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Antiplatelet Therapy in the Outpatient Setting2011 Recommendations

For more information, please visit theCanadian Cardiovascular Society (CCS)

Antiplatelet Guidelines atwww.ccsguidelineprograms.ca.

2

Table of Contents

Introduction and Rationale………….....................................…..3Antiplatelet Therapy (APT)…….............................……….........4APT for Secondary Prevention in First Year Post-ACS…..........5Post-discharge Management of STEMI….….............................6Post-discharge Management of NSTEACS…...........................7APT for Secondary Prevention in First Year Post-PCI…............8Post-Discharge Management of Patients Undergoing PCI.........9Management of Stable CAD…................................................10Key Considerations: APT Post-ACS/PCI…..........................…11APT for Secondary Prevention Post-CABG….........................12Management Post-CABG…....................................................13APT for Secondary Prevention of Cerebrovascular Disease....14Management of TIA and Ischemic Stroke….............................15Key Considerations: APT for Cerebrovascular Disease….......16APT for Vascular Prevention in Patients with PAD...............…17Management of Peripheral Arterial Disease….........................18Management Post-Peripheral Artery Surgery….......................19APT Primary Prevention of Vascular Events…........................20Primary Prevention…...............................................................21Key Considerations: APT for Primary Prevention.................…22APT in Patients with Diabetes…..............................................23

Management of Patients with Diabetes................................…24APT in Patients with Heart Failure........................................…25Management of Heart Failure…...............................................26Management of Chronic Kidney Disease….............................27Management in Pregnancy and Lactation…............................28Perioperative Management of: Patients on APT…..............................................................29 Patients taking ASA…........................................................30 Patients taking ASA and Clopidogrel.............................….31Key Considerations: Perioperative APT Management….....................................32Management of Minor Bleeding…........................................…33Key Considerations: Management of APT in Association with Minor Bleeding….34Combination Therapy with Warfarin and ASA......................…35Management of Patients Requiring Warfarin…........................36Interaction Between Clopidogrel and PPIs…...........................37Use of Proton-Pump Inhibitors….............................................38Interaction Between ASA and NSAIDS…................................39Use of NSAIDs in Patients on ASA…......................................40APT: Drug-Drug Interactions….................................................41

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Introduction and Rationale

2011 Canadian Antiplatelet Therapy Guidelines Development Methodology

• Identify relevant clinical guidelines for antiplatelet therapy.

• Assess quality using the AGREE (Appraisal of Guidelines for Research & Evaluation) instrument.

• Develop recommendations via consideration of:• Existing guidelines and their associated AGREE score.• Literature published subsequent to existing guidelines. • Expert opinion.

• Create graded recommendations using a system set forth by the Canadian Cardiovascular Society (CCS).

• Conduct an external review by Canadian experts in their respectivefieldswhowerenotinvolvedinthewritingprocess.

Antiplatelet therapy is underused in clinical practice.

Canadian physicians require guidance that is:• Clear.• Easily accessible.• Evidence-based.

4

Antiplatelet Therapy (APT)Platelets play a pivotal role in cardiovascular pathophysiology.

Antiplatelet agents are cornerstone therapy in patients with atherosclerotic vascular disease including CAD, cerebrovascular disease, and PAD.

• ASA• Clopidogrel• Dipyridamole

• Ticlopidine• Prasugrel • Ticagrelor

Rupture or erosion of atherosclerotic coronary

artery plaque

Platelet activation and aggregation

Intraarterial thrombosis and adverse cardiovascular

events

Available Agents

ASA: acetylsalicylic acid; CAD: coronary artery disease; PAD: peripheral artery disease.

5

APT for Secondary Prevention in First Year Post-ACS

Coronary Artery Disease

Contemporary Classification of ACS

Based on:• Appearance of presenting ECG.

• Subsequent measurement of cardiac biomarkers (e.g. troponin).

• ST-segment elevation on surface ECG typically indicates complete occlusion of a coronary artery.

• Biochemical evidence of myocardial necrosis.

• No ST-segment elevation on surface ECG typically indicates non-occlusive intracoronary thrombosis.

• Biochemical evidence of myocardial necrosis

• Negative biomarkers

STEMI NSTEACS

NSTEMI Unstable angina

ACS: acute coronary syndrome; APT: antiplatelet therapy; ECG: electrocardiogram; STEMI: ST-elevation myocardial infarction; NSTEACS: non-ST-elevation acute coronary syndrome; NSTEMI: non-ST-elevation myocardial infarction.

6

Post-discharge Management of STEMI

In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of the therapy (Class I, Level C). ADP: adenosine diphosphate; ASA: acetylsalicylic acid; CABG: coronary artery bypass graft; STEMI: ST-elevation myocardial infarction.

