1. Antiplatelet Therapy in the Catheterization Laboratory
Mechanisms ● Mortality ● Therapeutics
The Evolving Science and Controversial Landscape of
Antiplatelet Therapy in the
Catheterization Laboratory
PROGRAM CO-CHAIRMAN
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI
Chief of Cardiology, VA Boston Healthcare System | Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System | Senior Investigator, TIMI Group | Harvard Medical School | Boston, Massachusetts
PROGRAM CO-CHAIRMAN
Shamir Mehta, MD, MSc, FACC, FRCPC
Director, Interventional Cardiology | Hamilton Health Sciences | Associate Professor | McMaster University | Hamilton, Ontario, Canada

2. 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

3. Program Educational Objectives
As 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

4. Program Faculty Deepak L. Bhatt, MD, MPH,
FACC, FAHA, FSCAI
Program Co-Chairman
Chief of Cardiology
VA Boston Healthcare System
Director, Integrated Interventional Cardiovascular Program,   Brigham and Women’s Hospital and the VA Boston Healthcare System
Senior Investigator, TIMI Group
Harvard Medical School
Boston, Massachusetts
Sunil V. Rao, MD
Director of Cardiac Catheterization Laboratories
Veterans Administration Medical Center
Division of Cardiovascular Medicine
Duke University Medical Center
Durham, North Carolina
Shamir Mehta, MD, MSc, FACC, FRCPC
(Program Co-Chairman)
Director, Interventional Cardiology
Hamilton Health Sciences
Associate Professor | McMaster University
Hamilton, Ontario
Canada
Harold L. Dauerman, MD, FACC
Director, Cardiovascular Catheterization Laboratories
Professor of Medicine
University of Vermont Medical Center
Fletcher Allen Health Care
Burlington, Vermont

5. Faculty COI Financial Disclosures
Shamir Mehta, MD, MSc, FACC, FRCPC
Grant/Research Support: Bristol-Myers Squibb Company, GlaxoSmithKline, sanofi-aventis
Consultant: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventis
Honorarium: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventis
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI
Consultant: 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

6. Faculty COI Financial Disclosures
Harold L. Dauerman, MD, FACC
Current Research Grants: Medtronic, Abbott Vascular, Boston Scientific
Current Advisory Board or Consulting: BMS, The Medicines Company, St. Jude Medical, Abbott Vascular
Sunil V. Rao, MD
Consultant, Honoraria: Sanofi-Aventis/BMS, The Medicines Company, Terumo Corporation, Astra Zeneca, Eli Lilly/Daiichi-Sankyo
Research Funding: Cordis Corporation, Momenta Pharmaceuticals, Portola Pharmaceuticals
Off-label uses: 600 mg dose of Clopidogrel

7. Shamir Mehta, MD, MSc, FACC, FRCPC
Antiplatelet Therapy in PCI: Focus on Addressing the Triple End Points of Thrombosis, Bleeding, and Mortality—Connecting Evidence Across Recent Landmark Studies
Where 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, FRCPC
Director, Interventional Cardiology
Hamilton Health Sciences
Associate Professor
McMaster University
Hamilton, Ontario, Canada

8. OASIS-7
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 PCI
Shamir R. Mehta on behalf of the CURRENT Investigators
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 University and the trial was overseen by an international steering committee of experts.

9. Background Clopidogrel Aspirin
Clopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCI
Recent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effect
Aspirin
Dose of ASA varies between Europe and North America
No large-scale RCT’s have compared high ( mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI

10. Relative Risk Reduction
Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI
Relative Risk Reduction
PCI
No PCI
CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)
30%1
19%2
STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)
46%3
9%4
TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)
19%5
Not evaluated
1. Mehta SR, et al. Lancet 2001; 358(9281):
2. Fox KAA, et al. Circulation 2004;110:1202-8
3. Sabatine MS, et al. JAMA 2005; 294(10):
4. Chen ZM Lancet 2005;366:
5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

11. Study Design, Flow and 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%)
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):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose ( mg/d) vs Low dose ( mg/d)
Angio 24,769 (99%)
PCI 17,232
(70%)
No PCI 7,855 (30%)
No Sig. CAD 3,616
No Sig. CAD 3,616
CABG 1,809
CABG 1,809
CAD 2,430
Compliance:
Clopidogrel in 1st 7d d 2 d 7d
7d (median)
Efficacy Outcomes: CV Death, MI or stroke at day 30
Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)
Key Subgroup: PCI v No PCI
Complete Follow-up 99.8%

12. Baseline Characteristics and In Hospital Meds
Meds After Rand
Age (y)
61.4
GP IIb/IIIa inhibitor
31.8
Female
27.4%
Statin
87.2
UA/NSTEMI
70.8%
Beta Blocker
82.5
Rand to Angio
3.4 h
ACE/ARB
75.7
STEMI
29.2%
PPI
40*
0.5 h
H2 Blocker
11.3
Diabetes
23.4
Prior Stroke
4.1
Ischemic ECG Δ
80.8
↑ Biomarker 42
Variables 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

13. ASA Dose Comparison Primary Outcome and Bleedingmg mg HR
95% CI P
CV Death/MI/Stroke
PCI (2N=17,232)
4.2
4.1
0.98
0.76
No PCI (2N=7855)
4.7
4.4
0.92
0.44
Overall (2N=25,087)
0.96
0.47
Stent Thrombosis
2.1
1.9
0.91
0.37
TIMI Major Bleed
1.03
0.97
0.94
0.71
CURRENT Major Bleed
2.3
0.99
0.90
CURRENT Severe Bleed
1.7
1.00
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
No other significant differences between ASA dose groups

14. Clopidogrel Dose Comparison
Two Significant Interactions:
PCI v No PCI (P=0.016)
ASA dose (P=0.043)

15. Clopidogrel: Double vs Standard Dose
Primary Outcome
0.05
C Std, A Hi
C Double, A Lo
C Std, A Lo
0.04
C Double, A Hi
0.03
Cumulative Hazard
Clopidogrel Standard
Clopidogrel Double HR P
P Intn
ASA mg
4.6
3.8
0.83
0.036
0.043
ASA mg
4.2
4.5
1.07
0.43
0.02
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

