The Evolving Science and Controversial Landscape ofAntiplatelet Therapy in theCatheterization Laboratory Mechanisms Mortality TherapeuticsPROGRAM CO-CHAIRMANDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIChief of Cardiology, VA Boston Healthcare System | Director, Integrated Interventional Cardiovascular Program, Brigham and Womens Hospital and the VA Boston Healthcare System | Senior Investigator, TIMI Group | Harvard Medical School | Boston, MassachusettsPROGRAM CO-CHAIRMANShamir Mehta, MD, MSc, FACC, FRCPCDirector, Interventional Cardiology | Hamilton Health Sciences | Associate Professor | McMaster University | Hamilton, Ontario, Canada

Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program

Program Educational ObjectivesAs a result of this session, participants will be able to: Optimize anti-ischemic efficacy, while reducing bleeding related complications and adverse events in high risk, complex patients requiring antiplatelet therapy in the setting of PCI

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

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

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

Program Faculty

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIProgram Co-ChairmanChief of CardiologyVA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular Program, Brigham and Womens Hospital and the VA Boston Healthcare SystemSenior Investigator, TIMI GroupHarvard Medical SchoolBoston, MassachusettsSunil V. Rao, MDDirector of Cardiac Catheterization LaboratoriesVeterans Administration Medical CenterDivision of Cardiovascular MedicineDuke University Medical CenterDurham, North Carolina

Shamir Mehta, MD, MSc, FACC, FRCPC(Program Co-Chairman)Director, Interventional CardiologyHamilton Health SciencesAssociate Professor| McMaster University Hamilton, OntarioCanada Harold L. Dauerman, MD, FACCDirector, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Medical CenterFletcher Allen Health Care Burlington, Vermont

Faculty COI Financial Disclosures

Shamir 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, FSCAIConsultant: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Takeda, The Medicines Company, Vertex. Principal Investigator for several potentially related studies. His institution has received funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, The Medicines Company. This presentation discusses off-label and/or investigational uses of various drugs and devices

Faculty COI Financial Disclosures

Harold 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, MDConsultant, Honoraria: Sanofi-Aventis/BMS, The Medicines Company, Terumo Corporation, Astra Zeneca, Eli Lilly/Daiichi-SankyoResearch Funding: Cordis Corporation, Momenta Pharmaceuticals, Portola PharmaceuticalsOff-label uses: 600 mg dose of Clopidogrel

Antiplatelet Therapy in PCI: Focus on Addressing the Triple End Points of Thrombosis, Bleeding, and MortalityConnecting Evidence Across Recent Landmark StudiesWhere Do New Trials, New Potencies, and New Dosing Strategies Take Us? And How Should They Direct Our Care in the Cardiac Catheterization Laboratory? Moving into a New Era of Interventional Care

Shamir Mehta, MD, MSc, FACC, FRCPCDirector, Interventional CardiologyHamilton Health SciencesAssociate Professor McMaster University Hamilton, Ontario, Canada

CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCIOASIS-7Shamir R. Mehta on behalf of the CURRENT InvestigatorsDisclosures: 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 University and the trial was overseen by an international steering committee of experts.

BackgroundClopidogrelClopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCIRecent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effect

AspirinDose of ASA varies between Europe and North AmericaNo large-scale RCTs have compared high (300-325 mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI

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

1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.2. Fox KAA, et al. Circulation 2004;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.4. Chen ZM Lancet 2005;366:1607-215. Wiviott S et al. N Engl J Med 2007; 357: 200115.

Relative Risk ReductionPCINo PCICURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)30%119%2STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)46%39%4TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)19%5Not evaluated

Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (

Baseline Characteristics and In Hospital MedsVariables equally balanced among the randomized groups*38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose clopidogrel v 40% high dose clopidogrel

BaselineN=25,088Meds After RandN=25,088Age (y)61.4GP IIb/IIIa inhibitor31.8Female27.4%Statin87.2UA/NSTEMI70.8%Beta Blocker82.5 Rand to Angio3.4 hACE/ARB75.7STEMI29.2%PPI40* Rand to Angio0.5 hH2 Blocker11.3Diabetes23.4Prior Stroke4.1Ischemic ECG 80.8 Biomarker42

ASA Dose ComparisonPrimary Outcome and BleedingNo other significant differences between ASA dose groupsGI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

ASA 75-100 mgASA300-325 mgHR95% CIPCV Death/MI/StrokePCI (2N=17,232)4.24.10.980.84-1.130.76No PCI (2N=7855)4.74.40.920.75-1.140.44Overall (2N=25,087)4.44.20.960.85-1.080.47Stent Thrombosis2.11.90.910.73-1.120.37TIMI Major Bleed1.030.970.940.73-1.210.71CURRENT Major Bleed2.32.30.990.84-1.170.90CURRENT Severe Bleed1.71.71.000.83-1.211.00

Clopidogrel Dose ComparisonTwo Significant Interactions:

PCI v No PCI (P=0.016)

ASA dose (P=0.043)

DaysCumulative Hazard0.00.010.020.030.040.05036912151821242730C Std, A LoC Std, A HiC Double, A LoC Double, A HiClopidogrel: Double vs Standard Dose Primary Outcome

Clopidogrel StandardClopidogrel DoubleHRPP IntnASA 300-325 mg4.63.80.830.0360.043ASA 75-100 mg4.24.51.070.43

