The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization...

The Evolving Science and Controversial Landscape ofThe Evolving Science and Controversial Landscape of

Antiplatelet Therapy in theAntiplatelet Therapy in theCatheterization LaboratoryCatheterization Laboratory

Mechanisms Mechanisms ●● Mortality Mortality ●● Therapeutics Therapeutics

PROGRAM CO-CHAIRMANPROGRAM CO-CHAIRMANDeepak L. Bhatt, MD, MPH, FACC, Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIFAHA, FSCAIChief of Cardiology, VA Boston Chief of Cardiology, VA Boston Healthcare System | Director, Integrated Healthcare System | Director, Integrated Interventional Cardiovascular Program, Interventional Cardiovascular Program, Brigham and Women’s Hospital and the Brigham and Women’s Hospital and the VA Boston Healthcare System | Senior VA Boston Healthcare System | Senior Investigator, TIMI Group | Harvard Investigator, TIMI Group | Harvard Medical School | Boston, MassachusettsMedical School | Boston, Massachusetts

PROGRAM CO-CHAIRMANPROGRAM CO-CHAIRMANShamir Mehta, MD, MSc, Shamir Mehta, MD, MSc,

FACC, FRCPCFACC, FRCPCDirector, Interventional Cardiology | Director, Interventional Cardiology |

Hamilton Health Sciences | Hamilton Health Sciences | Associate Professor | McMaster Associate Professor | McMaster

University | Hamilton, Ontario, University | Hamilton, Ontario, CanadaCanada

Welcome and Program OverviewWelcome and Program Overview

CME-accredited symposium CME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC

Mission statement: Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes: Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI: COI: Full faculty disclosures provided in syllabus and at the Full faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program

Program Educational ObjectivesProgram Educational ObjectivesAs a result of this session, participants will be able to:As a result of this session, participants will be able to: ► Optimize anti-ischemic efficacy, while reducing bleeding related Optimize anti-ischemic efficacy, while reducing bleeding related

complications and adverse events in high risk, complex patients complications and adverse events in high risk, complex patients requiring antiplatelet therapy in the setting of PCIrequiring antiplatelet therapy in the setting of PCI

► Compare anti-ischemic effects, mortality data, bleeding Compare anti-ischemic effects, mortality data, bleeding complications, and drug-drug interactions among indicated complications, and drug-drug interactions among indicated antiplatelet agents in the setting of cardiac catheterizationantiplatelet agents in the setting of cardiac catheterization

► Analyze, compare, and assess the clinical implications of recent Analyze, compare, and assess the clinical implications of recent landmark trials in antiplatelet therapy among them, the CURRENT-landmark trials in antiplatelet therapy among them, the CURRENT-OASIS 7, PLATO, and TRITON-TIMI 38 trials; and how to make risk-OASIS 7, PLATO, and TRITON-TIMI 38 trials; and how to make risk-directed decisions in the setting of PCIdirected decisions in the setting of PCI

► List the safety, efficacy, and mortality reducing implications of new List the safety, efficacy, and mortality reducing implications of new dosing strategies for established oral antiplatelet therapies and their dosing strategies for established oral antiplatelet therapies and their implications for PCI-based management of high risk ACS and STEMIimplications for PCI-based management of high risk ACS and STEMI

Program FacultyProgram Faculty

Deepak L. Bhatt, MD, MPH, Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIFACC, FAHA, FSCAIProgram Co-ChairmanProgram Co-ChairmanChief of CardiologyChief of CardiologyVA Boston Healthcare SystemVA Boston Healthcare SystemDirector, Integrated Interventional Director, Integrated Interventional Cardiovascular Program, Cardiovascular Program, Brigham and Women’s Hospital and the VA Brigham and Women’s Hospital and the VA Boston Healthcare SystemBoston Healthcare SystemSenior Investigator, TIMI GroupSenior Investigator, TIMI GroupHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts Sunil V. Rao, MDSunil V. Rao, MDDirector of Cardiac Catheterization Director of Cardiac Catheterization LaboratoriesLaboratoriesVeterans Administration Medical CenterVeterans Administration Medical CenterDivision of Cardiovascular MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke University Medical CenterDurham, North CarolinaDurham, North Carolina

Shamir Mehta, MD, MSc, FACC, FRCPCShamir Mehta, MD, MSc, FACC, FRCPC(Program Co-Chairman)(Program Co-Chairman)

Director, Interventional CardiologyDirector, Interventional CardiologyHamilton Health SciencesHamilton Health Sciences

Associate Professor | McMaster UniversityAssociate Professor | McMaster University Hamilton, OntarioHamilton, Ontario

Canada Canada

Harold L. Dauerman, MD, FACCHarold L. Dauerman, MD, FACCDirector, Cardiovascular Catheterization Director, Cardiovascular Catheterization

Laboratories Laboratories Professor of Medicine Professor of Medicine

University of Vermont Medical CenterUniversity of Vermont Medical CenterFletcher Allen Health Care Fletcher Allen Health Care

Burlington, VermontBurlington, Vermont

Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

Shamir Mehta, MD, MSc, FACC, FRCPCShamir Mehta, MD, MSc, FACC, FRCPCGrant/Research Support: Bristol-Myers Squibb Company, GlaxoSmithKline, sanofi-aventisConsultant: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventisHonorarium: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventis

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIConsultant: Consultant: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Takeda, The Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Takeda, The Medicines Company, Vertex. Medicines Company, Vertex.

Principal Investigator for several potentially related studies. His institution has received Principal Investigator for several potentially related studies. His institution has received funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, The funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, The Medicines Company. Medicines Company.

This presentation discusses off-label and/or investigational uses of various drugs and This presentation discusses off-label and/or investigational uses of various drugs and devicesdevices

Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

Harold L. Dauerman, MD, FACCHarold L. Dauerman, MD, FACCCurrent Research Grants: Medtronic, Abbott Vascular, Boston ScientificCurrent Advisory Board or Consulting: BMS, The Medicines Company, St. Jude Medical, Abbott Vascular

Sunil V. Rao, MDSunil V. Rao, MDConsultant, Honoraria: Consultant, Honoraria: Sanofi-Aventis/BMS, The Medicines Company, Terumo Sanofi-Aventis/BMS, The Medicines Company, Terumo Corporation, Astra Zeneca, Eli Lilly/Daiichi-SankyoCorporation, Astra Zeneca, Eli Lilly/Daiichi-SankyoResearch Funding: Research Funding: Cordis Corporation, Momenta Pharmaceuticals, Portola Cordis Corporation, Momenta Pharmaceuticals, Portola PharmaceuticalsPharmaceuticalsOff-label uses: Off-label uses: 600 mg dose of Clopidogrel 600 mg dose of Clopidogrel

Antiplatelet Therapy in PCI: Focus on Antiplatelet Therapy in PCI: Focus on Addressing the Triple End Points of Addressing the Triple End Points of

Thrombosis, Bleeding, and Mortality—Thrombosis, Bleeding, and Mortality—Connecting Evidence Across Recent Landmark Connecting Evidence Across Recent Landmark

StudiesStudies

Where Do New Trials, New Potencies, and New Dosing Strategies Take Us? Where Do New Trials, New Potencies, and New Dosing Strategies Take Us? And How Should They Direct Our Care in the Cardiac Catheterization And How Should They Direct Our Care in the Cardiac Catheterization

Laboratory? Moving into a New Era of Interventional CareLaboratory? Moving into a New Era of Interventional Care

Shamir Mehta, MD, MSc, FACC, FRCPCShamir Mehta, MD, MSc, FACC, FRCPCDirector, Interventional CardiologyDirector, Interventional Cardiology

Hamilton Health SciencesHamilton Health SciencesAssociate Professor Associate Professor McMaster University McMaster University

Hamilton, Ontario, CanadaHamilton, Ontario, Canada

CURRENT OASIS 7: A 2X2 Factorial CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Randomized Trial of Optimal Clopidogrel and

Aspirin Dosing in Patients with ACS Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Undergoing an Early Invasive Strategy with

Intent For PCIIntent For PCI

CURRENT OASIS 7: A 2X2 Factorial CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Randomized Trial of Optimal Clopidogrel and

Aspirin Dosing in Patients with ACS Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Undergoing an Early Invasive Strategy with

Intent For PCIIntent For PCI

OASIS-7

Shamir R. Mehta on behalf of the CURRENT InvestigatorsShamir R. Mehta on behalf of the CURRENT InvestigatorsShamir R. Mehta on behalf of the CURRENT InvestigatorsShamir R. Mehta on behalf of the CURRENT Investigators

Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts. University and the trial was overseen by an international steering committee of experts.

Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts. University and the trial was overseen by an international steering committee of experts.

BackgroundBackground

ClopidogrelClopidogrel► Clopidogrel 300 mg followed by 75 mg daily reduces Clopidogrel 300 mg followed by 75 mg daily reduces

major CV events across the spectrum of ACS and PCImajor CV events across the spectrum of ACS and PCI

► Recent data suggest that Recent data suggest that doublingdoubling the loading and the loading and maintenance doses of clopidogrel results in a higher and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effectmore rapid antiplatelet effect

AspirinAspirin► Dose of ASA varies between Europe and North AmericaDose of ASA varies between Europe and North America

► No large-scale RCT’s have compared high (300-325 mg) No large-scale RCT’s have compared high (300-325 mg) versus low (75-100) dose aspirin in patients with ACS versus low (75-100) dose aspirin in patients with ACS undergoing PCIundergoing PCI

Relative Risk Relative Risk ReductionReduction

PCIPCI No PCINo PCI

CURE: CURE: Clopidogrel 300/75 mg v Placebo Clopidogrel 300/75 mg v Placebo (CVD/MI)(CVD/MI) 30%30%11 19%19%22

STEMI: STEMI: Clopidogrel 300/75 mg v Placebo Clopidogrel 300/75 mg v Placebo (CVD/MI)(CVD/MI) 46%46%33 9%9%44

TRITON: TRITON: Prasugrel v clopidogrel 300/75mg Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)(CVD/MI/Stroke) 19%19%55 Not Not

evaluatedevaluated

Benefits of Antiplatelet Therapy in ACS are Greater in Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCIPatients Undergoing PCI

1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.2. Fox KAA, et al. Circulation 2004;110:1202-82. Fox KAA, et al. Circulation 2004;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.4. Chen ZM Lancet 2005;366:1607-214. Chen ZM Lancet 2005;366:1607-215. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

Study Design, Flow and ComplianceStudy Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<72 h) Invasive Management with intended PCI

Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<72 h) Invasive Management with intended PCI


No Sig. CAD 3,616 CABG 1,809

Clopidogrel in 1Clopidogrel in 1stst 7d 7d 7 d 7 d 2 d 2 d 7d7d7d (median)7d (median)

Complete Complete Follow-up Follow-up

99.8%99.8%

Complete Complete Follow-up Follow-up

99.8%99.8%

Compliance:Compliance:Compliance:Compliance:

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<72 h) Invasive Management with intended PCI


Randomized to receive (2 X 2 factorial):Randomized to receive (2 X 2 factorial):CLOPIDOGREL: CLOPIDOGREL: Double-doseDouble-dose (600 mg then150 mg/d x 7d then 75 mg/d) (600 mg then150 mg/d x 7d then 75 mg/d) vsvs Standard Standard

dosedose (300 mg then 75 mg/d)(300 mg then 75 mg/d)ASA: ASA: High DoseHigh Dose (300-325 mg/d) (300-325 mg/d) vs vs Low doseLow dose (75-100 mg/d)(75-100 mg/d)

PCI 17,232(70%)