Percutaneousintervention

Increased risk of stentthrombosis

Medically managed

Prasugrel 10 mg daily may beconsidered in the absence of:

● increased bleeding risk● likely to undergo CABG within 7 days● history of stroke or transient ischemic attack (TIA)● age >75 years● weight <60 kg(Class IIa, Level B)

ASA 75-162 mg OD

Indefinite Therapy

(Class I, Level A)

If ASAintolerant

Clopidogrel 75 mgOD

Indefinite Therapy(Class IIa, Level B)

STEMI

Clopidogrel 75 mg OD or ticagrelor 90 mgBID in addition to ASA 75-162 mg daily for12 months (Class I, Level B). Continuation of combined therapy beyond 12 months may be

considered in patients with a high risk ofthrombosis and a low risk of bleeding

(Class IIb, Level C).

Clopidogrel 75 mg OD or ticagrelor 90 mgBID in addition to ASA 75-162 mg daily forat least 14 days (Class I, Level B) and up

to 12 months in the absence of an excessive risk of bleeding


Postdischarge Management of ST Segment Elevation Myocardial Infarction

7

Post-discharge Management of NSTEACS

In general, the ADP P2Y12 receptor antagonist added to ASA in the acute setting should be maintained for the duration of the therapy (Class I, Level C). ADP: adenosine diphosphate; ASA: acetylsalicylic acid; CABG: coronary artery bypass graft; NSTEACS: non-ST-elevation acute coronary syndrome.

If ASAintolerant

Clopidogrel 75 mgOD


ASA 75-162 mg OD

Indefinite Therapy(Class I, Level A)

NSTEACS

Percutaneousintervention

Increased risk of stentthrombosis

Medically managed

Prasugrel 10 mg daily may beconsidered in the absence of:

● increased bleeding risk● likely to undergo CABG within 7 days● history of stroke or transient ischemic attack (TIA)● age >75 years● weight <60 kg(Class IIa, Level B)

Clopidogrel 75 mg OD (Class I, Level A) or ticagrelor 90 mg BID (Class I, Level B) in addition to ASA 75-162 mg daily for 12

months. Continuation of combined therapy beyond 12 months may be considered in

patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C).

Clopidogrel 75 mg OD (Class I, Level A) or ticagrelor 90 mg BID (Class I, Level B) in

addition to ASA 75-162 mg daily for at least 1 month (Class I, Level A) and up to 12

months in the absence of an excessive risk of bleeding (Class I, Level B).

Postdischarge Management of Non-ST Segment Elevation Acute Coronary Syndrome

8

APT for Secondary Prevention in First Year Post-PCI

*Optimal duration of long-term DAPT currently under investigation. APT: antiplatelet therapy; BMS: bare-metal stent; DAPT: dual-antiplatelet therapy; DES: drug-eluting stent; PCI: percutaneous coronary intervention.

PCI is thrombogenic due to:• Mechanically induced plaque rupture

and vessel injury.

PLUS

• Implantation of metallic stent scaffolding.

Discontinuation of DAPT post-PCI is associated with ↑ risks of subacute (1-30 days) and late (30 days-1 year) stent thrombosis.*

Secondary prevention with DAPT • Use for 1 year post PCI.

• BMS: early discontinuation may be considered if there is a high risk of bleeding (e.g. major surgery).

• DES: do not discontinue prior to 1 year.

• Continuation beyond 1 year may be considered if there is a high risk of thrombosis and a low risk of bleeding.

Allows for:• Vessel healing.• Plaque stabilization.• Reendothelialization.

9

PercutaneousIntervention

ASA 75-162 mgOD


If ASAintolerant

Clopidogrel 75 mg OD

Indenfinite Therapy(Class IIa, Level B)

Clopidogrel 75 mg OD orticagrelor 90 mg BID in addition

to ASA 75-162 mg OD for atleast 1 month and up to 12 months (Class I, Level B).

Bare-metal stent

Dual-antiplatelettherapy may be

discontinued after aminimum of 2 weeks.

Increased stentthrombosis risk

Dual-antiplatelet therapy with prasugrel10 mg OD in addition to ASA 75-162 mg OD may be considered in the absence of:

• increased bleeding risk• likely to undergo CABG within 7 days• history of stroke or transient ischemic attack (TIA)• age >75 years• weight <60 kg

Clopidogrel 75 mg OD (Class I, Level A) orticagrelor 90 mg BID (Class I, Level B) in

addition to ASA 75-162 mg daily for at least 12 months.