Clopidogrel: Double vs Standard DosePrimary Outcome and Components

StandardDouble HR95% CIPIntn PCV Death/MI/StrokePCI (2N=17,232)4.53.90.850.74-0.990.0360.016No PCI (2N=7855)4.24.91.170.95-1.440.14Overall (2N=25,087)4.44.20.950.84-1.070.370MIPCI (2N=17,232)2.62.00.780.64-0.950.0120.025No PCI (2N=7855)1.41.71.250.87-1.790.23Overall (2N=25,087)2.21.90.860.73-1.030.097CV DeathPCI (2N=17,232)1.91.90.960.77-1.190.681.0No PCI (2N=7855)2.82.70.960.74-1.260.77Overall (2N=25,087)2.22.10.960.81-1.140.628StrokePCI (2N=17,232)0.40.40.880.55-1.410.590.50No PCI (2N=7855)0.80.91.110.68-1.820.67Overall (2N=25,087)0.50.50.990.70-1.390.950

Clopidogrel Double vs Standard DoseBleeding Overall Population

ClopidogrelStandardN=12579 DoubleN=12508HazardRatio95% CIPCURRENT Major2.02.51.251.05-1.470.01CURRENT Severe1.51.91.231.02-1.490.03Fatal0.110.13 1.150.56-2.350.71ICH0.05 0.03 0.670.19-2.37 0.53RBC transfusion 2U1.76 2.211.261.06-1.510.01CABG-related Major0.91.01.100.85-1.420.48

DaysCumulative Hazard0.00.0040.0080.012036912151821242730Clopidogrel Standard DoseClopidogrel Double Dose42% RRRHR 0.5895% CI 0.42-0.79P=0.001Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio Confirmed)

Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients

Day 30ClopidogrelStandardN=8684%Double N=8548%Hazard Ratio95% CIP valueStent Thrombosis2.31.60.710.57-0.890.002 Definite1.20.70.580.42-0.790.001MI2.62.00.780.64-0.950.012MI or stent thrombosis3.73.00.800.68-0.940.008CV Death1.91.90.960.77-1.190.68Stroke0.40.40.880.55-1.410.59CV Death/MI/Stroke4.53.90.850.74-0.990.036

DaysCumulative Hazard0.00.010.020.030.04036912151821242730Clopidogrel: Double vs Standard Dose Primary Outcome: PCI PatientsClopidogrel StandardClopidogrel DoubleHR 0.8595% CI 0.74-0.99P=0.03615% RRRCV Death, MI or Stroke

Clopidogrel Double vs Standard DoseBleeding PCI Population

ClopidogrelStandardN= 8684DoubleN=8548HazardRatio95% CIPCURRENT Major1.11.61.441.11-1.860.006CURRENT Severe0.81.11.391.02-1.900.034Fatal0.150.070.470.18-1.230.125ICH0.0350.0461.350.30-6.040.69RBC transfusion 2U0.911.351.491.11-1.980.007CABG-related Major0.10.11.690.61-4.70.31

0.501.50OverallNSTEMI/UA STEMIMaleFemale Age 65 yrsNon-DiabeticPrev DiabeticNo Inhosp GPIIb/IIIaGPIIb in hospNo Prot Pump InhibProt Pump InhibNon-smokerCurrent SmokerASA LowASA High1723210886 634613009 422310975 625713400 383112288 4936 7675 555710845 6380 8620 86124.54.25.04.15.83.07.14.25.63.96.03.85.74.93.84.24.83.93.64.23.64.62.76.03.64.93.54.73.24.24.62.64.33.50.8050.4190.7020.8360.4650.4080.0450.0240.501.503.73.64.03.54.62.95.23.64.13.15.23.14.83.93.43.63.83.03.12.83.03.02.24.42.83.62.54.12.33.33.52.13.22.70.2480.1480.4180.5670.8940.6130.0500.191CV Death, MI or StrokeMI or Stent ThrombosisClopidogrel: Double v Standard Dose PCI Cohort SubgroupsStd %Double %Std %Double %Intxn PIntxn PDouble Dose BetterDouble Dose BetterStd Dose BetterStd Dose Better2N

Clopidogrel: Double vs Standard Dose by ASA Factorial

ClopidogrelHR95% CIPP intnStandardDoubleCV Death/MI/Stroke (Overall)ASA High4.63.80.830.70-0.990.0360.043ASA Low4.24.51.070.91-1.270.42MI/Stent Thrombosis (PCI pts)ASA High3.82.70.710.56-0.900.0050.19ASA Low3.63.20.890.71-1.120.32Major Bleed(Overall)ASA High2.22.41.080.86-1.370.510.099ASA Low1.92.71.431.13-1.810.003

Definite Stent Thrombosis in 4 Groups (Angiographically Proven)DaysCumulative Hazard0.00.0040.0080.012036912151821242730C Standard, A LowC Standard, A HighC Double, A LowC Double, A High

Standard ClopidogrelDouble ClopidogrelHRPPIntnHigh ASA1.20.60.490.003Low ASA1.20.80.60.0580.35

ConclusionsClopidogrel Dose ComparisonDouble-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI.In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG).There was a modest excess in CURRENT-defined major bleeds but no difference in ICH, fatal bleeds or CABG-related bleeds.

ConclusionsASA Dose ComparisonNo significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

Clinical ImplicationsFor every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MIs and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, ICH, or CABG-related bleeds.Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.