No PCI 7,855 (30%)

Angio 24,769 (99%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Efficacy OutcomesEfficacy Outcomes:: CV Death, MI or stroke at day 30CV Death, MI or stroke at day 30Stent Thrombosis at day 30Stent Thrombosis at day 30

Safety OutcomesSafety Outcomes:: Bleeding (CURRENT defined Major/Severe and TIMI Major)Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: Key Subgroup: PCI v No PCIPCI v No PCI

Baseline Characteristics and In Hospital MedsBaseline Characteristics and In Hospital Meds

BaselineBaseline N=25,088N=25,088 Meds After Meds After RandRand N=25,088N=25,088

Age (y)Age (y) 61.461.4 GP IIb/IIIa GP IIb/IIIa inhibitorinhibitor 31.831.8

FemaleFemale 27.4%27.4% StatinStatin 87.287.2

UA/NSTEMIUA/NSTEMI 70.8%70.8% Beta BlockerBeta Blocker 82.582.5

Rand to AngioRand to Angio 3.4 h3.4 h ACE/ARBACE/ARB 75.775.7

STEMISTEMI 29.2%29.2% PPIPPI 40*40*

Rand to AngioRand to Angio 0.5 h0.5 h H2 BlockerH2 Blocker 11.311.3

DiabetesDiabetes 23.423.4

Prior StrokePrior Stroke 4.14.1

Ischemic ECG Ischemic ECG ΔΔ 80.880.8

↑ ↑ BiomarkerBiomarker 4242

Variables equally balanced among the randomized groupsVariables equally balanced among the randomized groups*38.6% low dose ASA v 41.4% high dose ASA and 40% standard *38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose clopidogrel v 40% high dose clopidogreldose clopidogrel v 40% high dose clopidogrel

ASA Dose ComparisonASA Dose ComparisonPrimary Outcome and BleedingPrimary Outcome and Bleeding

ASA ASA

75-100 mg75-100 mg

ASAASA300-325 300-325

mgmgHRHR 95% CI95% CI PP

CV Death/MI/StrokeCV Death/MI/Stroke

PCI (2N=17,232)PCI (2N=17,232) 4.24.2 4.14.1 0.980.98 0.84-1.130.84-1.13 0.760.76

No PCI (2N=7855)No PCI (2N=7855) 4.74.7 4.44.4 0.920.92 0.75-1.140.75-1.14 0.440.44

Overall (2N=25,087)Overall (2N=25,087) 4.44.4 4.24.2 0.960.96 0.85-1.080.85-1.08 0.470.47

Stent ThrombosisStent Thrombosis 2.12.1 1.91.9 0.910.91 0.73-1.120.73-1.12 0.370.37

TIMI Major BleedTIMI Major Bleed 1.031.03 0.970.97 0.940.94 0.73-1.210.73-1.21 0.710.71

CURRENT Major CURRENT Major BleedBleed 2.32.3 2.32.3 0.990.99 0.84-1.170.84-1.17 0.900.90

CURRENT Severe CURRENT Severe BleedBleed 1.71.7 1.71.7 1.001.00 0.83-1.210.83-1.21 1.001.00

No other significant differences between ASA dose groupsNo other significant differences between ASA dose groupsNo other significant differences between ASA dose groupsNo other significant differences between ASA dose groups

GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

Clopidogrel Dose ComparisonClopidogrel Dose Comparison

Two Significant Interactions:Two Significant Interactions:

1.1. PCI v No PCI (P=0.016)PCI v No PCI (P=0.016)

2.2. ASA dose (P=0.043)ASA dose (P=0.043)

DaysDays

Cum

ulat

ive

Haz

ard

Cum

ulat

ive

Haz

ard

0.0

0.0

0.01

0.01

0.02

0.02

0.03

0.03

0.04

0.04

0.05

0.05

00 33 66 99 1212 1515 1818 2121 2424 2727 3030

C Std, A LoC Std, A Lo

C Std, A HiC Std, A Hi

C Double, A LoC Double, A Lo

C Double, A HiC Double, A Hi

Clopidogrel Standard

Clopidogrel Double

HR P P Intn

ASA 300-325 mgASA 300-325 mg 4.6 3.8 0.83 0.0360.043

ASA 75-100 mgASA 75-100 mg 4.2 4.5 1.07 0.43

Clopidogrel: Double vs Standard Dose Primary Outcome

Clopidogrel: Double vs Standard DoseClopidogrel: Double vs Standard DosePrimary Outcome and ComponentsPrimary Outcome and Components

StandardStandard Double Double HRHR 95% CI95% CI PP Intn PIntn P


PCI (2N=17,232)PCI (2N=17,232) 4.54.5 3.93.9 0.850.85 0.74-0.990.74-0.99 0.0360.0360.0160.016

No PCI (2N=7855)No PCI (2N=7855) 4.24.2 4.94.9 1.171.17 0.95-1.440.95-1.44 0.140.14


MIMI

PCI (2N=17,232)PCI (2N=17,232) 2.62.6 2.02.0 0.780.78 0.64-0.950.64-0.95 0.0120.0120.0250.025

No PCI (2N=7855)No PCI (2N=7855) 1.41.4 1.71.7 1.251.25 0.87-1.790.87-1.79 0.230.23


CV DeathCV Death

PCI (2N=17,232)PCI (2N=17,232) 1.91.9 1.91.9 0.960.96 0.77-1.190.77-1.19 0.680.681.01.0

No PCI (2N=7855)No PCI (2N=7855) 2.82.8 2.72.7 0.960.96 0.74-1.260.74-1.26 0.770.77


StrokeStroke

PCI (2N=17,232)PCI (2N=17,232) 0.40.4 0.40.4 0.880.88 0.55-1.410.55-1.41 0.590.590.500.50

No PCI (2N=7855)No PCI (2N=7855) 0.80.8 0.90.9 1.111.11 0.68-1.820.68-1.82 0.670.67


Clopidogrel Double vs Standard DoseClopidogrel Double vs Standard DoseBleeding Overall PopulationBleeding Overall Population

ClopidogrelClopidogrel

StandardStandard

N=12579 N=12579

DoubleDouble

N=12508N=12508

HazardHazard

RatioRatio95% CI95% CI PP

CURRENT MajorCURRENT Major 2.02.0 2.52.5 1.251.25 1.05-1.471.05-1.47 0.010.01

CURRENT SevereCURRENT Severe 1.51.5 1.91.9 1.231.23 1.02-1.491.02-1.49 0.030.03

FatalFatal 0.110.11 0.130.13 1.151.15 0.56-2.350.56-2.35 0.710.71

ICHICH 0.05 0.05 0.030.03 0.670.67 0.19-2.37 0.19-2.37 0.530.53

RBC transfusion RBC transfusion ≥≥ 2U2U 1.761.76 2.212.21 1.261.26 1.06-1.511.06-1.51 0.010.01

CABG-related MajorCABG-related Major 0.90.9 1.01.0 1.101.10 0.85-1.420.85-1.42 0.480.48

DaysDays

Cum

ulat

ive

Haz

ard

Cum

ulat

ive

Haz

ard

0.0

0.0

0.00

40.

004

0.00

80.

008

0.01

20.

012

00 33 66 99 1212 1515 1818 2121 2424 2727 3030

Clopidogrel Standard DoseClopidogrel Standard Dose

Clopidogrel Double DoseClopidogrel Double Dose

42% 42% RRRRRR

HR 0.58HR 0.5895% CI 0.42-0.7995% CI 0.42-0.79

P=0.001P=0.001

Clopidogrel: Double vs Standard DoseClopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio Confirmed)Definite Stent Thrombosis (Angio Confirmed)

Clopidogrel: Double vs Standard DoseClopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI PatientsMajor Efficacy Outcomes in PCI Patients

Day 30

Clopidogrel

StandardN=8684

%

Double N=8548

%

Hazard Ratio

95% CIP

value


DefiniteDefinite 1.21.2 0.70.7 0.580.58 0.42-0.790.42-0.79 0.0010.001

MIMI 2.62.6 2.02.0 0.780.78 0.64-0.950.64-0.95 0.0120.012

MI or stent thrombosisMI or stent thrombosis 3.73.7 3.03.0 0.800.80 0.68-0.940.68-0.94 0.0080.008

CV DeathCV Death 1.91.9 1.91.9 0.960.96 0.77-1.190.77-1.19 0.680.68

StrokeStroke 0.40.4 0.40.4 0.880.88 0.55-1.410.55-1.41 0.590.59

CV Death/MI/StrokeCV Death/MI/Stroke 4.54.5 3.93.9 0.850.85 0.74-0.990.74-0.99 0.0360.036

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Clopidogrel: Double vs Standard Dose Primary Outcome: PCI PatientsPrimary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.85HR 0.8595% CI 0.74-0.9995% CI 0.74-0.99

P=0.036P=0.036

15% RRR15% RRR

CV Death, MI or StrokeCV Death, MI or Stroke

Clopidogrel Double vs Standard DoseClopidogrel Double vs Standard DoseBleeding PCI PopulationBleeding PCI Population


StandardStandard

N= 8684N= 8684

DoubleDouble

N=8548N=8548

HazardHazard


CURRENT MajorCURRENT Major 1.11.1 1.61.6 1.441.44 1.11-1.861.11-1.86 0.0060.006

CURRENT SevereCURRENT Severe 0.80.8 1.11.1 1.391.39 1.02-1.901.02-1.90 0.0340.034

FatalFatal 0.150.15 0.070.07 0.470.47 0.18-1.230.18-1.23 0.1250.125

ICHICH 0.0350.035 0.0460.046 1.351.35 0.30-6.040.30-6.04 0.690.69



0.500.50 1.501.50

OverallOverall

NSTEMI/UA NSTEMI/UA STEMISTEMI

MaleMaleFemale Female

Age <= 65 yrsAge <= 65 yrsAge > 65 yrsAge > 65 yrs

Non-DiabeticNon-DiabeticPrev DiabeticPrev Diabetic

No Inhosp GPIIb/IIIaNo Inhosp GPIIb/IIIaGPIIb in hospGPIIb in hosp

No Prot Pump InhibNo Prot Pump InhibProt Pump InhibProt Pump Inhib

Non-smokerNon-smokerCurrent SmokerCurrent Smoker

ASA LowASA LowASA HighASA High

1723217232

1088610886 63466346

1300913009 42234223

1097510975 62576257

1340013400 38313831

1228812288 49364936

76757675 55575557

1084510845 63806380

86208620 86128612

4.54.5

4.24.25.05.0

4.14.15.85.8

3.03.07.17.1

4.24.25.65.6

3.93.96.06.0

3.83.85.75.7

4.94.93.83.8

4.24.24.84.8

3.93.9

3.63.64.24.2

3.63.64.64.6

2.72.76.06.0

3.63.64.94.9

3.53.54.74.7

3.23.24.24.2

4.64.62.62.6

4.34.33.53.5

0.8050.805

0.4190.419

0.7020.702

0.8360.836

0.4650.465

0.4080.408

0.0450.045

0.0240.024

0.500.50 1.501.50

3.73.7

3.63.64.04.0

3.53.54.64.6

2.92.95.25.2

3.63.64.14.1

3.13.15.25.2

3.13.14.84.8

3.93.93.43.4

3.63.63.83.8

3.03.0

3.13.12.82.8

3.03.03.03.0

2.22.24.44.4

2.82.83.63.6

2.52.54.14.1

2.32.33.33.3

3.53.52.12.1

3.23.22.72.7

0.2480.248

0.1480.148

0.4180.418

0.5670.567

0.8940.894

0.6130.613

0.0500.050

0.1910.191

CV Death, MI or StrokeCV Death, MI or StrokeCV Death, MI or StrokeCV Death, MI or Stroke MI or Stent ThrombosisMI or Stent ThrombosisMI or Stent ThrombosisMI or Stent Thrombosis