16. Clopidogrel: Double vs Standard Dose Primary Outcome and ComponentsHR
95% CI P
Intn P
CV Death/MI/Stroke
PCI (2N=17,232)
4.5
3.9
0.85
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.95
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

17. Clopidogrel Double vs Standard Dose Bleeding Overall Population
Hazard
Ratio
95% CI P
CURRENT Major
2.0
2.5
1.25
0.01
CURRENT Severe
1.5
1.9
1.23
0.03
Fatal
0.11
0.13
1.15
0.71
ICH
0.05
0.67
0.53
RBC transfusion ≥ 2U
1.76
2.21
1.26
CABG-related Major
0.9
1.0
1.10
0.48

18. Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio Confirmed)
Clopidogrel Standard Dose
0.012
42%
RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58
95% CI
P=0.001
0.0 3 6 9 12 15 18 21 24 27 30
Days

19. Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients
Day 30
Clopidogrel
StandardN=8684 %
Double N=8548
Hazard Ratio
95% CI
P value
Stent Thrombosis
2.3
1.6
0.71
0.002
Definite
1.2
0.7
0.58
0.001 MI
2.6
2.0
0.78
0.012
MI or stent thrombosis
3.7
3.0
0.80
0.008
CV Death
1.9
0.96
0.68
Stroke
0.4
0.88
0.59
CV Death/MI/Stroke
4.5
3.9
0.85
0.036

20. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
15% RRR
0.04
Clopidogrel Double
0.03
Cumulative Hazard
0.02
HR 0.85
95% CI
P=0.036
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

21. Clopidogrel Double vs Standard Dose Bleeding PCI Population
Hazard
Ratio
95% CI P
CURRENT Major
1.1
1.6
1.44
0.006
CURRENT Severe
0.8
1.39
0.034
Fatal
0.15
0.07
0.47
0.125
ICH
0.035
0.046
1.35
0.69
RBC transfusion ≥ 2U
0.91
1.49
0.007
CABG-related Major
0.1
1.69
0.31

22. Clopidogrel: Double v Standard Dose PCI Cohort Subgroups
CV Death, MI or Stroke
MI or Stent Thrombosis 2N
Std %
Double %
Intxn P
Std %
Double %
Intxn P
Overall
17232
4.5
3.9
3.7
3.0
NSTEMI/UA
10886
4.2
3.6
3.6
3.1
0.805
0.248
STEMI
6346
5.0
4.2
4.0
2.8
Male
13009
4.1
3.6
3.5
3.0
0.419
0.148
Female
4223
5.8
4.6
4.6
3.0
Age <= 65 yrs
10975
3.0
2.7
2.9
2.2
0.702
0.418
Age > 65 yrs
6257
7.1
6.0
5.2
4.4
Non-Diabetic
13400
4.2
3.6
3.6
2.8
0.836
0.567
Prev Diabetic
3831
5.6
4.9
4.1
3.6
No Inhosp GPIIb/IIIa
12288
3.9
3.5
3.1
2.5
0.465
0.894
GPIIb in hosp
4936
6.0
4.7
5.2
4.1
No Prot Pump Inhib
7675
3.8
3.2
3.1
2.3
0.408
0.613
Prot Pump Inhib
5557
5.7
4.2
4.8
3.3
Non-smoker
10845
4.9
4.6
3.9
3.5
0.045
0.050
Current Smoker
6380
3.8
2.6
3.4
2.1
ASA Low
8620
4.2
4.3
3.6
3.2
0.024
0.191
ASA High
8612
4.8
3.5
3.8
2.7
Double Dose Better
Std Dose Better
Double Dose Better
Std Dose Better
0.50
1.50
0.50
1.50

23. Clopidogrel: Double vs Standard Dose
by ASA Factorial
Clopidogrel HR
95% CI P
P int’n
Standard
Double
CV Death/MI/Stroke (Overall)
ASA High
4.6
3.8
0.83
0.036
0.043
ASA Low
4.2
4.5
1.07
0.42
MI/Stent Thrombosis (PCI pts)
2.7
0.71
0.005
0.19
3.6
3.2
0.89
0.32
Major Bleed(Overall)
2.2
2.4
1.08
0.51
0.099
1.9
1.43
0.003

24. Definite Stent Thrombosis in 4 Groups (Angiographically Proven)
C Standard, A Low
0.012
C Standard, A High
C Double, A Low
0.008
Cumulative Hazard
C Double, A High
0.004
Standard Clopidogrel
Double Clopidogrel HR P
Intn
High ASA
1.2
0.6
0.49
0.003
Low ASA
0.8
0.058
0.35
0.0 3 6 9 12 15 18 21 24 27 30
Days

25. Conclusions Clopidogrel Dose Comparison
Double-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.

26. Conclusions ASA Dose Comparison
No significant difference in efficacy or bleeding between ASA mg and ASA mg.

27. Clinical Implications
For every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MI’s 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.