CURRENT-PCI findings How to translate into practice?OPTION 2PCIDouble dose (150 mg/day) for 6 days then 75 mg/dayNo PCI75 mg/dayACS (UA/NSTEMI or STEMI)600 mg load before AngiographyACS (UA/NSTEMI or STEMI)OPTION 1300 mg load before AngiographyPCI+ 300 mg loadDouble dose (150 mg/day) for 6 days then 75 mg/dayNo PCINo additional load75 mg/day

Clopidogrel and Proton Pump Inhibitors Is There an Interaction?Deepak L. Bhatt MD, MPH, FACC, FAHAChief of Cardiology, VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular Program at Brigham and Womens Hospital and the VA Boston Healthcare SystemSenior Investigator, TIMI Study GroupHarvard Medical School

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

CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI PatientsMI, stroke, or death ITT population* Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.Combined endpoint occurrence (%)Months from randomization27% RRRP=0.02Placebo*Clopidogrel*0510158.5%11.5%036912

Multivariable Predictors of Bleeding Events Discharge to 1 Year (n=1816)Aronow HD, et al. Am Heart J 2008 (published online Nov 2008)

VariableHazard Ratio (95% CI)X2P valueClopidogrel1.04 (0.75-1.44)0.050.82Age (per 10 years)1.26 (1.07-1.48)8.10.005CABG discharge-1 year32.15 (23.10-44.74)423.6

Kaplan Meier Estimates of Bleeding Risk 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 BleedingPlacebo + ASAClopidogrel + ASADays Since Randomization15601352704506308100.000080.000070.000060.000050.000040.000030.000020.000010Hazard Function/dBhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Algorithm to Assess GI Risk With Antiplatelet TherapyYesYesNoPPIYesYesBhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.Need for antiplatelet therapyAssess GI risk factorsTest for H pylori; treat if infectedHistory of ulcer complication History of ulcer disease (nonbleeding)

Dual antiplatelet therapy Concomitant anticoagulantMore than one risk factor:Aged 60 years or moreCorticosteroid useDyspepsia or GERD symptoms

Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolitePPIs are strong inhibitors of CYP2C19 activityClopidogrel and PPIs The OCLA studyPRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)Gilard et al. J Am Coll Cardiol 2008;51:256-60.p

Intake of PPIs Not Associated With Impaired Response to ClopidogrelSiller-Matula JM, et al. Am Heart J. 2009;157(1):148.e1-148.e5.Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.Adenosine diphosphateinduced platelet aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.Data are presented as mean and 95% CI. PPI, proton pump inhibitor; VASP, vasodilator-stimulated phosphoprotein.

Variability in Clopidogrel Responsiveness in a Diverse Population of 544Serebruany V, Steinhubl S et al. JACC 2005.D 5mM ADP Platelet Aggregation

Genetic Variations and Clopidogrel ResponseMega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.Pharmacokinetic ResponseRelative Percent Difference-50-40-30-20-100102030Pharmacodynamic ResponseAbsolute Difference-15-10-5051025

GenePercent Difference in AUC0-tP ValueCYP2C1932.4.001CYP2C96.8.59CYP2B615.7.03CYP3A55.6.59CYP1A211.2.45

GenePercent Difference in MPAP ValueCYP2C199.0.001CYP2C90.6.86CYP2B65.7.012CYP3A57.5.012CYP1A20.5.90

Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPIHo PM, et al. JAMA. 2009;301(9):937-944.

Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPIUnadjusted OR (95% CI)Adjusted OR (95% CI)OutcomeWith PPIWithout PPIWith PPIWithout PPIHo PM, et al. JAMA. 2009;301(9):937-944.

Primary outcome Death or rehospitalization for ACSSecondary outcomes Rehospitalization for ACS Revascularization procedures Death (all-cause)

14.816.213.29.210.87.705101520PPI at baseline (N=374)No PPI at baseline (N=1742)Primary 1-Year Endpoint:Death, MI or StrokeAllN=2116PlaceboN=1063ClopidogrelN=1053Results 1 Year Endpoint from CREDOUnadjusted DataP=0.001P=0.45Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

* Multivariate logistic regression model: PPI vs. no PPI within treatment stratum Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratumResults Clopidogrel GroupAdjusted DataDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

28 Days Death/MI/UTVRAdjusted OR (95% CI)p-value*One Year Death/MI/StrokeAdjusted HR (95% CI)p-valueClopidogrel / PPI(n=179)18/179 (10.2)1.8 (0.99, 3.23)0.05123/179 (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 stratumResults Placebo GroupAdjusted DataDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

28 Days Death/MI/UTVRAdjusted OR (95% CI)p-value*One Year Death/MI/StrokeAdjusted HR (95% CI)p-valuePlacebo / PPI(n=195)19/195 (9.8)1.4 (0.81, 2.41)0.22131/195 (16.2)1.6 (1.03, 2.34)0.035Placebo / No PPI(n=868)64/868 (7.4)91/868 (10.8)

Results 1 Year Primary Endpoint PPI at BaselineNo PPI at BaselineDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

Randomized TherapyDeath, MI or StrokeAdjusted HR (95% CI)P-valuePlacebo (N=195)16.2%0.77 (0.45, 1.33)0.35Clopidogrel (N=179)13.2%

Randomized TherapyDeath, MI or StrokeAdjusted HR (95% CI)P-valuePlacebo (N=868)10.8%0.75(0.55, 1.03)0.08Clopidogrel (N=874)7.7%

THE LANCET

CV death, MI or strokeDaysCLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11PPI use at randomization (n= 4529)ClopidogrelPrasugrelPRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

