplatelet therapy.41,42 Data do suggest abenefit for ASA monotherapy and clopidogrel monotherapy inpatients with symptomatic PAD (ie, patients with claudication,rest pain, or ischemic lesions).23,43-45 Adding dipyridamole toASA does not improve outcomes over ASA alone,43 and the com-bination of ASA and clopidogrel does not appear to provide sig-nificant clinical benefit.24

Based on studies conducted mostly in patients undergoing in-frainguinal bypass surgery, low-dose ASA therapy is recom-mended for patients who undergo arterial reconstruction, includ-ing aortobifemoral reconstructions, axillofemoral or bifemoralbypass, iliofemoral bypass, common femoral repair, and pro-fundaplasty.46

Epidemiologic evidence suggesting that abdominal aortic an-eurysm (AAA) may be a marker of subclinical atherosclerosis47

and the fact that many AAA risk factors are also atherosclerotic riskfactors48,49 indicate that antiplatelet therapy may be a valuabletreatment for preventing cardiovascular events in patients withAAA. In one study, low-dose ASA was associated with a reducedexpansion rate and a reduced risk of AAA surgery in patients whoseaortic size was 40 to 49 mm.50 Low-dose ASA is recommended forthose with an AAA, with the evidence stronger for those withclinical or subclinical PAD.

RECOMMENDATION

For patients with asymptomatic PAD with an ankle-brachial index �0.9, low-dose ASA (75-162 mg daily) maybe considered for those at high risk because of associatedatherosclerotic risk factors in the absence of risk factors forbleeding (Class IIb, Level C).

For patients with symptomatic PAD without overtCAD or cerebrovascular disease, low-dose ASA (75-162 mgdaily) or clopidogrel 75 mg daily is recommended, provid-ing the risk for bleeding is low (Class IIb, Level B). Thechoice of drug may depend on patient preference and costconsiderations.

For patients allergic or intolerant to ASA, use of clopi-dogrel is suggested (Class IIa, Level B).

For patients with intermittent claudication, dipyridamoleshould not be used in addition to ASA (Class III, Level C).

For patients with intermittent claudication, using clopi-dogrel 75 mg daily in addition to ASA 75 to 162 mg daily isnot recommended unless the patient is judged to be at highvascular risk along with a low risk of bleeding (Class IIb,Level B).

For patients with symptomatic PAD with overt CAD orcerebrovascular disease, antiplatelet therapy as indicated for theCAD and/or cerebrovascular status is recommended (Class I,Level A).

For patients with symptomatic PAD without compellingindications for oral anticoagulation such as atrial fibrillation orvenous thromboembolism, oral anticoagulation should not beadded to antiplatelet therapy (Class III, Level B).

For patients with symptomatic PAD with an indication fororal anticoagulation such as atrial fibrillation, venous throm-boembolism, heart failure (HF), or mechanical valves, anti-platelet therapy should not be added to oral anticoagulation(Class III, Level A).


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Long-term antiplatelet therapy with ASA 75 to 162 mgdaily should be given to patients who undergo lower-extremityballoon angioplasty with or without stenting for chronic symp-tomatic PAD (Class IIa, Level C). Anticoagulation with hepa-rin 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 thosewith infrainguinal grafts and a high risk of thrombosis or limbloss, combination therapy with a vitamin K antagonist andASA may be of benefit (Class IIb, Level C).

Low-dose ASA (75-162 mg daily) may be considered for allpatients with an AAA, particularly those with clinical or sub-clinical PAD (Class IIb, Level C).

Antiplatelet Therapy for the Primary Preventionof Vascular Events

Working Group: Alan D. Bell, MD, CCFP, and James D.Douketis, MD, FRCP

For the purpose of this guideline, primary prevention isdefined as antiplatelet strategies, administered to individualsfree of any evidence of manifest atherosclerotic disease in anyvascular bed, to prevent clinical vascular events or manifesta-tions thereof. These include, but are not limited to, syndromesof angina pectoris, myocardial infarction, ischemic stroke,TIA, intermittent claudication, and critical limb ischemia.

