Clopidogrel and ASA after CABG for NSTEMI

Clopidogrel and ASA after CABG for NSTEMI May 17, 2007 Justin Lee Pharmacy Resident University Health Network

Objectives At the end of this session, you should be able to: Explain the rationale for antiplatelet therapy post- NSTEMI and post-cabg Discuss the potential benefits and risks of combination therapy (clopidogrel( and ASA) Synthesize the current evidence and make an appropriate treatment recommendations on a patient- per-patient patient basis

Patient Case

Mr. R 59 yo caucasian male Reason for Admission Retrosternal chest pain radiating to the neck Partially responsive to medical therapy ECG suggestive of ischemia without ST elevation Tn = 18.29 CK = 1111 Diagnosis = NSTEMI

Past Medical History Coronary artery disease (CAD) RCA dissection (Aug 2002) Recurrent re-stenosis (Jan 2003, Aug 2003) NSTEMI (Feb 2007) Multiple PCI to LAD, LCx,, RCA 21 stents!!! Drug-eluting stent (Feb 2007) Peripheral vascular disease (PVD) Bilateral femoral popliteal bypass R carotid endartectomy,, residual left carotid stenosis Hypertension Dyslipidemia

Best Possible Medication History Indication CAD HTN Intermittent Claudication Medication EC ASA 325 mg po OD Clopidogrel 75 mg po OD Atenolol 50 mg po BID Ramipril 2.5 mg po OD Amlodipine 5 mg po OD Rosuvastatin 10 mg po OD Folic acid 5 mg po OD Nitroglycerin 0.4 mg Spray SL PRN Pentoxyfylline SR 400 mg po TID Cellulitis Cephalexein 500 mg po TID

HPI April 12, 2007 Sault Ste. Marie Hospital R leg - swelling and redness Fever and chills Rx Cephalexein x 10 d for R leg cellulitis April 20, 2007 Sault Ste. Marie Hospital Retrosternal chest pain radiating to the neck Rx Heparin, NTG, morphine Transfer to TGH due to residual chest pain

HPI April 20, 2007 TGH CCU Rx Eptifibatide Cath Lab Angiogram 80% stenosis LAD/Cx 70% stenosis LAD 100% stenosis RCA April 24, 2007 Clopidogrel continued until the time of operation CABG x 3

Angiogram Report

Medication in Hospital - Pre-CABG Indication CAD NSTEMI Medication UFH IV infusion NTG IV infusion Eptifibatide IV infusion EC ASA 325 mg po OD Clopidogrel 75 mg po OD Atenolol 50 mg po BID Rosuvastatin 10 mg po OD Folic acid 5 mg po OD Intermittent Claudication Ramipril 2.5 mg po OD - HOLD Amlodipine 5 mg po OD - HOLD Pentoxyfylline SR 400 mg po TID

Clinical Question Does the benefit of continuing the combination of clopidogrel 75 mg po OD and ASA 75-325 mg po OD outweigh the risks post-operatively operatively after CABG for NSTEMI?

What would you do? A) Start ASA alone 48 h post op B) Start ASA alone 10 d post op C) Start ASA + Clopidogrel 48 h post-op op D) Start ASA + Clopidogrel 10 d post-op op

NSTEMI, Graft Disease, Stent Thrombosis Why is the rationale for antiplatelet therapy?

NSTEMI Plaque rupture or erosion initiates cascade: Platelet activation Thrombosis Fibrin clot formation Fibrinolysis (exogenous or endogenous) paradoxically can lead to re-thrombosis Increase in thrombin generation Increase in platelet aggregation

Stent Thrombosis Bare surface of stents induce platelet adhesion, activation and thrombus formation Stents are gradually covered with endothelial cells that do not induce thrombus formation When process of endothelial growth is complete, there is decreased need for platelet inhibition

Stent Thrombosis Drug-eluting stents prevent re-stenosis release anti-proliferative drugs inhibit neointimal thickening of smooth muscle prevent healing growth of endothelial cells on stent surface stent struts remains exposed blood continues to flow over "bare" surface for prolonged period of time