Continuation of dual-antiplatelet therapybeyond 1 year may be considered as long

as the perceived risk of bleeding isdeemed acceptable (Class IIb, Level C).

Drug-eluting stentIncreasedbleeding

risk

Postdischarge Management of Patients Undergoing Percutaneous Coronary Intervention

Post-discharge Management of Patients Undergoing PCI

ASA: acetylsalicylic acid; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention.

10

Management of Stable CAD

ACS: acute coronary syndrome; ASA: acetylsalicylic acid; CAD: coronary artery disease.

ASA 75-162 mgOD


If ASA intolerant

ACS >1 yearpost event

Clopidogrel 75 mgOD


If high risk ofthrombosis and

low risk ofbleeding

Dual-antiplatelet therapywith ASA 75-162 mg OD

and clopidogrel 75 mg ODmay be considered (Class IIb, Level C).

Management of Stable Coronary Artery Disease

11

Key Considerations: APT Post-ACS/PCI

ACS: acute coronary syndrome; APT: antiplatelet therapy; ASA: acetylsalicylic acid; DAPT: dual-antiplatelet therapy; DES: drug-eluting stent; PCI: percutaneous coronary intervention.

• Provide lifetime APT to all patients post-ACS with or without PCI.

• Provide DAPT with ASA + P2Y12 inhibitor to all ACS patients.

• Know the type of stent your patient has inserted.

• Consider DAPT beyond 1 year in patients with high risk of thrombosis and low risk of bleeding.

DO• Use doses of ASA above 75-162 mg.

• Discontinue DAPT prior to 1 year without good reason.

• Discontinue DAPT in a patient with a DES prior to 1 year.

DON’T

12

APT for Secondary Prevention Post-CABG

APT: antiplatelet therapy; ASA: acetylsalicylic acid; CABG: coronary artery bypass graft.

APT is the gold standard in preventing saphenous vein graft closure after CABG.

• Givenindefinitelymayprevent adverse clinical events post-CABG.

• No evidence of improved arterial graft patency.

Warfarin appears to be as effective as

antiplatelet therapy in preventing saphenous

graft closure post-CABG, but it is associated with a higher risk of bleeding

complications.

• Recommended for patients allergic or intolerant to ASA.

• Safer than other available therapies (e.g. ticlopidine).

• No randomized trial has specificallystudiedtheefficacyofclopidogrelintheprevention of post-CABG vein graft closure.

ASA Clopidogrel

13

Management Post CABG

TheoutpatientmanagementofpatientsafterCABGisoutlinedinthisfigureandmayincludedual-antiplatelettherapywhenarecently stented vessel is not adequately bypassed. ASA: acetylsalicylic acid; ATP: antiplatelet therapy; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention.

Coronary ArteryBypass Graft

ASA 75-162 mgOD


In patients undergoing CABG afterPCI, dual-antiplatelet therapy with

ASA 75-162 mg daily andclopidogrel 75 mg daily may be

maintained for 9-12 months unlessthe stented vessel is adequatelybypassed (Class IIb, Level C).

If ASAintolerant

Clopidogrel 75 mgOD


Management Post Coronary Artery Bypass Graft

14

APT for Secondary Prevention of Cerebrovascular Disease

*95% CI: 9%-25% when the outcome is actively ascertained; †MI, stroke, and vascular death; ‡95% CI: 42%-46%. APT:antiplatelettherapy;ASA:acetylsalicylicacid;CI:confidenceinterval;DAPT:dual-antiplatelettherapy; ER: extended-release; MI: myocardial infarction; TIA: transient ischemic attack.

CerebrovascularDisease

Patients with TIA or ischemic stroke are at increased risk of recurrent stroke and other vascular events require lifetime APT.

Risks of TIA or ischemic stroke• Highest in the initial 2 days after the

event and may remain high for the subsequent 90 days.

• Overall risk at 90 days: ~17%.*

• Risk of combined vascular complications:† ~44%‡ at 10 years.

• Any of the following are recommended: • ASA 75-162 mg OD.• Clopidogrel 75 mg OD.• ASA 25 mg + ER-dipyridamole 200 mg BID.

• DAPT with ASA + clopidogrel may be considered for 30 days following high risk TIA or minor stroke, if the risk of bleeding is low.

• DAPT should not be used beyond 30 days for secondary stroke prevention.

Expedited evaluation and early treatment may lower the risk of stroke recurrence.

15

Management of TIA and Ischemic Stroke

TheoutpatientmanagementofTIAorischemicstrokeofnoncardiacorigincanincludedual-antiplatelettherapyforthefirstmonth.ASA: acetylsalicylic acid; ER: extended-release; TIA: transient ischemic attack.