Clopidogrel: Double v Standard DoseClopidogrel: Double v Standard DosePCI Cohort SubgroupsPCI Cohort Subgroups

Std %Std %Std %Std % Double %Double %Double %Double % Std %Std %Std %Std % Double %Double %Double %Double %Intxn PIntxn PIntxn PIntxn P Intxn PIntxn PIntxn PIntxn P

Double Dose Double Dose BetterBetter




Std Dose Std Dose BetterBetter




2N2N2N2N


HRHR 95% CI95% CI PP P int’nP int’nStandardStandard DoubleDouble

CV Death/MI/Stroke (Overall)CV Death/MI/Stroke (Overall)

ASA HighASA High 4.64.6 3.83.8 0.830.83 0.70-0.990.70-0.99 0.0360.0360.0430.043

ASA LowASA Low 4.24.2 4.54.5 1.071.07 0.91-1.270.91-1.27 0.420.42

MI/Stent Thrombosis (PCI pts)MI/Stent Thrombosis (PCI pts)

ASA HighASA High 3.83.8 2.72.7 0.710.71 0.56-0.900.56-0.90 0.0050.005 0.190.19

ASA LowASA Low 3.63.6 3.23.2 0.890.89 0.71-1.120.71-1.12 0.320.32

Major Bleed(Overall)Major Bleed(Overall)

ASA HighASA High 2.22.2 2.42.4 1.081.08 0.86-1.370.86-1.37 0.510.510.0990.099

ASA LowASA Low 1.91.9 2.72.7 1.431.43 1.13-1.811.13-1.81 0.0030.003

Clopidogrel: Double vs Standard Dose Clopidogrel: Double vs Standard Dose by ASA Factorialby ASA Factorial

Definite Stent Thrombosis in 4 Groups Definite Stent Thrombosis in 4 Groups (Angiographically Proven)(Angiographically Proven)

Days

Cum

ulat

ive

Haz

ard

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

C Standard, A Low

C Standard, A High

C Double, A Low

C Double, A High

Standard Standard ClopidogrelClopidogrel

Double Double ClopidogrelClopidogrel HRHR PP

PP

IntIntnn

High ASAHigh ASA 1.21.2 0.60.6 0.490.49 0.0030.003

Low ASALow ASA 1.21.2 0.80.8 0.60.6 0.0580.058 0.350.35

ConclusionsConclusionsClopidogrel Dose ComparisonClopidogrel Dose Comparison

1.1. Double-dose clopidogrel significantly reduced stent Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or thrombosis and major CV events (CV death, MI or stroke) in PCI.stroke) in PCI.

2.2. In patients not undergoing PCI, double dose clopidogrel In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for had no significant CAD or stopped study drug early for CABG).CABG).

3.3. There was a modest excess in CURRENT-defined There was a modest excess in CURRENT-defined major bleeds but no difference in ICH, fatal bleeds or major bleeds but no difference in ICH, fatal bleeds or CABG-related bleeds.CABG-related bleeds.

ConclusionsConclusionsASA Dose ComparisonASA Dose Comparison

►No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

Clinical ImplicationsClinical Implications

1.1. For every 1,000 patients with ACS receiving For every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days PCI, using double-dose clopidogrel for 7 days instead of standard dose will instead of standard dose will prevent an prevent an additional 6 MI’s and 7 stent thromboses additional 6 MI’s and 7 stent thromboses with with an excess of 3 severe bleeds and an excess of 3 severe bleeds and no increase no increase in fatal, ICH, or CABG-related bleedsin fatal, ICH, or CABG-related bleeds..

2.2. Patients not undergoing PCI should continue Patients not undergoing PCI should continue to use the standard dose regimen of to use the standard dose regimen of clopidogrel.clopidogrel.

CURRENT-PCI findings How to translate into practice?

OPTION 2OPTION 2

PCIPCI

Double dose Double dose (150 mg/day)(150 mg/day)for 6 days for 6 days

thenthen75 mg/day75 mg/day

No PCINo PCI

75 mg/day75 mg/day

ACSACS(UA/NSTEMI or (UA/NSTEMI or

STEMI)STEMI)600 mg load before600 mg load before

AngiographyAngiography

ACSACS(UA/NSTEMI or (UA/NSTEMI or

STEMI)STEMI)

OPTION 1OPTION 1

300 mg load before 300 mg load before AngiographyAngiography

PCIPCI

+ 300 mg load+ 300 mg load

Double dose Double dose (150 mg/day)(150 mg/day)for 6 days for 6 days

thenthen75 mg/day75 mg/day

No PCINo PCI

No additional No additional loadload

75 mg/day75 mg/day

Clopidogrel and Proton Pump Inhibitors Clopidogrel and Proton Pump Inhibitors – Is There an Interaction?– Is There an Interaction?

Deepak L. Bhatt MD, MPH, FACC, FAHADeepak L. Bhatt MD, MPH, FACC, FAHAChief of Cardiology, VA Boston Healthcare SystemChief of Cardiology, VA Boston Healthcare System

Director, Integrated Interventional Cardiovascular Program at Brigham and Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare SystemWomen’s Hospital and the VA Boston Healthcare System

Senior Investigator, TIMI Study GroupSenior Investigator, TIMI Study GroupHarvard Medical SchoolHarvard Medical School

ADP ReceptorsADP Receptors

Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.

CREDO: Long-Term (1 Year) Benefits of CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI PatientsClopidogrel in PCI Patients

MI, stroke, or death – ITT populationMI, stroke, or death – ITT population

* Plus ASA and other standard therapies.* Plus ASA and other standard therapies.

Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

Co

mb

ined

en

dp

oin

t C

om

bin

ed e

nd

po

int

occ

urr

ence

(%

)o

ccu

rren

ce (

%)

Months from randomizationMonths from randomization

27% RRR27% RRRPP=0.02=0.02

Placebo*Placebo*Clopidogrel*Clopidogrel*

00

55

1010

1515

8.5%8.5%

11.5%11.5%

00 33 66 99 1212

Multivariable Predictors of Bleeding EventsMultivariable Predictors of Bleeding EventsDischarge to 1 Year (n=1816)Discharge to 1 Year (n=1816)

Aronow HD, et alAronow HD, et al. Am Heart J . Am Heart J 2008 (published online Nov 2008)2008 (published online Nov 2008)

VariableVariable Hazard Ratio Hazard Ratio (95% CI)(95% CI) XX22 P valueP value

ClopidogrelClopidogrel 1.04 (0.75-1.44)1.04 (0.75-1.44) 0.050.05 0.820.82

Age (per 10 Age (per 10 years)years) 1.26 (1.07-1.48)1.26 (1.07-1.48) 8.18.1 0.0050.005

CABG discharge-CABG discharge-1 year1 year

32.15 (23.10-32.15 (23.10-44.74)44.74) 423.6423.6 <0.0001<0.0001

Kaplan Meier Estimates of Bleeding RiskKaplan Meier Estimates of Bleeding RiskDischarge to 1 Year (n=1816)Discharge to 1 Year (n=1816)

Variable

Placebo (n=914) Clopidogrel (n=902) p value

Any (major + minor) 71 (8.1%) 77 (8.9%) 0.60 Non-procedural 13 (1.5%) 15(1.7%) 0.69 Procedural 59(6.7%) 62 (7.1%) 0.76

CABG* 41 (4.7%) 41 (4.8%) 1.0 Non-CABG* 18 (2.0%) 21 (2.4%) 0.60

Major 34 (3.9%) 49 (5.6%) 0.09 Non-procedural 7 (0.8%) 11 (1.3%) 0.34

ICH 0 0 - GI 3 (0.3%) 10 (1.1%) 0.049 RPB 0 0 - Access site 0 0 - Other 4 (0.4%) 1 (0.1%) 0.37

Procedural 27 (3.1%) 38 (4.4%) 0.16 CABG* 23 (2.5%) 28 (3.1%) 0.48

ICH 0 0 - GI 0 0 - RPB 0 0 - Access site 0 0 - Other 23 (2.5%) 28 (3.1%) 0.45

Non-CABG* 4 (0.5%) 10 (1.1%) 0.10 ICH 0 0 - GI 0 3 (0.3%) 0.12 RPB 1 (0.1%) 0 1.0 Access site 0 1 (0.1%) 0.50 Other 3 (0.3%) 6 (0.7%) 0.34

Minor 37 (4.2%) 29 (3.3%) 0.34 Non-procedural 6 (0.7%) 5 (0.6%) 0.78 Procedural 32 (3.6%) 24 (2.8%) 0.29

CABG* 18 (2.1%) 13 (1.5%) 0.38 Non-CABG* 14 (1.6%) 11 (1.3%) 0.57

Timing of Severe or Moderate BleedingTiming of Severe or Moderate Bleeding

Placebo + ASA

Clopidogrel + ASA

Days Since RandomizationDays Since Randomization

15 60 135 270 450 630 810

0.00008

0.00007

0.00006

0.00005

0.00004

0.00003

0.00002

0.00001

0

Haz

ard

Fun

ctio

n/d

Haz

ard

Fun

ctio

n/d

Bhatt DL, Flather MD, Hacke W, et al.Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. J Am Coll Cardiol. 2007;49:1982-1988. 2007;49:1982-1988.

Algorithm to Assess GI Risk Algorithm to Assess GI Risk With Antiplatelet TherapyWith Antiplatelet Therapy

YesYes

Yes

NoNoPPI

YesYes

YesYes

Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.

Need for antiplatelet therapy

Assess GI risk factors

Test for H pylori; treat if infected

History of ulcer complication History of ulcer disease (nonbleeding)

Dual antiplatelet therapyConcomitant anticoagulant

More than one risk factor:Aged 60 years or more

Corticosteroid useDyspepsia or GERD symptoms

Clopidogrel is a prodrug; requires conversion by the liver primarily Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolitevia CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity

Clopidogrel and PPIs – The OCLA studyClopidogrel and PPIs – The OCLA study

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

Gilard et al. J Am Coll Cardiol 2008;51:256-60.

p<0.0001

Intake of PPIs Not Associated With Impaired Response to Clopidogrel

Siller-Matula JM, et al. Siller-Matula JM, et al. Am Heart J. Am Heart J. 2009;157(1):148.e1-148.e5.2009;157(1):148.e1-148.e5.

Platelet reactivity index in the VASP phosphorylation Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.pantoprazole or esomeprazole.

Adenosine diphosphateAdenosine diphosphate––induced platelet induced platelet aggregation in patients on clopidogrel with or aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.without PPI: pantoprazole or esomeprazole.

Data are presented as mean and 95% CI. PPI, proton pump inhibitor; Data are presented as mean and 95% CI. PPI, proton pump inhibitor; VASP, vasodilator-stimulated phosphoprotein.VASP, vasodilator-stimulated phosphoprotein.

Variability in Clopidogrel Responsiveness in a Diverse Population of 544

Serebruany V, Steinhubl S et al. JACC 2005.Serebruany V, Steinhubl S et al. JACC 2005.

M ADP Platelet AggregationM ADP Platelet Aggregation

Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response

Mega JL, Close SL, Wiviott SD, et alMega JL, Close SL, Wiviott SD, et al. . N Engl J Med.N Engl J Med. 2009;360:354-362. 2009;360:354-362.