Evidence from individual randomized clinical trials (eg, theBritish Doctors’ Study,51 Physician’s Health Study,52 and Wom-en’s Health Study53) and several meta-analyses of these and otherprimary prevention trials22,54 suggests that ASA monotherapy sig-nificantly reduces the relative risk of ischemic cardiovascularevents in patients without established cardiovascular disease. Theabsolute risk reduction, however, is small, resulting in very largenumbers needed to treat to prevent a single event. Further, thebenefit of ASA is accompanied by a significant increase in the riskof bleeding. Considering that the absolute net benefit of any in-tervention is dictated by the treatment effect, associated adverseevents, and absolute event rates, the low event rate in primaryprevention and increased risk of bleeding diminishes or possiblynullifies the absolute net benefit of ASA for primary prevention.Furthermore, most of the studies considered were conducted priorto the wide use of other primary risk reduction therapies, includ-ing statins and inhibitors of the renin-angiotensin-aldosterone sys-tem, which would likely further reduce the absolute event ratesand net benefit of ASA. Although vascular events are likely to havea greater impact on disability and mortality than is bleeding andalthough the cost of ASA is low, a clear margin of benefit mustapply before recommending a therapy to a vast, healthy popula-tion.

RECOMMENDATION

For men and women without evidence of manifest vas-cular disease, the use of ASA at any dose is not recommendfor routine use to prevent ischemic vascular events (ClassIII, Level A).

For men and women without evidence of manifest vas-cular disease, the use of clopidogrel 75 mg daily plus ASA atany dose is not recommended to prevent ischemic vascularevents (Class III, Level B).

In special circumstances in men and women withoutevidence of manifest vascular disease in whom vascular riskis considered high and bleeding risk low, ASA 75 to 162 mgdaily may be considered (Class IIb, Level C).

Use of Antiplatelet Therapy in Patients WithDiabetes

Working Group: Maria E. Kraw, MD, FRCP, and RémiRabasa-Lhoret, MD, PhD

The results of several observational studies,55,56 sub-group analyses of randomized clinical trials,52,53,57 the Jap-anese Primary Prevention of Atherosclerosis with Aspirinfor Diabetes,58 and Prevention of Progression of ArterialDisease and Diabetes42 trials conducted specifically in pa-tients with diabetes, and several meta-analyses22,59,60 sug-gest that ASA therapy for primary prevention may confersimilar, or even less, benefit for cardiovascular event reduc-tion in individuals with diabetes than in those without.Even if there was a 10% reduction in the risk of primaryevents, the number needed to treat in order to prevent 2major cardiovascular events would be 1000 patients for 1year. Taking into account rare but well-documented sideeffects such as major bleeding, such benefit might bequestionable, even with a low-cost medication such asASA.

In observational studies of secondary prevention withASA, patients with diabetes appear to derive less benefitfrom ASA than do those without diabetes.56,61,62 No large,randomized clinical trial has specifically examined the use ofASA for secondary prevention exclusively in patients withdiabetes. A meta-analysis of trials that assessed antiplateletvs control therapy in patients with diabetes failed to show astatistically significant reduction in the risk of serious vas-cular events.43 Because the number of events was muchhigher in patients with diabetes, the benefit in terms ofnumber of events prevented was comparable in patients with(42 events prevented for every 1000 patients treated) andwithout (35 events prevented for every 1000 patientstreated) diabetes.

ASA appears to be as effective as other antiplatelet agentsand may be the best choice given that it is the most widelystudied and the most economical. In patients who cannottolerate ASA or have a clear contraindication (eg, allergy,ASA-induced asthma), an alternate antiplatelet agent maybe used. Subgroup analysis of the Clopidogrel vs Aspirin inPatients at Risk of Ischaemic Events study showed thatclopidogrel significantly reduced the risk of ischemic eventscompared with ASA in patients with diabetes.62 Combina-tion therapy with ASA and either clopidogrel or prasugrel isbeneficial in patients with diabetes who experience ACS,7,63

but not in those who do.


