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PCI and platelet activation The early response to arterial wall injury is platelet activation and deposition over the injured arterial surface, creating the substrate for thrombosis Stent implantation appears to be associated with greater platelet activation than balloon angioplasty alone The magnitude of platelet activation is associated with an increased risk for adverse clinical events after coronary intervention S. Banai, M.D. Kabbani SS: Circulation. 2002;104:181–186 Myocardial necrosis after PCI Myocardial necrosis, assessed by CK-MB elevation, is relatively frequent after coronary intervention, occurring in up to 40% of cases 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 S. Banai, M.D. 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 PCI-related myocardial injury The Can most frequent complication after PCI be significantly reduced and outcome improved with appropriate pharmacological treatment before PCI S. Banai, M.D. The ARMYDA Study Atorvastatin for Reduction of MYocardial Damage during Angioplasty 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 (CKMB, troponin I, and myoglobin) in patients with stable angina S. Banai, M.D. Pasceri V: Circulation 2004;110:674-678 Conclusions: Pretreatment with atorvastatin significantly reduces procedural myocardial injury in elective PCI Incidence of postprocedural increase of CK-MB and troponin I >1, 2 to 5, and >5 times above upper normal limit (UNL) Peak values of CK-MB, troponin I, and myoglobin in statin vs placebo group S. Banai, M.D. Pasceri, V. et al. Circulation 2004;110:674-678 The ARMYDA-2 Study Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty To evaluate whether aggressive antiplatelet therapy with clopidogrel in patients undergoing PCI will reduce periprocedural MI and improve outcome S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 Study Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty 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% S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2: Number of events Event Clopidogrel 300 mg Clopidogrel 600 mg Death 0 0 Target vessel revascularization 0 1 15 5 MI S. Banai, M.D. 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 S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: Comparison of postprocedural elevation of CK-MB and troponin I in the 2 study arms 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 S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 ARMYDA-2 STUDY Results: Multivariable analysis 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) S. Banai, M.D. Patti, G. et al. Circulation 2005;111:2099-2106 Percentage of patients with any elevation of CKMB/troponin I Marker Clopidogrel 300 mg (%) Clopidogrel 600 mg (%) p CKMB 26 14 0.036 Troponin I 44 26 0.004 S. Banai, M.D. Bleeding events Event S. Banai, M.D. Clopidogrel 300 mg Clopidogrel 600 mg Major bleed (Hgb>5g/dL) 0 0 Minor bleed (Hgb<5g/dL) 1 (0.8%) 1 (0.8%) The ARMYDA-2 trial Conclusions: 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 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 S. Banai, M.D. The active metabolite exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y12 CLOPIDOGREL Clopidogrel: An inactive prodrug requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system C ADP ADP GPllb/llla Activation (Fibrinogen receptor) ASA Collagen thrombin TXA 2 COX TXA 2 S. Banai, M.D. COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2) Jarvis B, Simpson K. Drugs 2000; 60: 347–77 The thienopyridine clopidogrel A prodrug that needs to be metabolized to an active compound that targets the platelet Gi-coupled adenosine diphosphate (ADP) P2Y12 receptor 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 The active metabolite irreversibly binds to the P2Y12 receptor The major circulating metabolite of clopidogrel is a carboxylic acid derivate that completely lacks antiaggregatory activity S. Banai, M.D. Pharmacology of Clopidogrel Absorption (oral): rapid, not affected by food or antacids Metabolism: Half-life: rapid and extensive hepatic metabolism 8 hours (but has an irreversible effect on platelets, with a lifespan of approximately 7–10 days) Excretion: S. Banai, M.D. 50% in urine and 46% in feces, after 5 days Jarvis B, Simpson K. Drugs 2000; 60: 347–77 Clopidogrel Dosing 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 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 S. Banai, M.D. Loading Dose 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 The 3- to 7-day delay can be shortened to 6 hours with a loading dose of 300 mg 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 S. Banai, M.D. Hochholzer W: Circulation 2005;111:2560-2564 The benefit of a higher loading dose 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 The clinical benefit is measured by lower biomarkerdefined 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 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 S. Banai, M.D. Further platelet inhibition can be achieved with 600-mg Re-loading in patients with chronic clopidogrel therapy In both groups, 600 mg clopidogrel loading significantly inhibited ADPinduced expression of GP IIb/IIIa and Pselectin 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) S. Banai, M.D. Adnan Kastrati Circulation. 2004;110:1916-1919 Abciximab offers no additional benefit in the setting of Clopidogrel pretreatment S. Banai, M.D. Kastrati A: N Engl J Med 2004;350:232-238 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 S. Banai, M.D. Kastrati A: N Engl J Med 2004;350:232-238 Results: 4% event rate in both patient groups S. Banai, M.D. Kastrati A: N Engl J Med 2004;350:232-238 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 S. Banai, M.D. Kastrati A: N Engl J Med 2004;350:232-238 Abciximab offers no additional benefit in the setting of Clopidogrel pretreatment in Diabetics Randomized Clinical Trial of Abciximab in Diabetic Patients Undergoing Elective PCI After Treatment With a High Loading Dose of Clopidogrel 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 S. Banai, M.D. Julinda Mehilli, Circulation. 2004;110:3627-3635 Conclusions: 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 S. Banai, M.D. Mehilli J, Circulation 2004;110:3627-3635 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 Primary end point: Maximal ADP-induced (5 µmol/L) platelet aggregation 4 hours after administration of clopidogrel S. Banai, M.D. Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950 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 S. Banai, M.D. Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950 Plasma concentrations active metabolite clopidogrel carboxyl metabolite 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 300 mg (blue) 600 mg (red) 900 mg (cyan) S. Banai, M.D. von Beckerath, N. et al. Circulation 2005;112:2946-2950 Maximal ADP-induced platelet aggregation 4 hours after administration of a 300-, 600-, and 900- mg loading dose 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 S. Banai, M.D. von Beckerath, N. et al. Circulation 2005;112:2946-2950 Should we split the high dose? Administering 900 mg Clopidogrel in 2 separate doses may allow more complete absorption and, consequently, additional platelet inhibition compared with 600 mg However, the practicability of such an approach as a pretreatment before PCI is limited S. Banai, M.D. Nicolas von Beckerath Circulation. 2005;112:2946-2950 What can we reasonable conclude about antiplatelet therapy and PCI? 1. 2. 3. 4. augmenting aspirin with additional antiplatelet therapy reduces myonecrosis after PCI 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 for the types of patients evaluated thus far, intravenous GP IIb/IIIa inhibitors appear unnecessary when clopidogrel has been administered if circumstances restrict clopidogrel pretreatment, intravenous GP IIb/IIIa is a reasonable alternative S. Banai, M.D. Thank You S. Banai, M.D.