Antiplatelets Guidelines - Outpatient Setting - CCS 2011

7/29/2019 Antiplatelets Guidelines - Outpatient Setting - CCS 2011

1/14

Society Guidelines

The Use of Antiplatelet Therapy in the OutpatientSetting: Canadian Cardiovascular Society GuidelinesExecutive Summary

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

Wee Shian Chan, MD, FRCPC,dJames D. Douketis, MD, FRCPC,eAnil Gupta, MD, FRCPC,f

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

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

Rmi Rabasa-Lhoret, MD, PhD,kAshfaq Shuaib, MD, FRCPC,l Philip Teal, MD, FRCPC,m

Pierre Throux, MD,n

A. Graham Turpie, MD,o

Robert C. Welsh, MD, FRCPC, FACC,p

Jean-Franois Tanguay, MD, CSPQ, FRCPC, FACC, FAHA, FESCqaFrom the Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada;b Internal and Vascular Medicine, Centre Hospitalier Universitaire de Montral, Montral, Quebc, Canada;

cDepartment of Surgery, Montral Heart Institute, Montral, Quebc, Canada; d Department of Medicine, Womens College Hospital,Toronto, Ontario, Canada; e Vascular Medicine Institute, St. Josephs Healthcare, Hamilton, Ontario, Canada; fDepartment of Clinical Cardiology, Trillium Health Centre, Mississauga, Ontario, Canada; gDivision of Endocrinology, St. Michaels Hospital,

Toronto, Ontario, Canada; h Department of Vascular and Endovascular Surgery, Toronto General Hospital, Toronto, Ontario, Canada;iDivision 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 Montral, Dpartement de Nutrition, Universit de Montral,

Montral, Quebc, 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, Montral Heart Institute, Montral, Quebc,

Canada; o Division of Hematology & Thromboembolism (Emeritus), McMaster University, Hamilton, Ontario, Canada; p Department ofInterventional Cardiology, University of Alberta, Edmonton, Alberta, Canada; qDepartment of Medicine, Montral Heart Institute,

Universit de Montral, Montral, Quebc, Canada

ABSTRACTAntiplatelet agents are a cornerstone of therapy for patients with

atherosclerotic vascular disease. There is presently a lack of compre-

hensive guidelines focusing on the use of antiplatelet drugs in patients

currently manifesting or at elevatedrisk of cardiovascular disease. The

Canadian Antiplatelet Therapy Guidelines Committee reviewed exist

RSUMLes agents antiplaquettaires sont une des pierres angulaires du traite-

ment des patients ayant une maladie vasculaire athrosclrotique.

Les lignes directrices qui portent sur lutilisation des mdicaments

antiplaquettaires chez les patients qui manifestent ou qui sont ris-

que lev de maladie cardiovasculaire sont lheure actuelle incom

Thefull paper corresponding to this ExecutiveSummary will be publishedas a supplement to the Canadian Journal of CardiologyMay/June issue.

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

Corresponding author: Dr Jean-Franois Tanguay, Attention: ChantalSauv, Montreal Heart Institute, 5000 Belanger Street, #S-2260, Montreal,Qubec 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

medical literature and the best available evidence and clinical experience. It

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 app ropriate 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.

Canadian Journal of Cardiology 27 (2011) 208221

0828-282X/$ see front matter 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.doi:10.1016/j.cjca.2010.12.033
mailto:[email protected]://www.ccs.ca/http://www.ccsguidelineprograms.ca/http://www.ccsguidelineprograms.ca/http://www.ccsguidelineprograms.ca/http://www.ccs.ca/mailto:[email protected]


2/14

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, vasculardisease, theCanadianAntiplatelet 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

(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 ODoherty of the TIGC;and the editorial assistance of Melanie Leiby, PhD, of in-Science Communications, a Wolters Kluwer business. Au-

ing disease-based guidelines and subsequently published literature

andused expertopinion andreview to develop guidelineson the useof

antiplatelet therapy in the outpatient setting. This Executive Summary

provides an abbreviated version of the principal recommendations.

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 dis-

charged from hospital after acute coronary syndromes, percutaneous

coronary intervention, or 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 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, or

aspirin and nonsteroidal anti-inflammatory drugs, as well as for the

management of bleeding complications. The complete guidelines doc-

ument is published as a supplementary issue of the Canadian Journal

of Cardiology and is available at http://www.ccs.ca/.

pltes. Le comit canadien sur les directives pour le traitement antipla-

quettaire a pass en revue les lignes directrices des maladies et, sub-

squemment la littrature publie, et les revues et lopinion des experts

pour dvelopper des lignes directrices sur lutilisation de traitements an-

tiplaquettairesdans la prise en chargeexterne des patients.Ce sommaire

excutif fournit une version abrge des principales recommandations.

Le traitement antiplaquettaire semble gnralement sous-utilis, peut-

tre en partie en raison de labsence de directives claires et prouves. Ici,

nous donnons des lignes directrices spcifiques pour la prvention sec-

ondaire chez les patients en soins externes la suite de syndromes

coronaires aigus, dune intervention coronaire percutane, dun pontage

aortocoronarien; chez les patients avec une histoire dischmies

crbrales transitoires ou daccidents vasculaires crbraux, et chez les

patients avec une maladie artrielle priphrique. Lesquestions lies la

prvention primaire sont aussi abordes, en plus des contextes cliniques

particuliers comme le diabte, linsuffisance cardiaque, la maladie rnale

chronique, la grossesse ou lallaitement, et la gestion priopratoire.