TIA or ischemicstroke of

noncardiac origin

ASA 75-162 mg once daily

(Class I, Level A)

Clopidogrel 75 mgonce daily

(Class I, Level A)

ER-dipyridamole 200 mg twice daily plus

ASA 25 mg twice daily

(Class I, Level A)

The combination of ASA 75-162 mg daily plus clopidogrel 75 mg daily

in the first month after TIA or minor ischemic stroke may be superior to ASA alone in

patients not at a high risk of bleeding (Class IIb, Level C).

The combination of ASA 75-162 mg daily plus clopidogrel 75 mg daily should not be used for secondary

stroke prevention beyond 1 month unless otherwise indicated and

the risk of bleeding is low (Class III, Level B).

Management of TIA and Ischemic Stroke

16

Key Considerations: APT for Cerebrovascular Disease

APT: antiplatelet therapy; ASA: acetylsalicylic acid; DAPT: dual-antiplatelet therapy; TIA: transient ischemic attack.

• Provide lifetime antiplatelet therapy to all patients post-ischemic stroke or -TIA.

• Consider DAPT with ASA + clopidogrel in patients with a high risk of TIA or minor stroke for 30 days.

DO• Use DAPT with ASA + clopidogrel for

long-term secondary stroke prevention.

DON’T

17

APT for Vascular Prevention in Patients with PAD

*ABI <0.9.ABI: ankle-brachial index; APT: antiplatelet therapy; PAD: peripheral arterial disease.

Peripheral ArterialDisease

• Bruit found along major vessels, peripheral pulsations reduced or absent.

OR

• Abnormally enlarged artery (possible aneurysm).

• Usually harbour traditional risk factors.

• Evidence shows patients with ABI <0.9 present a cardiovascular morbidity and mortality rate approx. halfway between that of a patient with a normal ABI and that of a patient with claudication.

Characteristics

Vascular Risk

• Claudication.

OR

• Rest pain.

OR

• Ischemic lesions.

• High risk of cardiovascular events and total mortality, even when taking into account usual risk factors.

Asymptomatic PAD* Symptomatic PAD*

18

Management of Peripheral Arterial Disease

*AsymptomaticPADisdefinedbyanankle-brachialindex<0.9intheabsenceofclaudicationorothermanifestationssuchas obstructive vascular disease in the extremities; †For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B); ‡ForpatientswithPADwithanindicationfororalanticoagulationsuchasatrialfibrillation,venousthromboembolism, heart failure, or mechanical valves, antiplatelet therapy should not be added to oral anticoagulation (Class III, Level A).ASA: acetylsalicylic acid; CAD: coronary artery disease; PAD: peripheral arterial disease.

PeripheralArtery Disease

ASA† 75-162 mg OD may beconsidered for those at highrisk because of associated

atherosclerotic risk factors inthe absence of risk factors for bleeding (Class IIB, Level C).

ASA† 75-162 mg OD orclopidogrel 75 mg daily isrecommended providingthe risk for bleeding is low (Class IIb, Level B).

Antiplatelet therapy‡ asindicated for the CAD

and/or cerebrovascularstatus is recommended

(Class I, Level A).

Clopidogrel 75 mg OD inaddition to ASA† 75-162 mg

OD is not recommended unlessthe patient is judged to be at

high vascular risk along with a low risk of bleeding(Class IIb, Level B).

Symptomatic

Without overtCAD or

cerebrovasculardisease

With overt CAD or cerebrovascular

diseaseWith claudication

Asymptomatic*

Management of Peripheral Arterial Disease

19

Management Post-peripheral Artery Surgery

*For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B).The outpatient management of patients after peripheral arterial surgery or percutaneous revascularization or presenting an abdominal aortic aneurysm AAA. AAA: abdominal aortic aneurysm; ASA: acetylsalicylic acid; PAD: peripheral arterial disease.

Peripheral ArteryDisease with

Surgical Indication

In those with infrainguinalgrafts and a high risk of thrombosis or limb loss,

combination therapy with a vitamin K antagonist and ASA*

75-162 mg OD may be of benefit (Class IIB, Level C).

ASA* 75-162 mg OD shouldbe given to patients who undergo lower-extremity

balloon angioplasty with or without stenting for chronic

symptomatic PAD (Class IIa, Level C).

ASA* 75-162 mg OD maybe considered for all

patients with an AAA, particularly those with

clinical or subclinical PAD(Class IIb, Level C).

Management Post Peripheral Artery Surgery

20

APT Primary Prevention of Vascular Events

ASA: acetylsalicylic acid; APT: antiplatelet therapy; MI: myocardial infarction; TIA: transient ischemic attack.

