Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors?

Tony Gershlick Leicester UKAA 2006 Advisory Board :Speakers Bureau : Meeting sponsorships Eli Lilly :The Medicines Company: BMS : Sanofi No direct financial conflicts of interest

Stable / ACS:Planned /unplanned, Diabetic/ElderlyLesionSafe & Effective Outcome

Pre 1996 stent thrombosis rates 10 - 15%(50% death /AMI ) Since operators improvedstents improvedhigh pressure came and wentRoutine IVUS came and wentantiplatelet therapy introducedroutine stenting became routinenowstent thrombosis rates

4030201001 2 3 % of CD62 positive plateletsDay after interventionPTCA****StentActivation of platelets : stenting v PTCA

MACE in patients treated with antiplatelet v anti-coagulants12 0 4 8warfarin + ASATiclopidine + ASA6.20.5115.61.68.65.72.71 Hall P. et al. Circulation. 1996;93:215-222.2 Schmig A. et al. N Engl J Med. 1996; 334:1084-1089.3 More R. et al. Lancet. 1997;349:146-147.4 Urban P et al. Lancet. 1997; 340:146-147 Abstract. ISAR FANTASTIC STARS MATTIS CLASSICS (n= 517) (n=485) (n=1653) (n=350) (n=1020)

Abciximab in PTCA

Clopidogrel : Is it enough? Do we still need GP IIbIIIa? {Anti-thrombins?}

When start How much Which patients How longWhat trying to prevent

Effect of Timing of Loading Dose on MACE at 30d

0.40.60.81.01.2Hazard ratio (95% CI)

3 to

Clopidogrel Loading Dose and Clinical Outcome Patti Circulation 2005;111:2099-2106N=255 300mg/600 mg 4-8 hours pre

Clopidogrel LoadingKastrati et al Circulation 2004;110:1916-19

Overall Long-Term Results0.150.100.050.00100200300400Days of follow-up12.6%8.8%31% RRRP = 0.002 N = 2658Clopidogrel+ ASA*Placebo+ ASA*Cumulative Hazard RateComposite of CV death or MI from randomization to end of follow-upPCI-CURE

Clopidogrel in PCILoading dose of 600mg - > 6 hours pre ACS Continue maintenance dose for 12 monthsTop up to 600 mg ?? BMS 1 month

Clopidogrel Resistance in AMIMatetzky et al. Circulaion 2004;109:3171-75

Clopidogrel Resistance in non Emergent PCIHigh ex vivo platelet reactivity to ADP and rapid generation of fibrin are risk factors for ischaemic events in 6 months post PCI. 1 MACE rates varied between 10% to 32% at 6 months according to quartiles defined by platelet aggregation assays

Gurbel et al JACC 2005;46:1820-26

Lau et al. Circulation 2004;109:166-71Clopidogrel Response is Variable

Contribution of Hepatic P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance

Lau et al. Circulation 2004;109:166-71Clopidogrel response is variableIn contrast, rifampin, a CYP3A4 inducer, increased clopidogrel efficacy.

Thrombosis Rates Accordingto Selected Patient Characteristics*Antiplatelet Therapy discPrior Brachy Renal failureBifurcations ULMDiabetesUA* Premature discontinuation%

Outstanding Issues for Oral Antiplatelet Therapy Post PCIHow long to continue dual antiplatelet therapy post PCI with DES.? > 12 months

Need to screen for Plavix resistance ?

Use increased maintenance doses of plavix in some cases ?

How can we maximise drug compliance ?

ASA Resistance Important NOT ASA alone 3-6 /12Never - NO MEDICATION Dual till when ?AHG Website for Stent thrombosis

Limitations of ClopidogrelVariable response - ResistanceTime of onset of actionIrreversible

GP IIbIIIa Inhibitors Prasugrel (Lilly/Sankyo)Rapid onsetHigher and more consistent level of platelet inhibitionTRITON TIMI 38 trial (Prasugrel vs Clopidogrel PCI in ACS)

0246810121416EPICEPILOGCAPTURE%Death or non-fatal MI at 30 daysPlaceboAbciximab12.88.311.75.215.911.3p=0.008p