RECOMMENDATION

There is currently no evidence to recommend routine use ofASA at any dose for the primary prevention of vascular isch-emic events in patients with diabetes (Class III, Level A).

For patients with diabetes and aged �40 years and at lowrisk for major bleeding, low-dose ASA (75-162 mg daily)may be considered for primary prevention in patients withother cardiovascular risk factors for which its benefits areestablished (Class IIb, Level B).

Low-dose ASA therapy (75-162 mg daily) may be con-sidered for secondary prevention in patients with diabetesand manifest vascular disease for which its benefits are es-tablished (Class I, Level A).

Clopidogrel 75 mg daily may be considered for second-ary prevention in patients with diabetes who are unable totolerate ASA (Class IIa, Level B).

Use of Antiplatelet Therapy in Patients With HFWorking Group: Alan D. Bell, MD, CCPF, and James D.

Douketis, MD, FRCPTrials designed to investigate the role of antithrombotic and

antiplatelet therapies in reducing thromboembolic events inpatients with HF have failed to consistently demonstrate ben-efit. Early studies of warfarin in HF demonstrated significantbenefit, but results were confounded by inclusion of large num-bers of patients with atrial fibrillation and valvular heart dis-ease.64-67 A meta-analysis of the Warfarin/Aspirin Studyin Heart Failure and the Warfarin and Antiplatelet Therapyin Chronic Heart Failure trial, studies that compared war-farin with ASA in patients with HF who were in sinusrhythm, suggested a weak trend in favour of a lower mortal-ity rate with warfarin compared with ASA.68

Regardless of the presence of HF, antiplatelet therapyshould be used in all individuals with ischemic heart diseaseunless specifically contraindicated. Overall, there is no evi-dence that antiplatelet therapy provides benefit for patientswith HF of nonischemic etiology or benefit beyond the knownsecondary prevention in those with HF due to CAD. There islimited evidence to suggest that ASA may increase the second-ary risk of hospitalization for HF.

RECOMMENDATION

For individuals with HF of ischemic etiology, antiplate-let therapy should be dictated by the underlying CAD(Class IIa, Level A).

For individuals with HF of nonischemic etiology, rou-tine use of antiplatelet agents is not recommended (ClassIII, Level C).

Low-dose ASA (75 to 162 mg daily) and an ACE inhib-itor in combination may be considered for patients with HFwhen an indication for both drugs exists (Class IIa, Level B).

Use of Antiplatelet Therapy in Patients WithChronic Kidney Disease

Working Group: Neesh Pannu, MD, SM, FRCP, and
Alan D. Bell, MD, CCFP
There is little high-quality evidence to guide the use of ASAor other antiplatelet agents in patients with chronic kidneydisease (CKD) or end-stage renal disease (ESRD). A meta-analysis of studies of antiplatelet therapy for maintenance ofaccess patency among dialysis patients demonstrated a signifi-cant reduction in the relative risk of serious vascular eventsassociated with antiplatelet therapy, mainly ASA.43 The smallsize of the included studies precludes accurate estimation ofhazard ratios for bleeding events in this patient population. Forsecondary prevention, there is conflicting evidence related towhether a positive benefit-to-risk ratio is associated withASA69-75 or combination ASA-clopidogrel76-78 therapy in pa-tients with CKD. Conversely, subgroup analysis of TRITON-TIMI 38 revealed that patients with a creatinine clearance �60 mL per minute were likely to benefit the most from prasu-grel vs clopidogrel.79

Overall, consideration of antiplatelet therapy for primary orsecondary prevention of vascular events in patients with CKDand ESRD must include the dramatically increased risk of vas-cular disease (10- to 100-fold increased risk) vs the risk andpotential benefits of treatment.

RECOMMENDATION

ASA 75 to 162 mg daily may be considered for primaryprevention of ischemic vascular events in patients withESRD and a low risk of bleeding (Class IIb, Level C).