Primary Prevention of Vascular Events

• Maybedefinedasantiplateletstrategies,administeredtoindividualsfreeofanyevidenceofmanifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof.

• Atherosclerotic disease may include, but is not limited to:• Syndromes of angina pectoris.• MI.• Ischemic stroke.• TIA.• Intermittent claudication.• Critical limb ischemia.

Primary prevention

The benefits of ASA and APT for primary prevention have not been demonstrated.

21

Primary Prevention

Forthepurposeofthisguideline,primarypreventionisdefinedasantiplateletstrategies,administeredtoindividualsfreeofanyevidence of manifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof. ASA: acetylsalicylic acid.

In special circumstances in men and women without evidence of

manifest vascular disease in whom vascular risk is considered high and bleeding risk low, ASA

75-162 mg daily may be considered (Class IIb, Level C).

PrimaryPrevention

ASA at any dose is not recommended for

routine use to prevent ischemic vascular

events (Class III, Level A).

Clopidogrel plus ASA at any dose is not

recommended to prevent ischemic vascular events

(Class III, Level B).

Primary Prevention

22

Key Considerations: APT for Primary Prevention

ABI: ankle-brachial index; APT: antiplatelet therapy; ASA: acetylsalicylic acid.

• Consider ASA only where there is clear evidence of high risk:• Asymptomatic carotid stenosis.• Asymptomatic coronary atherosclerosis.• Reduced ABI.• End-stage renal disease.

DO• Use APT for primary prevention.

DON’T

23

APT in Patients with Diabetes

Diabetes

Patients with diabetes have a variety of risk factors and alterations to platelet function that predispose them to platelet activation and thrombosis.

The absence of clear primary prevention benefits for antiplatelet therapy in patients with diabetes may indicate that patients with diabetes are a specific subgroup of patients in

whom mechanisms such as ASA resistance are manifest.

Platelet alterations may include:• Increased platelet turnover.• Enhanced platelet aggregation.• Increased thromboxane synthesis.

Despite clear evidence of a procoagulant state in patients with diabetes, the balance between benefitsandpotentialharmofantiplatelettreatment appears less favourable in patients with diabetes compared with those in other high cardiovascular risk groups.

APT: antiplatelet therapy; ASA: acetylsalicylic acid.

24

Management of Patients with Diabetes

*For patients allergic or intolerant to ASA, use of clopidogrel 75 mg OD is suggested (Class IIa, Level B).ASA: acetylsalicylic acid.

Routine use of ASA* at any dose is not recommended for the primary prevention of vascular ischemic events

in patients with diabetes (Class III, Level A).

ASA* 75-162 mg OD may be considered for secondary

prevention in patients with diabetes and manifest vascular disease for which its benefits

are established(Class I, Level A).

Patients >40 years and at low risk for major bleeding, low-dose ASA* 75-162 mg OD may be considered for primary prevention in patients

with other cardiovascular risk factors for which its benefits are established (Class IIb, Level B).

Diabetes

Management of Patients with Diabetes

25

APT in Patients with Heart Failure

Heart Failure

Largely due to reduced cardiac output, HF is associated with increased risk of thromboembolic events and other ischemic cardiovascular events.

Antiplatelet therapy should be used in all patients with ischemic HF.*Limited evidence suggests ASA may ↑ secondary risk of hospitalization for HF.

HF aetiology:• Ischemic: 70% of patients.

• Hypertension and idiopathic causes: 30% of patients.

Despite HF being associated with a prothrombotic state, antiplatelet therapy is not recommended in the absence of coronary ischemia.

*NoevidenceofbenefitforpatientswithnonischemicHF(otherthanforsecondarypreventionofHFduetoCAD).APT: antiplatelet therapy; ASA: acetylsalicylic acid; CAD: coronary artery disease; HF: heart failure.

26

Management of Heart Failure

CAD: coronary artery disease.

Heart Failure

Ischemic

Antiplatelet therapyshould be dictated by the underlying CAD(Class IIa, Level A).

Routine use of antiplatelet agents is

not recommended(Class III, Level C).

Nonischemic

Management of Heart Failure

27

Management of Chronic Kidney Disease

Chronic Kidney Disease

Chronickidneydiseaseisdefinedasestimatedglomerularfiltrationrate(eGFR)orcreatinineclearance<60mL/min/1.73m2 (forpurposesofthisguideline,obtainedusingeitherCockcroft-GaultformulaorModificationofDietinRenalDisease[MDRD]equation); *For patients allergic or intolerant to ASA, use of clopidogrel 75 mg OD is suggested (Class IIa, Level B).ASA: acetylsalicylic acid; CKD: chronic kidney disease; ESRD: end-stage renal disease.

