Pocket Guide. Antiplatelet Therapy in the Outpatient Setting 2011 Recommendations. Leadership. Knowledge. Community.

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1 Pocket Guide Antiplatelet Therapy in the Outpatient Setting 2011 Recommendations For more information, please visit the Canadian Cardiovascular Society (CCS) Antiplatelet Guidelines at Leadership. Knowledge. Community.

2 2 Table of Contents Introduction and Rationale Antiplatelet Therapy (APT) APT for Secondary Prevention in First Year Post-ACS...5 Post-discharge Management of STEMI....6 Post-discharge Management of NSTEACS...7 APT for Secondary Prevention in First Year Post-PCI...8 Post-Discharge Management of Patients Undergoing PCI...9 Management of Stable CAD...10 Key Considerations: APT Post-ACS/PCI APT for Secondary Prevention Post-CABG...12 Management Post-CABG...13 APT for Secondary Prevention of Cerebrovascular Disease...14 Management of TIA and Ischemic Stroke...15 Key Considerations: APT for Cerebrovascular Disease...16 APT for Vascular Prevention in Patients with PAD Management of Peripheral Arterial Disease...18 Management Post-Peripheral Artery Surgery...19 APT Primary Prevention of Vascular Events...20 Primary Prevention...21 Key Considerations: APT for Primary Prevention APT in Patients with Diabetes...23 Management of Patients with Diabetes APT in Patients with Heart Failure Management of Heart Failure...26 Management of Chronic Kidney Disease...27 Management in Pregnancy and Lactation...28 Perioperative Management of: Patients on APT...29 Patients taking ASA...30 Patients taking ASA and Clopidogrel Key Considerations: Perioperative APT Management...32 Management of Minor Bleeding Key Considerations: Management of APT in Association with Minor Bleeding.34 Combination Therapy with Warfarin and ASA Management of Patients Requiring Warfarin...36 Interaction Between Clopidogrel and PPIs...37 Use of Proton-Pump Inhibitors...38 Interaction Between ASA and NSAIDS...39 Use of NSAIDs in Patients on ASA...40 APT: Drug-Drug Interactions...41

3 3 Introduction and Rationale Antiplatelet therapy is underused in clinical practice. Canadian physicians require guidance that is: Clear. Easily accessible. Evidence-based 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 respective fields who were not involved in the writing process.

4 4 Antiplatelet Therapy (APT) Platelets play a pivotal role in cardiovascular pathophysiology. Rupture or erosion of atherosclerotic coronary artery plaque Platelet activation and aggregation Intraarterial thrombosis and adverse cardiovascular events Antiplatelet agents are cornerstone therapy in patients with atherosclerotic vascular disease including CAD, cerebrovascular disease, and PAD. Available Agents ASA Clopidogrel Dipyridamole Ticlopidine Prasugrel Ticagrelor ASA: acetylsalicylic acid; CAD: coronary artery disease; PAD: peripheral artery disease.

5 APT for Secondary Prevention in First Year Post-ACS Contemporary Classification of ACS Based on: Appearance of presenting ECG. Subsequent measurement of cardiac biomarkers (e.g. troponin). 5 Coronary Artery Disease STEMI 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 NSTEACS Negative biomarkers 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 6 Post-discharge Management of STEMI STEMI Clopidogrel 75 mg OD Indefinite Therapy (Class IIa, Level B) If ASA intolerant ASA mg OD Indefinite Therapy (Class I, Level A) Medically managed Increased risk of stent thrombosis Percutaneous intervention Clopidogrel 75 mg OD or ticagrelor 90 mg BID in addition to ASA mg daily for at least 14 days (Class I, Level B) and up to 12 months in the absence of an excessive risk of bleeding (Class IIb, Level C). Clopidogrel 75 mg OD or ticagrelor 90 mg BID in addition to ASA mg daily for 12 months (Class I, Level B). Continuation of combined therapy beyond 12 months may be considered in patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C). Prasugrel 10 mg daily 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 (Class IIa, Level B) In general, the ADP P2Y 12 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.

7 7 Post-discharge Management of NSTEACS NSTEACS Clopidogrel 75 mg OD Indefinite Therapy (Class IIa, Level B) If ASA intolerant ASA mg OD Indefinite Therapy (Class I, Level A) Medically managed Increased risk of stent thrombosis Percutaneous intervention Clopidogrel 75 mg OD (Class I, Level A) or ticagrelor 90 mg BID (Class I, Level B) in addition to ASA 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). Clopidogrel 75 mg OD (Class I, Level A) or ticagrelor 90 mg BID (Class I, Level B) in addition to ASA 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). Prasugrel 10 mg daily 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 (Class IIa, Level B) In general, the ADP P2Y 12 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.