Graft Disease Saphenous venous graft (SVG) disease is clinically significant problem involving: Thrombosis Intimal hyperplasia Atherosclerosis High risk for subsequent ischemic events (death, MI, stroke) Curr Control Trials Cardiovasc Med 2005; 6: 15

Within 1 year, Graft Disease 15% of grafts will occlude Within 10 years, 60% of grafts are patent 50% of these grafts are free of significant stenosis Curr Control Trials Cardiovasc Med 2005; 6: 15

Antiplatelet Therapy for NSTEMI and CABG

Background Knowledge about antiplatelet therapy post- CABG is currently limited Evidence is primarily derived from myocardial infarction or angina pectoris trials Can we extrapolate this information to patients post-operatively operatively for patients who have undergone CABG for NSTEMI?

2002 ACC/AHA UA/NSTEMI Guidelines Clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month and up to 9 months Medical treatment for post-cabg patients should follow the same guidelines as for non post post-cabg patients with UA/NSTEMI

2004 ACC/AHA CABG Guidelines ASA 100 325 mg/d should be initiated within 48 h after CABG and continued indefinitely Protects against early graft closure Reduces subsequent mortality, MI, stroke Clopidogrel is alternative for ASA allergic patients No info on clopidogrel and ASA combination ACC/AHA 2004 Guideline Update for CABG

2004 CHEST Antithrombotic Therapy for CABG Guidelines ASA 75 325 mg/d should be initiated 6 h after CABG and continued indefinitely Clopidogrel 300 mg followed by 75 mg/d is alternative for ASA allergic patients CHEST 2004; 126: 600S-608S

2004 CHEST Antithrombotic Therapy for CABG Guidelines Patients who undergo CABG for NSTEMI, Clopidogrel 75 mg x 9-129 months in addition to treatment with aspirin Grade 1A Recommendation Rationale for recommendation High value on avoiding myocardial infarction Low value on avoiding bleeding complications CHEST 2004; 126: 600S-608S

Grade 1A Recommendation Strong recommendation Can apply to most patients in most circumstances without reservation Based on randomized controlled trials (RCTs) without important limitations Benefits / Risks are clear

What is the evidence? No RCTs to date formally test the hypothesis of dual antiplatelet therapy post-operatively operatively after CABG

CURE N Eng J Med 2001; 345: 494-502

Multi-national Multi-center Prospective Randomized Double-blinded blinded Placebo-controlled controlled Parallel-group Superiority trial CURE Trial

Study Design Patients with Acute Coronary Syndrome (unstable angina or non-st-segment elevation MI) Clopidogrel 300 mg loading dose R 3 m. Visit 6 m. Visit 9 m. Visit 12 m. or Final Visit Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) 3 months double-blind treatment 12 months Placebo + ASA 75-325 mg q.d.* (6303 patients) R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Day 1 Placebo loading dose Discharge Visit 1 m. Visit

Primary outcomes CURE Trial CV death / nonfatal MI / stroke CV death / nonfatal MI / stroke / refractory ischemia Secondary outcomes Severe or refractory ischemia Heart failure Need for revascularization

Key Inclusion Criteria Age 21 years Suspected UA or NSTEMI (no ST 1.0 mm) Presentation within 24 h after symptom onset ECG evidence of ischemia or elevated cardiac enzymes or troponin 2x ULN 1 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.) 2 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

Key Exclusion Criteria NYHA Class IV heart failure Uncontrolled hypertension At high risk for bleeding Eg. hemorrhagic stroke or intracranial hemorrhage Use of anticoagulants, clopidogrel, ticlopidine or NSAIDS Use of GP IIb/IIIa inhibitor within 3 days PCI or CABG within 3 months History of severe thrombocytopenia or neutropenia Contraindications to antithrombotics or antiplatelets

