1. S. Banai, M.D. Loading dose with Clopidogrel before PCI How high should we go? Shmuel Banai, MD Director, Interventional Cardiology Tel Aviv Medical Center

2. S. Banai, M.D. PCI and platelet activation u The early response to arterial wall injury is platelet activation and deposition over the injured arterial surface, creating the substrate for thrombosis u Stent implantation appears to be associated with greater platelet activation than balloon angioplasty alone u The magnitude of platelet activation is associated with an increased risk for adverse clinical events after coronary intervention Kabbani SS: Circulation. 2002;104:181–186

3. S. Banai, M.D. Myocardial necrosis after PCI u Myocardial necrosis, assessed by CK-MB elevation, is relatively frequent after coronary intervention, occurring in up to 40% of cases Klein LW: J Am Coll Cardiol. 1991; 17: 621–626 Abdelmeguid AE: Circulation. 1996; 94: 1528–1536 Brener SJ: Eur Heart J. 2002; 23: 869–876 Nallamothu BK: J Am Coll Cardiol. 2003; 42: 1412–1414 Ioannidis JPA: J Am Coll Cardiol. 2003; 42: 1406–1411 u Although most patients remain asymptomatic with no changes in cardiac function, even a mild release of CK-MB is associated with higher mortality during follow-up

4. S. Banai, M.D. PCI-related myocardial injury u The most frequent complication after PCI u Can be significantly reduced and outcome improved with appropriate pharmacological treatment before PCI

5. S. Banai, M.D. The ARMYDA Study Randomized, placebo-controlled trial to evaluate the effect of pretreatment with atorvastatin (40mg) started 1 week before elective PCI on the release of markers of cardiac damage (CK- MB, troponin I, and myoglobin) in patients with stable angina Pasceri V: Circulation 2004;110:674-678 Atorvastatin for Reduction of MYocardial Damage during Angioplasty

6. S. Banai, M.D. Pasceri, V. et al. Circulation 2004;110:674-678 Incidence of postprocedural increase of CK-MB and troponin I >1, 2 to 5, and >5 times above upper normal limit (UNL) Conclusions: Pretreatment with atorvastatin significantly reduces procedural myocardial injury in elective PCI Peak values of CK-MB, troponin I, and myoglobin in statin vs placebo group

7. S. Banai, M.D. To evaluate whether aggressive antiplatelet therapy with clopidogrel in patients undergoing PCI will reduce periprocedural MI and improve outcome The ARMYDA-2 Study Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty Patti, G. et al. Circulation 2005;111:2099-2106

8. S. Banai, M.D. 255 pts with stable CAD or non-ST ACS, randomized to 300 or 600 mg of Clopidogrel 4-8 h before PCI Primary end point: A composite of death, MI or TVR at 30 days non-ST-elevation MI -25% complex lesions - 75% DES -20% IIb/IIIa blockers -13% Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 Study Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty

9. S. Banai, M.D. ARMYDA-2: Number of events EventClopidogrel 300 mg Clopidogrel 600 mg Death00 Target vessel revascularization 01 MI155

10. S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: ARMYDA-2 STUDY Results: 30-day occurrence of death, MI, or TVR in patients receiving 600-mg versus the 300-mg loading regimen of clopidogrel The primary end points occurred in: 4% of pts with 600 mg versus 12% with 300 mg

11. S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: ARMYDA-2 STUDY Results: Comparison of postprocedural elevation of CK-MB and troponin I in the 2 study arms

12. S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: Baseline and peak values of CK-MB, troponin I, and myoglobin

13. S. Banai, M.D. Pretreatment with 600-mg loading dose of clopidogrel significantly reduced the risk of periprocedural MI (OR 0.48; 95% CI 0.15 to 0.97; P=0.044) Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: ARMYDA-2 STUDY Results: Multivariable analysis

14. S. Banai, M.D. Percentage of patients with any elevation of CKMB/troponin I MarkerClopidogrel 300 mg (%) Clopidogrel 600 mg (%) p CKMB26140.036 Troponin I44260.004

15. S. Banai, M.D. Bleeding events EventClopidogrel 300 mg Clopidogrel 600 mg Major bleed (Hgb>5g/dL) 00 Minor bleed (Hgb<5g/dL) 1 (0.8%)

16. S. Banai, M.D. The ARMYDA-2 trial Conclusions: u Pretreatment with a 600-mg loading dose of clopidogrel given 6 hours before the procedure is safe and, as compared with the 300-mg dose, reduces periprocedural MI and improves short-term prognosis in patients undergoing PCI u The low risk of this pharmacological regimen may support its routine use in patients before planned coronary angioplasty and may influence practice patterns with regard to antiplatelet therapy before PCI