Risk of CV Events with Different Types of PPIsRabeprazole not included due to small sample size (n=66)

Type of PPIClopidogrelHR (95% CI)CV death, MI or strokePrasugrelHR (95% CI)CV death, MI or strokeOmeprazole(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)

Clopidogrel and the Optimization of GI Events Trial COGENT

Conclusions Dual antiplatelet therapy reduces important ischemic events after PCI, ACSGI bleeding is the most common form of major bleeding that occursLogical, though not proved, that prophylactic PPI reduces this GI bleeding Patients prescribed PPI are a higher risk than those who are notWhile pathways for an interaction exist, unclear degree of clinical relevance

Antiplatelet Therapy in High Risk Patients:Does One Size Fit All?Harold L. Dauerman, MDDirector, Cardiovascular Catheterization Laboratories Professor of MedicineUniversity 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 Therapy

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

STEMI:The Vermont AlgorithmUFH (60 U/Kg)Beta Blockers only if HTN UFH or BivalirudinBeta Blockers ONLY if HTNPCI Capability or < 60 minute Transfer TimeNo PCI Capability and > 60 minute Transfer TimePrimary PCI with Stenting:GPI/Thrombectomy if Large Thrombusor as Bailout; Otherwise, Bivalirudin Alone90 minutesTo OpenArtery Lytic ContraindicatedEmergent TransferFull Dose Ly tic and UFHTransfer from Community ERTo PCI SiteIf no CP and less than 50% ST Elevations, PCI at 12-24Hours with StentIf Reperfusion Fails,Emergent PCI with StentASA/ClopidogrelStatinGroin ClosureCardiac RehabLopressor 12.5 bidTransferRescue PCI:Class I IndicationThe NSTEMI Paradigmof 4-48 HoursASA 325 poClopidogrel600 poClopidogrel 300 poContinue bivalirudin for 2 hours after PCI

Guigliano, RNEJM 2009:

The EARLY ACS TRIAL

No Clear Benefit of UpstreamGPI

One Size Does Fit AllGiugliano, NEJM 2009

FINESSE: Keeping the Simple Algorithm IntactEllis SG et al. N Engl J Med 2008;358:2205-2217

End pointPrimary PCI (%)Abciximab-facilitated (%)Combination (abciximab/reteplase)-facilitated (%)p, combination-facilitated vs primary PCIp, combination-facilitated vs abciximab-facilitatedCardiogenic shock6.84.85.3NSNSVF0.40.20.6NSNSTIMI major bleeding2.64.14.80.025NSTIMI minor bleeding4.36.09.7

Bleeding Complications and theElderly Patient Ahmed and Dauerman, Circulation: Cardiovascular Interventions September 2009Major vascular complications, %**Arterial injury and/or arterial injury-related bleeding among womenN=13,653 patients undergoing PCIP

Both Bleeding and Thrombotic Events MatterCK-MB Symptomatic MITVRDEATHTVRBleedingCK-MB Symptomatic MIDEATHGPI AntagonistsBivalirudin19982009Adapted from Dauerman HL, J Am Coll Feb 2007Prasugrel and Ticagrelor

Wiviott, S. D. et al. Circulation 2007;116:2923-2932Prevention of Thrombotic Complications:Pharmacology of New ADP Receptor AntagonistsNovel ADP receptor antagonists: Ticagrelor and prasugrelMore potent inhibition of platelet aggregationEarlier inhibition of platelet aggregationPRINCIPLE-TIMI44: Phase II pharmacokinetic studyVasodilator-stimulated phosphoprotein (VASP): Assessment of the extent of phosphorylation of VASP reflects specifically inhibition of the P2Y12 receptor

Stent Thrombosis and TRITON TIMI 38

01230306090180270360450HR 0.48 P

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

CURRENT OASIS-7: S. Mehta, ESC 2009Safety/efficacy for 300 mg in elderlyUnknown risk of 600 mg loading dose12 month compliance Defining optimum loading dose Defining optimum timing of load Defining maintenance dose 12 month complianceNo safety or efficacy data Risk/benefit in patients with high incidence of bleeding complications Risk/benefit in patients with increased potential for CABG during follow up 12 month compliance Potential for switching high bleeding risk patients to clopidogrel after 30 days. HL Dauerman, Am J Cardiology 2009FibrinolysisPrimary PCIAspirinClopidogrelPrasugrel

Alexander, K. P. et al. Circulation 2007;115:2549-2569The Platelet Gap in Clinical Trials: TRITON TIMI 3813% Elderly EnrollmentNSTE ACS Populations (n=1,190,721)Proportion of Age Group > 75 Years (%)18%38%

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We Can Not Have a Simple Statewide ACS Algorithm with Prasugrel

BOVERALLNo GPIGPIDESBMSDMNo DM>7565-74 60CrCl < 601420Wiviott SD, NEJM 357: 2001-2015, 2007

Net Clinical Benefit Analysis:Do Not Load Prasugrel For Our 87-Year-Old Patient OVERALL>=60 kg< 60 kg< 75>=75NoYes0.512Prior Stroke / TIAAgeWgtRisk (%)+ 37-16-1-16+3-14-13Prasugrel BetterClopidogrel BetterHRPint = 0.006Pint = 0.18Pint = 0.36

Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033 Selective Cardiology-Guided Loading and Continuation

Controlling Bleeding Risk with a Switching Strategy for Prasugrel: Prasugrel 10 mg = Clopidogrel 600 mgPayne et al. Platelets. 2008;19(4):275-281