Antiplatelet therapy should be considered for secondaryprevention in patients with CKD and manifest vascular diseasefor which its benefits are established (Class IIa, Level C).

Use of Antiplatelet Therapy in Women Who ArePregnant or Breastfeeding

Working Group: Wee Shian Chan, MD, FRCPThere are no clinical trials demonstrating the efficacy of

antiplatelet therapy or relative superiority of types of antiplate-let therapy in pregnant women with coexisting cardio- or cere-brovascular diseases. Data from randomized trials in which thebenefits of ASA were investigated for primary and secondaryprevention of preeclampsia and improved pregnancy rates inwomen who undertake assisted reproductive technology sug-gest that ASA use does not increase maternal or fetal bleedingrisks, placenta abruption, or congenital defects.80-85 Similarly,a meta-analysis of observational studies investigating first-tri-mester ASA exposure reported that ASA use was not associatedwith an overall increased risk of congenital malformations, al-though a significantly increased risk of gastroschisis was re-ported.86 In several small trials of preeclampsia prevention,dipyridamole was not associated with fetal malformations, andin several case studies, no adverse fetal events were reportedwhen clopidogrel was used throughout pregnancy.87-91

Although maternal ASA ingestion is associated with excre-tion of salicylate and salicylate metabolites in breast milk,92 theuse of low-dose ASA (50-150 mg daily) during breastfeedinghas not been reported to result in adverse infant outcomes andis mostly considered safe. There is no data on the safety of
dipyridamole and clopidogrel in breastfeeding.


215

RECOMMENDATION

For cardio- or cerebrovascular disease in which antiplate-let therapy would be indicated in nonpregnant women,there should be similar considerations for its use in preg-nancy (Class IIa, Level A).

Low-dose ASA (75 to 162 mg daily) is likely safe for useduring the first trimester of pregnancy (Class IIa, Level A).Low-dose ASA can be used safely during the second andthird trimesters of pregnancy (Class I, Level of Evidence A).

Use of antiplatelet agents other than low-dose ASA forcardio- or cerebrovascular indications during pregnancyshould be considered only if maternal benefits clearly out-weigh potential fetal risks (Class IIb, Level C).

Low-dose ASA (75 to 162 mg daily) may be consideredfor use in breastfeeding women (Class I, Level C). Use ofagents other than low-dose ASA by breastfeeding mothersshould be considered only after weighing maternal benefitswith potential risks for the newborn (Class IIb, Level C).

Management of Patients on Antiplatelet TherapyWho Require a Surgical or Other InvasiveProcedure

Working Group: James D. Douketis, MD, FRCPC, andA. Graham Turpie, MD

The majority of evidence for the management of perioperativeantiplatelet therapy comes from case-control studies. These stud-ies suggest that continuing ASA monotherapy is safe for patientsundergoing gastrointestinal endoscopy,93 polypectomy,94 bronchos-copy,95 dental procedures,96,97 dermatologic procedures,98-100

and cataract removal.101 The evidence for clopidogrel mono-therapy or combined ASA/clopidogrel therapy in patients under-going these procedures is lacking.

In patients who are receiving antiplatelet therapy and requireelective noncardiac surgery, there are no randomized trials or non-randomized studies that compare the benefits and risks of continu-ing such drugs as opposed to temporarily interrupting their usearound the time of surgery. The available evidence suggests a ben-efit of perioperative ASA continuation but also indicates potentialharm related to increased perioperative bleeding.102-104 A risk-benefit assessment infers that the benefits of ASA treatment maybe limited to patients with prior cardiovascular disease (given re-duction in vascular mortality). For stent recipients receiving ASAand clopidogrel who require noncardiac surgery, there is an in-creased risk for stent thrombosis in the postoperative period. Theavailable evidence suggests the risk of stent thrombosis in BMSand DES recipients is lowest when surgery is performed �3months or �1 year after stent implantation, respectively.105-108