17. S. Banai, M.D. CLOPIDOGREL ASA COX ADP C GPllb/llla (Fibrinogen receptor) Collagen thrombin TXA 2 Activation TXA 2 COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA 2 (thromboxane A 2 ) Jarvis B, Simpson K. Drugs 2000; 60: 347–77 The active metabolite exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y 12 Clopidogrel: An inactive prodrug requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system

18. S. Banai, M.D. Clopidogrel: an inactive prodrug that requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system to an active metabolite that exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y 12 ADP / ATP P2Y 1 P2X 1 P2T 12 Gi 2 coupled Gq coupled Ca 2+ cAMP Platelet shape change Transient aggregation No effect on fibrinogen receptor Cation influx Calcium mobilization Fibrinogen receptor activation Thromboxane A 2 generation Sustained aggregation response

19. S. Banai, M.D. u A prodrug that needs to be metabolized to an active compound that targets the platelet G i -coupled adenosine diphosphate (ADP) P2Y12 receptor u Clopidogrel is oxidized in a cytochrome P450 (CYP) monooxygenase-dependent way to 2-oxo-clopidogrel, an intermediate metabolite that is further hydrolyzed to the active thiol metabolite of clopidogrel u The active metabolite irreversibly binds to the P2Y12 receptor u The major circulating metabolite of clopidogrel is a carboxylic acid derivate that completely lacks antiaggregatory activity The thienopyridine clopidogrel

20. S. Banai, M.D. u Absorption (oral): rapid, not affected by food or antacids u Metabolism: rapid and extensive hepatic metabolism u Half-life: 8 hours (but has an irreversible effect on platelets, with a lifespan of approximately 7–10 days) u Excretion: 50% in urine and 46% in feces, after 5 days Pharmacology of Clopidogrel Jarvis B, Simpson K. Drugs 2000; 60: 347–77

21. S. Banai, M.D. Clopidogrel Dosing u 1977: The 75-mg once-daily dose was approved by the FDA after the CAPRIE trial showed superior reduction of adverse cardiovascular events with clopidogrel versus aspirin The 75-mg once-daily dose had been used in CAPRIE because it produced inhibition of platelet aggregation equivalent to that produced by ticlopidine 250 mg administered twice daily u 2002: FDA approval for the 300-mg loading dose in patients with ACS after the CURE trial demonstrated a reduction of adverse cardiovascular events with dual antiplatelet therapy versus aspirin

22. S. Banai, M.D. Loading Dose u Without a loading dose, clopidogrel 75 mg daily induces inhibition of ADP-induced platelet aggregation as early as 2 hours after the first dose but requires 3 to 7 days to achieve maximal inhibition of platelet aggregation u The 3- to 7-day delay can be shortened to 6 hours with a loading dose of 300 mg u With 600 mg loading ( as compared with the 300-mg dose) : the maximal platelet inhibition is achieved at 2 hours the level of inhibition of platelet aggregation is increased the number of low responders decreased Bates ER: Circulation 2005;111:2557-2559 Hochholzer W: Circulation 2005;111:2560-2564

23. S. Banai, M.D. The benefit of a higher loading dose u The advantage of using the higher loading dose is the maximal drug effect during the periprocedural period when pretreatment has not been given, a common occurrence with ad hoc PCI u The clinical benefit is measured by lower biomarker- defined periprocedural MI rates, as has been seen with periprocedural platelet inhibition with GP IIb/IIIa inhibitor agents, and with the 600 mg Clopidogrel pre-treatment in the ARMYDA-2 trial

24. S. Banai, M.D. Should patients who are on chronic clopidogrel therapy receive the 600 mg pretreatment regimen? Many patients presenting for PCI are already treated with clopidogrel. Should these patients receive the 600-mg pretreatment regimen? The answer is yes! Additional, significant inhibition of platelet aggregation is achieved when a 600-mg dose is administered to patients already receiving clopidogrel 75 mg daily

25. S. Banai, M.D. Further platelet inhibition can be achieved with 600-mg Re-loading in patients with chronic clopidogrel therapy Adnan Kastrati Circulation. 2004;110:1916-1919  In both groups, 600 mg clopidogrel loading significantly inhibited ADP- induced expression of GP IIb/IIIa and P- selectin receptors  In the chronic therapy group, loading with 600 mg clopidogrel yielded further inhibition of platelet aggregation in addition to that achieved by the maintenance dose of 75 mg/d, from 52±14% to 33±12% (P<0.001)