ASA* 75-162 mg OD may beconsidered for primary

prevention of ischemic vascular events in patients with ESRD

and a low risk of bleeding(Class IIb, Level C).

Chronic KidneyDisease

Antiplatelet therapy should be considered for secondary

prevention in patients with CKD and manifest vascular disease

for which its benefits areestablished (Class IIa, Level C).

Management of Chronic Kidney Disease

28

Management in Pregnancy and Lactation

Pregnancy and Breastfeeding

*Use of antiplatelet agents other than low-dose ASA for cardio- or cerebrovascular indications during pregnancy and lactation shouldonlybeconsideredifmaternalbenefitsclearlyoutweighpotentialfetal/infantrisks(ClassIIb,LevelC).ASA: acetylsalicylic acid.

ASA* 75-162 mg OD may beconsidered for use inbreastfeeding women

(Class I, Level C).

Pregnancy andLactation

ASA* 75-162 mg OD is likely safe for use

during the firsttrimester of pregnancy

(Class IIa, Level A).

ASA* can be used safely during the second and

third trimester ofpregnancy

(Class I, Level A).

For cardio- or cerebrovascular disease in which antiplatelet therapy would be indicated innonpregnant women, there

should be similar considerationsfor its use in pregnancy


Management in Pregnancy and Lactation

29

Perioperative Management of Patients on APT

Periprocedural Management

• Neurosurgery (intracranial or spinal surgery)• Cardiac surgery (coronary artery bypass or heart valve replacement)• Major vascular surgery (abdominal aortic

aneurysm repair, aortofemoral bypass)• Major urologic surgery (prostatectomy,

bladder tumour resection)• Major lower limb orthopaedic surgery

(hip/knee joint replacement)

• Lung resection surgery• Intestinal anastomosis surgery• Permanent pacemaker insertion or internal

defibrillatorplacement• Selected procedures (kidney biopsy,

pericardiocentesis, colonic polypectomy)• Other intra-abdominal surgery• Other intrathoracic surgery• Other orthopaedic surgery

• Other vascular surgery• Selected procedures (prostate or cervical

biopsy)

• Other intra-abdominal surgery• Other intrathoracic surgery• Other orthopaedic surgery

• Other vascular surgery• Selected procedures (prostate or cervical

biopsy)

• Laproscopic cholecystectomy• Laproscopic inguinal hernia repair• Dental procedures• Dermatologic procedures• Ophthalmologic procedures

• Coronary angiography• Gastroscopy or colonoscopy• Selected procedures (bone marrow

or lymph node biopsy, thoracentesis, paracentesis, arthrocentesis)

• Single tooth extraction or teeth cleaning• Skin biopsy or selected skin cancer removal

• Cataract removal

Very High Risk

High Risk

Intermediate Risk

Low Risk

Very Low Risk

Relative risk of bleeding associated with common surgical and non-surgical procedures.

APT: antiplatelet therapy.

30

Perioperative Management of Patients taking ASA

The perioperative antiplatelet management will vary depending on the risk of bleeding related to the diagnostic or surgical procedure and the risk of cardiovascular ischemic event. ASA: acetylsalicylic acid; CABG: coronary artery bypass graft.

Patients having minor dental(extraction, root canal), eye(cataract), or skin (biopsy,

skin cancer excision)procedure may continue ASA

without interruption(Class IIa, Level A).

Patient receivingASA requiring

procedure

Diagnostictest/procedureArthrocentesisMinor dental, eye,

skin procedureNoncardiac

surgeryCABG

surgery

Patients having a diagnostic test/procedure associated with a

low risk for bleeding may continueASA without interruption; patients

having a test associated with a highrisk for bleeding should stop ASA

7-10 days before the test/procedure(Class IIa, Level C).

Patients havingarthrocentesis may

continue ASA withoutinterruption


Patients should stop ASA 7-10days before surgery if the risk for cardiovascular events islow and continue ASA if thecardiovascular risk is high

(Class IIa, Level B).

Patients should continue ASA up to the time of surgerywithout interruption

(Class I, Level B).

Perioperative Management of Patients taking ASA

31

Perioperative Management of Patients taking ASA and Clopidogrel

The perioperative antiplatelet management of patients receiving dual-antiplatelet therapy after a coronary stent will vary depending on the type of stent and the urgency of the surgery. ASA: acetylsalicylic acid; BMS: bare-metal stent; CABG: coronary artery bypass graft; DES: drug-eluting stent.