Des recommandations sont donnes tant pour les interactions phar-

macologiques qui peuvent survenir durant un traitement combin avec la

warfarine, le clopidogrel et les inhibiteurs de la pompe protons, ou

laspirine et les mdicaments anti-inflammatoires non strodaux, que

pour la gestion des complications hmorragiques. Le document entier

des lignes directrices a t publi dans un numro supplmentaire du

Journal canadien de cardiologie et est disponible au http://www.ccs.ca/.

Table 1. Grading system used in the preparation of the Canadian Cardiovascular Society Antiplatelet Therapy Guideline

Class of recommendation Level of evidence

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

A: 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 favour

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

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

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

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

Bell et al.Outpatient Antiplatelet Therapy

209
http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/http://www.ccs.ca/


3/14

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-Franois 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 nonST-elevation ACS (NSTEACS), regardlessof the management strategy,7whereas the Clopidogrel as AdjunctiveReperfusion TherapyThrombolysis in Myocardial Infarction 28trial8 andClopidogrel andMetoprolol 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 thecommonunderlying pathophysiologyof all types ofACS are the basis for continuingtherapyinpatientswithSTEMIafterhospital discharge. Thecurrent reality isthat 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 theTrial to Assess Improve-ment in Therapeutic Outcomes by Optimizing Platelet Inhibitionwith Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRI-TON-TIMI 38)suggest that combinationtherapy with ASAandthe

P2Y12 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.10Results of the Platelet InhibitionandPatientOutcomestrialsuggestthatcombinationtherapywiththeP2Y12 inhibitor ticagrelor improves clinical outcomes without in-creasingoverallmajorbleeding, however,nonproceduralmajorbleed-ing was significantly increased.11

RECOMMENDATION

For allpatients with ACSwho survive to hospitaldischarge,indefinite therapy with low-dose ASA (75-162 mg daily) isrecommended (Class I, Level A). For patients allergic to or

intolerant 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 in

addition 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).

Forpatients presenting with NSTEACS who aremanaged 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 priordocumented 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 be

avoided in patients with an increased bleeding risk, likely to un-dergo CABG within 7 days, with a history of stroke or transientischemicattack (TIA), aged75years,orweighing60kg(ClassIII, Level B).

For patients with ACS, ticagrelor 90 mg twice daily may beadded toASA 75to 162 mgdailyfor 12months (Class I,Level B).(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-Franois 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 2randomized clinical trials did not show a benefit for con-

210 Canadian Journal of Cardiology Volume 27 2011


4/14

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 (Class

IIa, 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, orweighing60 kg (Class III, Level B).

For patients with ACS who undergo stent implantation,ticagrelor90 mg twice daily may beadded toASA 75to 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 PCIWorking Group: Anil Gupta, MD, FRCPC, and Pierre

Throux, MDAs 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,20-22with 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.24However, 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 Prevention

Following CABG

Working Group: Raymond Cartier, MDASA isrecognizedas the standardofcareforpreventingsaphenous

vein graft closure after CABG andis generallycontinuedindefinitely,given its benefit in preventing subsequent clinical events.25A largemeta-analysis showedthat low(approximately 100mg)andmedium(approximately 325 mg) daily doses of ASA were more effective thanhigh-dose(approximately975mg)ASAinpreventing saphenousveingraftocclusionandcaused lessgastrointestinal sideeffects.26Althoughticlopidineprovides a benefitsimilartothat ofASAin preventing graftclosure,27,28 it is not recommended for use because of its relativelypoor safetyandtolerabilityprofile. Despite a lack ofdirectclinical trialevidence, clopidogrel is recommended for patients who have under-gone CABG and who are allergic to or intolerant of ASA. Evidence

from the CURE and Clopidogrel for the Reduction of IschemicEventsDuringObservationclinical trialssuggests that although com-bination ASA-clopidogrel therapy may decrease therisk of cardiovas-cular events in patients who undergo CABG, it also significantly in-creases therisk of bleeding.13,29There 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


211


5/14

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 ticlopidine250 mg twicedailybecauseofthe 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.34-36As 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 patients

not 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: Andr 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, anabnormally enlargedartery leadingto 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

andthefact thatmany AAA riskfactorsarealsoatheroscleroticriskfactors48,49 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 reduced

expansion rate anda reduced riskofAAAsurgeryin patients whoseaorticsizewas40to49mm.50Low-dose ASA is recommendedforthose with an AAA, with the evidence stronger for those withclinical or subclinical PAD.

RECOMMENDATION

For patients with asymptomatic PAD with an ankle-brachial index0.9, 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 mg

daily) 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,antiplatelettherapyas 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).

Forpatients with symptomatic PADwith anindicationfororal 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).