Gene

Percent Difference in

AUC0-t P Value

CYP2C19 −32.4 .001CYP2C9 −6.8 .59

CYP2B6 −15.7 .03

CYP3A5 5.6 .59CYP1A2 11.2 .45

Pharmacokinetic ResponsePharmacokinetic Response

Relative Percent DifferenceRelative Percent Difference-50 -40 -30 -20 -10 0 10 20 30

Pharmacodynamic ResponsePharmacodynamic Response

Gene

Percent Difference in

ΔMPA P ValueCYP2C19CYP2C19 −−9.09.0 .001.001

CYP2C9CYP2C9 −−0.60.6 .86.86

CYP2B6CYP2B6 −−5.75.7 .012.012

CYP3A5CYP3A5 7.57.5 .012.012

CYP1A2CYP1A2 0.50.5 .90.90

Absolute DifferenceAbsolute Difference-15 -10 -5 0 5 10 25

Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Ho PM, et al. Ho PM, et al. JAMAJAMA. 2009;301(9):937-944.. 2009;301(9):937-944.

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since DischargeDays Since Discharge

Pro

port

ion

of

Pro

port

ion

of

Dea

ths

or R

ecur

rent

AC

SD

eath

s or

Rec

urre

nt A

CS

Neither clopidogrel nor PPINeither clopidogrel nor PPIPPI without clopidogrelPPI without clopidogrelClopidogrel + PPIClopidogrel + PPIClopidogrel without PPIClopidogrel without PPI

Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI

Primary outcomePrimary outcome Death or rehospitalization for ACSDeath or rehospitalization for ACS

Secondary outcomesSecondary outcomes Rehospitalization for ACSRehospitalization for ACS

Revascularization proceduresRevascularization procedures

Death (all-cause)Death (all-cause)

0 1 2 3 0 1 2 3

Unadjusted OR Unadjusted OR (95% CI)(95% CI)

Adjusted OR Adjusted OR (95% CI)(95% CI)OutcomeOutcome

With PPIWith PPIWithout PPIWithout PPI With PPIWith PPIWithout PPIWithout PPI

Ho PM, et al. Ho PM, et al. JAMAJAMA. 2009;301(9):937-944.. 2009;301(9):937-944.

14.816.2

13.2

9.29.210.810.8

7.77.7

00

55

1010

1515

2020

PPI at baseline (N=374)PPI at baseline (N=374)

No PPI at baseline (N=1742)No PPI at baseline (N=1742)

Primary 1-Year Endpoint:Primary 1-Year Endpoint:Death, MI or StrokeDeath, MI or Stroke

AllAllN=2116N=2116

PlaceboPlaceboN=1063N=1063

ClopidogrelClopidogrelN=1053N=1053

Results – 1 Year Endpoint from CREDOResults – 1 Year Endpoint from CREDOUnadjusted DataUnadjusted Data

P=0.001P=0.001

P=0.45P=0.45

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

28 Days Death/MI/

UTVR

Adjusted OR (95% CI)

p-value*

One Year Death/MI/

Stroke

Adjusted HR (95% CI)

p-value†

Clopidogrel / PPI(n=179)

18/179 (10.2)

1.8 (0.99, 3.23)

0.051

23/179 (13.2)

1.6 (1.02, 2.63)

0.043Clopidogrel / No PPI(n=874)

47/874 (5.4)

66/874 (7.7)

* Multivariate logistic regression model: PPI vs. no PPI within treatment stratum† Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum

Results – Clopidogrel GroupResults – Clopidogrel GroupAdjusted DataAdjusted Data


28 Days Death/MI/

UTVR

Adjusted OR (95% CI)

p-value*

One Year Death/MI/

Stroke

Adjusted HR (95% CI)

p-value†

Placebo / PPI(n=195)

19/195 (9.8)

1.4 (0.81, 2.41)

0.221

31/195 (16.2)

1.6 (1.03, 2.34)

0.035Placebo / No PPI(n=868)

64/868 (7.4)

91/868 (10.8)

* Multivariate logistic regression model: PPI vs. no PPI within treatment stratum† Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum

Results – Placebo GroupResults – Placebo GroupAdjusted DataAdjusted Data


Results – 1 Year Primary Endpoint Results – 1 Year Primary Endpoint

Randomized Randomized TherapyTherapy

Death, MI Death, MI or Strokeor Stroke

Adjusted HR Adjusted HR (95% CI)(95% CI)

P-valueP-value

Placebo Placebo (N=195)(N=195) 16.2%16.2%

0.77 0.77 (0.45, 1.33)(0.45, 1.33) 0.350.35

Clopidogrel (N=179)

13.2%

Randomized Randomized TherapyTherapy

Death, MI Death, MI or Strokeor Stroke

Adjusted HR Adjusted HR (95% CI)(95% CI)

P-valueP-value

Placebo Placebo (N=868)(N=868) 10.8%10.8%

0.750.75(0.55, 1.03)(0.55, 1.03) 0.080.08

Clopidogrel (N=874)

7.7%

PPI at Baseline

No PPI at Baseline

P-value for P-value for interaction interaction between between randomized randomized therapy and therapy and baseline PPIbaseline PPIP=0.69P=0.69


THE LANCET

CV

dea

th,

MI

or s

trok

eC

V d

eath

, M

I or

str

oke

DaysDays

CLOPIDOGREL CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGRELPRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

Type of PPIClopidogrel

HR (95% CI)CV death, MI or stroke

PrasugrelHR (95% CI)

CV death, MI or stroke

Omeprazole

(n=1675)0.91 (0.72-1.15) 1.04 (0.81-1.34)

Pantoprazole

(n=1844)0.94 (0.74-1.18) 1.09 (0.86-1.39)

Esomeprazole

(n=613)1.07 (0.75-1.52) 0.86 (0.55-1.33)

Lansoprazole

(n=441)1.00 (0.63-1.59) 0.98 (0.61-1.57)

Risk of CV Events with Different Types of PPIsRisk of CV Events with Different Types of PPIs

Rabeprazole not included due to small sample size (n=66)

Clopidogrel and the Optimization of GI Events Trial – COGENT

Conclusions

► Dual antiplatelet therapy reduces important ischemic events Dual antiplatelet therapy reduces important ischemic events after PCI, ACSafter PCI, ACS

► GI bleeding is the most common form of major bleeding that GI bleeding is the most common form of major bleeding that occursoccurs

► Logical, though not proved, that prophylactic PPI reduces this Logical, though not proved, that prophylactic PPI reduces this GI bleeding GI bleeding

► Patients prescribed PPI are a higher risk than those who are Patients prescribed PPI are a higher risk than those who are notnot

► While pathways for an interaction exist, unclear degree of While pathways for an interaction exist, unclear degree of clinical relevanceclinical relevance

Antiplatelet Therapy in Antiplatelet Therapy in High Risk Patients:High Risk Patients:

Does One Size Fit All?Does One Size Fit All?

Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization LaboratoriesDirector, Cardiovascular Catheterization Laboratories

Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of Vermont

An 87-year-old woman presents with a non ST-elevation MI to a community hospital. She lives independently and takes care of her disabled husband. Hemodynamically, she is stable, but has pulmonary edema. She is transferred to UVM for cath/PCI. Her creatinine is 1.3 and the Hct is 34. PMH includes NIDDM and gastroesophageal reflux. LAD has slow flow..

Adapted from HL Dauerman, New Insights into Atherothrombosis 2009 (Editor DL Bhatt)

Defining Current Options for Antiplatelet TherapyDefining Current Options for Antiplatelet Therapy

1.1.Should this community hospital have a single algorithm for care?Should this community hospital have a single algorithm for care?2.2.Upstream or downstream GPI?Upstream or downstream GPI?3.3.Clopidogrel or prasugrel?Clopidogrel or prasugrel?4.4.What if this patient was in your emergency department?What if this patient was in your emergency department?

STEMI:The Vermont Algorithm

UFH (60 U/Kg)Beta Blockers only if HTN

UFH or BivalirudinBeta Blockers ONLY if HTN

PCI Capability or < 60 minute Transfer Time

No PCI Capability and > 60 minute Transfer

Time

Primary PCI with Stenting:Primary PCI with Stenting:GPI/Thrombectomy if Large ThrombusGPI/Thrombectomy if Large Thrombus

or as Bailout; Otherwise, Bivalirudin Aloneor as Bailout; Otherwise, Bivalirudin Alone

90 minutesTo Open

Artery Lytic Lytic

ContraindicatedContraindicated

Emergent Transfer

Full Dose Ly tic and UFHFull Dose Ly tic and UFH

Transfer from Transfer from Community ERCommunity ER

To PCI SiteTo PCI Site

If no CP and less than 50% If no CP and less than 50% ST Elevations, PCI at 12-24ST Elevations, PCI at 12-24

Hours with StentHours with Stent

If Reperfusion Fails,Emergent PCI with Stent

ASA/ClopidogrelStatin

Groin ClosureCardiac Rehab

Lopressor 12.5 bid

TransferTransfer

Rescue PCI:

Class I Indication

The NSTEMI Paradigm

of 4-48 Hours

ASA 325 po

ClopidogrelClopidogrel600 po600 po

Clopidogrel Clopidogrel 300 po300 po

Continue bivalirudin for Continue bivalirudin for 2 hours after PCI2 hours after PCI

Guigliano, RGuigliano, RNEJM 2009:NEJM 2009:

The EARLY ACS The EARLY ACS TRIALTRIAL

No Clear Benefit No Clear Benefit of Upstreamof UpstreamGPIGPI

One Size Does Fit One Size Does Fit AllAll

Giugliano, NEJM 2009Giugliano, NEJM 2009

FINESSE: FINESSE: Keeping the Simple Algorithm IntactKeeping the Simple Algorithm Intact

End pointEnd point Primary Primary PCI (%)PCI (%)

AbciximabAbciximab-facilitated -facilitated

(%)(%)

Combination Combination (abciximab/(abciximab/

reteplase)-reteplase)-facilitated (%)facilitated (%)

p, combination-p, combination-facilitated vs facilitated vs primary PCIprimary PCI

p, p, combination-combination-facilitated vs facilitated vs abciximab-abciximab-facilitatedfacilitated

Cardiogenic Cardiogenic shockshock

6.86.8 4.84.8 5.35.3 NSNS NSNS

VFVF 0.40.4 0.20.2 0.60.6 NSNS NSNS

TIMI major TIMI major bleedingbleeding

2.62.6 4.14.1 4.84.8 0.0250.025 NSNS

TIMI minor TIMI minor bleedingbleeding

4.34.3 6.06.0 9.79.7 <0.001<0.001 0.0060.006

TIMI major or TIMI major or minor bleedingminor bleeding

6.96.9 10.110.1 14.514.5 <0.001<0.001 0.0080.008

Ellis SG et al. N Engl J Med 2008;358:2205-2217

Bleeding Complications and theElderly Patient

Ahmed and DauermanAhmed and Dauerman, Circulation: Cardiovascular Interventions , Circulation: Cardiovascular Interventions September 2009September 2009

Maj

or v

ascu

lar

com

plic

atio

ns,

%*

Maj

or v

ascu

lar

com

plic

atio

ns,

%*

*Arterial injury and/or arterial injury-related bleeding among women*Arterial injury and/or arterial injury-related bleeding among womenN=13,653 patients undergoing PCIN=13,653 patients undergoing PCI

P<0.001P<0.001

Both Bleeding and Thrombotic Events MatterBoth Bleeding and Thrombotic Events Matter

CK-MB Symptomatic MI

TVR

DEATH

TVRBleeding

CK-MB Symptomatic MI

DEATH

GPI Antagonists

BivalirudinBivalirudin

19981998 20092009

Adapted from Dauerman HL, J Am Coll Feb 2007Adapted from Dauerman HL, J Am Coll Feb 2007

Prasugrel and TicagrelorPrasugrel and Ticagrelor

Wiviott, S. D. et al. Wiviott, S. D. et al. CirculationCirculation 2007;116:2923-2932 2007;116:2923-2932

Prevention of Thrombotic Complications:Pharmacology of New ADP Receptor Antagonists

► Novel ADP receptor Novel ADP receptor antagonists: Ticagrelor and antagonists: Ticagrelor and prasugrelprasugrel

► More potent inhibition of More potent inhibition of platelet aggregationplatelet aggregation

► Earlier inhibition of platelet Earlier inhibition of platelet aggregationaggregation

► PRINCIPLE-TIMI44: Phase II PRINCIPLE-TIMI44: Phase II pharmacokinetic studypharmacokinetic study

► Vasodilator-stimulated Vasodilator-stimulated phosphoprotein (VASP): phosphoprotein (VASP): Assessment of the extent of Assessment of the extent of phosphorylation of VASP reflects phosphorylation of VASP reflects specifically inhibition of the specifically inhibition of the P2Y12 receptorP2Y12 receptor

Stent Thrombosis and TRITON TIMI 38

00

11

22

33

00 3030 6060 9090 180180 270270 360360 450450

HR 0.48HR 0.48P <0.0001P <0.0001

Prasugrel Prasugrel

ClopidogrelClopidogrel2.42.4

(142)(142)

NNT= 77NNT= 77

1.1 1.1 (68)(68)

DaysDays

En

dpo

int

En

dpo

int ( (

%%))

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Wiviott SD et al Wiviott SD et al NEJMNEJM 2007;357: 2001. 2007;357: 2001.