Diagnostic test/procedureArthrocentesisMinor dental, eye,

skin procedure Noncardiac

surgeryCABG

surgery

Patients should continue ASA until the time of

surgery but stop clopidogrel at least 5 days before

surgery (Class I, Level B). Urgent

No Yes

Whenever possible, elective surgery should be deferred for at least 6 weeks after

BMS placement and at least 12 months after DES

placement (Class I, Level B).

For patients with a BMS who require surgery within 6 weeks of placement,

ASA and clopidogrel should be continued in the perioperative period

(Class I, Level B).For patients with a DES who require

surgery within 12 months of placement, ASA and clopidogrel should

be continued in the perioperative period (Class I, Level B).

Patients having minor dental (extraction, root

canal), eye (cataract), or skin (biopsy, skin cancer

excision) procedure should stop clopidogrel

7-10 days before the procedure if it can be done safely (Class IIa, Level C).

Patients should stop clopidogrel 7-10 days before the procedure

if it can be done safely


Patients should stop clopidogrel 7-10 days before the procedure if it can be done so safely (Class IIb, Level C); patients should also stop

ASA before diagnostic tests associated with a high risk for bleeding (Class IIa, Level C).

Perioperative Managementof Patients taking ASA and Clopidogrel

Patient receiving ASA + clopidogrel for a

coronary stent- requiring procedure

32

Key Considerations: Perioperative APT Management

ASA: acetylsalicylic acid; APT: antiplatelet therapy; BMS: bare-metal stent; DAPT: dual-antiplatelet therapy; DES: drug-eluting stent.

• Delay procedures in patients taking DAPT.

• Stop clopidogrel for 7-10 days prior if it can be done so safely.

• Stop ASA for 7-10 days for high-risk surgical procedures.

DO• Discontinue DAPT prior to 1 year in patients

with a DES.

• Discontinue DAPT prior to 6 weeks in patient with a BMS.

• Stop ASA for minor procedures including:• Arthrocentesis. • Dental procedures.• Cataract surgery.• Skin excisions.

DON’T

33

Management of Minor Bleeding

The management of patients on antiplatelet therapy with minor bleeding is outlined and may include further investigation for patients who develop ecchymosis or petechiae.ASA: acetylsalicylic acid.

In the absence of superimposed abnormalities in hemostatic function, antiplatelet drugs can be continued

with clinical observation, whereas in patients with thrombocytopenia or a coagulopathy, ASA (or clopidogrel) should be stopped pending further

investigations(Class IIa, Level C).

Patients who develop ecchymosis and petechiae should undergo testing with a complete blood

count and internationalnormalized ratio (INR) and

activated partial thromboplastin time (aPTT)

(Class IIa, Level C).

Patients in whom there is excessive bleeding after a dental

procedure should receiveapplication of local pressure

and/or use of tranexamic acid mouthwash 2-4 times daily for 1-2

days(Class IIa, Level C).

Patient onantiplatelet therapywith minor bleeding

Patients in whomsubconjunctival bleedingdevelops should continue

treatment and bemonitored for bleeding

(Class IIa, Level C).

Management of Minor Bleeding

34

Key Considerations: Management of APT in Association with Minor Bleeding

APT: antiplatelet therapy; aPTT: activated partial thromboplastin time; INR: international normalized ratio.

• If persistent, check:• Complete blood count.• INR and aPTT.

DO• Stop antiplatelet therapy for:• Ecchymosis.• Petechiae.• Subconjunctival hemorrhage.• Epistaxis.• Dental/gingival bleeding (tranexamic acid

mouthwash).

DON’T

35

Combination Therapy with Warfarin and ASA

Combination Therapy

Possible clinical scenarios for combination therapy:1. Both coagulation- and platelet-mediated pathways involved in 1 disease (e.g. ACS).

2. Patient has 2 diseases, 1 treated with an anticoagulant and 1 with APT (e.g. patients with bothatrialfibrillationandCAD,orthosewithbothVTEandCAD).

Warfarin• Typically used for primary and secondary

prevention of thromboembolic events.

ASA• Typically used for primary and secondary

prevention of atherothrombotic events.

ACS: acute coronary syndrome; APT: antiplatelet therapy; ASA: acetylsalicylic acid; CAD: coronary artery disease; VTE: venous thromboembolism.

36

Management of Patients Requiring Warfarin

The management of patients requiring warfarin therapy requires an assessment of the risk of bleeding and the medical conditions for which combination therapy may be reasonable. ACS: acute coronary syndrome; ASA: acetylsalicylic acid; BMS: bare-metal stent; CABG: coronary artery bypass graft; DES: drug-eluting stent; INR: international normalized ratio.