Newer Drugs for ACS and STEMI:Mortality Benefit Can Not Be IgnoredSeptember 1, 2009

Should This Reversible Drug Become a Standard?Side Effects and Non-CABG Related Bleeding ComplicationsA. Schomig, NEJM Editorial, 2009

Defining Current Options for Antiplatelet TherapyShould this community hospital have a single algorithm for care?Upstream or downstream GPI?Clopidogrel or prasugrel?What if this patient was in your emergency department?If a default universal algorithm is used, then it must default to safety: clopidogrel load only.No GPI upstream or downstream.ASA 325 mg po x 1, clopidogrel 600 po x 1, 150 po qd in hospital, then 75 qd for 1 year with ASA 81 qd indefinitely.PPI was not initially given but 4 weeks later, reflux occurred, and PPI was initiated. No change in Tx.The future of the PCI center: EDASA 325 mg and then decision re: prasugrel vs clopidogrel by telephone consult with interventional cardiologist in cath lab or on cardiac floor.

ConclusionsAntiplatelet Therapy Across the SpectrumAlgorithms for ACS and STEMI care have advanced care in terms of quality and efficiency

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

The advent of prasugrel and ticagrelor potentially removes the decision re: choice of a second antiplatelet agent from the emergency department and back into the realm of cardiology-based clinical judgment. One Size Does Not Fit All

Sunil V. Rao MDDirector of Cardiac Catheterization LaboratoriesThe Duke Clinical Research InstituteThe Durham VA Medical CenterDuke University Medical CenterBleeding is the Red line in the sand for Antiplatelet therapy: Avoiding Complications in the Cath Lab & Beyond

Bleeding and antiplatelet therapyIssues we will discussReducing events among clopidogrel hyporesponders is a clinical priorityIntensification of antiplatelet effect is associated with improvement in some ischemic outcomes, but what about the bleeding?Acute CABG-related bleedingChronic bleeding riskCan we compare safety results from different clinical trials?In the modern era of multiple antiplatelet options, what factors must be weighed in making the therapeutic decision?

The Current Egalitarian Strategy of Antiplatelet Therapy During And After PCI: The More The Merrier for Everyone!Single Antiplatelet RxDual Antiplatelet RxHigher IPAReduction in Ischemic EventsIncrease in Major BleedsAdapted from Gibson, AHA 2007

IPA Responses to ClopidogrelAdapted from: Serebruany V et al. J Am Coll Cardiol. 2005.

Risk vs. Benefit What Affects Efficacy and Safety?

Major Bleeding: Incidence* inClinical Trials with Active AgentClop + ASAPras + ASATicag + ASAClop + ASA600mg + 325 mgYusuf S NEJM 2001Wiviott SD NEJM 2007Wallentin L NEJM 2009Mehta SR NEJM 2009

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

DefinitionTIMI1GUSTO2 CURE3TrialTRITONCHARISMACUREMajor fatal / life threatening or severe bleedingFatal / life threatening (related to instrumentation, spontaneous, trauma), ICH, Hb 5 g/dL, or absolute HCT 15%Fatal, ICH, or causes haemodynamic compromise and requires interventionFatal / Life threateningFatal, ICH, requires surgery, hypotension requiring inotropes, Hb 5 g/dL, or transfusion 4 U Other majorDisabling, intraocular with vision loss, or transfusion 2-3 U

PLATO4PLATOFatal / Life threateningFatal, ICH, intrapericardial with tamponade, hypovolaemic shock / hypotension requiring pressors or surgery, Hb >5 g/dL, or transfusion 4 U

Other majorDisabling (intraocular with permanent vision loss), Hb 3-5 g/dL, or transfusion 2-3 U

Bleeding and Evidence-based TherapiesN=2498 ACS patients from the PREMIER RegistryDischarge ASA and thienopyridinePts. with bleeding vs. pts. without bleedingWang TY, et. al. Circulation 2008Discharge

1 Month

6 Months

1 YearAspirinOR (95% CI)ThienopyridineOR (95% CI)0.5 1.0 2.00.5 1.0 2.00.45 (0.31, 0.64)0.68 (0.50, 0.92)0.63 (0.46, 0.87)0.62 (0.42, 0.91)0.94 (0.66, 1.34)0.83 (0.59, 1.17)1.06 (0.78, 1.45)1.12 (0.81, 1.55)

Nuisance Bleeding and Drug DiscontinuationN=2360 unselected pts. receiving DESProspective data collectionMajor events adjudicatedSerebruany bleeding classification*Roy P, et. al. AJC 2008*Alarming bleeding = ICH, life-threatening, + transfusionInternal bleeding = hematoma, epistaxis, mouth or vaginal,Melena, IO, hematuria or hematemesisNuisance bleeding = bruising, petechiae, ecchymosis

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PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine TherapySpertus JA, et al. Circulation. 2006

CURE Major Bleeding *Includes fatal bleeding**Includes life-threatening & fatal bleedingYusuf S, et. al. NEJM 2001P=NSP=0.13P=0.001%

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Clopidogrel and ASA for NSTE ACS CABG-Related Bleeding in CUREp=0.001Clopidogrel d/c> 5 daysClopidogrel d/c< 5 daysCure Investigators, NEJM 2001

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North45.94543.9

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

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

*Other standard therapies were used as appropriate. .CURE: Major Bleeding by Aspirin Dose Through Follow-UpPeters RJ, et al. Circulation. 2003