8 8 APT for Secondary Prevention in First Year Post-PCI PCI is thrombogenic due to: Mechanically induced plaque rupture and vessel injury. PLUS Implantation of metallic stent scaffolding. 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. Vessel healing. Allows for: Plaque stabilization. Reendothelialization. Discontinuation of DAPT post-pci is associated with risks of subacute (1-30 days) and late (30 days-1 year) stent thrombosis.* *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.

9 9 Post-discharge Management of Patients Undergoing PCI Percutaneous Intervention Clopidogrel 75 mg OD Indenfinite Therapy (Class IIa, Level B) If ASA intolerant ASA mg OD Indefinite Therapy (Class I, Level A) Bare-metal stent Increased bleeding risk Drug-eluting stent Clopidogrel 75 mg OD or ticagrelor 90 mg BID in addition to ASA mg OD for at least 1 month and up to 12 months (Class I, Level B). Dual-antiplatelet therapy may be discontinued after a minimum of 2 weeks. Clopidogrel 75 mg OD (Class I, Level A) or ticagrelor 90 mg BID (Class I, Level B) in addition to ASA mg daily for at least 12 months. Increased stent thrombosis risk Dual-antiplatelet therapy with prasugrel 10 mg OD in addition to ASA 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 Continuation of dual-antiplatelet therapy beyond 1 year may be considered as long as the perceived risk of bleeding is deemed acceptable (Class IIb, Level C). ASA: acetylsalicylic acid; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention.

10 10 Management of Stable CAD Management of Stable Coronary Artery Disease ACS >1 year post event Clopidogrel 75 mg OD Indefinite Therapy (Class IIa, Level B) If ASA intolerant ASA mg OD Indefinite Therapy (Class I, Level A) If high risk of thrombosis and low risk of bleeding Dual-antiplatelet therapy with ASA mg OD and clopidogrel 75 mg OD may be considered (Class IIb, Level C). ACS: acute coronary syndrome; ASA: acetylsalicylic acid; CAD: coronary artery disease.

11 11 Key Considerations: APT Post-ACS/PCI DO Provide lifetime APT to all patients post-acs with or without PCI. Provide DAPT with ASA + P2Y 12 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. DON T Use doses of ASA above mg. Discontinue DAPT prior to 1 year without good reason. Discontinue DAPT in a patient with a DES prior to 1 year. ACS: acute coronary syndrome; APT: antiplatelet therapy; ASA: acetylsalicylic acid; DAPT: dual-antiplatelet therapy; DES: drug-eluting stent; PCI: percutaneous coronary intervention.

12 12 APT for Secondary Prevention Post-CABG APT is the gold standard in preventing saphenous vein graft closure after CABG. ASA Given indefinitely may prevent adverse clinical events post-cabg. No evidence of improved arterial graft patency. Clopidogrel Recommended for patients allergic or intolerant to ASA. Safer than other available therapies (e.g. ticlopidine). No randomized trial has specifically studied the efficacy of clopidogrel in the prevention of post-cabg vein graft closure. 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. APT: antiplatelet therapy; ASA: acetylsalicylic acid; CABG: coronary artery bypass graft.

13 13 Management Post CABG Coronary Artery Bypass Graft Clopidogrel 75 mg OD Indefinite Therapy (Class IIa, Level B) If ASA intolerant ASA mg OD Indefinite Therapy (Class I, Level A) In patients undergoing CABG after PCI, dual-antiplatelet therapy with ASA mg daily and clopidogrel 75 mg daily may be maintained for 9-12 months unless the stented vessel is adequately bypassed (Class IIb, Level C). The outpatient management of patients after CABG is outlined in this figure and may include dual-antiplatelet therapy when a recently stented vessel is not adequately bypassed. ASA: acetylsalicylic acid; ATP: antiplatelet therapy; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention.

14 APT for Secondary Prevention of Cerebrovascular Disease 14 Cerebrovascular Disease 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 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. *95% CI: 9%-25% when the outcome is actively ascertained; MI, stroke, and vascular death; 95% CI: 42%-46%. APT: antiplatelet therapy; ASA: acetylsalicylic acid; CI: confidence interval; DAPT: dual-antiplatelet therapy; ER: extended-release; MI: myocardial infarction; TIA: transient ischemic attack.