An 87-Year-Old Woman Presents with a NSTEMI to a Community Hospital:

Should the 2010 algorithm include prasugrel 60 mg load in ED or prior to transfer for all ACS patients? Clopidogrel 600 mg load? Other?

Adapted from HL Dauerman, New Insights into Atherothrombosis 2009 (Editor DL Bhatt)

Challenges in Developing ACS AlgorithmsChallenges in Developing ACS Algorithms

Acute Dose: 162 vs 325 mg Chronic Dose: 81 vs 325Acute Dose: 162 vs 325 mg Chronic Dose: 81 vs 325

CURRENT OASIS-7: S. Mehta, ESC 2009CURRENT OASIS-7: S. Mehta, ESC 2009

•Safety/efficacy for 300 mg in elderlySafety/efficacy for 300 mg in elderly•Unknown risk of 600 mg loading doseUnknown risk of 600 mg loading dose•12 month compliance12 month compliance

• Defining optimum loading doseDefining optimum loading dose• Defining optimum timing of loadDefining optimum timing of load• Defining maintenance doseDefining maintenance dose• 12 month compliance12 month compliance

No safety or efficacy dataNo safety or efficacy data

• Risk/benefit in patients with highRisk/benefit in patients with high incidence of bleeding complicationsincidence of bleeding complications• Risk/benefit in patients with increasedRisk/benefit in patients with increased potential for CABG during follow uppotential for CABG during follow up• 12 month compliance12 month compliance• Potential for switching high bleeding risk Potential for switching high bleeding risk patients to clopidogrel after 30 dayspatients to clopidogrel after 30 days..

HL Dauerman, Am J Cardiology 2009HL Dauerman, Am J Cardiology 2009

FibrinolysisFibrinolysis Primary PCIPrimary PCI

AspirinAspirin


PrasugrelPrasugrel

Alexander, K. P. et al. Circulation 2007;115:2549-2569Alexander, K. P. et al. Circulation 2007;115:2549-2569

The Platelet Gap in Clinical Trials:The Platelet Gap in Clinical Trials: TRITON TIMI 38—13% Elderly EnrollmentTRITON TIMI 38—13% Elderly Enrollment

NSTE ACS Populations (n=1,190,721)NSTE ACS Populations (n=1,190,721)

Pro

port

ion

of A

ge G

roup

P

ropo

rtio

n of

Age

Gro

up >>

75

Yea

rs (

%)

75

Yea

rs (

%)

18%18%

38%38%

We Can Not Have a Simple Statewide ACS We Can Not Have a Simple Statewide ACS Algorithm with PrasugrelAlgorithm with Prasugrel

BB

OVERALLOVERALL

No GPINo GPIGPIGPI

DESDESBMSBMS

DMDMNo DMNo DM

>75>7565-7465-74

<65<65

FemaleFemaleMaleMale

STEMISTEMIUA/NSTEMIUA/NSTEMI

0.50.5 11 22Prasugrel BetterPrasugrel Better Clopidogrel BetterClopidogrel BetterHRHR

AgeAge

Risk Reduction (%)Risk Reduction (%)1818

21211212

2525141466

14143030

20201818

21211616

1919

2121

CV Death, MI, Stroke:CV Death, MI, Stroke:Is Prasugrel Effective in the Elderly?Is Prasugrel Effective in the Elderly?

CrCl > 60CrCl > 60CrCl < 60CrCl < 60 1414

2020

Wiviott SD, Wiviott SD, NEJMNEJM 357: 2001-2015, 2007 357: 2001-2015, 2007

Net Clinical Benefit Analysis:Do Not Load Prasugrel For Our 87-Year-Old Patient

OVERALLOVERALL

>=60 kg>=60 kg

< 60 kg< 60 kg

< 75< 75

>=75>=75

NoNo

YesYes

0.50.5 11 22

PriorPrior Stroke / TIA Stroke / TIA

AgeAge

WgtWgt

Risk (%)Risk (%)+ 37+ 37

-16-16

-1-1

-16-16

+3+3

-14-14

-13-13

Prasugrel BetterPrasugrel Better Clopidogrel BetterClopidogrel BetterHRHR

PPint int = 0.006= 0.006

PPint int = 0.18= 0.18

PPint int = 0.36= 0.36

Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033

Selective Cardiology-Guided Loading and ContinuationSelective Cardiology-Guided Loading and Continuation

Controlling Bleeding Risk with a Switching Strategy for Controlling Bleeding Risk with a Switching Strategy for Prasugrel: Prasugrel 10 mg = Clopidogrel 600 mgPrasugrel: Prasugrel 10 mg = Clopidogrel 600 mg

Payne et al. Platelets. 2008;19(4):275-281 Payne et al. Platelets. 2008;19(4):275-281

Newer Drugs for ACS and STEMI:Mortality Benefit Can Not Be Ignored

September 1, 2009September 1, 2009

Should This Reversible Drug Become a Standard?Side Effects and Non-CABG Related Bleeding Complications

A. Schomig, NEJM Editorial, 2009A. Schomig, NEJM Editorial, 2009

Defining Current Options for Antiplatelet TherapyDefining Current Options for Antiplatelet Therapy1.1.Should this community hospital have a single algorithm for care?Should this community hospital have a single algorithm for care?2.2.Upstream or downstream GPI?Upstream or downstream GPI?3.3.Clopidogrel or prasugrel?Clopidogrel or prasugrel?4.4.What if this patient was in your emergency department?What if this patient was in your emergency department?

► If a default universal algorithm is used, If a default universal algorithm is used, then it must default to safety: then it must default to safety: clopidogrel clopidogrel load only.load only.

► No GPI upstream or downstream.No GPI upstream or downstream.

► ASA 325 mg po x 1, clopidogrel 600 po x ASA 325 mg po x 1, clopidogrel 600 po x 1, 150 po qd in hospital, then 75 qd for 1 1, 150 po qd in hospital, then 75 qd for 1 year with ASA 81 qd indefinitely.year with ASA 81 qd indefinitely.

► PPI was not initially given but 4 weeks PPI was not initially given but 4 weeks later, reflux occurred, and PPI was later, reflux occurred, and PPI was initiated. No change in Tx.initiated. No change in Tx.

► The future of the PCI center: ED—ASA The future of the PCI center: ED—ASA 325 mg and then decision re: prasugrel vs 325 mg and then decision re: prasugrel vs clopidogrel by telephone consult with clopidogrel by telephone consult with interventional cardiologist in cath lab or on interventional cardiologist in cath lab or on cardiac floorcardiac floor..

ConclusionsConclusionsAntiplatelet Therapy Across the SpectrumAntiplatelet Therapy Across the Spectrum

► Algorithms for ACS and STEMI care Algorithms for ACS and STEMI care have advanced care in terms of have advanced care in terms of quality and efficiencyquality and efficiency

► Some aspects of our algorithms can Some aspects of our algorithms can be simple and clearer (GPI use, be simple and clearer (GPI use, aspirin and clopidogrel dosing)aspirin and clopidogrel dosing)

► The advent of prasugrel and The advent of prasugrel and ticagrelor potentially removes the ticagrelor potentially removes the decision re: choice of a second decision re: choice of a second antiplatelet agent from the antiplatelet agent from the emergency department and back emergency department and back into the realm of cardiology-based into the realm of cardiology-based clinical judgment.clinical judgment.

One Size Does Not Fit All

Sunil V. Rao MDSunil V. Rao MDDirector of Cardiac Catheterization LaboratoriesDirector of Cardiac Catheterization Laboratories

The Duke Clinical Research InstituteThe Duke Clinical Research InstituteThe Durham VA Medical CenterThe Durham VA Medical CenterDuke University Medical CenterDuke University Medical Center

Bleeding is the Bleeding is the Red Red line in the line in the sand for Antiplatelet therapy: sand for Antiplatelet therapy: Avoiding Complications in the Avoiding Complications in the

Cath Lab & BeyondCath Lab & Beyond

Bleeding and antiplatelet therapyBleeding and antiplatelet therapyIssues we will discuss

► Reducing events among clopidogrel hyporesponders is Reducing events among clopidogrel hyporesponders is a clinical prioritya clinical priority

► Intensification of antiplatelet effect is associated with Intensification of antiplatelet effect is associated with improvement in some ischemic outcomes, but what improvement in some ischemic outcomes, but what about the bleeding?about the bleeding? Acute – CABG-related bleedingAcute – CABG-related bleeding Chronic bleeding riskChronic bleeding risk

► Can we compare safety results from different clinical Can we compare safety results from different clinical trials?trials?

► In the modern era of multiple antiplatelet options, what In the modern era of multiple antiplatelet options, what factors must be weighed in making the therapeutic factors must be weighed in making the therapeutic decision?decision?

The Current Egalitarian Strategy of Antiplatelet Therapy During And After PCI: The More The Merrier for Everyone!

Single Single Antiplatelet RxAntiplatelet Rx

Dual Dual Antiplatelet RxAntiplatelet Rx

Higher Higher IPAIPA

Reduction in

IschemicEvents

Increase in

Major Bleeds

Adapted from Gibson, AHA 2007

Increasingly narrow

therapeutic window

IPA Responses to ClopidogrelIPA Responses to Clopidogrel

Δ 5µM ADP-Induced Platelet Aggregation (%)Δ 5µM ADP-Induced Platelet Aggregation (%)

≤ -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Num

ber

of P

atie

nts

Num

ber

of P

atie

nts

Greater antiplatelet effect may address

this group

What effect does greater platelet

inhibition have on bleeding?

Adapted from: Serebruany V et al. J Am Coll Cardiol. 2005. Adapted from: Serebruany V et al. J Am Coll Cardiol. 2005.

Risk vs. Benefit – Risk vs. Benefit – What Affects Efficacy and Safety?What Affects Efficacy and Safety?