6/14

Long-term antiplatelet therapy with ASA 75 to 162 mgdaily should be given to patientswho undergo lower-extremityballoonangioplastywithor withoutstenting for chronicsymp-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)maybe considered forallpatients with an AAA, particularly those with clinical or sub-clinical PAD (Class IIb, Level C).

Antiplatelet Therapy for the Primary Prevention

of 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,51Physicians Health Study,52 and Wom-ens Health Study53) and several meta-analyses of these and otherprimary prevention trials22,54 suggeststhatASA 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, mostof thestudies 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. Althoughvascularevents 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 mg

daily may be considered (Class IIb, Level C).

Use of Antiplatelet Therapy in Patients With

Diabetes

Working Group: Maria E. Kraw, MD, FRCP, and RmiRabasa-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 Aspirin

for 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 patients

treated) diabetes.ASA appears to be as effective as other antiplatelet agents

and 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.


213


7/14

RECOMMENDATION

There is currently no evidence to recommend routineuse 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 aged40yearsand atlowrisk 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 HF

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

Trials designed to investigate the role of antithrombotic andantiplatelet therapies in reducing thromboembolic events inpatients with HF have failed to consistently demonstrate ben-efit. Early studies of warfarin in HF demonstrated significantbenefit, butresults 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, andAlan 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 small

size 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 and

potential 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 withCKD and manifestvasculardiseasefor 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 ofdipyridamole and clopidogrel in breastfeeding.



8/14

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 use

during 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,93polypectomy,94bronchos-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 require

electivenoncardiac surgery,there are no randomized trials or non-randomizedstudiesthatcomparethe benefitsand 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. The

available evidence suggests the risk of stent thrombosis in BMSand DES recipients is lowest when surgery is performed 3months or1 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.109-111In clopidogrel-treated patients whorequireCABG,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 therelative risks ofischemic events and bleeding.112For 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 highischemic 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 continue

ASAwithoutinterruption, whereaspatientsundergoinga 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 a

BMS 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 whoare 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 whoare receiving ASA and areundergoing a minor

dental, 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 whoare 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 whoarereceiving 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 should

continue ASA up to the time of surgery (Class I, Level B).Patients who are receiving ASA and clopidogrel should con-tinue ASAuntil thetimeof surgerybutdiscontinue 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, nonlife-threaten-ing minor bleeding is common, particularly in those also re-


215


9/14

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 assessingtheincidence,consequence, andclinicalmanagement ofantiplate-let drugassociated minor bleedingare 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 fibrillationand CAD, relevant datato assess the efficacy of combined warfarin-ASA compared withwarfarin alone is derived from a subgroup analysis of warfarin-treatedpatients in theStrokePreventionUsing an OralThrombinInhibitor in Atrial Fibrillation trials, which compared warfarin(target INR, 2.0-3.0) with ximelagatran for stroke prevention inpatients with atrial fibrillation.113This 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 doesnotappear to be compellingevidence thatcombinationwarfarin-ASA therapy is more effective thanwarfarinalone in pre-venting cardiac and other thromboembolic outcomes in patientswitheitherchronic CADor chronicatrial fibrillationor in patientswith both CAD and atrial fibrillation.

Combination warfarin-ASA therapy is of known benefit inpatients with a mechanical prosthetic heart valve.115 Otherconditionsfor which combination warfarin-ASA therapy is rea-sonable include patients with atrial fibrillation or venousthromboembolism 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-thirdsof clopidogrelrecipientsreceivea protonpump inhibitor (PPI) for the treatment of a concomitant acid-related disorder.118Several pharmacodynamic interaction studies

suggest 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 the

Optimization of Gastrointestinal Events randomized trial showedthat during a total follow-up of 180 days, combination clopi-dogrel-omeprazole therapydidnotsignificantly increasethe riskofthe 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 bleedingin patients witha history of uppergastrointestinal bleeding and suggests they are appropriate for pa-tients with multiple risk factors for gastrointestinal bleeding whorequire antiplatelet therapy.134Routine prophylactic use of PPIs



10/14

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) havebeen completed, laboratory stud-ies135-140 and observational and epidemiologic data141-145havesuggested 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 does

not 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 traditional

NSAIDs increase cardiovascular risk and, if possible, shouldbe avoided in patients at risk of ischemic vascular events(Class III, Level A).

References

1. Abramson BL, Huckell V, Anand S, et al. Canadian CardiovascularSociety Consensus Conference: peripheral arterial disease - executivesummary. Can J Cardiol 2005;21:997-1006.

2. Bhattacharyya OK, Shah BR, Booth GL. Management of cardiovasculardisease in patients with diabetes: the 2008 Canadian Diabetes Associa-tion guidelines. CMAJ 2008;179:920-6.

3. Love MP, Schampaert E, Cohen EA, et al. The Canadian Association

of Interventional Cardiology and the Canadian Cardiovascular Soci-

ety joint statement on drug-eluting stents. Can J Cardiol 2007;23:

121-3.

4. Lindsay P, Bayley M, McDonald A, Graham ID, Warner G, Phillips S.

Toward a more effective approach to stroke: Canadian Best Practice

Recommendations for Stroke Care. CMAJ 2008;178:1418-25.

