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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
Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
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
Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
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
CV Death/MI/StrokeCV Death/MI/Stroke
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
Overall (2N=25,087)Overall (2N=25,087) 4.44.4 4.24.2 0.950.95 0.84-1.070.84-1.07 0.3700.370
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
Overall (2N=25,087)Overall (2N=25,087) 2.22.2 1.91.9 0.860.86 0.73-1.030.73-1.03 0.0970.097
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
Overall (2N=25,087)Overall (2N=25,087) 2.22.2 2.12.1 0.960.96 0.81-1.140.81-1.14 0.6280.628
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
Overall (2N=25,087)Overall (2N=25,087) 0.50.5 0.50.5 0.990.99 0.70-1.390.70-1.39 0.9500.950
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
Stent ThrombosisStent Thrombosis 2.32.3 1.61.6 0.710.71 0.57-0.890.57-0.89 0.0020.002
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
ClopidogrelClopidogrel
StandardStandard
N= 8684N= 8684
DoubleDouble
N=8548N=8548
HazardHazard
RatioRatio95% CI95% CI PP
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
RBC transfusion RBC transfusion ≥≥ 2U2U 0.910.91 1.351.35 1.491.49 1.11-1.981.11-1.98 0.0070.007
CABG-related MajorCABG-related Major 0.10.1 0.10.1 1.691.69 0.61-4.70.61-4.7 0.310.31
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
Double Dose Double Dose BetterBetter
Double Dose Double Dose BetterBetter
Double Dose Double Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
2N2N2N2N
ClopidogrelClopidogrel
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
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†
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
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
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
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
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
ClopidogrelClopidogrel
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
ClopidogrelClopidogrel
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
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
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
ClopidogrelClopidogrel
StandardStandard
N= 8684N= 8684
DoubleDouble
N=8548N=8548
HazardHazard
RatioRatio95% CI95% CI PP
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
RBC transfusion RBC transfusion ≥≥ 2U2U 0.910.91 1.351.35 1.491.49 1.11-1.981.11-1.98 0.0070.007
CABG-related MajorCABG-related Major 0.10.1 0.10.1 1.691.69 0.61-4.70.61-4.7 0.310.31
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
Double Dose Double Dose BetterBetter
Double Dose Double Dose BetterBetter
Double Dose Double Dose BetterBetter
Double Dose Double Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
Std Dose Std Dose BetterBetter
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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