15 15 Management of TIA and Ischemic Stroke TIA or ischemic stroke of noncardiac origin The combination of ASA 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). The combination of ASA 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). ER-dipyridamole 200 mg twice daily plus ASA 25 mg twice daily (Class I, Level A) Clopidogrel 75 mg once daily (Class I, Level A) ASA mg once daily (Class I, Level A) The outpatient management of TIA or ischemic stroke of non cardiac origin can include dual-antiplatelet therapy for the first month. ASA: acetylsalicylic acid; ER: extended-release; TIA: transient ischemic attack.

16 16 Key Considerations: APT for Cerebrovascular Disease DO 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. DON T Use DAPT with ASA + clopidogrel for long-term secondary stroke prevention. APT: antiplatelet therapy; ASA: acetylsalicylic acid; DAPT: dual-antiplatelet therapy; TIA: transient ischemic attack.

17 APT for Vascular Prevention in Patients with PAD 17 Peripheral Arterial Disease Characteristics Vascular Risk Bruit found along major vessels, peripheral pulsations reduced or absent. OR Asymptomatic PAD* 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. Claudication. OR Rest pain. OR Symptomatic PAD* Ischemic lesions. High risk of cardiovascular events and total mortality, even when taking into account usual risk factors. *ABI <0.9. ABI: ankle-brachial index; APT: antiplatelet therapy; PAD: peripheral arterial disease.

18 18 Management of Peripheral Arterial Disease Peripheral Artery Disease ASA mg OD may be considered for those at high risk because of associated atherosclerotic risk factors in the absence of risk factors for bleeding (Class IIB, Level C). Asymptomatic * Symptomatic With claudication With overt CAD or cerebrovascular disease Without overt CAD or cerebrovascular disease Clopidogrel 75 mg OD in addition to ASA mg OD is not recommended unless the patient is judged to be at high vascular risk along with a low risk of bleeding (Class IIb, Level B). Antiplatelet therapy as indicated for the CAD and/or cerebrovascular status is recommended (Class I, Level A). ASA mg OD or clopidogrel 75 mg daily is recommended providing the risk for bleeding is low (Class IIb, Level B). *Asymptomatic PAD is defined by an ankle-brachial index <0.9 in the absence of claudication or other manifestations such as obstructive vascular disease in the extremities; For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B); For patients with PAD with an indication for oral anticoagulation such as atrial fibrillation, venous thromboembolism, heart failure, or mechanical valves, antiplatelet therapy should not be added to oral anticoagulation (Class III, Level A). ASA: acetylsalicylic acid; CAD: coronary artery disease; PAD: peripheral arterial disease.

19 19 Management Post-peripheral Artery Surgery Management Post Peripheral Artery Surgery ASA * mg OD may be considered for all patients with an AAA, particularly those with clinical or subclinical PAD (Class IIb, Level C). Peripheral Artery Disease with Surgical Indication ASA * mg OD should be given to patients who undergo lower-extremity balloon angioplasty with or without stenting for chronic symptomatic PAD (Class IIa, Level C). In those with infrainguinal grafts and a high risk of thrombosis or limb loss, combination therapy with a vitamin K antagonist and ASA * mg OD may be of benefit (Class IIB, Level C). *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.

20 20 APT Primary Prevention of Vascular Events Primary Prevention of Vascular Events Primary prevention May be defined as antiplatelet strategies, administered to individuals free of any evidence of manifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof. Atherosclerotic disease may include, but is not limited to: Syndromes of angina pectoris. MI. Ischemic stroke. TIA. Intermittent claudication. Critical limb ischemia. The benefits of ASA and APT for primary prevention have not been demonstrated. ASA: acetylsalicylic acid; APT: antiplatelet therapy; MI: myocardial infarction; TIA: transient ischemic attack.

21 21 Primary Prevention 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 mg daily may be considered (Class IIb, Level C). Primary Prevention Primary Prevention 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). For the purpose of this guideline, primary prevention is defined as antiplatelet strategies, administered to individuals free of any evidence of manifest atherosclerotic disease in any vascular bed, to prevent clinical vascular events or manifestations thereof. ASA: acetylsalicylic acid.

22 22 Key Considerations: APT for Primary Prevention DO Consider ASA only where there is clear evidence of high risk: Asymptomatic carotid stenosis. Asymptomatic coronary atherosclerosis. Reduced ABI. End-stage renal disease. DON T Use APT for primary prevention. ABI: ankle-brachial index; APT: antiplatelet therapy; ASA: acetylsalicylic acid.