5. Bell AD, Roussin A, Cartier R, et al. Canadian Cardiovascular Societyguidelines on the use of antiplatelet therapy in the outpatient setting.

Can J Cardiol 2011. In press.

6. AGREE Collaboration. Development and validation of an international

appraisal instrument for assessing the quality of clinical practice guide-

lines: the AGREE project. Qual Saf Health Care 2003;12:18-23.

7. Yusuf S, Zhao F, Mehta SR,Chrolavicius S, Tognoni G, FoxKK. Effects

of clopidogrel in addition to aspirin in patients with acute coronary

syndromes without ST-segment elevation. N Engl J Med 2001;345:

494-502.

8. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to

aspirin and fibrinolytic therapy for myocardial infarction with ST-seg-

ment elevation. N Engl J Med 2005;352:1179-89.

9. Chen ZM,JiangLX, Chen YP,et al.Addition of clopidogrel to aspirin in

45,852 patients with acute myocardial infarction: randomised placebo-

controlled trial. Lancet 2005;366:1607-21.

10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopi-

dogrel in patients with acute coronary syndromes. N Engl J Med 2007;

357:2001-15.

11. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel

in patients with acute coronary syndromes. N Engl J Med 2009;361:

1045-57.

12. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopi-

dogrel and aspirin followed by long-term therapy in patients undergoing

percutaneous coronary intervention: the PCI-CURE study. Lancet2001;358:527-33.

13. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pre-

treatment before percutaneous coronary intervention in patients with

ST-elevation myocardial infarction treated with fibrinolytics: the PCI-

CLARITY study. JAMA 2005;294:1224-32.

14. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual

oral antiplatelet therapy following percutaneous coronary intervention: a

randomized controlled trial. JAMA 2002;288:2411-20.

15. Cannon CP, Harrington RA, 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. Lan-

cet 2010;375:283-93.

16. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events

after clopidogrel discontinuation may limit the benefit of drug-eluting

stents: an observational study of drug-eluting versus bare-metal stents.

J Am Coll Cardiol 2006;48:2584-91.

17. Spertus JA, 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. Cir-

culation 2006;113:2803-9.

18. Tanzilli G, Greco C, Pelliccia F, et al. Effectiveness of two-year clopi-

dogrel aspirin in abolishing the risk of very late thrombosis after

drug-eluting stent implantation (from the TYCOON [two-year ClOpi-

dOgrel need] study). Am J Cardiol 2009;104:1357-61.


217


11/14

19. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet

therapy after implantation of drug-eluting stents. N Engl J Med

2010;362:1374-82.

20. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in

unstable angina: results of a Canadian multicenter trial. N Engl J Med

1985;313:1369-75.

21. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for

the prevention of cardiovascular disease: a systematic review. JAMA2007;297:2018-24.

22. 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. Lancet 2009;373:

1849-60.

23. CAPRIE Steering Committee. A randomised, blinded, trial of clopi-

dogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).Lancet 1996;348:1329-39.

24. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus

aspirin alone for the prevention of atherothrombotic events. N Engl

J Med 2006;354:1706-17.

25. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guidelineupdate for coronary artery bypass graft surgery: a report of the American

College of Cardiology/American Heart Association Task Force on Prac-

tice Guidelines (Committee to Update the 1999 Guidelines for Coro-

nary Artery Bypass Graft Surgery). Circulation 2004;110:e340-437.

26. Fremes SE, Levinton C, Naylor CD, Chen E, Christakis GT, Goldman

BS. Optimal antithrombotic therapy following aortocoronary bypass: a

meta-analysis. Eur J Cardiothorac Surg 1993;7:169-80.

27. Chevign M, David JL, Rigo P, Limet R. Effect of ticlopidine on saphe-

nous vein bypass patency rates: a double-blind study. Ann Thorac Surg

1984;37:371-8.

28. Limet R, David JL, Magotteaux P, Larock MP, 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. J Thorac Cardiovasc Surg 1987;94:773-83.

29. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination

of clopidogrel and aspirin in patients undergoing surgical revasculariza-

tion for non-ST-elevation acute coronary syndrome: the Clopidogrel in

Unstable angina to prevent Recurrent ischemic Events (CURE) trial.

Circulation 2004;110:1202-8.

30. Gao C, Ren C, Li D, Li L. Clopidogrel and aspirin versus clopidogrel

alone on graft patency after coronary artery bypass grafting. Ann Thorac

Surg 2009;88:59-62.

31. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after

cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry

1999;66:255.

32. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopi-

dine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215-20.

33. Hass WK,Easton JD, Adams HP Jr,et al. A randomized trial comparing

ticlopidine hydrochloride with aspirin for the prevention of stroke in

high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl

J Med 1989;321:501-7.

34. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release di-

pyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;

359:1238-51.

35. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A.

European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic

acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13.

36. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus

dipyridamole versus aspirin alone after cerebral ischaemia of arterial or-

igin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665-73.

37. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recog-

nition, and treatment of cardiovascular risk factors in outpatients with

atherothrombosis. JAMA 2006;295:180-9.

38. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel

compared with clopidogrel alone after recent ischaemic stroke or tran-sient ischaemic attack in high-risk patients (MATCH): randomised,

double-blind, placebo-controlled trial. Lancet 2004;364:331-7.

39. Kennedy J, Hill MD,Ryckborst KJ,Eliasziw M, Demchuk AM,Buchan

AM. Fast assessment of stroke and transient ischaemic attack to prevent

early recurrence (FASTER): a randomised controlled pilot trial. Lancet

Neurol 2007;6:961-9.

40. Geraghty OC, Kennedy J, Chandratheva A, Marquardt L, Buchan AM,

Rothwell PM. 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. Cerebrovasc Dis 2010;29:460-7.

41. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of car-

diovascular events in a general population screened for a low ankle bra-chial index: a randomized controlled trial. JAMA 2010;303:841-8.

42. BelchJ, 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 dia-

betes and asymptomatic peripheral arterial disease. BMJ 2008;337:

a1840.

43. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of

randomised trials of antiplatelet therapy for prevention of death, myo-

cardial infarction, and stroke in high riskpatients.BMJ 2002;324:71-86.

44. Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet

therapy for the prevention of myocardial infarction, stroke or vascular

death in patients with peripheral vascular disease. Br J Surg 2001;88:

787-800.

45. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the preven-

tion of cardiovascular events in patients with peripheral artery disease: a

meta-analysis of randomized trials. JAMA 2009;301:1909-19.

46. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery

occlusive disease: American College of Chest Physicians evidence-based

clinical practice guidelines (8th ed.). Chest 2008;133:815S-43S.

47. Freiberg MS, Arnold AM, Newman AB, Edwards MS, Kraemer KL,

Kuller LH. Abdominal aortic aneurysms, increasing infrarenal aortic di-

ameter, and risk of total mortality and incident cardiovascular disease

events: 10-year follow-up data from the Cardiovascular Health Study.

Circulation 2008;117:1010-7.

48. Zankl AR, Schumacher H, Krumsdorf U, Katus HA, Jahn L, Tiefen-

bacher CP. Pathology, natural history and treatmentof abdominal aortic

aneurysms. Clin Res Cardiol 2007;96:140-51.

49. Grootenboer N, Bosch JL, Hendriks JM, van Sambeek MR. Epidemiol-

ogy, aetiology, risk of rupture and treatment of abdominal aortic aneu-

rysms: does sex matter? Eur J Vasc Endovasc Surg 2009;38:278-84.

50. Lindholt JS, Sorensen HT, Michel JB, Thomsen HF, Henneberg EW.

Low-dose aspirin may prevent growth and later surgical repair of medi-

um-sized abdominal aortic aneurysms. Vasc Endovascular Surg 2008;42:

329-34.

51. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily

aspirin in British male doctors. Br Med J (Clin ResEd) 1988;296:313-6.



12/14

52. Steering Committee of the Physicians Health Study Research Group.

Final reporton theaspirin component of theongoing Physicians Health

Study. N Engl J Med 1989;321:129-35.

53. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.

Inflammation, aspirin, and the risk of cardiovascular disease in appar-

ently healthy men. N Engl J Med 1997;336:973-9.

54. BergerJS, Roncaglioni MC,AvanziniF, Pangrazzi I, Tognoni G, Brown

DL. Aspirin for the primary prevention of cardiovascular events inwomen and men: a sex-specific meta-analysis of randomized controlled

trials. JAMA 2006;295:306-13.

55. Ong G, Davis TM, Davis WA. Aspirin is associated with reduced car-

diovascular and all-cause mortality in type 2 diabetes in a primary pre-

vention setting: the Fremantle Diabetes study. Diabetes Care 2010;33:

317-21.

56. Leung WY, So WY, Stewart D, et al. Lack of benefits for prevention of

cardiovascular disease with aspirin therapy in type 2 diabetic patients: a

longitudinal observational study. Cardiovasc Diabetol 2009;8:57.

57. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nico-

lucci A. Primary prevention of cardiovascular events with low-dose aspi-

rin and vitamin E in type 2 diabetic patients: results of the PrimaryPrevention Project (PPP) trial. Diabetes Care 2003;26:3264-72.

58. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for pri-

mary prevention of atherosclerotic events in patients with type 2 diabe-

tes: a randomized controlled trial. JAMA 2008;300:2134-41.

59. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary preven-

tion of cardiovascular events in people with diabetes: meta-analysis of

randomised controlled trials. BMJ 2009;339:b4531.

60. Calvin AD, Aggarwal NR, Murad MH, et al. Aspirin for the primary

prevention of cardiovascular events: a systematic review and meta-anal-

ysis comparing patients with and without diabetes. Diabetes Care 2009;

32:2300-6.

61. Cubbon RM, Gale CP, Rajwani A, et al. Aspirin and mortality in pa-tients with diabetes sustaining acute coronary syndrome. Diabetes Care

2008;31:363-5.

62. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ.

Amplified benefit of clopidogrel versus aspirin in patients with diabetes

mellitus. Am J Cardiol 2002;90:625-8.