Across Study Comparism PRISM/CUREClopidogrel is no alternative for the high risk ACS patient

Are both necessary Is there sufficient effect with clopidogrel (upfront) GP IIbIIIa in the era of Clopidogrel pre-treatment

Tc

EPISTENT by ticlopidine pretreatment

Death, MI and Urgent Reinterventions at 30 days

p=0.012 p

Stone, Circulation 2002;105:2347-54

TARGET

Peri-procedural MI rates in pts with ACS

% of patients

P = 0.01

P = 0.10

Enrolled in total: 2116No Pre Rx: n=1063Pre Rx: n=1053

15% of pts not included in results, because they didnt undergo PCI.One press release mentioned n=917 and n= 903 resp. Another press release mentioned n=851 and n=893.Took the 917 and 903 from theHeart.org.

JACC 2004 Jan 21;43(2):162-8. Dalby et al , 48% inhibition Clopidogrel 80% GP IIbIIIa (p

Who doesnt need GP IIbIIIa ?Clopidogrel is a potent anti-platelet agent

Efficacy of Abciximab is compellingNumber of patients who undergoing PCI is largeAgents are expensive and carry some safety risksOptimal would be to select patients who benefit most

Dilemma

PPT format(Power Point 4.0)

Which Patients should be Treated??

ISAR-REACTAbciximab in Low to Intermediate Risk PCI after Plavix loadingKastrati et al NEJM 2004;350:232-38.

ISAR-REACTSafety% of patientsMajor TIMI bleedMinor TIMI bleedThrombocytopeniaTransfusionsP=0.37P=0.38P=0.002P=0.007Kastrati A, et.al. NEJM 2004; 350 (3): 232-238.

ISAR-REACTPrimary Endpoint at 30 DaysComposite of Death, MI or Urgent TVR% of PatientsCompositeMIUrgent TVRDeath/MIDeathP=NS for allKastrati A, et.al. NEJM 2004; 350 (3): 232-238.

ISAR-REACTPrimary Endpoint at 30 DaysIncidence and Relative Risk of the Primary EndpointKastrati A, et.al. NEJM 2004; 350 (3): 232-238.

1 Year Mortality in Diabetics Following PCI with and without AbciximabEnhanced Survival Benefit of Abciximab in DiabeticsEPIC, EPILOG, and EPISTENT - Meta-Analysis03012015021027030036001234Days of RandomizationDeath (%)566090180240330 2.0%p = 0.0314.52.5JACC 2000; 35:922-28PlaceboAbciximabn = 574n = 888Diabetics

*AMI

30 Day Composite Endpoint - Death, MI, or Urgent TVR

RAPPORT Circ 1998; 98: 735; ISAR-2 JACC 2000; 35:915; ADMIRAL Montalescot NEJM 2001;344:1895, CADILLAC Stone TCT 2000

51%p=0.03

53%p=0.04

59%p=0.010

RAPPORT, ISAR 2, ADMIRAL, CADILLAC

30%p=0.04

*in hospital*

6 Month Mortality in Primary PCI Trials

RAPPORT Circ 1998; 98: 735; ISAR-2 JACC 2000; 35:915; ADMIRAL Montalescot NEJM 2001;344:1895;, CADILLAC Stone TCT 2000

RAPPORT, ISAR 2, ADMIRAL, CADILLAC, CADILLAC Registry

Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel

AMI as early as possible Inadequate stent deploymentEvidence I.C thrombus COMPLEX PCIClopidogrel resistance

DiabeticsACSStenting as perfect as possible reduces complications

Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel

AMI as early as possible Inadequate stent deploymentEvidence I.C thrombus COMPLEX PCIClopidogrel resistance

Diabetics - BVR Which studies ?