Aspirin DosePlacebo + Aspirin*Clopidogrel + Aspirin*75-100 mg1.9%3.0%101-199 mg2.8%3.4%200-325 mg3.7%4.9%

Clopidogrel: Double vs Standard Dose by ASA FactorialMehta SR, et. al. NEJM 2009TIMI Major bleeding:600 mg vs. 300 mg Clop 0.5% vs. 0.5%, P=0.50325 mg ASA vs. 100 mg ASA 1.03% vs. 0.97%, P=0.71

ClopidogrelHR95% CIPP intnStandardDoubleCV Death/MI/Stroke (Overall)ASA High4.63.80.830.70-0.990.0360.043ASA Low4.24.51.070.91-1.270.42MI/Stent Thrombosis (PCI pts)ASA High3.82.70.710.56-0.900.0050.19ASA Low3.63.20.890.71-1.120.32Major Bleed (Overall)ASA High2.22.41.080.86-1.370.510.099ASA Low1.92.71.431.13-1.810.003

Clopidogrel and bleedingAdding clopidogrel to ASA increases bleeding risk overallNo increase in life-threatening or fatal bleedingIncreased risk of CABG-related bleeding, but to reduce this risk, discontinue clopidogrel 5d priorHigher clopidogrel and ASA dose associated with better ischemic outcomes in PCI patientsIncreased bleeding risk, but no increase in fatal bleeding or TIMI major bleeding

-20.00.020.040.060.080.0100.0Inhibition of platelet aggregation (%)Response to prasugrelResponse to clopidogrelClopidogrel responderClopidogrel non-responderInterpatient variabilityInterpatient variabilityResponder = 25% IPA at 4 and 24 hoursBrandt JT, et al. Am Heart J. 2007;153:66.e9-e16.Clopidogrel vs. Prasugrel At 24 hrs (healthy volunteers)Overcoming clopidogrel hyporesponsivenessChange the drug

Bleeding EventsSafety Cohort (N=13,457)% EventsARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0% P=0.74 ARD 0.3% P=0.002 ClopidogrelPrasugrel ICH in Pts w Prior Stroke/TIA (N=518)Clop 0 (0) % Pras 6 (2.3)% (P=0.02)

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TRITON-TIMI 38Early and late non CABG bleedingWiviott S, et. al. NEJM 2007

Net Clinical Benefit:Bleeding Risk SubgroupsPost-hoc Analysis OVERALL 60 kg< 60 kg< 75 75NoYes0.512Prior stroke / TIAAgeWgtRisk (%)+ 54-16-1-16+3-14-13HRPint = .006Pint = .18Pint = .36Wiviott SD, NEJM, 2007

Modified Folts Model of Thrombosis and Haemostasis in Anaesthetised DogsBalancing Efficacy and Safety: Antithrombotic Effect vs Bleeding Time*A compound chemically indistinguishable from prasugrel.Adapted from van Giezen JJJ, et al. 9th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 2008AZD6140ClopidogrelAZD11703072*

PLATO - Total Major BleedingMajor 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;357:200115; *Proportion of patients (%); NS = not significant Wallentin L, et. al. NEJM 2009

PLATO - Non-CABG and CABG-related Major BleedingWallentin L, et. al. NEJM 2009

Offset of Ticagrelor and ClopidogrelStorey RF, et. al. JACC 2007

Newer Oral Antiplatelet AgentsPrasugrel and ticagrelor provide greater platelet inhibition compared with clopidogrelPrasugrel is associated with increases in major bleeding, fatal bleeding, and CABG-related bleedingUnacceptable risks in age > 75 yrs, Weight < 60 kg, Prior stroke/TIATicagrelor associated with improved survival and no increase in bleeding overall, but increases in non-CABG related bleeding

Making Decisions: The Clinical Necessity of Comparing Across Trials

CURRENT PCIN=17,232TRITONN=13,608PLATON=18,624CV Death, MI or Stroke 15% 21% (w high dose ASA) 19% 16% 16% in deathDefinite Stent Thrombosis 42% 51% (w high dose ASA) 58% 33%TIMI Major BleedNo increase 32%No increaseCABG-related BleedingNo increase 4-foldNo increase 19-25% in non-CABG bldFatal bleedingNo increase 4-foldNo increase

PRT060128 (Elinogrel) A Reversible P2Y12 InhibitorN= 50 pts with HPR on 75 mg clopidogrel dailyGurbel PA, AHA 2008

INNOVATE-PCI Trial800 elective PCI patientsClopidogrelLoad 90d therapyPRT 128IV- Oral for 90d24 hr death/MI/TVR60d death/MI/TVR24 hr & 60d Clinically relevant major/minor bleeding24 hr & 60d Nuisance bleeding24 hr & 60d TIMI Major and Minor bleeding

Bleeding and Antiplatelet TherapyConclusions (1)Several options for oral antiplatelet therapy now exist (with more coming)New options address undertreatmentIncrease ASA + Clopidogrel dosePrasugrelTicagrelorEfficacy signal improved with all of the above strategies compared with control arm with some caveatsCURRENT PCI subgroup experienced benefitTRITON No medical therapy; No benefit in age 75 years, prior TIA/Stroke, low body weight