““Major” Bleeding: Incidence* inMajor” Bleeding: Incidence* inClinical Trials with Active AgentClinical Trials with Active Agent

Clop + ASA Pras + ASA Ticag + ASA Clop + ASA600mg + 325 mgYusuf S NEJM 2001Yusuf S NEJM 2001

Wiviott SD NEJM 2007Wiviott SD NEJM 2007Wallentin L NEJM 2009Wallentin L NEJM 2009Mehta SR NEJM 2009Mehta SR NEJM 2009

DefinitionDefinition TIMITIMI11 GUSTOGUSTO22 CURECURE33

TrialTrial TRITONTRITON CHARISMACHARISMA CURECUREMajor Major ––

fatal / life fatal / life threatening threatening or severe or severe bleedingbleeding

Fatal / life Fatal / life threatening threatening (related to (related to

instrumentation, instrumentation, spontaneous, spontaneous, trauma), ICH, trauma), ICH,

Hb ↓ ≥5 g/dL, or Hb ↓ ≥5 g/dL, or absolute absolute

HCT ↓ ≥15%HCT ↓ ≥15%

Fatal, ICH, Fatal, ICH, or causes or causes

haemodynamic haemodynamic compromise and compromise and

requires requires interventionintervention

Fatal / Life threateningFatal / Life threatening

Fatal, ICH, requires Fatal, ICH, requires surgery, hypotension surgery, hypotension requiring inotropes, requiring inotropes,

Hb ↓ ≥5 g/dL, Hb ↓ ≥5 g/dL, or transfusion ≥4 Uor transfusion ≥4 U

Other majorOther major

Disabling, intraocular Disabling, intraocular with vision loss, or with vision loss, or transfusion 2-3 Utransfusion 2-3 U

ICH = intracranial haemorrhage; PLATO = ICH = intracranial haemorrhage; PLATO = Platelet Inhibition and Patient Outcomes.Platelet Inhibition and Patient Outcomes.1.1.Chesebro, JH et alChesebro, JH et al. Circulation 1987 . Circulation 1987 2.2.GUSTO Investigators. NEJM 1993GUSTO Investigators. NEJM 19933. 3. Yusuf S, et al. N Engl J Med. 2001;345:494-502. Yusuf S, et al. N Engl J Med. 2001;345:494-502. 4. 4. Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851.

PLATO4

PLATOFatal / Life threatening

Fatal, ICH, intrapericardial with tamponade,

hypovolaemic shock / hypotension requiring pressors or surgery,

Hb ↓ >5 g/dL, or transfusion ≥4 U

Other major

Disabling (intraocular with permanent vision loss),

Hb ↓ 3-5 g/dL, or transfusion 2-3 U

““Major” Bleeding Data ElementsMajor” Bleeding Data Elements

Bleeding and Evidence-based TherapiesBleeding and Evidence-based TherapiesN=2498 ACS patients from the PREMIER RegistryN=2498 ACS patients from the PREMIER Registry

Discharge ASA and thienopyridineDischarge ASA and thienopyridinePts. with bleeding vs. pts. without bleedingPts. with bleeding vs. pts. without bleeding

Wang TY, et. al. Circulation 2008Wang TY, et. al. Circulation 2008

DischargeDischarge

1 Month1 Month

6 Months6 Months

1 Year1 Year

AspirinAspirinOR (95% CI)OR (95% CI)

ThienopyridineThienopyridineOR (95% CI)OR (95% CI)

0.5 1.0 2.00.5 1.0 2.0 0.5 1.0 2.00.5 1.0 2.0

0.45 (0.31, 0.64)0.45 (0.31, 0.64)

0.68 (0.50, 0.92)0.68 (0.50, 0.92)

0.63 (0.46, 0.87)0.63 (0.46, 0.87)

0.62 (0.42, 0.91)0.62 (0.42, 0.91)

0.94 (0.66, 1.34)0.94 (0.66, 1.34)

0.83 (0.59, 1.17)0.83 (0.59, 1.17)

1.06 (0.78, 1.45)1.06 (0.78, 1.45)

1.12 (0.81, 1.55)1.12 (0.81, 1.55)

““Nuisance” Bleeding and Drug DiscontinuationNuisance” Bleeding and Drug Discontinuation

► N=2360 unselected N=2360 unselected pts. receiving DESpts. receiving DES

► Prospective data Prospective data collectioncollection

► Major events Major events adjudicatedadjudicated

► Serebruany Serebruany bleeding bleeding classificationclassification*

Roy P, et. al. AJC 2008

*Alarming bleeding = ICH, life-threatening, + transfusion*Alarming bleeding = ICH, life-threatening, + transfusionInternal bleeding = hematoma, epistaxis, mouth or vaginal,Internal bleeding = hematoma, epistaxis, mouth or vaginal,Melena, IO, hematuria or hematemesisMelena, IO, hematuria or hematemesisNuisance bleeding = bruising, petechiae, ecchymosisNuisance bleeding = bruising, petechiae, ecchymosis

% d

isco

ntin

ued

% d

isco

ntin

ued

PREMIER Registry: Mortality Among PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine TherapyPatients Continuing vs Discontinuing Thienopyridine Therapy

Spertus JA, et al. Circulation. 2006 Spertus JA, et al. Circulation. 2006

1515

1010

55

00

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

ContinuedContinuedDiscontinuedDiscontinued

P<0.001P<0.001

MonthsMonths

CURE – Major Bleeding CURE – Major Bleeding

*Includes fatal bleeding*Includes fatal bleeding**Includes life-threatening & fatal bleeding**Includes life-threatening & fatal bleeding

Yusuf S, et. al. NEJM 2001Yusuf S, et. al. NEJM 2001

P=NSP=NS

P=0.13P=0.13

P=0.001P=0.001

%%

Clopidogrel and ASA for NSTE ACS Clopidogrel and ASA for NSTE ACS CABG-Related Bleeding in CURECABG-Related Bleeding in CURE

p=0.001p=0.001

Clopidogrel d/cClopidogrel d/c> 5 days> 5 days

Clopidogrel d/cClopidogrel d/c> 5 days> 5 days

Clopidogrel d/cClopidogrel d/c<< 5 days 5 days

Clopidogrel d/cClopidogrel d/c<< 5 days 5 days

Cure Investigators, NEJM 2001Cure Investigators, NEJM 2001Cure Investigators, NEJM 2001Cure Investigators, NEJM 2001

Events Saved vs Life-threatening Bleeding Over Time: Events Saved vs Life-threatening Bleeding Over Time: Net Net Clinical Benefit of ClopidogrelClinical Benefit of Clopidogrel

Months of follow-upMonths of follow-up

Eve

nts/

1000

pat

ient

s tr

eate

dE

vent

s/10

00 p

atie

nts

trea

ted

-5-5

00

55

1010

1515

2020

2525

00 33 66 99 1212

Events Saved: CV death, MI, strokeEvents Saved: CV death, MI, stroke

Life-threatening bleedingLife-threatening bleeding

Yusuf S et al for the CURE Trial Investigators. Yusuf S et al for the CURE Trial Investigators. CirculationCirculation. 2003;107:966. 2003;107:966

*Other standard therapies were used as appropriate. *Other standard therapies were used as appropriate. ..

CURE: Major Bleeding by Aspirin CURE: Major Bleeding by Aspirin Dose Through Follow-UpDose Through Follow-Up

Peters RJ, et al. Circulation. 2003Peters RJ, et al. Circulation. 2003

Aspirin DosePlacebo + Aspirin*

Clopidogrel + Aspirin*

75-100 mg 1.9% 3.0%

101-199 mg 2.8% 3.4%

200-325 mg 3.7% 4.9%

ClopidogrelClopidogrel HRHR 95% CI95% CI PP P int’nP int’n

StandardStandard DoubleDoubleCV Death/MI/Stroke (Overall)

ASA High 4.6 3.8 0.83 0.70-0.99 0.0360.043

ASA Low 4.2 4.5 1.07 0.91-1.27 0.42

MI/Stent Thrombosis (PCI pts)

ASA High 3.8 2.7 0.71 0.56-0.90 0.005 0.19

ASA Low 3.6 3.2 0.89 0.71-1.12 0.32

Major Bleed (Overall)

ASA High 2.2 2.4 1.08 0.86-1.37 0.510.099

ASA Low 1.9 2.7 1.43 1.13-1.81 0.003

Clopidogrel: Double vs Standard Dose by ASA Factorial

Mehta SR, et. al. NEJM 2009Mehta SR, et. al. NEJM 2009

TIMI Major bleeding:TIMI Major bleeding:600 mg vs. 300 mg Clop – 0.5% vs. 0.5%, P=0.50600 mg vs. 300 mg Clop – 0.5% vs. 0.5%, P=0.50

325 mg ASA vs. ≤ 100 mg ASA – 1.03% vs. 0.97%, P=0.71325 mg ASA vs. ≤ 100 mg ASA – 1.03% vs. 0.97%, P=0.71

Clopidogrel and bleedingClopidogrel and bleeding

► Adding clopidogrel to ASA increases bleeding risk Adding clopidogrel to ASA increases bleeding risk overalloverall No increase in life-threatening or fatal bleedingNo increase in life-threatening or fatal bleeding

► Increased risk of CABG-related bleeding, but to Increased risk of CABG-related bleeding, but to reduce this risk, discontinue clopidogrel 5d priorreduce this risk, discontinue clopidogrel 5d prior

► Higher clopidogrel and ASA dose associated with Higher clopidogrel and ASA dose associated with better ischemic outcomes in PCI patientsbetter ischemic outcomes in PCI patients Increased bleeding risk, but no increase in fatal Increased bleeding risk, but no increase in fatal

bleeding or TIMI major bleedingbleeding or TIMI major bleeding

-20.0

0.0

20.0

40.0

60.0

80.0

100.0

Inhi

bitio

n of

pla

tele

t agg

rega

tion

(%)

Response to prasugrelResponse to clopidogrel

Clopidogrel responderClopidogrel non-responder

Inte

rpat

ient

var

iabi

lity

Interpatient variability

Responder = ≥ 25% IPA at 4 and 24 hours

Brandt JT, et al. Am Heart J. 2007;153:66.e9-e16.