Patients who develop ACS that is treated with medical therapy alone, combination warfarin (target INR, 2.0-3.0)/ASA (75-162 mg daily)

therapy is reasonable for up to 12 weeks, at which time ASA may be withdrawn if there are no further

cardiac events(Class IIb, Level C).

Patients with a mechanical prosthetic heart valve, combination warfarin

(target INR, 2.0-3.0) and ASA 75-162 mg daily should be considered, especially in

patients with any mechanical mitral valve or in patients with an older

caged-ball or bileaflet mechanical aortic valve


Patient with anindication for

warfarin therapy

Management of Patients Requiring Warfarin

Although there is insufficient evidence to provide graded recommendations, otherconditions for which combinationwarfarin/antiplatelet therapy is reasonableinclude:

• Patients who have an indication for long-term warfarin therapy and undergo CABG.• Patients with atrial fibrillation who develop a stroke syndrome despite therapeutic anticoagulation with warfarin.• Patients receiving long-term warfarin who receive a coronary stent, 6 weeks of combination warfarin-ASA-clopidogrel is reasonable for patients with a BMS and 12 months of this treatment is reasonable for patients with a DES, with the caveat that a BMS is preferred over a DES in this clinical setting.

37

Interaction Between Clopidogrel and PPIs

Drug Interactions

Clopidogrel requires activation by cytochrome P450 isozyme CYP2C19 in the liver.

The management of patients on dual antiplatelet therapy may include the use of proton-pump inhibitors with minimal inhibition of cytochrome P2C19 in patients considered at increased risk of upper gastrointestinal bleeding. PPI: proton-pump inhibitor.

Interaction with PPIs

• May inhibit CYP2C19• Lansoprazole• Omeprazole• Esomeprazole

• Pantoprazole

Stronginhibitors

Weakinhibitor

38

Use of Proton-Pump Inhibitors

PPI: proton-pump inhibitor.

Use of proton-pumpinhibitors in patients

taking clopidogrel

Patient at risk ofupper

gastrointestinalbleeding

The pharmacodynamic interaction between clopidogrel and PPIs and the initial findings from observational

studies suggested an increased risk of cardiovascular events in concomitant users of clopidogrel and PPIs. Recently published data from a randomized clinical

trial suggest that this risk is likely clinicallyinsignificant. Nevertheless, because of potential

limitations with study design and patients recruited, PPIs that minimally inhibit CYP2C19 are preferred for

patients taking clopidogrel who are considered to be at increased risk of upper gastrointestinal bleeding

(Class IIb, Level B).

Use of Proton-Pump Inhibitiors

39

Interaction Between ASA and NSAIDs

ASA binds irreversibly to serine residue at position 529 of platelet COX-1, preventing platelet aggregation.

*InpatientsonASA,theuseoftraditionalNSAIDsshouldbeavoidedandifananti-inflammatorydrugisrequired,aspecificcycloxygenase-2 inhibitor should be considered. ASA:acetylsalicylicacid;COX-1:cycloxygenase-1;NSAID:non-steroidalanti-inflammatorydrug.

Interaction with NSAIDs*

• Traditional NSAIDs form a reversible complex with COX-1, dependent on serum concentrations of the drug with dissociation, platelets assume normal function.

• May inhibit binding of ASA to COX-1.

40

Use of NSAIDs in Patients on ASA

ASA:acetylsalicylicacid;Coxib:cycloxygenase-2inhibitor;NSAID:non-steroidalanti-inflammatorydrug.

Use of NSAIDs inpatients on ASA

Individuals taking ASA for vascular protection should avoid the concomitant use of traditional (non-coxib)

NSAIDs(Class III, Level C).

If a patient taking ASA for vascular protection requires an anti-inflammatory drug, specific

coxibs should be chosen over traditional NSAIDs(Class III, Level C).

All NSAIDs and coxibs should be avoided in patients at increased cardiovascular risk (Class III, Level A).

Use of NSAIDs in Patients on ASA

41

APT: Drug-Drug Interactions

APT: antiplatelet therapy; ASA: acetylsalicylic acid; Coxib: cycloxygenase-2 inhibitor; CV: cardiovascular; NSAID:non-steroidalanti-inflammatorydrug;PPI:proton-pumpinhibitor;UGI:uppergastrointestinal.

• Use PPIs with minimal effect on CYP2C19 in patients at increased risk of UGI bleeding taking clopidogrel.

• Use coxibs over traditional NSAIDs in patients taking ASA for CV prevention but only if absolutely necessary.

DO• Use PPIs that inhibit CYP2C19 in patients

taking clopidogrel or prasugrel.

• Use NSAIDs or coxibs in patients at increased risk of vascular events.

DON’T

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