Bleeding and Antiplatelet TherapyConclusions (2)With similar efficacy signals across trials, assessing bleeding is importantDiffering definitions across trials make it difficult to compare, butGeneral conceptsClopidogrel + ASA = greater bleeding than ASA alonePrasugrel + ASA = greater bleeding than clopidogrel + ASATicagrelor + ASA = greater non-CABG related bleeding than clopidogrel + ASA (but no difference in CABG-related bleeding)

Bleeding and Antiplatelet TherapyConclusions (3)In the era of three therapeutic options to increase the efficacy of antiplatelet agents, the literature provides support for the following strategies to reduce bleeding risk:Clopidogrel Discontinue prior to CABG, reduce ASA dosePrasugrel No clear strategy to reduce bleeding risk and maintain the efficacy signalTicagrelor Need more data on how to reduce non-CABG related bleeding risk

Case Study in Antiplatelet TherapyAudience Response SystemHarold L. Dauerman, MDDirector, Cardiovascular Catheterization Laboratories Professor of MedicineUniversity of Vermont

A 62-Year-Old Male Presents With Chest Pain for Four Hours to a Non-PCI Community Hospital28 Miles by HighwayCommunity ED Activates UVM Cath Lab: Prepare Transfer for Primary PCI

Question # 1The initial ED antiplatelet therapy should be:

ASA 325 mg and then 325 qd indefinitely ASA 81 mg and then 81 qd indefinitely ASA 325 mg and then change to 81 mg after 24 hours ASA 325 mg and then change to 81 mg at discharge ASA 325 mg and then change to 81 mg after a month or if GI side effects

ASA Dose ComparisonPrimary Outcome and Bleeding

ASA 75-100 mgASA300-325 mgHR95% CIPCV Death/MI/StrokePCI (2N=17,232)4.24.10.980.84-1.130.76No PCI (2N=7855)4.74.40.920.75-1.140.44Overall (2N=25,087)4.44.20.960.85-1.080.47Stent Thrombosis2.11.90.910.73-1.120.37TIMI Major Bleed1.030.970.940.73-1.210.71CURRENT Major Bleed2.32.30.990.84-1.170.90CURRENT Severe Bleed1.71.71.000.83-1.211.00

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:

Replace clopidogrel 600 mg with prasugrel 60 mg for all STEMI patients Put prasugrel in community algorithm with guidelines to use only in selected patients, based on bleeding risks Require a phone call to a cardiologist to determine, on an individual patient basis whether clopidogrel or prasugrel is optimal No longer give clopidogrel prior to transfer: rather, await arrival at PCI center for decision on second antiplatelet agent by cath lab team Do not change the algorithm: Continue 600 mg clopidogrel loading as standard of care

The ED Attending Gathers More Clinical InformationNIDDMNo prior h/o bleedingHTN and Cr 1.6No prior stroke/TIARemote smoker; COPD on PRN InhalerOccasional reflux symptoms

Question # 3 The Patient is Being Packaged for Transfer:What Is Your Antiplatelet Therapy of Choice Now?

Give 600 mg clopidogrel in ED prior to transfer for PCI Give 60 mg prasugrel in ED prior to transfer for PCI Define anatomy and, if not surgical, give 600 mg of clopidogrel Define anatomy, and if not surgical, give 60 mg prasugrel Give a GPI to almost all STEMI patients; then, give clopidogrel 600 mg after anatomy defined.

Non-Surgical AnatomyPCI Anatomy Defined as BelowLow Risk STEMI AnatomyHigh Risk STEMI Anatomy

Question # 4 You Have to Make A Choice NowNot Surgical AnatomyHigh risk anatomy: 60 mg prasugrel High risk anatomy: but still 600 mg clopidogrel Will wait and see how the PCI goes, and then decide post-PCI on choice of antiplatelet agent Depends if I am using a GPIif GPI is used, clopidogrel 600 mg is my choice. Other factors will guide my prasugrel vs clopidogrel decision

Question 5: RCA Was Stented with DESClopidogrel 600 mg Was Already Loaded Prior to Transfer: How Will I Continue to Sequence Antiplatelet Therapy?Clopidogrel 150 mg qd x 7 days, then 75 qd Clopidogrel 150 qd in hospital, then 75 qd Clopidogrel 75 qd x 12 months Switch to prasugrel 10 mg qd x 15 months Switch to prasugrel 10 mg qd for 30 days and then clopidogrel 75 qd x 11 months

DaysCumulative Hazard0.00.0040.0080.012036912151821242730Clopidogrel Standard DoseClopidogrel Double Dose42% RRRHR 0.5895% CI 0.42-0.79P=0.001Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis

Clopidogrel Double vs Standard Dose Bleeding PCI Population1ICH, Hb drop 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or Hb 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of 4 units

ClopidogrelStandardN= 8684DoubleN=8548HazardRatio95% CIPTIMI Major10.50.51.060.70-1.610.79CURRENT Major21.11.61.441.11-1.860.006CURRENT Severe30.81.11.391.02-1.900.034Fatal0.150.070.470.18-1.230.125ICH0.0350.0461.350.30-6.040.69RBC transfusion 2U0.911.351.491.11-1.980.007CABG-related Major0.10.11.690.61-4.70.31

Question 6: RCA Stented with DESPrasugrel was loaded prior to transfer or in cath lab: Follow-Uporal antiplatelet therapy should consist of . . .Prasugrel 10 mg po qd in hospital, then switch to clopidogrel 75 qd x 12 months Prasugrel 10 mg po qd x 7 days, then clopidogrel 75 qd x 12 months Prasugrel 10 mg po qd x 30 days, then clopidogrel 75 mg x 11 months. Prasugrel 10 mg po qd for a minimum of 12 months Clopodigrel 150 mg po qd 7 days and then 75 mg po for 12 months

Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033 Prasugrel for 3 Days, 30 Days or 15 Months?