28. CURRENT-PCI findings How to translate into practice?
OPTION 2
OPTION 1
ACS (UA/NSTEMI or STEMI)
ACS (UA/NSTEMI or STEMI)
300 mg load before Angiography
600 mg load before Angiography
PCI
No PCI
PCI
No PCI
+ 300 mg load
No additional load
Double dose (150 mg/day) for 6 days then 75 mg/day
75 mg/day
Double dose (150 mg/day) for 6 days then 75 mg/day
75 mg/day

29. 29

30. Clopidogrel and Proton Pump Inhibitors – Is There an Interaction?
Deepak L. Bhatt MD, MPH, FACC, FAHA
Chief of Cardiology, VA Boston Healthcare System
Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System
Senior Investigator, TIMI Study Group
Harvard Medical School

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

32. CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients
MI, stroke, or death – ITT population 15
Placebo*
Clopidogrel*
11.5%
27% RRR
P=0.02 10
8.5%
Combined endpoint occurrence (%) 5
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, , p=0.02).
Reference:
Steinhubl S, Berger P, Tift Mann III J, et al. JAMA. 2002;Vol 288,No 19: 3 6 9 12
Months from randomization
* Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:

33. Multivariable Predictors of Bleeding Events Discharge to 1 Year (n=1816)
Hazard Ratio (95% CI) X2
P value
Clopidogrel
1.04 ( )
0.05
0.82
Age (per 10 years)
1.26 ( )
8.1
0.005
CABG discharge-1 year
32.15 ( )
423.6
<0.0001
Aronow HD, et al. Am Heart J 2008 (published online Nov 2008)

34. Kaplan Meier Estimates of Bleeding Risk Discharge to 1 Year (n=1816)

35. Timing of Severe or Moderate Bleeding
Placebo + ASA
Clopidogrel + ASA
Hazard Function/d 15 60
135
270
450
630
810
Days Since Randomization
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:

36. Algorithm to Assess GI Risk With Antiplatelet Therapy
Need for antiplatelet therapy
Yes
Assess GI risk factors
History of ulcer complication History of ulcer disease (nonbleeding)
Dual antiplatelet therapy Concomitant anticoagulant
Test for H pylori; treat if infected
Yes
According to the consensus document:
If a patient needs antiplatelet therapy, the clinician should assess the patient’s 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 older
The patient uses corticosteroids
The patient has dyspepsia or symptoms of gastroesophageal reflux disease. No
Yes
More than one risk factor:
Aged 60 years or more
Corticosteroid use
Dyspepsia or GERD symptoms
PPI
Yes
Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.
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. 36

37. Clopidogrel and PPIs – The OCLA study
Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite
PPIs are strong inhibitors of CYP2C19 activity
PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)
Poor responders = 16 placebo and 39 in omeprazole
PRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI rechecked
Graph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically?
p<0.0001
Gilard et al. J Am Coll Cardiol 2008;51:

38. Intake of PPIs Not Associated With Impaired Response to Clopidogrel
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 diphosphate–induced 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 diphosphate–induced 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.
Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.
Adenosine diphosphate–induced 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.
Siller-Matula JM, et al. Am Heart J. 2009;157(1):148.e1-148.e5.
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.

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

40. Genetic Variations and Clopidogrel Response
Percent Difference in AUC0-t
P Value
CYP2C19
−32.4
.001
CYP2C9
−6.8
.59
CYP2B6
−15.7
.03
CYP3A5
5.6
CYP1A2
11.2
.45
Pharmacokinetic Response
-50
-40
-30
-20
-10 10 20 30
Relative Percent Difference
Gene
Percent Difference in ΔMPA
P Value
CYP2C19
−9.0
.001
CYP2C9
−0.6
.86
CYP2B6
−5.7
.012
CYP3A5
7.5
CYP1A2
0.5
.90
Pharmacodynamic Response
-15
-10 -5 5 10 25
Absolute Difference
Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:

41. Deaths or Recurrent ACS
Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI
0.70
0.60
0.50
0.40
0.30
0.20
0.10 90
180
270
360
450
540
630
720
810
900
990
1080
Days Since Discharge
Deaths or Recurrent ACS
Proportion of
Neither clopidogrel nor PPI
PPI without clopidogrel
Clopidogrel + PPI
Clopidogrel without PPI
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, 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, ).
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<.001). However, this association appeared to be attenuated when comparing periods of use of clopidogrel plus PPI use with periods without use of either clopidogrel or PPI (shown in figure on slide).
Ho PM, et al. JAMA. 2009;301(9):
Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):

42. Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
Outcome
Primary outcome
Death or rehospitalization for ACS
Secondary outcomes
Rehospitalization for ACS
Revascularization procedures
Death (all-cause)
Without PPI
With PPI
Without PPI
With PPI
Ho PM, et al. JAMA. 2009;301(9):

43. Results – 1 Year Endpoint from CREDO
Unadjusted Data
Primary 1-Year Endpoint:
Death, MI or Stroke 20
P=0.45
PPI at baseline (N=374)
P=0.001 15
16.2
No PPI at baseline (N=1742)
14.8
13.2 10
10.8
9.2
No PPI p-value is 0.035
7.7 5
All
N=2116
Placebo
N=1063
Clopidogrel
N=1053
Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD 43

44. One Year Death/MI/Stroke
Results – Clopidogrel Group
Adjusted Data
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)
0.043
Clopidogrel / 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
Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD 44

45. One Year Death/MI/Stroke
Results – Placebo Group
Adjusted Data
28 Days Death/MI/UTVR
Adjusted OR (95% CI) p-
value*
One Year Death/MI/Stroke
Adjusted HR (95% CI)
p-value†
Placebo / PPI
(n=195)
19/195 (9.8)
1.4
(0.81, 2.41)
0.221
31/195 (16.2)
1.6
(1.03, 2.34)
0.035
Placebo / 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
Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD

46. Results – 1 Year Primary Endpoint
PPI at Baseline
Randomized Therapy
Death, MI or Stroke
Adjusted HR (95% CI)
P-value
Placebo (N=195)
16.2%
0.77
(0.45, 1.33)
0.35
Clopidogrel (N=179)
13.2%
P-value for interaction between randomized therapy and baseline PPI
P=0.69
No PPI at Baseline
Randomized Therapy
Death, MI or Stroke
Adjusted HR (95% CI)
P-value
Placebo (N=868)
10.8%
0.75
(0.55, 1.03)
0.08
Clopidogrel (N=874)
7.7%
Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD

47. THE LANCET

48. Primary endpoint stratified by use of a PPI
PPI use at randomization (n= 4529)
Clopidogrel
Prasugrel
CV death, MI or stroke
CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI
PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI
Days 48

49. Risk of CV Events with Different Types of PPIs
Type of PPI
Clopidogrel
HR (95% CI)
CV death, MI or stroke
Prasugrel
Omeprazole
(n=1675)
0.91 ( )
1.04 ( )
Pantoprazole
(n=1844)
0.94 ( )
1.09 ( )
Esomeprazole
(n=613)
1.07 ( )
0.86 ( )
Lansoprazole
(n=441)
1.00 ( )
0.98 ( )
Rabeprazole not included due to small sample size (n=66) 49

50. Clopidogrel and the Optimization of GI Events Trial – COGENT50

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

52. Antiplatelet Therapy in High Risk Patients: Does One Size Fit All?
Harold L. Dauerman, MD
Director, Cardiovascular Catheterization Laboratories
Professor of Medicine
University of Vermont

53. 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)

54. 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?