63. Wiviott SD, Braunwald E, Angiolillo DJ,et al.Greater clinical benefitof

more intensive oral antiplatelet therapy with prasugrel in patients with

diabetes mellitus in the trial to assess improvement in therapeutic out-

comes by optimizing platelet inhibition with prasugrel: Thrombolysis in

Myocardial Infarction 38. Circulation 2008;118:1626-36.

64. GriffithGC, Stragnell R,LevinsonDC, Moore FJ,Ware AG. A study of

the beneficial effects of anticoagulant therapy in congestive heart failure.

Ann Intern Med 1952;37:867-87.

65. Harvey WP, Finch CA. Dicumarol prophylaxis of thromboembolic dis-

ease in congestive heart failure. N Engl J Med 1950;242:208-11.

66. Lip GY, Gibbs CR. Anticoagulation for heart failure in sinus rhythm: a

Cochrane systematic review. QJM 2002;95:451-9.

67. Wishart JH, Chapman CB. Dicumarol therapy in congestive heart fail-

ure. N Engl J Med 1948;239:701-4.

68. Cleland JG, Ghosh J, Freemantle N, et al. Clinical trials update and

cumulative meta-analyses from the American College of Cardiology:

WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-

US, RIO-Lipids and cardiac resynchronisation therapy in heart failure.

Eur J Heart Fail 2004;6:501-8.

69. Ezekowitz J, McAlister FA, Humphries KH, et al. The association

among renal insufficiency, pharmacotherapy, and outcomes in 6,427

patients with heart failure andcoronaryartery disease. J Am Coll Cardiol

2004;44:1587-92.

70. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angio-

tensin-converting enzyme inhibitor therapy in patients with end-stage

renal disease and an acute myocardial infarction. J Am Coll Cardiol

2003;42:201-8.

71. McCullough PA, Sandberg KR, Borzak S, Hudson MP, Garg M, Man-

ley HJ. Benefits of aspirin and beta-blockade after myocardial infarction

in patients with chronic kidney disease. Am Heart J 2002;144:226-32.

72. Shlipak MG,Heidenreich PA,Noguchi H, Chertow GM,Browner WS,

McClellan MB. Association of renal insufficiency with treatment and

outcomes aftermyocardial infarctionin elderly patients.Ann Intern Med

2002;137:555-62.

73. Keough-Ryan TM, Kiberd BA, Dipchand CS, et al. Outcomes of acute

coronary syndrome in a large Canadian cohort: impact of chronic renal

insufficiency, cardiac interventions,and anemia. Am J KidneyDis 2005;

46:845-55.

74. Ethier J, Bragg-Gresham JL, Piera L, et al. Aspirin prescription and

outcomes in hemodialysis patients: the Dialysis Outcomes and Practice

Patterns Study (DOPPS). Am J Kidney Dis 2007;50:602-11.

75. Ishani A, Herzog CA, Collins AJ, Foley RN. Cardiac medications and

their association with cardiovascular events in incident dialysis patients:

cause or effect? Kidney Int 2004;65:1017-25.

76. Keltai M, Tonelli M, Mann JF, et al. Renal function and outcomes in

acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev

Rehabil 2007;14:312-8.

77. Dasgupta A, SteinhublSR, Bhatt DL,et al.Clinicaloutcomesof patients

with diabetic nephropathy randomized to clopidogrel plus aspirin versus

aspirin alone (a post hoc analysis of the Clopidogrel for High Athero-

thrombotic Risk and Ischemic Stabilization, Management, and Avoid-

ance [CHARISMA] trial). Am J Cardiol 2009;103:1359-63.

78. Best PJ, Steinhubl SR, Berger PB, et al. The efficacy and safety of short-

and long-term dual antiplatelet therapy in patients with mild or moder-

ate chronic kidney disease: results from the Clopidogrel for the Reduc-

tion of Events During Observation (CREDO) trial. Am Heart J 2008;

155:687-93.

79. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet

therapy for reduction of ischaemic events including stent thrombosis in

patients with acute coronary syndromes treated with percutaneous cor-

onary intervention and stenting in the TRITON-TIMI 38 trial: a sub-

analysis of a randomised trial. Lancet 2008;371:1353-63.

80. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet

agents for prevention of pre-eclampsia: a meta-analysis of individual

patient data. Lancet 2007;369:1791-8.

81. Duley L,Henderson-Smart DJ,Meher S, King JF.Antiplateletagents for

preventingpre-eclampsia and its complications. Cochrane Database Syst

Rev 2007;2:CD004659.

82. Gelbaya TA, Kyrgiou M, Li TC, Stern C, Nardo LG. Low-dose aspirin

for in vitro fertilization: a systematic review and meta-analysis. Hum

Reprod Update 2007;13:357-64.

83. Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or antico-

agulants for treating recurrent miscarriage in women without antiphos-

pholipid syndrome. Cochrane Database Syst Rev 2009;1:CD004734.

84. Poustie VJ, Dodd S, Drakeley AJ. Low-dose aspirin for in vitro fertilisa-

tion. Cochrane Database Syst Rev 2007;4:CD004832.


219


13/14

85. Ruopp MD, Collins TC, Whitcomb BW, Schisterman EF. Evidence of

absence or absence of evidence? A reanalysis of the effects of low-doseaspirin in in vitro fertilization. Fertil Steril 2008;90:71-6.

86. Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirinconsumption during the first trimester of pregnancy and congenital

anomalies: a meta-analysis. Am J Obstet Gynecol 2002;187:1623-30.

87. Al-Aqeedi RF, Al-Nabti AD. Drug-eluting stent implantation for acute

myocardialinfarction during pregnancy with use of glycoprotein IIb/IIIainhibitor, aspirin and clopidogrel. J Invasive Cardiol 2008;20:E146-9.

88. Boztosun B, Olcay A, Avci A, Kirma C. Treatment of acute myocardial

infarction in pregnancy with coronary artery balloon angioplasty andstenting: use of tirofiban and clopidogrel. Int J Cardiol 2008;127:413-6.

89. Cuthill JA,Young S, Greer IA,Oldroyd K. Anaestheticconsiderationsin

a parturient with critical coronary artery disease and a drug-eluting stent

presenting for caesarean section. Int J Obstet Anesth 2005;14:167-71.

90. Klinzing P, Markert UR, Liesaus K, Peiker G. Case report: successfulpregnancy and delivery after myocardial infarction and essential throm-

bocythemia treated with clopidogrel. Clin Exp Obstet Gynecol 2001;28:

215-6.

91. Kuczkowski KM. Clopidogrel and pregnancy: a situation pregnant withdanger? Arch Gynecol Obstet 2009;280:693-4.

92. Ptter J, Satravaha P, Stockhausen H. Quantitative analysis of the main

metabolites of acetylsalicylicacid. Comparative analysis in theblood and

milk of lactating women Z Geburtshilfe Perinatol 1974;178:135-8.

93. Yousfi M, Gostout CJ, Baron TH, et al. Postpolypectomy lower gastro-

intestinal bleeding: potential role of aspirin. Am J Gastroenterol 2004;99:1785-9.

94. Sawhney MS, Salfiti N, Nelson DB, Lederle FA, Bond JH. Risk factors

for severe delayed postpolypectomy bleeding. Endoscopy 2008;40:

115-9.

95. Herth FJ, Becker HD, Ernst A. Aspirin does not increase bleeding com-

plications after transbronchial biopsy. Chest 2002;122:1461-4.96. Ardekian L, Gaspar R, Peled M, Brener B, Laufer D. Does low-dose

aspirin therapy complicate oral surgical procedures? J Am Dent Assoc

2000;131:331-5.

97. Madan GA, Madan SG, Madan G, Madan AD. Minor oral surgerywithout stopping daily low-dose aspirin therapy: a study of 51 patients.

J Oral Maxillofac Surg 2005;63:1262-5.

98. Billingsley EM, Maloney ME. Intraoperative and postoperative bleeding

problems in patients taking warfarin, aspirin, and nonsteroidal antiin-flammatory agents: a prospective study. Dermatol Surg 1997;23:381-3;

discussion, 384-5.

99. Kargi E, Babuccu O, Hosnuter M, Babuccu B, Altinyazar C. Complica-

tions of minor cutaneous surgery in patients under anticoagulant treat-ment. Aesthetic Plast Surg 2002;26:483-5.

100. Bartlett GR. Does aspirin affect the outcome of minor cutaneous sur-

gery? Br J Plast Surg 1999;52:214-6.

101. Katz J, Feldman MA, Bass EB, et al. Risks and benefits of anticoagulant

and antiplatelet medication use before cataract surgery. Ophthalmology

2003;110:1784-8.

102. Pulmonary Embolism PreventionTrial Steering Committee. Prevention

of pulmonaryembolismand deep vein thrombosis with low dose aspirin:

Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-

302.

103. BurgerW, Chemnitius JM,Kneissl GD,Rcker G. Low-dose aspirin forsecondarycardiovascularprevention: cardiovascular risksafter its periop-

erative withdrawal versus bleeding riskswith its continuation: review andmeta-analysis. J Intern Med 2005;257:399-414.

104. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic reviewand meta-analysis on the hazards of discontinuing or not adhering to

aspirin among 50,279 patients at risk for coronary artery disease. EurHeart J 2006;27:2667-74.

105. Nuttall GA, Brown MJ, Stombaugh JW, et al. Time and cardiac risk of

surgery after bare-metal stent percutaneous coronary intervention. An-esthesiology 2008;109:588-95.

106. Schouten O, van Domburg RT, Bax JJ, et al. Noncardiac surgery aftercoronary stenting: early surgery and interruption of antiplatelet therapyareassociated with an increase in major adverse cardiac events. J Am Coll

Cardiol 2007;49:122-4.

107. Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiacsurgery after percutaneous coronary intervention with drug-eluting

stents. Anesthesiology 2008;109:596-604.

108. Cruden NL, Harding SA, Flapan AD, et al. Previous coronary stent

implantation and cardiac events in patients undergoing noncardiac sur-gery. Circ Cardiovasc Interv 2010;3:236-42.

109. Sethi GK, Copeland JG, Goldman S, Moritz T, Zadina K, HendersonWG. Implications of preoperative administration of aspirin in patients

undergoing coronary artery bypass grafting. Department of VeteransAffairs Cooperative Study on Antiplatelet Therapy. J Am Coll Cardiol

1990;15:15-20.

