Initiating Antiplatelet Therapy in Patients with Atherothrombosis

1. Initiating Antiplatelet Therapy in Patients with Atherothrombosis Sunil V. Rao MD Durham VA Medical Center Duke Clinical Research Institute Duke University Medical Center

2. NSTE ACS

4. Plateletaggregation Plateletactivation ADP Collagen TXA2 Fibrinogen Fibrin Thrombin THROMBUS PlasmaClottingcascade TissueFactor Prothrombin Thrombus formation Thrombin and platelets play a central role

5. Clopidogrel Indications Clopidogrel is indicated for the reduction of atherothrombotic events Recent MI, Recent Stroke, or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death. Acute Coronary Syndrome For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel has been shown to decrease the rate of a combined end point of cardiovascular death, MI, or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia. For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty. Clopidogrel prescribing information, sanofi-aventis US, LLC

6. Clopidogrel Clinical Trials Overview Clopidogrelvs aspirin Clopidogrel + aspirin vs placebo + aspirin Clopidogrel + aspirin vs placebo + aspirin Clopidogrel + aspirin vs placebo + aspirin

9. Early Benefit of Dual Antiplatelet Therapy in ACS:Death/MI/Ischemia < 24 Hrs in CURE 0.025 RR=0.67 P=0.002 Placebo 0.020 0.015 Cumulative hazard rates 0.010 Clopidogrel 0.005 0 Hours after randomization —Berger P, Steinhubl S. Circ 2002

10. Effects of Clopidogrel on Combined End Point (Death, Reinfarction, or Stroke) by Treatment Interval Clopidogrel better Clopidogrel

11. Effects of Clopidogrel on Bleeding Rate by Treatment Interval The overall incidence of major bleeding (including life-threatening and other major bleeding) was: Clopidogrel + ASA = 3.7% Clopidogrel + ASA = 2.7% P=0.001 Placebo + ASA Clopidogrel + ASA Placebo + ASA Clopidogrel + ASA

12. 2007 ACC/AHA Guidelines for UA/NSTEMI • Aspirin should be administered to UA/NSTEMI patients as soonas possible after hospital presentation and continued indefinitelyin patients not known to be intolerant of that medication. (Levelof Evidence: A) • Clopidogrel (loadingdose followed by daily maintenance dose)*should be administeredto UA/NSTEMI patients who are unableto take ASA because ofhypersensitivity or major gastrointestinalintolerance. (Levelof Evidence: A) Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at: http://www.acc.org/qualityandscience/clinical/topic/topic.htm#MAccessed August 7, 2007.

13. 2007 ACC/AHA Guidelines for UA/NSTEMI • For UA/NSTEMI patients in whom an initial invasive strategyis selected: • Eitherclopidogrel (loading dose followed by daily maintenance dose)*or an intravenous GP IIb/IIIa inhibitor shouldbe initiated before diagnostic angiography (upstream) (Level of Evidence:A) • For UA/NSTEMI patients in whom aninitial conservative (i.e.,noninvasive) strategy is selected: • Clopidogrel(loading dose followed by dailymaintenance dose) should beadded to ASA and anticoagulanttherapy as soon as possible afteradmission and administeredfor at least 1 month (Level of Evidence:A) and ideally up to1 year. (Level of Evidence: B) Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at: http://www.acc.org/qualityandscience/clinical/topic/topic.htm#MAccessed August 7, 2007.

17. The Major Bleeding Rate Was Increased When Clopidogrel Was Administered <5 Days Before CABG in CURE Major bleeding rate in patients undergoing CABG according to whether therapy is stopped or continued 5 days before CABG1 Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued five days prior to surgery. Placebo + ASA Clopidogrel + ASA

18. Clopidogrel + Aspirin Placebo + Aspirin Aspirin Dose (+ standard therapy*) (+ standard therapy*) * Other standard therapies were given at the physician’s discretion Clopidogrel prescribing information. sanofi-aventis US, LLC CURE Trial Investigators. N Engl J Med. 2001;345;494-502. *Other standard therapies were given at physician’s discretion. Clopidogrel prescribing information. sanofi-aventis U.S. LLC CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

19. 2007 ACC/AHA Guidelines for UA/NSTEMI • For UA/NSTEMI patients inwhom CABG is selected as a postangiographymanagement strategy: • Continue ASA. (Level of Evidence:A) • Discontinue clopidogrel5 to 7 d before elective CABG.(Levelof Evidence: B) • More urgentsurgery, if necessary, maybe performedby experienced surgeonsif the incremental bleedingrisk isconsidered acceptable. (Levelof Evidence: C) Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at: http://www.acc.org/qualityandscience/clinical/topic/topic.htm#MAccessed August 7, 2007.

20. Fox KAA, et. al. Circulation 2004

24. Clopidogrel Clinical Trials Overview Clopidogrelvs aspirin Clopidogrel + aspirin vs placebo + aspirin Clopidogrel + aspirin vs placebo + aspirin Clopidogrel + aspirin vs placebo + aspirin

25. Acute MI Platelet Activation by Fibrinolytics Normalized Maximal Aggregation Rate t-PA SK 1.5 1.0 0.5 150 100 0 200 50 250 Time (min) Rudd and Loscalzo, CircRes ‘90 Rabbit model, .05mM ADP as agonist SGE; 0802-3, 22

27. * All treated patients received aspirin. Clopidogrel prescribing information. sanofi-aventis US, LLC

29. Clopidogrel prescribing information. sanofi-aventis US, LLC

31. * The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event. Clopidogrel prescribing information. sanofi-aventis US, LLC

32. Major bleeding defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL. Subgroups of patients defined by baseline characteristics, and type of fibrinolysis or heparin therapy. Clopidogrel prescribing information, sanofi-aventis US, LLC

33. Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery. LBB-left bundle branch block; UFH = unfractionated heparin; LMWH = low molecular weight heparin. American Heart Association. Circulation. 2005;112:IV-89-IV-110.

37. Evidence-based Antithrombotic Pharmacology:Conclusions • Therapy directed at the platelet is the cornerstone of Atherothrombosis management • ASA and Clopidogrel • CURE, COMMIT, & CLARITY Trials support their role across the spectrum of risk • Administer early and at discharge

38. Evidence-based Antithrombotic Pharmacology:Conclusions • Bleeding is an issue with dual antiplatelet therapy • CABG – wait 5-7 days; outcomes improved if on clopidogrel • Long-term – reduce ASA dose • Guidelines are important • Adherence improves survival • Don’t forget about the medically managed patients