ISAR-REACT 2Abciximab in High {ACS} Risk PCI after Clopidogrel loadingPatients with ACS (Trop+ or ST-depression) undergoing PCI (STEMI excluded). Primary endpoint: composite of death, MI, urg. Revasc within 30 days. Ones to watch for at ACC

ACUITY Design

HORIZONS3 400 STEMI

ASA 300mgClopidogrel 300-600mg

UH BivalirudinGP IIb/IIIa {bail-out IIbIIIa} Cath Lab

TAXUS BMS CABG 3 : 1[ 2250 : 750]1,6 moThe independently adjudicated 30-day rates of a. Primary - The composite of major adverse ischaemic events and major bleeding (net clinical benefit) b. Major Secondary - Major adverse ischaemic events (death, reinfarction, stent thrombosis, disabling stroke or ischaemic target vessel revascularisation) c. Major secondary - Major bleeding

Summary & Conclusions Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors?YES

Prasugrel Phase 3 Stent Trial DesignClopidogrel 75 mg/day + ASAPrasugrel 10 mg/day + ASALast pt followed for 6 m (med =12m, max =15 m)20 EPs (30, 90 d): CVD/MI/CVA; CVD/MI/uTVRClopidogrel300 mg LD / 75 mg MD+ ASAPrasugrel60 mg LD/ 10 mg MD+ ASA Mod - Hi Risk UA/NSTEMISTEMIAntithrombinGP IIb/IIIa at MD discretion10 Endpoint(end of FU): CVD/MI/CVA 20 EP (end of FU): CVD/MI/CVA/Hosp for Rec IschStratified Randomization:UA/NSTEMI vs STEMIPlanned PCI for ACS

Heart Care Centers of Illinois

Clinical Outcomes, Comparison to CADILLAC* 2 Strokes Post CABG*

JUMBO -TIMI 26 Study DesignStudy Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIaMaintenance Rx for 30 daysDouble-blind, Double DummyElective or Urgent PCI w stentASA 325 mg900 patientsParallel RandomizationPrasugrelLoading Dose 40 mgMaint. Dose 7.5 mgN=200PrasugrelLoading Dose 60 mgMaint. Dose 10 mgN=200ClopidogrelLoading Dose 300 mgMaint. Dose 75 mgN=2501o endpoint: Significant (non-CABG) bleeding through 30 d

2o endpoints:Major bleeding (non-CABG) through 30 dCV MACE through 30 dComponent clinical endpointsPrasugrelLoading Dose 60 mgMaint. Dose 15 mgN=250

Clinical Target Vessel Thrombosis

P= NS6/2544/6502/1991/2001/251Target Vessel Revasc or Documented Total OcclusionR/NRR=0.25 [0.1, 0.9]P = 0.03Prasugrel LD/MDTreatment Group

JUMBO -TIMI 26 Study DesignStudy Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIaMaintenance Rx for 30 daysDouble-blind, Double DummyElective or Urgent PCI w stentASA 325 mg900 patientsParallel RandomizationPrasugrelLoading Dose 40 mgMaint. Dose 7.5 mgN=200PrasugrelLoading Dose 60 mgMaint. Dose 10 mgN=200ClopidogrelLoading Dose 300 mgMaint. Dose 75 mgN=2501o endpoint: Significant (non-CABG) bleeding through 30 d

2o endpoints:Major bleeding (non-CABG) through 30 dCV MACE through 30 dComponent clinical endpointsPrasugrelLoading Dose 60 mgMaint. Dose 15 mgN=250

Clinical Target Vessel Thrombosis

P= NS6/2544/6502/1991/2001/251Target Vessel Revasc or Documented Total OcclusionR/NRR=0.25 [0.1, 0.9]P = 0.03Prasugrel LD/MDTreatment Group

How important are the enzyme leaks ?represent micro infarcts unimportant < x3 adverse prognosis markers only any rise is dangerous small percent avoid at all cost surgeons are worse unpredictable interventionist knows immediacy not good select patients (?) everyone should have GP IIb/IIIa RB only a (small) percent patients +?