55. STEMI: ASA 325 po Transfer PCI Capability or No PCI Capability and
The Vermont Algorithm
PCI Capability or
< 60 minute Transfer Time
No PCI Capability and
> 60 minute Transfer Time
ASA
325 po
UFH or Bivalirudin
Beta Blockers ONLY if HTN
UFH (60 U/Kg)
Beta Blockers only if HTN
Clopidogrel
600 po
90 minutes
To Open
Artery
Clopidogrel
300 po
Emergent Transfer
Lytic
Contraindicated
Primary PCI with Stenting:
GPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Alone
Rescue PCI:
Class I Indication
Continue bivalirudin for 2 hours after PCI
If Reperfusion Fails,
Emergent PCI with Stent
Full Dose Ly tic and UFH
ASA/Clopidogrel
Statin
Groin Closure
Cardiac Rehab
Lopressor 12.5 bid
Transfer
If no CP and less than 50%
ST Elevations, PCI at 12-24
Hours with Stent
Transfer from
Community ER
To PCI Site
The NSTEMI Paradigm
of 4-48 Hours 55

56. No Clear Benefit of Upstream GPI One Size Does Fit All
Guigliano, R
NEJM 2009:
The EARLY ACS
TRIAL
No Clear Benefit of Upstream
GPI
One Size Does Fit All
Giugliano, NEJM 2009

57. FINESSE: Keeping the Simple Algorithm Intact
End point
Primary PCI (%)
Abciximab-facilitated (%)
Combination (abciximab/
reteplase)-facilitated (%)
p, combination-facilitated vs primary PCI
p, combination-facilitated vs abciximab-facilitated
Cardiogenic shock
6.8
4.8
5.3 NS VF
0.4
0.2
0.6
TIMI major bleeding
2.6
4.1
0.025
TIMI minor bleeding
4.3
6.0
9.7
<0.001
0.006
TIMI major or minor bleeding
6.9
10.1
14.5
0.008
Ellis SG et al. N Engl J Med 2008;358: 57

58. Bleeding Complications and the Elderly Patient
Major vascular complications, %*
*Arterial injury and/or arterial injury-related bleeding among women
N=13,653 patients undergoing PCI
Ahmed and Dauerman, Circulation: Cardiovascular Interventions September 2009 58 58

59. Both Bleeding and Thrombotic Events Matter
1998
2009
Bleeding
TVR
TVR
Bivalirudin
DEATH
DEATH
GPI Antagonists
Prasugrel and Ticagrelor
CK-MB Symptomatic MI
CK-MB Symptomatic MI
Adapted from Dauerman HL, J Am Coll Feb 2007 59 59

60. Prevention of Thrombotic Complications: Pharmacology of New ADP Receptor Antagonists
Novel ADP receptor antagonists: Ticagrelor and prasugrel
More potent inhibition of platelet aggregation
Earlier inhibition of platelet aggregation
PRINCIPLE-TIMI44: Phase II pharmacokinetic study
Vasodilator-stimulated phosphoprotein (VASP): Assessment of the extent of phosphorylation of VASP reflects specifically inhibition of the P2Y12 receptor
Wiviott, S. D. et al. Circulation 2007;116:

61. Stent Thrombosis and TRITON TIMI 38
Any Stent at Index PCI N= 12,844
2.4 (142)
Clopidogrel 2
Endpoint (%)
1.1 (68) 1
Prasugrel
HR 0.48 P <0.0001
NNT= 77 30 60 90
180
270
360
450
Days
Wiviott SD et al NEJM 2007;357: 2001. 61

62. 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)

63. CURRENT OASIS-7: S. Mehta, ESC 2009
Challenges in Developing ACS Algorithms
Fibrinolysis Primary PCI
Aspirin
Acute Dose: 162 vs 325 mg Chronic Dose: 81 vs 325
CURRENT OASIS-7: S. Mehta, ESC 2009
Safety/efficacy for 300 mg in elderly
Unknown risk of 600 mg loading dose
12 month compliance
Defining optimum loading dose
Defining optimum timing of load
Defining maintenance dose
12 month compliance
Clopidogrel
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.
Prasugrel
No safety or efficacy data
HL Dauerman, Am J Cardiology 2009

64. The Platelet Gap in Clinical Trials:
TRITON TIMI 38—13% Elderly Enrollment
38%
Proportion of Age Group > 75 Years (%)
18%
NSTE ACS Populations (n=1,190,721)
Alexander, K. P. et al. Circulation 2007;115:

65. We Can Not Have a Simple Statewide ACS Algorithm with Prasugrel

66. Is Prasugrel Effective in the Elderly?
CV Death, MI, Stroke:
Is Prasugrel Effective in the Elderly?
Risk Reduction (%) 18
UA/NSTEMI B 21
STEMI
Male 21
Female 12
<65 25
Age
65-74 14
>75 6
No DM 14 DM 30
BMS 20
DES 18
GPI 21
No GPI 16 14
CrCl < 60 20
CrCl > 60 19
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR
Wiviott SD, NEJM 357: , 2007 66

67. Net Clinical Benefit Analysis: Do Not Load Prasugrel For Our 87-Year-Old Patient
Risk (%)
Yes
+ 37
Prior Stroke / TIA
-16 No
Pint = 0.006 -1
>=75
Age
Pint = 0.18
-16
< 75
< 60 kg +3
Wgt
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR 67

68. Selective Cardiology-Guided Loading and Continuation
Antman, E. M. et al. J Am Coll Cardiol 2008;51: 68

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

70. Newer Drugs for ACS and STEMI: Mortality Benefit Can Not Be Ignored
September 1, 2009

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

72. 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?
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: ED—ASA 325 mg and then decision re: prasugrel vs clopidogrel by telephone consult with interventional cardiologist in cath lab or on cardiac floor.