The preponderance of evidence suggests ASA can be con-tinued in the perioperative period in patients who undergoCABG.109-111 In clopidogrel-treated patients who require CABG,no studies have directly assessed clopidogrel use in the periopera-tive period. The decision of when to perform CABG in patientsreceiving ASA and clopidogrel is dependent on the relative risks ofischemic events and bleeding.112 For patients with a low ischemicrisk, clopidogrel should be discontinued for 5 days prior to sur-gery. For patients with a high ischemic risk and low bleeding risk,surgery can be performed immediately. If a patient has both high
ischemic and high bleeding risk, clopidogrel should be discontin-
ued for 3 to 5 days prior to CABG. In all cases, preoperative andpostoperative strategies that minimize the risk of major bleedingand transfusion should be implemented.112

RECOMMENDATION

Patients who are receiving ASA and undergoing a diagnos-tic test associated with a low risk for bleeding may continueASA without interruption, whereas patients undergoing a non-cardiac procedure associated with a high risk for bleedingshould discontinue ASA 7 to 10 days before the procedure(Class IIa, Level C). Patients who are receiving ASA and clopi-dogrel should discontinue clopidogrel 7 to 10 days before theprocedure if it can be done safely (Class IIb, Level C); ASAshould also be discontinued before diagnostic tests associatedwith a high risk for bleeding (Class IIa, Level C).

Whenever possible, elective surgery in patients receivingASA and clopidogrel secondary to coronary stent implantationshould be deferred for at least 6 weeks after BMS placementand at least 12 months after DES placement (Class I, Level B).

For patients who are receiving ASA and clopidogrel for aBMS and require urgent surgery within 6 weeks of place-ment, ASA and clopidogrel should be continued in the peri-operative period (Class I, Level B). For patients who arereceiving ASA and clopidogrel for a DES and require urgentsurgery within 12 months of placement, ASA and clopi-dogrel should be continued in the perioperative period(Class I, Level B).

Patients who are receiving ASA and are to have arthrocen-tesis may continue ASA through the time of the procedure(Class IIb, Level C). Patients who are receiving ASA and clopi-dogrel should discontinue clopidogrel 7 to 10 days before theprocedure if it can be done safely (Class IIb, Level C).

Patients who are receiving ASA and are undergoing a minordental, eye, or skin procedure or surgery may continue ASAaround the time of the procedure (Class IIa, Level A). Patientswho are receiving ASA and clopidogrel should discontinueclopidogrel 7 to 10 days before the procedure if it can be donesafely (Class IIa, Level C).

Patients who are receiving ASA and require elective noncar-diac surgery should discontinue ASA 7 to 10 days prior tosurgery if the risk for cardiovascular events is low but continuetherapy if cardiovascular risk is high (Class IIa, Level B). Pa-tients who are receiving ASA and clopidogrel, who are likely tobe at high cardiovascular risk, should continue ASA up to sur-gery (Class IIa, Level C) but discontinue clopidogrel 7 to 10days before surgery if it can be done safely (Class IIb, Level C).

Patients who are receiving ASA and require CABG shouldcontinue ASA up to the time of surgery (Class I, Level B).Patients who are receiving ASA and clopidogrel should con-tinue ASA until the time of surgery but discontinue clopidogrelat least 5 days before surgery (Class I, Level B).

Management of Antiplatelet Therapy inAssociation With Minor Bleeding

Working Group: James D. Douketis, MD, FRCP, and A.Graham Turpie, MD

In patients receiving antiplatelet drugs, non–life-threaten-
ing minor bleeding is common, particularly in those also re-


ceiving anticoagulant therapy (warfarin or heparin) or systemiccorticosteroids or with comorbidities such as chronic renal orhepatic disease. In general, minor bleeding is self-limiting anddoes not require medical attention. Studies specifically assessingthe incidence, consequence, and clinical management of antiplate-let drug–associated minor bleeding are lacking. Therefore, the rec-ommendations herewith are based on expert opinion alone andshould be interpreted in this context.