26. S. Banai, M.D. Abciximab offers no additional benefit in the setting of Clopidogrel pretreatment Kastrati A: N Engl J Med 2004;350:232-238

27. S. Banai, M.D. Study design and objectives 2159 patients with CAD who underwent a PCI: All patients were pretreated with a 600-mg dose of clopidogrel at least two hours before the procedure N=1079 - abciximab N=1080 - placebo Primary end point: Composite of death, MI, and urgent TVR within 30 days Kastrati A: N Engl J Med 2004;350:232-238

28. S. Banai, M.D. Results: 4% event rate in both patient groups Kastrati A: N Engl J Med 2004;350:232-238

29. S. Banai, M.D. conclusion  In patients at low and intermediate risk who undergo elective PCI after pretreatment with a 600-mg loading dose of clopidogrel at least two hours before the procedure, the additional use of abciximab is associated with no clinically measurable benefit within the first 30 days Kastrati A: N Engl J Med 2004;350:232-238

30. S. Banai, M.D. Randomized Clinical Trial of Abciximab in Diabetic Patients Undergoing Elective PCI After Treatment With a High Loading Dose of Clopidogrel Julinda Mehilli, Circulation. 2004;110:3627-3635 Abciximab offers no additional benefit in the setting of Clopidogrel pretreatment in Diabetics Study: 701 diabetic patients with CAD who underwent elective PCI after pretreatment with a 600-mg dose of clopidogrel >2 hours before the procedure 351 patients - abciximab 350 patients - placebo Primary end point: composite of death and MI at 1 year

31. S. Banai, M.D. There is no significant impact of abciximab on the risk of death and MI in diabetic patients undergoing PCI after pretreatment with a 600-mg loading dose of clopidogrel at least 2 hours before the procedure Conclusions: Mehilli J, Circulation 2004;110:3627-3635

32. S. Banai, M.D. How High Should We Go? Absorption, Metabolization, and Antiplatelet Effects of 300, 600, and 900-mg Loading Doses of Clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950 Primary end point : Maximal ADP-induced (5 µmol/L) platelet aggregation 4 hours after administration of clopidogrel

33. S. Banai, M.D. Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel  Sixty patients with suspected or documented CAD admitted for coronary angiography were included They were allocated to clopidogrel loading doses of 300, 600, or 900 mg in a double-blinded, randomized manner  Plasma concentrations of the active thiol metabolite, unchanged clopidogrel, and the inactive carboxyl metabolite of clopidogrel were determined before and serially after drug administration Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950

34. S. Banai, M.D. von Beckerath, N. et al. Circulation 2005;112:2946-2950 Plasma concentrations  Loading with 600 mg resulted in higher plasma concentrations of active metabolite, clopidogrel, and carboxyl metabolite compared with loading with 300 mg (P 0.03)  With 900 mg, no further increase in plasma concentrations of active metabolite and clopidogrel (P 0.38) was achieved active metabolite clopidogrel carboxyl metabolite 300 mg (blue) 600 mg (red) 900 mg (cyan)

35. S. Banai, M.D. Maximal ADP-induced platelet aggregation 4 hours after administration of a 300-, 600-, and 900- mg loading dose von Beckerath, N. et al. Circulation 2005;112:2946-2950 An increase of the clopidogrel loading dose from 600 to 900 mg does not result in further suppression of platelet aggregation caused by a failed increase in plasma concentration of the drug This suggests that intestinal absorption becomes the bottleneck when single doses exceeding 600 mg are administered

36. S. Banai, M.D. Should we split the high dose? u Administering 900 mg Clopidogrel in 2 separate doses may allow more complete absorption and, consequently, additional platelet inhibition compared with 600 mg u However, the practicability of such an approach as a pretreatment before PCI is limited Nicolas von Beckerath Circulation. 2005;112:2946-2950

37. S. Banai, M.D. What can we reasonable conclude about antiplatelet therapy and PCI? 1.augmenting aspirin with additional antiplatelet therapy reduces myonecrosis after PCI 2.according to the information currently available, if clopidogrel is selected, the dose should be 600 mg and the drug should be administered at least 2 hours before PCI 3. for the types of patients evaluated thus far, intravenous GP IIb/IIIa inhibitors appear unnecessary when clopidogrel has been administered 4.if circumstances restrict clopidogrel pretreatment, intravenous GP IIb/IIIa is a reasonable alternative

38. S. Banai, M.D. Thank You