73. Conclusions Antiplatelet Therapy Across the Spectrum
Algorithms 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

74. Bleeding is the Red line in the sand for Antiplatelet therapy: Avoiding Complications in the Cath Lab & Beyond
Sunil V. Rao MD
Director of Cardiac Catheterization Laboratories
The Duke Clinical Research Institute
The Durham VA Medical Center
Duke University Medical Center

75. Bleeding and antiplatelet therapy Issues we will discuss
Reducing events among clopidogrel hyporesponders is a clinical priority
Intensification of antiplatelet effect is associated with improvement in some ischemic outcomes, but what about the bleeding?
Acute – CABG-related bleeding
Chronic bleeding risk
Can 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?

76. Single Antiplatelet Rx
The Current Egalitarian Strategy of Antiplatelet Therapy During And After PCI: The More The Merrier for Everyone!
Reduction in Ischemic Events
Increasingly narrow therapeutic window
Increase in Major Bleeds
Dual Antiplatelet Rx
Single Antiplatelet Rx
Higher IPA
Adapted from Gibson, AHA 2007

77. IPA Responses to Clopidogrel
New
Δ 5µM ADP-Induced Platelet Aggregation (%)
≤ -20
[-10,0]
[11,20]
[31,40]
[51,60]
[71,80]
[91,100]
Number of Patients
Greater antiplatelet effect may address this group
What effect does greater platelet inhibition have on bleeding?
Serebruany.J Am Coll Cardiol.Jan. 2005/p247/c1/ figure 1
Wide inter-patient variability in the ex vivo measurement of the response to oral antiplatelet therapies has been recognized for nearly 40 years, although the clinical implications of this phenomenon have yet to be confirmed in large-scale clinical trials. This has led some clinicians to classify patients as “responders” and “non-responders,” implying that clopidogrel resistance is an all-or-none clinical phenomenon.
Serebruany and colleagues conducted secondary post hoc analyses of an existing dataset consisting of volunteers with multiple risk factors (n=94), patients after coronary stenting (n=405), patients with heart failure (n=25), and patients with a recent ischemic stroke (n=20).
Response of the 544 individuals to clopidogrel followed a normal, bell-shaped distribution. When a patient’s responsiveness was described in terms of change in maximal aggregation in response to 5 μM/L ADP, the mean change in platelet aggregation, with standard deviation was 41.9, ±20.8%. If hyporesponsiveness and hyperresponsiveness to clopidogrel are considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyperresponsiveness in these patients was 4.8% and 4.2%, respectively. The inhibition of aggregation by clopidogrel as determined by light-transmittance aggregometry correlated well (r=0.72) with inhibition of platelet activation as determined by flow cytometric measurement of PECAM-1 expression.
Thus, a minority of subjects are indeed hypo- and hyperresponders (approximately 5% for each), and may be at higher risk for vascular or bleeding events, respectively, after uniform clopidogrel dosing.
Serebruany.J Am Coll Cardiol.Jan. 2005/p247/c1/ figure 1
Serebruany.J Am Coll Cardiol.Jan. 2005/p247/c1/lines 12-16, line 24, c2/lines 13-14
Serebruany.J Am Coll Cardiol.Jan. 2005/p246/c2/lines 20-22, p248/c2/ lines 5-10, lines 14-21, p248/c1, figure 3, p250/c1/ line 48, c2/lines 1-5
Adapted from: Serebruany V et al. J Am Coll Cardiol
Serebruany.J Am Coll Cardiol.Jan. 2005/p247/c1/ figure 1
Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:

78. Risk vs. Benefit – What Affects Efficacy and Safety?
Clinical efficacy with antiplatelet drugs is affected by their potency and by genomics for drugs that are metabolized. On the other hand, safety (bleeding) is affected not only by the potency of the antiplatelet effect, but also by concomitant drugs (e.g., ASA and its dose), as well as by the risk posed by surgery

79. “Major” Bleeding: Incidence* in Clinical Trials with Active Agent
Before discussing the issue of bleeding and how it enters into therapeutic decisions, we must realize that the definition of Major bleeding used in clinical trials has varied. This influences the reported incidence of bleeding and makes it difficult to compare the relative safety of available agents.
Clop + ASA
Pras + ASA
Ticag + ASA
Clop + ASA
600mg mg
Yusuf S NEJM 2001
Wiviott SD NEJM 2007
Wallentin L NEJM 2009
Mehta SR NEJM 2009

80. “Major” Bleeding Data Elements
Definition
TIMI1
GUSTO2
CURE3
Trial
TRITON
CHARISMA
CURE
Major –
fatal / life threatening or severe bleeding
Fatal / life threatening (related to instrumentation, spontaneous, trauma), ICH, Hb ↓ ≥5 g/dL, or absolute
HCT ↓ ≥15%
Fatal, ICH,
or causes haemodynamic compromise and requires intervention
Fatal / Life threatening
Fatal, ICH, requires surgery, hypotension requiring inotropes,
Hb ↓ ≥5 g/dL,
or transfusion ≥4 U
Other major
Disabling, intraocular
with vision loss, or transfusion 2-3 U
PLATO4
PLATO
Fatal / 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
Listed here are the data elements of the various bleeding definitions used in the antiplatelet therapy trials. Because of the difficulties in comparing these different definitions we can compare similar data elements across trials, or compare definitions that are reconstructed post-hoc (like TIMI major for example).
ICH = intracranial haemorrhage; PLATO = Platelet Inhibition and Patient Outcomes.
Chesebro, JH et al. Circulation 1987
GUSTO Investigators. NEJM 1993
3. Yusuf S, et al. N Engl J Med. 2001;345:
4. Cannon CP, et al. J Am Coll Cardiol. 2007;50: 80