110. Merritt JC, Bhatt DL. The efficacy and safety of perioperative antiplate-

let therapy. J Thromb Thrombolysis 2004;17:21-7.

111. Bybee KA, Powell BD, Valeti U, et al. Preoperative aspirin therapy is

associated with improved postoperative outcomes in patients under-going coronary artery bypass grafting. Circulation 2005;112(suppl

9):I286-92.

112. Fitchett D, Eikelboom J, Fremes S, et al. Dual antiplatelet therapy in

patients requiring urgent coronary artery bypass grafting surgery: a po-

sition statement of the Canadian Cardiovascular Society. Can J Cardiol2009;25:683-9.

113. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combin-ing aspirin with anticoagulant therapy in patients with atrial fibrillation:an exploratory analysis of stroke prevention using an oral thrombin in-

hibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006;152:967-73.

114. Johnson SG, Rogers K, Delate T, Witt DM. Outcomes associatedwith combin ed antiplatelet and anticoagulant therapy. Chest 2008;

133:948-54.

115. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oralanticoagulant therapy compared with oral anticoagulant therapy aloneamong patients at risk for cardiovascular disease: a meta-analysis of ran-

domized trials. Arch Intern Med 2007;167:117-24.

116. Srensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding inpatients with acute myocardial infarction treated with different combi-

nations of aspirin, clopidogrel,and vitamin K antagonists in Denmark: aretrospective analysis of nationwide registry data. Lancet 2009;374:1967-74.

117. Olson KL, Delate T, Johnson SG, Wilson ED, Witt DM. Incidence ofhemorrhage among anticoagulated patients receiving antiplatelet ther-

apy after percutaneous coronary intervention. J Thromb Thrombolysis2010;29:316-21.

118. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associ-ated with concomitant use of clopidogrel and proton pump inhibitorsfollowing acute coronary syndrome. JAMA 2009;301:937-44.



14/14

119. Li XQ, Andersson TB, Ahlstrm M, Weidolf L. Comparison of inhibi-

tory effects of the proton pump-inhibiting drugs omeprazole, esomepra-

zole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome

P450 activities. Drug Metab Dispos 2004;32:821-7.

120. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the

antiplatelet action of clopidogrel associated with aspirin: the random-

ized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study.

J Am Coll Cardiol 2008;51:256-60.

121. Sibbing D, MorathT, StegherrJ, etal. Impactof protonpump inhibitors

on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:

714-9.

122. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and

pantoprazole influence on a high 150-mg clopidogrel maintenance dose:

the PACA (Proton Pump Inhibitors And Clopidogrel Association) pro-

spective randomized study. J Am Coll Cardiol 2009;54:1149-53.

123. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a

drug interaction between clopidogrel and proton pump inhibitors. J Am

Coll Cardiol 2008;52:1038-9; author reply, 9.

124. Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization for pa-

tients using clopidogrel with a proton pump inhibitor. Arch Intern Med

2010;170:704-10.

125. Evanchan J, Donnally MR,Binkley P, Mazzaferri E. Recurrence of acute

myocardial infarction in patients discharged on clopidogrel anda proton

pump inhibitor after stent placement for acute myocardial infarction.

Clin Cardiol 2010;33:168-71.

126. Gaglia MA Jr, Torguson R, Hanna N, et al. Relation of proton pump

inhibitor use after percutaneous coronary intervention with drug-eluting

stents to outcomes. Am J Cardiol 2010;105:833-8.

127. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the

drug interaction between proton pump inhibitors and clopidogrel.

CMAJ 2009;180:713-8.

128. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular out-

comes and mortality in patients using clopidogrel with proton pumpinhibitors after percutaneous coronary intervention or acute coronary

syndrome. Circulation 2009;120:2322-9.

129. Kwok CS,Loke YK.Meta-analysis: theeffectsof protonpump inhibitors

on cardiovascular events and mortality in patients receiving clopidogrel.

Aliment Pharmacol Ther 2010;31:810-23.

130. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use

of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern

Med 2010;152:337-45.

131. Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treat-

ment with omeprazole on the effectiveness of clopidogrel drug therapy

during the first year after successful coronary stenting. Can J Cardiol

2010;26:e54-7.

132. ODonoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic

effect and clinical efficacy of clopidogrel and prasugrel with or without aproton-pump inhibitor: an analysis of two randomised trials. Lancet

2009;374:989-97.

133. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without

omeprazolein coronary artery disease.N Engl J Med 2010;363:1909-17.

134. Abraham NS, HlatkyMA, Antman EM, etal.ACCF/ACG/AHA 2010 expert

consensus document on the concomitant use of proton pump inhibitors and

thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expertconsensus document on reducingthegastrointestinal risks ofantiplatelettherapyand NSAID use. J Am Coll Cardiol 2010;56:2051-66.

135. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase in-hibitors and the antipl

Antiplatelets Guidelines - Outpatient Setting - CCS 2011

Documents

Transcript of Antiplatelets Guidelines - Outpatient Setting - CCS 2011