The CAPTURE trial of ReoPro 18 hrs before PCI

ISAR-2 - Outcomes through 30 DaysPrimary PCI for AMI

ADMIRAL - Angiographic AnalysisTIMI 3 Flow Prior To PCITIMI 3 Flow Post PCI5.410.816.825.8020406080100% of Patientsp = 0.01p = 0.006TIMI 3 FlowTIMI 2/3 FlowNEJM 2001; 341:1895-190386.792.682.895.195.994.3p = 0.04p = 0.33p = 0.04ImmediatelyPost-PCI24 hourPost-PCI6 monthPost-PCIAbciximab (n = 101)Placebo (n = 92)Primary PCI for AMI

ADMIRAL - 1 Endpoint through 6 MonthsDeath, re-MI or Urgent TVRPrimary PCI for AMI

ADMIRAL - Place/Time of AdministrationPrimary PCI for AMI

PCI:Which Antiplatelet Therapy ?Dr. Niall Mulvihill

St. Jamess Hospital and Trinity College, Dublin

Platelet Adhesion and ActivationAggregation of platelets into a thrombus PlateletsEndothelial cells

Subendothelial spacePlatelets adhering to subendothelial spacePlatelet thrombusNormal platelets in flowing bloodPlatelets adhering to damaged endothelium and undergoing activation

Platelet Activation PathwaysPlatelet AggregationFibrinogenFibrinogen Binding SiteADPThrombinPlateletHerbert. Exp Opin Invest Drugs 1994;3:449-455.

Aspirin in PCI

Antithrombotic Trialists Collaboration: Reduction in Risk of Vascular Deaths Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.*Coronary artery disease, peripheral arterial disease, high risk of embolism and other high risk conditions (including hemodialysis, diabetes mellitus, carotid disease)

ASA Resistance in PCIChen et al. J Amer Coll Cardiol 2004;43:1122-6 ASA/clopidogrel (n=151), 19.2% ASA resistant ASA resistant ASA sensitive

Aspirin ResistanceDo patients who suffer a thrombotic event while taking aspirin exhibit aspirin resistance ?Reports of aspirin resistance vary from 5-40%Aspirin inhibits COX1 - but resistance assays do not measure activity of this enzymeMost resistance assays are strongly affected by pathways of platelet activation other than COX1

Aspirin ResistanceRecent report suggests aspirin (325mg) resistance is

ADP Receptor Antagonists in PCI

Antithrombotic effects after 3 hours of high-dose clopidogrel

5432100102030405060Platelet Deposition (x109)TimeControls (6)2mg/kg Clopidogrel20mg/kg Clopidogrel

Efficacy of Aspirin and ADP-Receptor Antagonist Combinations in Reducing Death, MI and Revascularization in Stent Patients1 Hall P. et al. Circulation. 1996;93:215-222.2 Schmig A. et al. N Engl J Med. 1996; 334:1084-1089.3 More R. et al. Lancet. 1997;349:146-147.4 Urban P et al. Lancet. 1997; 340:146-147 Abstract.ASA + TICASA onlyASA + Warfarin2.46.23.63.90.61.60.803.05.08.012STARS (1997)3ISAR (1997)2MATTIS (1997)4Hall (1996)1N = 226N = 350N = 517N = 165211.05.6Cumulative Event Rate (%)

Advantages of Clopidogrel over TiclopidineTiclopidine Neutropenia, ThrombocytopeniaTTP, HUSTwice a day

PCI-CUREPCIPLACEBO + ASA *CLOPIDOGREL+ ASA *30 days post PCIEnd of follow-upUp to 12 monthsafter randomizationOpen-label thienopyridinePretreatmentOpen-label thienopyridinePretreatmentN = 2,658 patients undergoing PCI* In combination with standard therapyN = 1345N = 1313CUREPCI-CURERPCI-CURE

CREDOPCIPLACEBO + ASA *CLOPIDOGREL300 mg3-24h pre-PCI+ ASA *30 days post PCIEnd of follow-upUp to 12 monthsafter randomizationClopidogrel 75 QDPretreatmentClopidogrel 75 QDPretreatmentN = 2,116 patients undergoing elective PCI* In combination with standard therapyN = 1345N = 1313R

CREDO Study: Long-Term (1 Year) Benefits of Clopidogrel in PCIMI, Stroke, or CV Death* Plus ASA and other standard therapies Combined Endpoint Occurrence (%)Months From Randomization27% RRRP=0.02Placebo*Clopidogrel*0510158.5%11.5%036912Steinhubl S, et al. JAMA. 2002; 288:2411-20