81. Bleeding and Evidence-based Therapies N=2498 ACS patients from the PREMIER Registry
Discharge ASA and thienopyridine
Pts. with bleeding vs. pts. without bleeding
Aspirin
OR (95% CI)
Thienopyridine
OR (95% CI)
0.45 (0.31, 0.64)
0.62 (0.42, 0.91)
Discharge
1 Month
6 Months
1 Year
0.68 (0.50, 0.92)
0.83 (0.59, 1.17)
0.63 (0.46, 0.87)
1.06 (0.78, 1.45)
Regardless of the bleeding definition that is used, the occurrence of a hemorrhagic complication is associated with a significant decrease in long-term medication adherence as seen in this study from the PREMIER registry
0.94 (0.66, 1.34)
1.12 (0.81, 1.55)
Wang TY, et. al. Circulation 2008

82. “Nuisance” Bleeding and Drug Discontinuation
N=2360 unselected pts. receiving DES
Prospective data collection
Major events adjudicated
Serebruany bleeding classification*
% discontinued
Even “nuisance’ bleeding can impact adherence. In this study, 11% of patients with nuisance bleeding discontinued their clopidogrel despite having a DES
*Alarming bleeding = ICH, life-threatening, + transfusion
Internal bleeding = hematoma, epistaxis, mouth or vaginal,
Melena, IO, hematuria or hematemesis
Nuisance bleeding = bruising, petechiae, ecchymosis
Roy P, et. al. AJC 2008

83. PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine Therapy15 10 5
Mortality (%) 1 2 3 4 6 7 8 9 11 12
Continued
Discontinued
P<0.001
Months
Nonadherence is, in turn, associated with increased mortality. This demonstrates the circular link between so-called safety (bleeding) and efficacy
Spertus JA, et al. Circulation. 2006

84. CURE – Major Bleeding % P=0.001 P=0.13 P=NS *Includes fatal bleeding
**Includes life-threatening & fatal bleeding
Yusuf S, et. al. NEJM 2001

85. Clopidogrel and ASA for NSTE ACS CABG-Related Bleeding in CURE
Clopidogrel d/c
< 5 days
Clopidogrel d/c
> 5 days
In the CURE trial, there was an association between receiving clop within 5d of CABG and an increased risk of bleeding. This is likely due to the fact that it takes approximately 5d to generate new platelets. These data provide an algorithm for how to deal with bleeding in the setting of dual antiplatelet therapy and impending CABG. The strategy for newer antiplatelets is as yet unclear.
p=0.001
Cure Investigators, NEJM 2001

86. Events Saved vs Life-threatening Bleeding Over Time: Net Clinical Benefit of Clopidogrel
Months of follow-up
Events/1000 patients treated -5 5 10 15 20 25 3 6 9 12
Events Saved: CV death, MI, stroke
Life-threatening bleeding
In the CURE study, the number of major vascular events saved during any period was much greater than the risk of bleeding requiring intervention (life-threatening bleeding was given the same weight as death, MI, or stroke).
Overall, there were 664 patients with one of the above events in the clopidogrel plus aspirin (ASA) group (10.6%) vs 785 (12.5%) in the placebo plus ASA group (RRR=16%, 95% CI 0.76 to 0.93, P<0.001). Subdivision of data into events that occurred during the first 30 days (RRR=15%, 95% CI 0.74 to 0.99) and beyond (RRR=17%, 95% CI 0.72 to 0.96) indicated consistency in results.
Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966
Approved E-NEWSLETTER

87. CURE: Major Bleeding by Aspirin Dose Through Follow-Up
Placebo + Aspirin*
Clopidogrel + Aspirin* mg
1.9%
3.0% mg
2.8%
3.4% mg
3.7%
4.9%
The incidence of major bleeding increased with increasing aspirin dose in both treatment groups, with the highest incidence among patients receiving more than 200 mg of aspirin. This gives us a strategy for dealing with long-term bleeding.
*Other standard therapies were used as appropriate. .
Peters RJ, et al. Circulation. 2003
Peters RJ, Mehta SR, Fox KA, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:

88. Clopidogrel: Double vs Standard Dose by ASA FactorialHR
95% CI P
P int’n
Standard
Double
CV Death/MI/Stroke (Overall)
ASA High
4.6
3.8
0.83
0.036
0.043
ASA Low
4.2
4.5
1.07
0.42
MI/Stent Thrombosis (PCI pts)
2.7
0.71
0.005
0.19
3.6
3.2
0.89
0.32
Major Bleed (Overall)
2.2
2.4
1.08
0.51
0.099
1.9
1.43
0.003
As you’ve heard, increased dosing of clopidogrel and ASA provides a substantial protection against stent thrombosis. When comparing the various doses of clopidogrel and ASA studied in the CURRENT trial, one can see that there is a trend toward higher bleeding when the dose of clopidogrel or ASA is increased, but this does not reach statistical signfiicance.
TIMI Major bleeding:
600 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=0.71
Mehta SR, et. al. NEJM 2009

89. Clopidogrel and bleeding
Adding clopidogrel to ASA increases bleeding risk overall
No increase in life-threatening or fatal bleeding
Increased risk of CABG-related bleeding, but to reduce this risk, discontinue clopidogrel 5d prior
Higher clopidogrel and ASA dose associated with better ischemic outcomes in PCI patients
Increased bleeding risk, but no increase in fatal bleeding or TIMI major bleeding

90. Overcoming clopidogrel hyporesponsiveness Change the drug
Clopidogrel vs. Prasugrel At 24 hrs (healthy volunteers)
100.0
80.0
Interpatient variability
60.0
Inhibition of platelet aggregation (%)
40.0
Interpatient variability
20.0
Another option to increase the antiplatelet effect is to use newer more potent agents like prasugrel. As seen here, prasugrel reduces the interpatient variability in response and general provides greater inhibition of platelet aggregation compared with clopidogrel.
0.0
Clopidogrel responder
Clopidogrel non-responder
-20.0
Response to clopidogrel
Response to prasugrel
Responder = ≥ 25% IPA at 4 and 24 hours
Brandt JT, et al. Am Heart J. 2007;153:66.e9-e16.