RECOMMENDATION

Patients who are receiving ASA or ASA and clopidogreland who develop ecchymosis and petechiae should undergotesting with a complete blood count and international nor-malized ratio (INR) and activated partial thromboplastintime monitoring to investigate for thrombocytopenia or acoagulopathy (Class IIa, Level C). In the absence of super-imposed abnormalities in haemostatic function, antiplateletdrugs can be continued with clinical observation, whereas inpatients with thrombocytopenia or a coagulopathy, ASA (orclopidogrel) should be stopped pending further investiga-tions (Class IIa, Level C).

Patients who are receiving ASA or ASA and clopidogreland in whom there is excessive bleeding after a dental pro-cedure should receive application of local pressure and/oruse of tranexamic acid mouthwash 2 to 4 times daily for 1 to2 days (Class IIa, Level C).

Patients who are receiving ASA or ASA and clopidogreland in whom subconjunctival bleeding develops shouldcontinue treatment and be monitored for bleeding (ClassIIa, Level C).

Combination Therapy With Warfarin and ASA:When to Use, When to Consider, When to Avoid

Working Group: James D. Douketis, MD, FRCP, and A.Graham Turpie, MD

In patients with both atrial fibrillation and CAD, relevant datato assess the efficacy of combined warfarin-ASA compared withwarfarin alone is derived from a subgroup analysis of warfarin-treated patients in the Stroke Prevention Using an Oral ThrombinInhibitor in Atrial Fibrillation trials, which compared warfarin(target INR, 2.0-3.0) with ximelagatran for stroke prevention inpatients with atrial fibrillation.113 This analysis suggested a lack ofbenefit for combination warfarin-ASA therapy. In a retrospectivecohort study of more than 4000 warfarin-treated patients man-aged by a specialized anticoagulation clinic, there were no signifi-cant differences in rates of coronary events or thromboembolismin patients receiving combination warfarin-ASA therapy com-pared with those receiving warfarin alone.114 Taken together,there does not appear to be compelling evidence that combinationwarfarin-ASA therapy is more effective than warfarin alone in pre-venting cardiac and other thromboembolic outcomes in patientswith either chronic CAD or chronic atrial fibrillation or in patientswith both CAD and atrial fibrillation.

Combination warfarin-ASA therapy is of known benefit inpatients with a mechanical prosthetic heart valve.115 Otherconditions for which combination warfarin-ASA therapy is rea-sonable include patients with atrial fibrillation or venous
thromboembolism who are receiving long-term warfarin and
develop an ACS treated with medical therapy alone, patientswho have an indication for long-term warfarin therapy andundergo CABG, and patients with atrial fibrillation who de-velop a stroke syndrome despite therapeutic anticoagulationwith warfarin. In patients receiving long-term warfarin whoundergo coronary stent implantation, it is reasonable to coad-minister warfarin, ASA, and clopidogrel for at least 6 weeks,although patients with a DES may require such therapy forat least 12 months, or possibly longer.116,117

RECOMMENDATION

In patients with a mechanical prosthetic heart valve,combination warfarin (target INR, 2.0-3.0) and ASA 75 to162 mg daily should be considered, especially in patientswith any mechanical mitral valve or in patients with an oldercaged-ball or bileaflet mechanical aortic valve (Class IIa,Level A).

In patients who have a clinical indication for long-termwarfarin and develop an ACS that is treated with medicaltherapy alone, combination warfarin (target INR, 2.0-3.0)and ASA (75 to 162 mg daily) therapy is reasonable for up to12 weeks, at which time ASA may be withdrawn if there areno further cardiac events (Class IIb, Level C).