Overall Results: Efficacy Significant benefit to dual antiplatelets 20% RRR in primary outcome at mean of 9 months 9.3% vs 11.4%, p < 0.001 Significant reductions in: In-hospital severe ischemia (RRR 26%) Recurrent angina (RRR 9%) Heart failure (RRR 18%)

Overall Results: Safety Significant 1% absolute increase in major bleeding with dual antiplatelet therapy 3.7% vs 2.7%, RR 1.38, p = 0.001 Impact on life-threatening bleeding was not statistically significant 2.1% vs 1.8%, p = 0.13 No differences in thrombocytopenia or neutropenia

What were the results in patients undergoing CABG for NSTEMI?

CURE Surgical Revascularization Subgroup Analysis Circulation 2004; 110: 1202-1208. 1208.

Study Population CURE 12 562 patients PCI 2 658 patients (21.2%) CABG 2072 patients (16.5%) Medical Therapy 7985 patients (62.3%) Placebo 1061 patients Clopidogrel 1011 patients No CABG patients were lost to follow-up 1928 of the CABG patients (93.0%) stopped the study drug before surgery 1451 of these patients (70.0%) resumed the study drug after surgery

Baseline Characteristics No significant differences between treatment arms Population Characteristics Male Hypertensive Smoker No previous revascularization ASA + UFH/LMWH No GP IIb/IIa Inh

Results: Primary Outcome Non-significant trend toward benefit in CABG subgroup CABG (Any Time) RR 0.89 95% CI 0.71-1.11 Consistent with treatment effect observed in different therapy groups and overall CURE trial

Results: Primary Outcome Trend of greater benefit in those undergoing CABG during their initial hospitalization

Timing of Benefit Benefit driven by protection prior to CABG Overall - RR 0.89, 95% CI 0.71-1.11 1.11 Pre-CABG - RR 0.82, 95% CI 0.58-1.16 Post-CABG - RR 0.97, 95% CI 0.74-1.26 Does this data imply anything regarding the potential benefit of continuing dual antiplatelet post-cabg? Benefit may be driven by acute protective effects associated with NSTEMI vs SVG disease Post-CABG benefit may be nominal Hypothesis-generating, but more research needed

Timing of Benefit Hypothesis: Benefit may be primarily associated with protection against acute effects of NSTEMI vs SVG disease

Results: Bleeding Post-operatively, operatively, strong trend towards: Major bleeding RR 1.27, 95% CI 0.96-1.69 Life threatening bleeding RR 1.30, 95% CI 0.90-1.83

Results: Major Bleeding Non-significant trend towards increased major bleeding CABG (Any Time) RR 1.27 95% CI 0.96-1.69 Trend of higher risk of bleeding than medical management

Risk of Bleeding Incidence (%) 10 8 6 4 2 Major Bleeding After CABG 8.3 6.6 6.7 5.3 Incidence (%) 2 1.5 1 0.5 Life Threatening Bleeding After CABG 1.9 1.6 1 1.1 0 Placebo Clopidogrel 0 Placebo Clopidogrel Post CABG Within 7 d Post CABG Within 7 d Post CABG: RR 1.3, 95% CI 0.93-1.74 Within 7 d: RR 1.3, 95% CI 0.90-1.80 Post CABG: RR 1.2, 95% CI 0.90-1.83 Within 7 d: RR 1.3, 95% CI 0.91-1.95 Majority of bleeds occurred within 7 d after CABG Non-significant trend towards increased bleeding with clopidogrel

Risk of Bleeding Effect of Discontinuation Time on Bleeding Risk Reduction (RR) 2 1.5 1 0.5 0 1.53 0.83 Major Bleed 1.55 0.89 Life Threatening Bleed <= 5 d > 5 NOTE: 95% CI for all comparison cross 1 Trend to increased major bleeding if clopidogrel stopped 5 d prior to CABG Trend to decreased bleeding if clopidogrel stopped > 5 d prior to CABG