Clopidogrel vs. Prasugrel At 24 hrs (healthy volunteers)

Overcoming clopidogrel hyporesponsivenessOvercoming clopidogrel hyporesponsivenessChange the drugChange the drug

Bleeding EventsBleeding EventsSafety Cohort Safety Cohort (N=13,457)(N=13,457)

% E

vent

s%

Eve

nts

ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03

NNH=167 NNH=167

ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01

ARD 0.2%ARD 0.2%P=0.23P=0.23

ARD 0%ARD 0%P=0.74P=0.74

ARD 0.3%ARD 0.3%P=0.002P=0.002


PrasugrelPrasugrel

ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA

(N=518)(N=518)

Clop 0 (0) % Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)%

(P=0.02) (P=0.02)

TRITON-TIMI 38TRITON-TIMI 38Early and late non CABG bleedingEarly and late non CABG bleeding

Wiviott S, et. al. NEJM 2007Wiviott S, et. al. NEJM 2007

Net Clinical Benefit:Net Clinical Benefit:Bleeding Risk SubgroupsBleeding Risk Subgroups

Post-hoc AnalysisPost-hoc Analysis

OVERALLOVERALL

≥ ≥ 60 kg60 kg

< 60 kg< 60 kg

< 75< 75

≥ ≥ 7575

NoNo

YesYes

0.50.5 11 22

PriorPrior stroke / TIA stroke / TIA

AgeAge

WgtWgt

Risk (%)Risk (%)+ 54+ 54

-16-16

-1-1

-16-16

+3+3

-14-14

-13-13

HRHR

PPint int = .006= .006

PPint int = .18= .18

PPint int = .36= .36

Wiviott SD, NEJM, 2007Wiviott SD, NEJM, 2007

Modified Folts Model of Thrombosis and Haemostasis in Anaesthetised Dogs

Balancing Efficacy and Safety:Balancing Efficacy and Safety: Antithrombotic Effect vs Bleeding Time Antithrombotic Effect vs Bleeding Time

*A compound chemically indistinguishable from prasugrel.*A compound chemically indistinguishable from prasugrel.Adapted from van Giezen JJJ, et al.Adapted from van Giezen JJJ, et al. 9th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 20089th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 2008

AZD6140 Clopidogrel

AZD11703072*

PLATO - Total Major BleedingPLATO - Total Major Bleeding

Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;

*Proportion of patients (%); NS = not significant

NSNS

NSNS

NSNS

NSNS

NSNS

00

K-M

est

imat

ed r

ate

(% p

er y

ear)

K-M

est

imat

ed r

ate

(% p

er y

ear)

PLATO major PLATO major bleedingbleeding

11

22

33

44

55

66

77

88

99

1010

1212

1111

1313

TIMI major TIMI major bleedingbleeding

Red cell Red cell

transfusiontransfusion**

PLATO life-PLATO life-threatening/threatening/

fatal bleedingfatal bleeding

Fatal bleedingFatal bleeding

11.611.611.211.2

7.97.9 7.77.7

8.98.9 8.98.9

5.85.8 5.85.8

0.30.3 0.30.3

TicagrelorTicagrelorClopidogrelClopidogrel

Wallentin L, et. al. NEJM 2009Wallentin L, et. al. NEJM 2009

PLATO - Non-CABG and CABG-related Major BleedingPLATO - Non-CABG and CABG-related Major Bleeding

p=0.026p=0.026

p=0.025p=0.025

NSNS

NSNS

99K

-M e

stim

ated

rat

e (

% p

er y

ear)

K-M

est

imat

ed r

ate

(%

per

yea

r)

Non-CABGNon-CABGPLATO majorPLATO major

bleedingbleeding

88

77

66

55

44

33

22

11

00Non-CABGNon-CABGTIMI major TIMI major bleedingbleeding

CABGCABGPLATO major PLATO major

bleedingbleeding

CABG CABG TIMI major TIMI major bleedingbleeding

4.54.5

3.83.8

2.82.8

2.22.2

7.47.4

7.97.9

5.35.3

5.85.8

TicagrelorTicagrelorClopidogrelClopidogrel

Wallentin L, et. al. NEJM 2009Wallentin L, et. al. NEJM 2009

Offset of Ticagrelor and ClopidogrelOffset of Ticagrelor and Clopidogrel

Storey RF, et. al. JACC 2007Storey RF, et. al. JACC 2007

• After 24 hrs, the antiplateleteffect of Ticagreloris higher thanClopidogrel

• In PLATO, Ticagrelorwas discontinued 24-72hbefore CABG, allowingdrug to wear off

• ? If the non-CABGrelated bleeding is higher because of the persistent greater effect

Newer Oral Antiplatelet AgentsNewer Oral Antiplatelet Agents

► Prasugrel and ticagrelor provide greater platelet Prasugrel and ticagrelor provide greater platelet inhibition compared with clopidogrelinhibition compared with clopidogrel

► Prasugrel is associated with increases in major Prasugrel is associated with increases in major bleeding, fatal bleeding, and CABG-related bleedingbleeding, fatal bleeding, and CABG-related bleeding Unacceptable risks in age > 75 yrs, Weight < 60 Unacceptable risks in age > 75 yrs, Weight < 60

kg, Prior stroke/TIAkg, Prior stroke/TIA

► Ticagrelor associated with improved survival and no Ticagrelor associated with improved survival and no increase in bleeding overall, but increases in non-increase in bleeding overall, but increases in non-CABG related bleedingCABG related bleeding

Making Decisions: The Clinical Necessity of Making Decisions: The Clinical Necessity of Comparing Across TrialsComparing Across Trials

CURRENT PCICURRENT PCIN=17,232N=17,232

TRITONTRITONN=13,608N=13,608

PLATOPLATON=18,624N=18,624

CV Death, MI or StrokeCV Death, MI or Stroke↓ ↓ 15%15%

↓ ↓ 21% (w high dose 21% (w high dose ASA)ASA)

↓ ↓ 19%19%↓ ↓ 16%16%

↓ ↓ 16% in death16% in death

Definite Stent Definite Stent ThrombosisThrombosis

↓ ↓ 42%42%

↓ ↓ 51% (w high dose 51% (w high dose ASA)ASA)

↓ ↓ 58%58% ↓ ↓ 33%33%

TIMI Major BleedTIMI Major Bleed No increaseNo increase ↑ ↑ 32%32% No increaseNo increase

CABG-related BleedingCABG-related Bleeding No increaseNo increase ↑ ↑ 4-fold4-foldNo increaseNo increase

↑ ↑ 19-25% in 19-25% in non-CABG bldnon-CABG bld

Fatal bleeding No increase ↑ 4-fold No increase

PRT060128 (Elinogrel) – A Reversible PRT060128 (Elinogrel) – A Reversible P2Y12 InhibitorP2Y12 Inhibitor

N= 50 pts with HPR on 75 mg clopidogrel daily

00

2020

4040

6060

8080

ScreenScreen PredosePredose 4h4h 6h6h 24h24h 7-10 d7-10 d

Max

imum

Agg

rega

tion

(%)

Max

imum

Agg

rega

tion

(%)

p<0.001p<0.001 p<0.001p<0.001

5M ADP-Induced Aggregation

Gurbel PA, AHA 2008Gurbel PA, AHA 2008

INNOVATE-PCI TrialINNOVATE-PCI Trial800 elective PCI patients800 elective PCI patients

ClopidogrelClopidogrel-LoadLoad

- 90d therapy90d therapy

PRT 128PRT 128-IVIV

- Oral for 90d- Oral for 90d

24 hr death/MI/TVR24 hr death/MI/TVR60d death/MI/TVR60d death/MI/TVR

24 hr & 60d Clinically relevant major/minor bleeding24 hr & 60d Clinically relevant major/minor bleeding24 hr & 60d Nuisance bleeding24 hr & 60d Nuisance bleeding

24 hr & 60d TIMI Major and Minor bleeding24 hr & 60d TIMI Major and Minor bleeding

800 elective PCI patients

Clopidogrel-Load

- 90d therapy

PRT 128-IV

- Oral for 90d

24 hr death/MI/TVR60d death/MI/TVR

24 hr & 60d Clinically relevant major/minor bleeding

24 hr & 60d Nuisance bleeding24 hr & 60d TIMI Major and Minor bleeding

Bleeding and Antiplatelet TherapyBleeding and Antiplatelet TherapyConclusions (1)Conclusions (1)

► Several options for oral antiplatelet therapy now exist (with Several options for oral antiplatelet therapy now exist (with more coming)more coming)

► New options address “undertreatment”New options address “undertreatment” Increase ASA + Clopidogrel doseIncrease ASA + Clopidogrel dose PrasugrelPrasugrel TicagrelorTicagrelor

► Efficacy signal improved with all of the above strategies Efficacy signal improved with all of the above strategies compared with control arm with some caveatscompared with control arm with some caveats CURRENT – PCI subgroup experienced benefitCURRENT – PCI subgroup experienced benefit TRITON – No medical therapy; No benefit in age ≥ 75 TRITON – No medical therapy; No benefit in age ≥ 75

years, prior TIA/Stroke, low body weightyears, prior TIA/Stroke, low body weight

Bleeding and Antiplatelet TherapyBleeding and Antiplatelet TherapyConclusions (2)

With similar efficacy signals across trials, assessing With similar efficacy signals across trials, assessing bleeding is importantbleeding is important► Differing definitions across trials make it difficult to compare, Differing definitions across trials make it difficult to compare,

but…but…

► General conceptsGeneral concepts Clopidogrel + ASA Clopidogrel + ASA = greater bleeding than ASA alone= greater bleeding than ASA alone

Prasugrel + ASA Prasugrel + ASA = greater bleeding than clopidogrel + ASA= greater bleeding than clopidogrel + ASA

Ticagrelor + ASA Ticagrelor + ASA = greater non-CABG related bleeding than = greater non-CABG related bleeding than clopidogrel + ASA (but no difference in CABG-related bleeding)clopidogrel + ASA (but no difference in CABG-related bleeding)

Bleeding and Antiplatelet TherapyBleeding and Antiplatelet TherapyConclusions (3)Conclusions (3)

In the era of three therapeutic options to In the era of three therapeutic options to increase the efficacy of antiplatelet agents, the increase the efficacy of antiplatelet agents, the literature provides support for the following literature provides support for the following strategies to reduce bleeding risk:strategies to reduce bleeding risk:► Clopidogrel – Discontinue prior to CABG, reduce Clopidogrel – Discontinue prior to CABG, reduce

ASA doseASA dose

► Prasugrel – No clear strategy to reduce bleeding Prasugrel – No clear strategy to reduce bleeding risk and maintain the efficacy signalrisk and maintain the efficacy signal

► Ticagrelor – Need more data on how to reduce Ticagrelor – Need more data on how to reduce non-CABG related bleeding risknon-CABG related bleeding risk

Case Study in Antiplatelet Therapy—Case Study in Antiplatelet Therapy—Audience Response SystemAudience Response System

Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization LaboratoriesDirector, Cardiovascular Catheterization Laboratories

Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of Vermont

A 62-Year-Old Male Presents With Chest Pain for A 62-Year-Old Male Presents With Chest Pain for Four Hours to a Non-PCI Community HospitalFour Hours to a Non-PCI Community Hospital

28 Miles by Highway28 Miles by Highway Community ED Activates UVM Community ED Activates UVM Cath Lab: Prepare Transfer for Cath Lab: Prepare Transfer for

Primary PCIPrimary PCI

Question # 1Question # 1The initial ED antiplatelet therapy should be:

a) b) c) d) e)

9% 7%

35%

21%28%

a)a) ASA 325 mg and then 325 qd ASA 325 mg and then 325 qd indefinitelyindefinitely

b)b) ASA 81 mg and then 81 qd ASA 81 mg and then 81 qd indefinitelyindefinitely

c)c) ASA 325 mg and then change to ASA 325 mg and then change to 81 mg after 24 hours81 mg after 24 hours

d)d) ASA 325 mg and then change to ASA 325 mg and then change to 81 mg at discharge81 mg at discharge

e)e) ASA 325 mg and then change to ASA 325 mg and then change to 81 mg after a month or if GI side 81 mg after a month or if GI side effectseffects

ASA Dose ComparisonASA Dose ComparisonPrimary Outcome and BleedingPrimary Outcome and Bleeding

ASA ASA

75-100 mg75-100 mg

ASAASA300-325 300-325

mgmgHRHR 95% CI95% CI PP


PCI (2N=17,232)PCI (2N=17,232) 4.24.2 4.14.1 0.980.98 0.84-1.130.84-1.13 0.760.76

No PCI (2N=7855)No PCI (2N=7855) 4.74.7 4.44.4 0.920.92 0.75-1.140.75-1.14 0.440.44



TIMI Major BleedTIMI Major Bleed 1.031.03 0.970.97 0.940.94 0.73-1.210.73-1.21 0.710.71

CURRENT Major CURRENT Major BleedBleed 2.32.3 2.32.3 0.990.99 0.84-1.170.84-1.17 0.900.90