91. Bleeding Events Safety Cohort (N=13,457)
ICH in Pts w Prior Stroke/TIA (N=518)
Clopidogrel
Prasugrel
Clop 0 (0) % Pras 6 (2.3)% (P=0.02)
% Events
This increased inhibition comes at a cost, however. Again, we cannot compare across trials unless we are comparing similar definitions or data elements. As seen here, prasugrel + ASA is associated with greater life-threatening and fatal bleeding compared with clopidogrel + ASA.
ARD 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 0.3% P=0.002
ARD 0% P=0.74 91 91

92. TRITON-TIMI 38 Early and late non CABG bleeding
In the TRITON Trial, the investigators also looked at life-threatening bleeding at two pre-specified times: from randomization to Day 3 and from Day 3 to end of study. Unlike the CURE Trial, a higher rate of life-threatening bleeding was found in the prasugrel group as compared to the clopidogrel group from the time of randomization to day 3 (0.4% vs. 0.3%; HR, 1.38; 95% CI, 0.79 to 2.41; P=0.26) and from day 3 to the end of the study (1.0% vs. 0.6%; HR, 1.60; 95% CI, 1.05 to 2.44; P=0.03). Importantly, there are no data to suggest that reducing the ASA dose will mitigate the risk of long-term bleeding seen with prasugrel
Wiviott S, et. al. NEJM 2007
Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITON–TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:

93. Net Clinical Benefit: Bleeding Risk Subgroups
Post-hoc Analysis
Risk (%)
Prior stroke / TIA
Yes
+ 54 No
-16
Pint = .006 -1
Age
≥ 75
Pint = .18
-16
< 75
Wgt
< 60 kg +3
Pint = .36
The bleeding risk is unacceptably high in some subgroups, like those with prior stroke/TIA, patients ≥ age 75, and those with a body weight < 60 kg
≥ 60 kg
-14
OVERALL
-13
0.5 1 2 HR
Wiviott SD, NEJM, 2007

94. Balancing Efficacy and Safety: Antithrombotic Effect vs Bleeding Time
Modified Folts Model of Thrombosis and Haemostasis in Anaesthetised Dogs
AZD6140
Clopidogrel
AZD *
Another agent that provides more potent platelet inhibition is ticagrelor. Because it reversibly inhibits the P2Y12 receptor, it potentially has a wider therapeutic window than either clopidogrel or prasugrel.
*A compound chemically indistinguishable from prasugrel.
Adapted from van Giezen JJJ, et al.
9th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 2008

95. PLATO - Total Major BleedingNS
K-M estimated rate (% per year)
PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13
TIMI major bleeding
Red cell transfusion*
PLATO life-threatening/ fatal bleeding
Fatal bleeding
11.6
11.2
7.9
7.7
8.9
5.8
0.3
Ticagrelor
Clopidogrel
Indeed, in the overal trial, there was no significant increase in major bleeding, life-threatening bleeding, or fatal bleeding with ticagrelor compared with clopidogrel.
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
Wallentin L, et. al. NEJM 2009

96. PLATO - Non-CABG and CABG-related Major BleedingNS 9
K-M estimated rate (% per year)
Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1
Non-CABG TIMI major bleeding
CABG PLATO major bleeding
CABG TIMI major bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel
However, non CABG-related bleeding was higher. This again underscores how greater platelet inhibition comes at the cost of increased bleeding. The reversible nature of ticagrelor can be very helpful in situations where timely restoration of normal platelet function is needed, like before CABG.
Wallentin L, et. al. NEJM 2009

97. Offset of Ticagrelor and Clopidogrel
After 24 hrs,
the antiplatelet
effect of Ticagrelor
is higher than
Clopidogrel
In PLATO, Ticagrelor
was discontinued 24-72h
before CABG, allowing
drug to wear off
? If the non-CABG
related bleeding is
higher because of the
persistent greater effect
Storey RF, et. al. JACC 2007

98. Newer Oral Antiplatelet Agents
Prasugrel and ticagrelor provide greater platelet inhibition compared with clopidogrel
Prasugrel is associated with increases in major bleeding, fatal bleeding, and CABG-related bleeding
Unacceptable risks in age > 75 yrs, Weight < 60 kg, Prior stroke/TIA
Ticagrelor associated with improved survival and no increase in bleeding overall, but increases in non-CABG related bleeding

99. Making Decisions: The Clinical Necessity of Comparing Across Trials
CURRENT PCI
N=17,232
TRITON
N=13,608
PLATO
N=18,624
CV Death, MI or Stroke
↓ 15%
↓ 21% (w high dose ASA)
↓ 19%
↓ 16%
↓ 16% in death
Definite Stent Thrombosis
↓ 42%
↓ 51% (w high dose ASA)
↓ 58%
↓ 33%
TIMI Major Bleed
No increase
↑ 32%
CABG-related Bleeding
↑ 4-fold
↑ 19-25% in non-CABG bld
Fatal bleeding

100. PRT060128 (Elinogrel) – A Reversible P2Y12 Inhibitor N= 50 pts with HPR on 75 mg clopidogrel daily20 40 60 80
Screen
Predose 4h 6h
24h
7-10 d
Maximum Aggregation (%)
p<0.001
5M ADP-Induced Aggregation
Gurbel PA, AHA 2008