Time after Administration (hours)04244810060200Muller I et al. Heart. 2001;85:92-3Ticlopidine 2x 500mg, then 250mg BIDClopidogrel 300mg, then 75mg QDClopidogrel 600mg, then 75mg BID% of 20M ADP-induced aggregation

Clopidogrel Loading Dose

Addressing Clopidogrel ResistanceHigher loading doseHigher maintenance doseAdditional antiplatelet agents? Adding cytochrome P450 inducers

Time after Administration (hours)04244810060200Muller I et al. Heart. 2001;85:92-3Ticlopidine 2x 500mg, then 250mg BIDClopidogrel 300mg, then 75mg QDClopidogrel 600mg, then 75mg BID% of 20M ADP-induced aggregation

Clopidogrel Loading Dose

Clopidogrel Loading and Clincal OutcomePatti et al Circulation 2005;111:2099-2106

Triple Antiplatelet TherapyCilostazol is a phosphodiesterase III inhibitor with similar antiplatelet effects to clopidogrel

Addition of cilostazol to aspirin and clopidogrel provided additional supression of P-selectin (marker of platelet activation)Lee et al JACC 2005;46:1833-37

Dual versus Triple TherapyLee et al JACC 2005;46:1833-37

Dual (n=1,597)Triple (n=1,415)P-valueStent Thrombosis0.5%0.1%0.024Acute Stent thrombosis0.2%0%NsSubacute stent thrombosis0.3%0.1%nsPrimary EP: Death, MI or ST0.8%0.3%0.085

Prasugrel Phase 3 Stent Trial DesignClopidogrel 75 mg/day + ASAPrasugrel 10 mg/day + ASALast pt followed for 6 m (med =12m, max =15 m)20 EPs (30, 90 d): CVD/MI/CVA; CVD/MI/uTVRClopidogrel300 mg LD / 75 mg MD+ ASAPrasugrel60 mg LD/ 10 mg MD+ ASA Mod - Hi Risk UA/NSTEMISTEMIAntithrombinGP IIb/IIIa at MD discretion10 Endpoint(end of FU): CVD/MI/CVA 20 EP (end of FU): CVD/MI/CVA/Hosp for Rec IschStratified Randomization:UA/NSTEMI vs STEMIPlanned PCI for ACS

Clopidogrel Nonresponders: A Comparison With Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Receptor Antagonist

Outstanding Issues for Oral Antiplatelet Therapy Post PCIDo we need to consider triple antiplatelet therapy +/- higher maintenance dose of clopidogrel for high risk PCI ?

AMI LM stenting Multivessel stenting

GP IIb/IIIa Receptor Antagonists in PCI

Platelet Activation PathwaysPlatelet AggregationFibrinogenFibrinogen Binding SiteADPThrombinPlateletHerbert. Exp Opin Invest Drugs 1994;3:449-455.

Data on file, Centocor

Is Reopro necessary in Elective PCI when patients are appropriately loaded with Clopidogrel ?

TARGET: Clopidogrel pre-treatment

Chan et al. J Amer Coll Cardiol 2003; 42:1196Clopidogrel pre-treatment: RR = 0.61 (0.44-0.84) P=0.003

ISAR-REACTAbciximab in Low to Intermediate Risk PCI after Plavix loadingKastrati et al NEJM 2004;350:232-38.

ISAR-REACTAbciximab in Low to Intermediate Risk PCI after Plavix loadingKastrati et al NEJM 2004;350:232-38.

ISAR-REACTAbciximab in Low to Intermediate Risk PCI after Plavix loadingKastrati et al NEJM 2004;350:232-38.