Interaction Between Clopidogrel and ProtonPump Inhibitors

Working Group: Wee Shian Chan, MD, FRCP, and AlanD. Bell, MD, CCFP

As many as two-thirds of clopidogrel recipients receive a protonpump inhibitor (PPI) for the treatment of a concomitant acid-related disorder.118 Several pharmacodynamic interaction studiessuggest that omeprazole reduces the antiplatelet effect of clopi-dogrel,119-122 and results of observational studies have raised con-cerns that the dual use of clopidogrel and a PPI might lead to anincreased risk of adverse cardiovascular outcomes compared withpatients receiving clopidogrel without a concomitant PPI.118,123-

129 Product monographs for clopidogrel recommend that con-comitant use of clopidogrel and PPIs be discouraged.

However, there is also observational data showing no effectof concomitant clopidogrel and PPI use on adverse out-comes,130-137 and a post hoc analysis of the TRITON-TIMI 38randomized clinical trial revealed no increased risk of adverse car-diovascular outcomes associated with dual use of a PPI and eitherclopidogrel or prasugrel.132 Results of the Clopidogrel and theOptimization of Gastrointestinal Events randomized trial showedthat during a total follow-up of 180 days, combination clopi-dogrel-omeprazole therapy did not significantly increase the risk ofthe adjudicated composite cardiovascular outcome of cardiovas-cular death, nonfatal myocardial infarction, CABG, PCI, or isch-emic stroke (4.9% with clopidogrel plus omeprazole vs 5.7% withclopidogrel alone; hazard ratio, 0.99; 95% CI, 0.68-1.44).133

Recent guidance published jointly by the American College ofCardiology Foundation, American College of Gastroenterology,and American Heart Association recommends the use of PPIs toreduce gastrointestinal bleeding in patients with a history of uppergastrointestinal bleeding and suggests they are appropriate for pa-tients with multiple risk factors for gastrointestinal bleeding who
require antiplatelet therapy.134 Routine prophylactic use of PPIs


217

and H2 blockers in patients at lower risk of upper gastrointestinalbleeding is not recommended. The guidance also states that deci-sions regarding the concomitant use of PPIs and thienopyridinesmust balance overall cardiovascular and gastrointestinal risks andbenefits.y

RECOMMENDATION

The pharmacodynamic interaction between clopidogreland PPIs and the initial findings from observational studiessuggested an increased risk of cardiovascular events in con-comitant users of clopidogrel and PPIs. Recently publisheddata from a randomized clinical trial suggest that this risk islikely clinically insignificant.133 Nevertheless, because ofpotential limitations with study design and patients re-cruited, PPIs that minimally inhibit cytochrome P4502C19 are preferred for patients taking clopidogrel who areconsidered to be at increased risk of upper gastrointestinalbleeding (Class IIb, Level B).

Interaction Between ASA and NonsteroidalAnti-Inflammatory Drugs

Working Group: Alan D. Bell, MD, CCFP, and WeeShian Chan, MD, FRCP

Although no randomized trials examining the clinical effectof an interaction between ASA and nonsteroidal anti-inflam-matory drugs (NSAIDs) have been completed, laboratory stud-ies135-140 and observational and epidemiologic data141-145 havesuggested an adverse effect. This interaction has importantclinical consequences because, unlike coxibs, traditionalNSAIDs may inhibit ASA binding to platelet cyclooxygen-ase-1. The reversible binding of traditional NSAIDs doesnot offer a consistent antiplatelet effect or the vascular pro-tection afforded by the irreversible binding of ASA.146-150

RECOMMENDATION

Individuals taking low-dose ASA (75 to 162 mg daily)for vascular protection should avoid the concomitant use oftraditional (non–cyclooxygenase-2 inhibitor) NSAIDs(Class III, Level C).

If a patient taking low-dose ASA (75 to 162 mg daily) forvascular protection requires an anti-inflammatory drug,specific cyclooxygenase-2 inhibitors should be chosen overtraditional NSAIDS (Class IIb, Level C).

Both cyclooxygenase-2 inhibitors and traditionalNSAIDs increase cardiovascular risk and, if possible, shouldbe avoided in patients at risk of ischemic vascular events(Class III, Level A).

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The Use of Antiplatelet Therapy in the Outpatient Setting

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