23 23 Diabetes APT in Patients with Diabetes Patients with diabetes have a variety of risk factors and alterations to platelet function that predispose them to platelet activation and thrombosis. 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 benefits and potential harm of antiplatelet treatment appears less favourable in patients with diabetes compared with those in other high cardiovascular risk groups. 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. APT: antiplatelet therapy; ASA: acetylsalicylic acid.

24 24 Management of Patients with Diabetes ASA * 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). Diabetes 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). Patients >40 years and at low risk for major bleeding, low-dose ASA * 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). *For patients allergic or intolerant to ASA, use of clopidogrel 75 mg OD is suggested (Class IIa, Level B). ASA: acetylsalicylic acid.

25 Heart Failure 25 APT in Patients with Heart Failure Largely due to reduced cardiac output, HF is associated with increased risk of thromboembolic events and other ischemic cardiovascular events. 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. Antiplatelet therapy should be used in all patients with ischemic HF.* Limited evidence suggests ASA may secondary risk of hospitalization for HF. *No evidence of benefit for patients with nonischemic HF (other than for secondary prevention of HF due to CAD). APT: antiplatelet therapy; ASA: acetylsalicylic acid; CAD: coronary artery disease; HF: heart failure.

26 26 Management of Heart Failure Heart Failure Nonischemic Ischemic Routine use of antiplatelet agents is not recommended (Class III, Level C). Antiplatelet therapy should be dictated by the underlying CAD (Class IIa, Level A). CAD: coronary artery disease.

27 27 Management of Chronic Kidney Disease Chronic Kidney Disease Antiplatelet therapy should be considered for secondary prevention in patients with CKD and manifest vascular disease for which its benefits are established (Class IIa, Level C). Chronic Kidney Disease ASA * mg OD may be considered for primary prevention of ischemic vascular events in patients with ESRD and a low risk of bleeding (Class IIb, Level C). Chronic kidney disease is defined as estimated glomerular filtration rate (egfr) or creatinine clearance <60 ml/min/1.73 m 2 (for purposes of this guideline, obtained using either Cockcroft-Gault formula or Modification of Diet in Renal Disease [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.

28 28 Management in Pregnancy and Lactation Pregnancy and Breastfeeding ASA* mg OD may be considered for use in breastfeeding women (Class I, Level C). Pregnancy and Lactation For cardio- or cerebrovascular disease in which antiplatelet therapy would be indicated in nonpregnant women, there should be similar considerations for its use in pregnancy (Class IIa, Level A). ASA* mg OD is likely safe for use during the first trimester of pregnancy (Class IIa, Level A). ASA* can be used safely during the second and third trimester of pregnancy (Class I, Level A). *Use of antiplatelet agents other than low-dose ASA for cardio- or cerebrovascular indications during pregnancy and lactation should only be considered if maternal benefits clearly outweigh potential fetal/infant risks (Class IIb, Level C). ASA: acetylsalicylic acid.

29 Perioperative Management of Patients on APT 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) Other intra-abdominal surgery Other intrathoracic surgery Other orthopaedic surgery 29 Periprocedural Management Relative risk of bleeding associated with common surgical and non-surgical procedures. Very High Risk High Risk Intermediate Risk Low Risk Very Low Risk APT: antiplatelet therapy. Laproscopic cholecystectomy Laproscopic inguinal hernia repair Dental procedures Dermatologic procedures Ophthalmologic procedures Single tooth extraction or teeth cleaning Skin biopsy or selected skin cancer removal Lung resection surgery Intestinal anastomosis surgery Permanent pacemaker insertion or internal defibrillator placement Selected procedures (kidney biopsy, pericardiocentesis, colonic polypectomy) Other vascular surgery Selected procedures (prostate or cervical biopsy) Coronary angiography Gastroscopy or colonoscopy Selected procedures (bone marrow or lymph node biopsy, thoracentesis, paracentesis, arthrocentesis) Cataract removal

30 30 Perioperative Management of Patients taking ASA Patient receiving ASA requiring procedure CABG surgery Noncardiac surgery Minor dental, eye, skin procedure Arthrocentesis Diagnostic test/procedure Patients should continue ASA up to the time of surgery without interruption (Class I, Level B). Patients should stop ASA 7-10 days before surgery if the risk for cardiovascular events is low and continue ASA if the cardiovascular risk is high (Class IIa, Level B). 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). Patients having arthrocentesis may continue ASA without interruption (Class IIb, Level C). Patients having a diagnostic test/procedure associated with a low risk for bleeding may continue ASA without interruption; patients having a test associated with a high risk for bleeding should stop ASA 7-10 days before the test/procedure (Class IIa, Level C). 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.

