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PCI and platelet activation

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

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PCI and platelet activation

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  1. PCI and platelet activation The early response to arterial wall injury is platelet activation and depositionover the injured arterial surface, creating the substrate forthrombosis Stent implantation appears to be associated with greater platelet activation than balloon angioplasty alone The magnitude of platelet activation is associatedwith an increased risk for adverse clinical events after coronaryintervention Kabbani SS: Circulation. 2002;104:181–186

  2. 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 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

  3. PCI-related myocardial injury • The most frequent complication after PCI • Can be significantly reducedand outcome improved with appropriate pharmacological treatmentbefore PCI

  4. 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 (CK-MB, troponin I, and myoglobin) in patients with stable angina Pasceri V: Circulation 2004;110:674-678

  5. Conclusions: Pretreatment with atorvastatin significantly reduces procedural myocardial injury inelective 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 Pasceri, V. et al. Circulation 2004;110:674-678

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

  7. 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% Patti, G. et al. Circulation 2005;111:2099-2106

  8. ARMYDA-2: Number of events

  9. 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 Patti, G. et al. Circulation 2005;111:2099-2106

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

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

  12. 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) Patti, G. et al. Circulation 2005;111:2099-2106

  13. Percentage of patients with any elevation of CKMB/troponin I

  14. Bleeding events

  15. The ARMYDA-2 trial Conclusions: Pretreatment witha 600-mg loading dose of clopidogrel given 6 hours before theprocedure is safe and, as compared with the 300-mg dose, reducesperiprocedural MI and improves short-termprognosis in patients undergoing PCI The low risk of this pharmacological regimen may support itsroutine use in patients before planned coronary angioplastyand may influence practice patterns with regard to antiplatelettherapy before PCI

  16. CLOPIDOGREL C ADP ADP Collagen thrombin TXA GPllb/llla (Fibrinogen receptor) Activation 2 ASA COX TXA 2 The activemetabolite exerts its antiplatelet effect by noncompetitiveinhibition of the platelet ADP receptor subtype P2Y12 Clopidogrel: Aninactive prodrug requires in vivo conversion in the liverby the cytochrome P450 (CYP) 3A4 enzyme system COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2) Jarvis B, Simpson K. Drugs 2000; 60: 347–77

  17. The thienopyridine clopidogrel A prodrug that needs to bemetabolized to an active compound that targets the plateletGi-coupled adenosine diphosphate (ADP) P2Y12 receptor Clopidogrel is oxidized in a cytochrome P450 (CYP)monooxygenase-dependent way to 2-oxo-clopidogrel, an intermediatemetabolite that is further hydrolyzed to the active thiol metaboliteof clopidogrel The active metabolite irreversibly binds tothe P2Y12 receptor The major circulatingmetabolite of clopidogrel is a carboxylic acid derivate thatcompletely lacks antiaggregatory activity

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

  19. Clopidogrel Dosing 1977: The75-mg once-daily dose was approved by the FDA after the CAPRIE trial showedsuperior reduction of adverse cardiovascular events with clopidogrelversus aspirin The 75-mg once-daily dose had been used in CAPRIEbecause it produced inhibition of platelet aggregation equivalentto 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 withdual antiplatelet therapy versus aspirin

  20. Loading Dose Without a loading dose, clopidogrel 75 mg daily induces inhibitionof ADP-induced platelet aggregation as early as 2 hours afterthe first dose but requires 3 to 7 days to achieve maximal inhibitionof platelet aggregation The 3- to 7-day delay can be shortenedto 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 numberof low responders decreased Bates ER: Circulation 2005;111:2557-2559 Hochholzer W: Circulation 2005;111:2560-2564

  21. The benefit of a higher loading dose The advantage of using the higher loading dose is the maximal drug effect during the periprocedural periodwhen pretreatment has not been given, a common occurrence withad hoc PCI The clinical benefit is measuredby lower biomarker-defined periprocedural MI rates, as has beenseen with periprocedural platelet inhibition with GP IIb/IIIa inhibitor agents, and with the 600 mg Clopidogrel pre-treatment in the ARMYDA-2 trial

  22. Should patients who are on chronic clopidogrel therapy receive the 600 mg pretreatment regimen? The answer is yes! Additional, significantinhibition of platelet aggregation is achieved when a 600-mg dose is administeredto patients already receiving clopidogrel 75 mgdaily Many patients presentingfor PCI are already treated with clopidogrel.Should these patients receive the 600-mg pretreatment regimen?

  23. Further platelet inhibition can be achievedwith 600-mg Re-loading in patientswith chronic clopidogrel therapy • In both groups, 600 mg clopidogrel loading significantly inhibitedADP-induced expression of GP IIb/IIIa and P-selectinreceptors • In the chronic therapy group, loading with 600 mg clopidogrelyielded further inhibition of platelet aggregation in addition to that achieved by the maintenancedose of 75 mg/d, from 52±14% to 33±12% (P<0.001) Adnan KastratiCirculation. 2004;110:1916-1919

  24. Abciximab offersno additional benefit in the setting of Clopidogrel pretreatment Kastrati A: N Engl J Med 2004;350:232-238

  25. 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

  26. Results: 4% event rate in both patient groups Kastrati A: N Engl J Med 2004;350:232-238

  27. 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

  28. Abciximab offersno 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 Julinda Mehilli, Circulation. 2004;110:3627-3635

  29. 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

  30. 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 (5µmol/L) platelet aggregation 4 hours after administrationof clopidogrel Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950

  31. Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel Sixty patients with suspected ordocumented CAD admitted for coronary angiography were included They wereallocated to clopidogrel loading doses of 300, 600, or900 mg in a double-blinded, randomized manner Plasma concentrationsof the active thiol metabolite, unchanged clopidogrel, and theinactive carboxyl metabolite of clopidogrel were determinedbefore and serially after drug administration Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950

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

  33. Maximal ADP-induced platelet aggregation 4 hours after administration of a 300-, 600-, and 900- mg loading dose An increaseof the clopidogrel loading dose from 600 to 900 mg does notresult in further suppression of platelet aggregationcaused by a failed increase in plasma concentration of the drug This suggeststhat intestinal absorption becomes the bottleneck when singledoses exceeding 600 mg are administered von Beckerath, N. et al. Circulation 2005;112:2946-2950

  34. Should we split the high dose? Administering 900 mg Clopidogrelin 2 separate doses may allow more complete absorption and,consequently, additional platelet inhibition compared with 600mg However, the practicability of such an approach as a pretreatmentbefore PCI is limited Nicolas von Beckerath Circulation. 2005;112:2946-2950

  35. What can we reasonableconclude about antiplatelet therapy and PCI? augmentingaspirin with additional antiplatelet therapy reduces myonecrosisafter PCI according to the information currently available,if clopidogrel is selected, the dose should be 600 mg and thedrug should be administered at least 2 hours before PCI for the types of patients evaluated thus far, intravenous GPIIb/IIIa inhibitors appear unnecessary when clopidogrel hasbeen administered if circumstances restrict clopidogrelpretreatment, intravenous GP IIb/IIIa is a reasonable alternative

  36. Thank You

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