101. INNOVATE-PCI Trial 800 elective PCI patients Clopidogrel Load
90d therapy
PRT 128 IV
- Oral for 90d
24 hr death/MI/TVR
60d death/MI/TVR
24 hr & 60d Clinically relevant major/minor bleeding
24 hr & 60d Nuisance bleeding
24 hr & 60d TIMI Major and Minor bleeding
Clopidogrel
Load
90d therapy
PRT 128 IV
- Oral for 90d
24 hr death/MI/TVR
60d death/MI/TVR
24 hr & 60d Clinically relevant major/minor bleeding
24 hr & 60d Nuisance bleeding
24 hr & 60d TIMI Major and Minor bleeding

102. Bleeding and Antiplatelet Therapy Conclusions (1)
Several options for oral antiplatelet therapy now exist (with more coming)
New options address “undertreatment”
Increase ASA + Clopidogrel dose
Prasugrel
Ticagrelor
Efficacy signal improved with all of the above strategies compared with control arm with some caveats
CURRENT – PCI subgroup experienced benefit
TRITON – No medical therapy; No benefit in age ≥ 75 years, prior TIA/Stroke, low body weight

103. Bleeding and Antiplatelet Therapy Conclusions (2)
With similar efficacy signals across trials, assessing bleeding is important
Differing definitions across trials make it difficult to compare, but…
General concepts
Clopidogrel + ASA = greater bleeding than ASA alone
Prasugrel + ASA = greater bleeding than clopidogrel + ASA
Ticagrelor + ASA = greater non-CABG related bleeding than clopidogrel + ASA (but no difference in CABG-related bleeding)

104. Bleeding and Antiplatelet Therapy Conclusions (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 dose
Prasugrel – No clear strategy to reduce bleeding risk and maintain the efficacy signal
Ticagrelor – Need more data on how to reduce non-CABG related bleeding risk

105. Case Study in Antiplatelet Therapy— Audience Response System
Harold L. Dauerman, MD
Director, Cardiovascular Catheterization Laboratories
Professor of Medicine
University of Vermont

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

107. Question # 1 The 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

108. ASA Dose Comparison Primary Outcome and Bleedingmg mg HR
95% CI P
CV Death/MI/Stroke
PCI (2N=17,232)
4.2
4.1
0.98
0.76
No PCI (2N=7855)
4.7
4.4
0.92
0.44
Overall (2N=25,087)
0.96
0.47
Stent Thrombosis
2.1
1.9
0.91
0.37
TIMI Major Bleed
1.03
0.97
0.94
0.71
CURRENT Major Bleed
2.3
0.99
0.90
CURRENT Severe Bleed
1.7
1.00

109. 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

110. The ED Attending Gathers More Clinical Information
NIDDM
No prior h/o bleeding
HTN and Cr 1.6
No prior stroke/TIA
Remote smoker; COPD on PRN Inhaler
Occasional reflux symptoms

111. 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.

112. Non-Surgical Anatomy PCI Anatomy Defined as Below
Low Risk STEMI Anatomy
High Risk STEMI Anatomy

113. Question # 4 You Have to Make A Choice Now—Not Surgical Anatomy
High 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 GPI—if GPI is used, clopidogrel 600 mg is my choice.
Other factors will guide my prasugrel vs clopidogrel decision

114. Question 5: RCA Was Stented with DES Clopidogrel 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

115. Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis
Clopidogrel Standard Dose
0.012
42%
RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58
95% CI
P=0.001
0.0 3 6 9 12 15 18 21 24 27 30
Days

116. Clopidogrel Double vs Standard Dose Bleeding PCI Population
Hazard
Ratio
95% CI P
TIMI Major1
0.5
1.06
0.79
CURRENT Major2
1.1
1.6
1.44
0.006
CURRENT Severe3
0.8
1.39
0.034
Fatal
0.15
0.07
0.47
0.125
ICH
0.035
0.046
1.35
0.69
RBC transfusion ≥ 2U
0.91
1.49
0.007
CABG-related Major
0.1
1.69
0.31
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

117. Question 6: RCA Stented with DES Prasugrel was loaded prior to transfer or in cath lab: Follow-Up oral 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

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

119. 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

120. Clopidogrel: Double v Standard Dose PCI Cohort Subgroups
CV Death, MI or Stroke
MI or Stent Thrombosis 2N
Std %
Double %
Intxn P
Std %
Double %
Intxn P
Overall
17232
4.5
3.9
3.7
3.0
NSTEMI/UA
10886
4.2
3.6
3.6
3.1
0.805
0.248
STEMI
6346
5.0
4.2
4.0
2.8
Male
13009
4.1
3.6
3.5
3.0
0.419
0.148
Female
4223
5.8
4.6
4.6
3.0
Age <= 65 yrs
10975
3.0
2.7
2.9
2.2
0.702
0.418
Age > 65 yrs
6257
7.1
6.0
5.2
4.4
Non-Diabetic
13400
4.2
3.6
3.6
2.8
0.836
0.567
Prev Diabetic
3831
5.6
4.9
4.1
3.6
No Inhosp GPIIb/IIIa
12288
3.9
3.5
3.1
2.5
0.465
0.894
GPIIb in hosp
4936
6.0
4.7
5.2
4.1
No Prot Pump Inhib
7675
3.8
3.2
3.1
2.3
0.408
0.613
Prot Pump Inhib
5557
5.7
4.2
4.8
3.3
Non-smoker
10845
4.9
4.6
3.9
3.5
0.045
0.050
Current Smoker
6380
3.8
2.6
3.4
2.1
ASA Low
8620
4.2
4.3
3.6
3.2
0.024
0.191
ASA High
8612
4.8
3.5
3.8
2.7
Double Dose Better
Std Dose Better
Double Dose Better
Std Dose Better
0.50
1.50
0.50
1.50

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

122. Question 9: You’re 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