31 31 Perioperative Management of Patients taking ASA and Clopidogrel Patient receiving ASA + clopidogrel for a coronary stentrequiring procedure CABG surgery Noncardiac surgery Minor dental, eye, skin procedure Arthrocentesis Diagnostic test/procedure Patients should continue ASA until the time of surgery but stop clopidogrel at least 5 days before surgery (Class I, Level B). No Urgent Yes 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 (Class IIb, Level C). 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). 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). 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.

32 32 Key Considerations: Perioperative APT Management DO 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. DON T 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. ASA: acetylsalicylic acid; APT: antiplatelet therapy; BMS: bare-metal stent; DAPT: dual-antiplatelet therapy; DES: drug-eluting stent.

33 33 Management of Minor Bleeding Patients in whom there is excessive bleeding after a dental procedure should receive application of local pressure and/or use of tranexamic acid mouthwash 2-4 times daily for 1-2 days (Class IIa, Level C). Patient on antiplatelet therapy with minor bleeding Patients in whom subconjunctival bleeding develops should continue treatment and be monitored for bleeding (Class IIa, Level C). Patients who develop ecchymosis and petechiae should undergo testing with a complete blood count and international normalized ratio (INR) and activated partial thromboplastin time (aptt) (Class IIa, Level C). 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). 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.

34 34 Key Considerations: Management of APT in Association with Minor Bleeding DO If persistent, check: Complete blood count. INR and aptt. DON T Stop antiplatelet therapy for: Ecchymosis. Petechiae. Subconjunctival hemorrhage. Epistaxis. Dental/gingival bleeding (tranexamic acid mouthwash). APT: antiplatelet therapy; aptt: activated partial thromboplastin time; INR: international normalized ratio.

35 35 Combination Therapy with Warfarin and ASA Combination Therapy Warfarin Typically used for primary and secondary prevention of thromboembolic events. ASA Typically used for primary and secondary prevention of atherothrombotic events. 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 both atrial fibrillation and CAD, or those with both VTE and CAD). ACS: acute coronary syndrome; APT: antiplatelet therapy; ASA: acetylsalicylic acid; CAD: coronary artery disease; VTE: venous thromboembolism.

36 36 Management of Patients Requiring Warfarin Patient with an indication for warfarin therapy Patients who develop ACS that is treated with medical therapy alone, combination warfarin (target INR, )/ASA ( 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, ) and ASA 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 (Class IIa, Level A). Although there is insufficient evidence to provide graded recommendations, other conditions for which combination warfarin/antiplatelet therapy is reasonable include: 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. 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.

37 37 Interaction Between Clopidogrel and PPIs Drug Interactions Clopidogrel requires activation by cytochrome P450 isozyme CYP2C19 in the liver. Interaction with PPIs May inhibit CYP2C19 Lansoprazole Omeprazole Esomeprazole Pantoprazole Strong inhibitors Weak inhibitor 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.

38 38 Use of Proton-Pump Inhibitors Use of Proton-Pump Inhibitiors Use of proton-pump inhibitors in patients taking clopidogrel Patient at risk of upper gastrointestinal bleeding 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 clinically insignificant. 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). PPI: proton-pump inhibitor.

39 39 Interaction Between ASA and NSAIDs ASA binds irreversibly to serine residue at position 529 of platelet COX-1, preventing platelet aggregation. 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. *In patients on ASA, the use of traditional NSAIDs should be avoided and if an anti-inflammatory drug is required, a specific cycloxygenase-2 inhibitor should be considered. ASA: acetylsalicylic acid; COX-1: cycloxygenase-1; NSAID: non-steroidal anti-inflammatory drug.

40 40 Use of NSAIDs in Patients on ASA Use of NSAIDs in Patients on ASA Use of NSAIDs in patients on ASA All NSAIDs and coxibs should be avoided in patients at increased cardiovascular risk (Class III, Level A). 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). Individuals taking ASA for vascular protection should avoid the concomitant use of traditional (non-coxib) NSAIDs (Class III, Level C). ASA: acetylsalicylic acid; Coxib: cycloxygenase-2 inhibitor; NSAID: non-steroidal anti-inflammatory drug.

41 41 APT: Drug-Drug Interactions DO 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. DON T Use PPIs that inhibit CYP2C19 in patients taking clopidogrel or prasugrel. Use NSAIDs or coxibs in patients at increased risk of vascular events. APT: antiplatelet therapy; ASA: acetylsalicylic acid; Coxib: cycloxygenase-2 inhibitor; CV: cardiovascular; NSAID: non-steroidal anti-inflammatory drug; PPI: proton-pump inhibitor; UGI: upper gastrointestinal.