Question # 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 . . .Give any PPI for 12 months Not give any PPI unless patient develops GI symptoms Give only pantoprozole, not omeprazole, for 12 months Give PPI only if using prasugrel Give H2-blocker and use PPI only if symptoms occur

0.501.50OverallNSTEMI/UA STEMIMaleFemale Age 65 yrsNon-DiabeticPrev DiabeticNo Inhosp GPIIb/IIIaGPIIb in hospNo Prot Pump InhibProt Pump InhibNon-smokerCurrent SmokerASA LowASA High1723210886 634613009 422310975 625713400 383112288 4936 7675 555710845 6380 8620 86124.54.25.04.15.83.07.14.25.63.96.03.85.74.93.84.24.83.93.64.23.64.62.76.03.64.93.54.73.24.24.62.64.33.50.8050.4190.7020.8360.4650.4080.0450.0240.501.503.73.64.03.54.62.95.23.64.13.15.23.14.83.93.43.63.83.03.12.83.03.02.24.42.83.62.54.12.33.33.52.13.22.70.2480.1480.4180.5670.8940.6130.0500.191CV Death, MI or StrokeMI or Stent ThrombosisClopidogrel: Double v Standard Dose PCI Cohort SubgroupsStd %Double %Std %Double %Intxn PIntxn PDouble Dose BetterDouble Dose BetterStd Dose BetterStd Dose Better2N

Question 8: The NICE (UK) Group has recommended prasugrel only if patient has STEMI, Diabetes or Stent Thrombosis on ClopidogrelAgreewill use prasugrel only for these indications Disagreewill use prasugrel more broadly Disagreewill use prasugrel in less patients due to CURRENT OASIS-7 data and high-dose clopidogrel option Disagreebased on CURRENT OASIS-7, clopidogrel remains standard of care

Question 9: Youre at TCT 2010 and ticagrelor has been approved:For this STEMI patient, you will:Start with ticagrelor Start with clopidogrel Start with prasugrel Depends on cost of ticagrelor Depends on whether GPI is being used for STEMI Need more trial data and analysis

************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, and 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).

Reference:Steinhubl S, Berger P, Tift Mann III J, et al. JAMA. 2002;Vol 288,No 19:2411-2420.****According to the consensus document:If a patient needs antiplatelet therapy, the clinician should assess the patients GI risk factors. [Bhatt p7]If the patient has a history of ulcer complication or of nonbleeding ulcer disease, evaluate whether H pylori infection is present and treat if indicated, before starting chronic antiplatelet tharapy. [Bhatt p7,8]Proton pump inhibitors should be prescribed if the patient has GI bleeding, is receiving dual antiplatelet therapy, or is receiving a concomitant anticoagulant. [Bhatt p7]If none of these risk factors are present, the patient should still receive a proton pump inhibitor if more than one of the following apply: [Bhatt p7]The patient is age 60 or olderThe patient uses corticosteroidsThe patient has dyspepsia or symptoms of gastroesophageal reflux disease.Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation 2008 in press; epub Oct 3 ahead of print.*Poor responders = 16 placebo and 39 in omeprazolePRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI recheckedGraph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically?*Responsiveness to clopidogrel was assessed by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 300 patients with coronary artery disease undergoing PCI. All patients received a clopidogrel loading dose (600 mg) at the start of clopidogrel treatment. Patients had been on clopidogrel (75 mg/d) and aspirin (100 mg/d) treatment for 3 months on average (at least 5 days) at the time of inclusion.The mean platelet reactivity index (PRI, assessed by the VASP assay) was similar in patients with any PPI (n=226; PRI = 51%) or without any PPI (n=74; PRI = 49%; P=.724) treatment. Likewise, the adenosine diphosphateinduced platelet aggregation did not differ significantly between patients with or without PPI treatment (45 vs 41 U; P=.619). Similarly, as shown in the figures on the slide, there was no difference in the PRI or the adenosine diphosphateinduced platelet aggregation between patients with pantoprazole (n=152; PRI = 50%; aggregation = 47 U), esomeprazole (n=74; PRI = 54%; aggregation = 42 U), or without PPI (n=74; PRI = 49%; aggregation = 40 U; P=.382).Thus, in contrast to the reported negative omeprazole-clopidogrel drug interaction, the intake of pantoprazole or esomeprazole is not associated with impaired response to clopidogrel.Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009;157(1):148.e1-148.e5.*In this retrospective cohort study by Ho and colleagues, concomitant use of clopidogrel and a proton pump inhibitor (PPI) after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without a PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.Of 8205 patients with ACS taking clopidogrel after hospital discharge, 63.9% (n=5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n=2961) were not prescribed PPI. Median follow-up after hospital discharge was 521 days (interquartile range, 305-779 days). Death or rehospitalization for ACS occurred in 20.8% (n=615) of patients prescribed clopidogrel without PPI and 29.8% (n=1561) of patients prescribed clopidogrel plus PPI.In multivariable analysis, use of clopidogrel plus PPI at any point in time was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio, 1.25; 95% CI, 1.11-1.41).In multivariable analyses with medication use as a time-varying covariate, periods of use of clopidogrel without PPI were associated with a significantly lower risk of adverse events compared with periods without the use of either clopidogrel or PPI (P