CURRENT Severe CURRENT Severe BleedBleed 1.71.7 1.71.7 1.001.00 0.83-1.210.83-1.21 1.001.00

Question # 2 The current STEMI algorithm mandates 600 mg clopidogrel prior to transfer:

However, some cardiologists would like this algorithm to be updated. You would:

a) b) c) d) e)

4%

20%

30%29%

16%

a)a) Replace clopidogrel 600 mg with Replace clopidogrel 600 mg with prasugrel 60 mg for all STEMI patientsprasugrel 60 mg for all STEMI patients

b)b) Put prasugrel in community algorithm Put prasugrel in community algorithm with guidelines to use only in selected with guidelines to use only in selected patients, based on bleeding riskspatients, based on bleeding risks

c)c) Require a phone call to a cardiologist to Require a phone call to a cardiologist to determine, on an individual patient basis determine, on an individual patient basis whether clopidogrel or prasugrel is whether clopidogrel or prasugrel is optimaloptimal

d)d) No longer give clopidogrel prior to No longer give clopidogrel prior to transfer: rather, await arrival at PCI transfer: rather, await arrival at PCI center for decision on second antiplatelet center for decision on second antiplatelet agent by cath lab teamagent by cath lab team

e)e) Do not change the algorithm: Continue Do not change the algorithm: Continue 600 mg clopidogrel loading as standard 600 mg clopidogrel loading as standard of careof care

The ED Attending Gathers More The ED Attending Gathers More Clinical InformationClinical Information

► NIDDMNIDDM

► No prior h/o bleedingNo prior h/o bleeding

► HTN and Cr 1.6HTN and Cr 1.6

► No prior stroke/TIANo prior stroke/TIA

► Remote smoker; COPD Remote smoker; COPD on PRN Inhaleron PRN Inhaler

► Occasional reflux Occasional reflux symptomssymptoms

Question # 3 Question # 3 The Patient is Being Packaged for Transfer:The Patient is Being Packaged for Transfer:

What Is Your Antiplatelet Therapy of Choice Now?What Is Your Antiplatelet Therapy of Choice Now?

a) b) c) d) e)

50%

17%10%8%

15%

a)a) Give 600 mg clopidogrel in ED prior Give 600 mg clopidogrel in ED prior to transfer for PCIto transfer for PCI

b)b) Give 60 mg prasugrel in ED prior to Give 60 mg prasugrel in ED prior to transfer for PCItransfer for PCI

c)c) Define anatomy and, if not surgical, Define anatomy and, if not surgical, give 600 mg of clopidogrelgive 600 mg of clopidogrel

d)d) Define anatomy, and if not surgical, Define anatomy, and if not surgical, give 60 mg prasugrelgive 60 mg prasugrel

e)e) Give a GPI to almost all STEMI Give a GPI to almost all STEMI patients; then, give clopidogrel 600 patients; then, give clopidogrel 600 mg after anatomy defined.mg after anatomy defined.

Non-Surgical AnatomyNon-Surgical AnatomyPCI Anatomy Defined as BelowPCI Anatomy Defined as Below

Low Risk STEMI Anatomy High Risk STEMI Anatomy

Question # 4Question # 4 You Have to Make A Choice Now—Not Surgical AnatomyYou Have to Make A Choice Now—Not Surgical Anatomy

a) b) c) d) e)

67%

24%

0%5%5%

a) High risk anatomy: 60 mg prasugrel

b) High risk anatomy: but still 600 mg clopidogrel

c) Will wait and see how the PCI goes, and then decide post-PCI on choice of antiplatelet agent

d) Depends if I am using a GPI—if GPI is used, clopidogrel 600 mg is my choice.

e) Other factors will guide my prasugrel vs clopidogrel decision

Question 5: RCA Was Stented with DESQuestion 5: RCA Was Stented with DESClopidogrel 600 mg Was Already Loaded Prior to Transfer: How Will I Clopidogrel 600 mg Was Already Loaded Prior to Transfer: How Will I

Continue to Sequence Antiplatelet Therapy?Continue to Sequence Antiplatelet Therapy?

a) b) c) d) e)

48%

9%16%20%

7%

a) Clopidogrel 150 mg qd x 7 days, then 75 qd

b) Clopidogrel 150 qd in hospital, then 75 qd

c) Clopidogrel 75 qd x 12 months

d) Switch to prasugrel 10 mg qd x 15 months

e) Switch to prasugrel 10 mg qd for 30 days and then clopidogrel 75 qd x 11 months

DaysDays

Cum

ulat

ive

Haz

ard

Cum

ulat

ive

Haz

ard

0.0

0.0

0.00

40.

004

0.00

80.

008

0.01

20.

012

00 33 66 99 1212 1515 1818 2121 2424 2727 3030

Clopidogrel Standard DoseClopidogrel Standard Dose

Clopidogrel Double DoseClopidogrel Double Dose

42% 42% RRRRRR

HR 0.58HR 0.5895% CI 0.42-0.7995% CI 0.42-0.79

P=0.001P=0.001

Clopidogrel: Double vs Standard DoseClopidogrel: Double vs Standard DoseDefinite Stent ThrombosisDefinite Stent Thrombosis

Clopidogrel Double vs Standard DoseClopidogrel Double vs Standard Dose Bleeding PCI Population Bleeding PCI Population


StandardStandard

N= 8684N= 8684

DoubleDouble

N=8548N=8548

HazardHazard


TIMI MajorTIMI Major11 0.50.5 0.50.5 1.061.06 0.70-1.610.70-1.61 0.790.79

CURRENT MajorCURRENT Major22 1.11.1 1.61.6 1.441.44 1.11-1.861.11-1.86 0.0060.006

CURRENT SevereCURRENT Severe33 0.80.8 1.11.1 1.391.39 1.02-1.901.02-1.90 0.0340.034

FatalFatal 0.150.15 0.070.07 0.470.47 0.18-1.230.18-1.23 0.1250.125

ICHICH 0.0350.035 0.0460.046 1.351.35 0.30-6.040.30-6.04 0.690.69



11ICH, Hb drop ICH, Hb drop ≥ ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal22Severe bleed + disabling or intraocular or requiring transfusion of Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units2-3 units33Fatal or Fatal or ↓Hb ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

11ICH, Hb drop ICH, Hb drop ≥ ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal22Severe bleed + disabling or intraocular or requiring transfusion of Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units2-3 units33Fatal or Fatal or ↓Hb ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Question 6: RCA Stented with DESPrasugrel was loaded prior to transfer or in cath lab: Follow-Up

oral antiplatelet therapy should consist of . . .

a) b) c) d) e)

0% 0% 0%0%0%

a) Prasugrel 10 mg po qd in hospital, then switch to clopidogrel 75 qd x 12 months

b) Prasugrel 10 mg po qd x 7 days, then clopidogrel 75 qd x 12 months

c) Prasugrel 10 mg po qd x 30 days, then clopidogrel 75 mg x 11 months.

d) Prasugrel 10 mg po qd for a minimum of 12 months

e) Clopodigrel 150 mg po qd 7 days and then 75 mg po for 12 months

Antman, E. M. et al. Antman, E. M. et al. J Am Coll Cardiol J Am Coll Cardiol 2008;51:2028-20332008;51:2028-2033

Prasugrel for 3 Days, 30 Days or 15 Months?Prasugrel for 3 Days, 30 Days or 15 Months?

Question # 7Question # 7 The patient has a history of GE Reflux and is committed to

dual antiplatelet therapy for 12 months. He is placed on long-term clopidogrel therapy: You would . . .

a) b) c) d) e)

16%22%

35%

14%12%

a) Give any PPI for 12 months

b) Not give any PPI unless patient develops GI symptoms

c) Give only pantoprozole, not omeprazole, for 12 months

d) Give PPI only if using prasugrel

e) Give H2-blocker and use PPI only if symptoms occur

0.50 1.50

OverallOverall

NSTEMI/UA NSTEMI/UA STEMISTEMI

MaleMaleFemale Female

Age <= 65 yrsAge <= 65 yrsAge > 65 yrsAge > 65 yrs

Non-DiabeticNon-DiabeticPrev DiabeticPrev Diabetic

No Inhosp GPIIb/IIIaNo Inhosp GPIIb/IIIaGPIIb in hospGPIIb in hosp

No Prot Pump InhibNo Prot Pump InhibProt Pump InhibProt Pump Inhib

Non-smokerNon-smokerCurrent SmokerCurrent Smoker

ASA LowASA LowASA HighASA High

1723217232

1088610886 63466346

1300913009 42234223

1097510975 62576257

1340013400 38313831

1228812288 49364936

76757675 55575557

1084510845 63806380

86208620 86128612

4.54.5

4.24.25.05.0

4.14.15.85.8

3.03.07.17.1

4.24.25.65.6

3.93.96.06.0

3.83.85.75.7

4.94.93.83.8

4.24.24.84.8

3.93.9

3.63.64.24.2

3.63.64.64.6

2.72.76.06.0

3.63.64.94.9

3.53.54.74.7

3.23.24.24.2

4.64.62.62.6

4.34.33.53.5

0.8050.805

0.4190.419

0.7020.702

0.8360.836

0.4650.465

0.4080.408

0.0450.045

0.0240.024

0.50 1.50

3.73.7

3.63.64.04.0

3.53.54.64.6

2.92.95.25.2

3.63.64.14.1

3.13.15.25.2

3.13.14.84.8

3.93.93.43.4

3.63.63.83.8

3.03.0

3.13.12.82.8

3.03.03.03.0

2.22.24.44.4

2.82.83.63.6

2.52.54.14.1

2.32.33.33.3

3.53.52.12.1

3.23.22.72.7

0.2480.248

0.1480.148

0.4180.418

0.5670.567

0.8940.894

0.6130.613

0.0500.050

0.1910.191

CV Death, MI or StrokeCV Death, MI or StrokeCV Death, MI or StrokeCV Death, MI or Stroke MI or Stent ThrombosisMI or Stent ThrombosisMI or Stent ThrombosisMI or Stent Thrombosis

Clopidogrel: Double v Standard DoseClopidogrel: Double v Standard DosePCI Cohort SubgroupsPCI Cohort Subgroups

Std %Std % Double %Double % Std %Std % Double %Double %Intxn PIntxn P Intxn PIntxn P









2N2N

Question 8: The NICE (UK) Group has recommended Question 8: The NICE (UK) Group has recommended prasugrel only if patient has prasugrel only if patient has STEMI, Diabetes or Stent STEMI, Diabetes or Stent

Thrombosis on ClopidogrelThrombosis on Clopidogrel

a) b) c) d)

35%

19%10%

35%

a) Agree—will use prasugrel only for these indications

b) Disagree—will use prasugrel more broadly

c) Disagree—will use prasugrel in less patients due to CURRENT OASIS-7 data and high-dose clopidogrel option

d) Disagree—based on CURRENT OASIS-7, clopidogrel remains standard of care

Question 9: You’re at TCT 2010 and ticagrelor has been Question 9: You’re at TCT 2010 and ticagrelor has been approved:approved:

For this STEMI patient, you will:For this STEMI patient, you will:

a) b) c) d) e) f)

10% 10%

60%

10%

0%

10%

a)a) Start with ticagrelorStart with ticagrelor

b)b) Start with clopidogrelStart with clopidogrel

c)c) Start with prasugrelStart with prasugrel

d)d) Depends on cost of ticagrelorDepends on cost of ticagrelor

e)e) Depends on whether GPI is being Depends on whether GPI is being used for STEMIused for STEMI

f)f) Need more trial data and analysisNeed more trial data and analysis

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The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization...

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