Does the benefit outweigh the risk? Number of Events/1000 Patients Treated 25 20 15 10 5 0 23 CV Death / Myocardial Infarction / Stroke 7 Bleeding Caused 4 LT Bleed Caused Events Pre-CABG

Does the benefit outweigh the risk? Number of Events/1000 Patients Treated 18 16 14 12 10 8 6 4 2 0 6 CV Death / Myocardial Infarction / Stroke 17 Bleeding Caused Events Post-CABG 14 LT Bleed Caused Recall bleeding driven by acute post-operative bleeding complications with 7 d post-op

Does the benefit outweigh the risk? Benefit appears driven by pre-cabg outcomes Excess bleeding was limited to patients who discontinued clopidogrel within 5 d before CABG Risk is driven by pre-op decision to use clopidogrel Majority of major bleeds (67%) occurred within 7 days after CABG Median time to clopidogrel restart post-op op was 10 d

Does the benefit outweigh the risk? Benefit in CABG subgroup is relatively small and not significant

Study Strengths Intention-to to-treat treat analysis was performed Overall results in CABG subgroup were consistent with overall CURE population Impact of study drug was well-described Event rates for various discontinuation times documented

Study Limitations Data for patients proceeding to CABG is a post- hoc analysis Although results in this subgroup are consistent with the overall trial population, trial was not powered to show a treatment effect 75.3% of patients who stopped the study medication before surgery restarted it Further reduction power to show treatment effect In intention-to to-treat treat analysis, this would cause: Underestimate of treatment benefit Underestimate of bleeding risk

Study Limitations Protocol did not dictate timing of discontinuation of study drug pre-cabg Variable bleeding risk depending on timing! Protocol did not dictate timing of restart of study drug post-cabg Variable outcome depending on timing? Median time to restart was 10 days

What would you do? A) Start ASA alone 48 h post op B) Start ASA alone 10 d post op C) Start ASA + Clopidogrel 48 h post-op op D) Start ASA + Clopidogrel 10 d post-op op

Applying the Evidence to Your Patient Weigh risks and benefits of the following: Protection of functional stents Drug-eluting stents (DES) if < 1 year old Bare metal stents (BMS) if < 1 month old Antiplatelet therapy for NSTEMI Primary prevention of SVG disease Patient specific risk factors for bleeding

Application to Mr. R Risk of stent thrombosis of his unprotected DES was very high Post-operative operative bleeding complications were ruled out Clopidogrel was restarted 2 days post-op op

Application to Mr. R CURE data should be applied cautiously Mr. R would not have been a CURE patient given: Recent PCI < 3 months ago Use of GP IIb/IIIa IIIa inhibitor Use of clopidogrel pre-nstemi High risk of bleeding complications given his clopidogrel was continued until the time of CABG

Conclusions Using an EBM approach, All NSTEMI patients proceeding to CABG should receive dual antiplatelet therapy with ASA and clopidogrel for a duration up to 12 months Elective CABG should be delayed whenever possible to allow for clopidogrel to be discontinued for >5 days Wait 7-107 days before restarting clopidogrel to minimize bleeding risk unless there is a compelling indication to restart earlier

Unresolved Questions Opportunity that the benefit of dual antiplatelet therapy post-cabg for NSTEMI can be refuted with further study If true benefit, What is the optimal time to restart? Does clopidogrel require a loading dose? Is there a difference between LIMA and SVG?

Future Study: CASCADE Prospective, randomized, double-blinded blinded placebo-controlled controlled trial Intervention Clopidogrel 75 mg/d + ASA 162 mg/d vs. ASA 162 mg/d alone 1 year duration starting on the day of surgery Patient population Patients undergoing multi-vessel elective or urgent CABG using at least 2 SVGs

Future Study: CASCADE Primary Outcome Reduction of vein graft intimal hyperplasia Secondary Outcomes Patency and stenosis as demonstrated by coronary and graft angiography Estimated Time of Completion November 2007

Discussion & Questions