Low to Intermediate Risk PCIAspirin 300mg bolus and 75mg daily maintenanceClopidogrel 600mg bolusClopidogrel 75mg maintenance x 12 months

Moderate to High Risk PCIAspirin 300mg bolus and 75mg daily maintenanceClopidogrel 600mg bolusClopidogrel 75mg (150mg) maintenance x 12 monthsReopro bolus and infusion periprocedure

Future of Antiplatelet therapy for PCINew ADP receptor antagonistsHigher maintenance doses of ADP receptor antagonists in high risk casesTriple antiplatelet therapy

When investigating the effect of pre-treatment with a 300 mg loading dose of clopidogrel, the investigators looked at the time when the loading dose was administered, to establish whether this could have an impact on the outcome.The mean duration between study drug loading dose and PCI was 9.8 hours. 51% of patients (n=893) received the loading dose between 3 and 6 hours before the PCI; 49% (n=851) received the loading dose between 6 and 24 hours prior to the intervention.In those patients who received the loading dose immediately prior to the PCI (under six hours), no benefit of clopidogrel pre-treatment was found.However, in those patients in whom pretreatment was initiated 6 hours prior to PCI, those randomized to clopidogrel experienced a 38.6% relative risk reduction in the combined endpoint of death, MI, and UTVR at 28 days that reached borderline statistical significance (95% CI, -1.6 62.9, p=0.05).These data suggest that when a 300mg loading dose of clopidogrel is administered more than six hours prior to a PCI, it offers benefit in the reduction of subsequent ischemic events.

Reference:Steinhubl S, Berger P, Tift Mann III J et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411-2420.;

For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a 31% RRR (8.8% clopidogrel vs. 12.6% placebo, P = 0.002).The curves diverged early and continued to separate over the course of 12 months. This end point included events that were prevented prior to PCI, in addition to those following the procedure.There were consistent reductions in MI or cardiovascular death in almost every subgroup examinedThe incidence of stent thrombosis according to selected patient characteristics was 29% in pts with premature antiplatelet therapy discontinuation, 8.7% in prior brachytherapy at the target vessel, 5.5% with renal failure, 3.5% in bifurcations, 3.2% in unprotected left main treated, 2.6% in diabetes, and 1.3% in unstable angina

Severe : Hemodynamic compromise or IC BleedModerate: TransfusionSlide 5Under normal conditions, platelets neither adhere to, nor are activated by the vascular endothelium. However, damage to the endothelium or disruption of plaque exposes the flowing blood to a variety of thrombogenic elements. Circulating platelets bear receptors that bind to components of the subendothelial matrix and plaque, including collagen, fibronectin, and von Willebrand factor, on contact. During platelet activation, cell surface receptors for fibrinogen are activated. Fibrinogen may form multiple bonds with these receptors, causing platelets to aggregate into a thrombus via fibrinogen bridges.

Slide 7Platelets bear receptors for several activating mediators, including thromboxane A2, thrombin, ADP, and several others. These mediators activate platelets through a number of internal responses, ultimately resulting in activation of the fibrinogen binding site, namely the Gp IIb/IIIa receptor. Binding of fibrinogen by the activated Gp IIb/IIIa receptor results in platelet aggregation and thrombus formation.11. Herbert JM. Clopidogrel and antiplatelet therapy. Exp Opin Invest Drugs 1994;3:449-455.

1This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group).Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (> 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months).Medications at time of randomization may include heparin or lowmolecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physicians discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST-segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group).Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (> 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months).Medications at time of randomization may include heparin or lowmolecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physicians discretion.. The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI. The CREDO results demonstrate the benefits of long-term (1 year) administration of clopidogrel plus ASA and other standard therapies in patients undergoing PCI, with or without stent. For the entire study population, long-term clopidogrel treatment was associated with a 27% reduction in the relative risk of the combined endpoint of death, MI, or stroke at 1 year. This result was statistically significant (8.5% clopidogrel vs. 11.5% placebo, 95% CI, 3.9-44.4, P=0.02).

Steinhubl S, Berger P, Tift Mann III J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. JAMA. 2002;288:2411-2420.Effect of high loading dose of clopidogrel on ADP induced platelet aggregation.

Patients were randomised into 3 treatment arms: ticlopidine 2500mg plus 2250mg daily thereafter (n=10)clopidogrel 300mg loading dose plus 175mg daily (n=10)clopidogrel 600mg loading dose plus 275mg daily thereafter (n=10).

All patients received aspirin 2100mg/day concomitantly. Platelet aggregation was studied after stimulation with ADP (20mol/l) by light transmittance aggregometry in citrated platelet rich plasma.

*Significant difference (p