1. Debate: Clopidogrel - PPI Interaction: More Needs to Be Learned The Warning Is an Overreaction
Peter Berger, MD
Director, Center for Clinical Studies
Interventional Cardiologist
Geisinger Clinic
CRT Feb. 2011

2. Potential Conflicts of Interest
Consultant: AstraZeneca, Boehringer Ingelheim, Eli Lilly/Daiichi-Sankyo, Medicure, Accumetrics, Ortho McNeil (each for less than $10,000)
Research funding for Geisinger Clinic for studies on which I am the Principle Investigator: Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, The Medicines Company, and Corgenix/Aspirinworks (all for more than $10,000).

3. OPTIMUS: Diabetic Pts Hyporesponsive to Clopidogrel
64.3±6
p=0.4
62.5±11
100
p<0.0001
100
p=0.5
64.9±9
67.4±6 80
63.1±7 80
52.3±13
Maximal ADP (20mmol/L) platelet aggregation (%)
Maximal ADP (20mmol/L) platelet aggregation (%) 60 60 40 40
75 mg for 30 days
150 mg for 30 days
75 mg for 90 days 20 20 30 60 30 60 90 90
Day
Day
64 pts are 66% of 98 studied; all hyporesponsive
Angiolillo DJ et al. Circulation. 2007;115:

4. OSASIS 7- CURRENT 25,087 ACS or STEMI Pts PCI planned < 24 hrs
No restriction on GP IIb/IIIa inhibitors
Clopidogrel 600 mg
150 mg from Day 2 to Day 7
75mg from Day 8 to 30
Clopidogrel 300 mg
75 mg from Day 2 to 30
CURRENT/OASIS-7 is a Phase III, multinational, multicenter, randomized, factorial design, parallel-group study comparing 2 regimens of clopidogrel (high vs. standard dose) in a double-blind fashion and 2 regimens of ASA (high vs. low dose) in an open-label fashion in patients with non-ST-segment elevation ACS managed with an early invasive strategy with intent for PCI as early as possible within 24 hours.
Each patient will be treated and followed for 30 days.
ASA 300 mg Day 1
75–100 mg from Day 2 to 30
ASA 300 mg Day 1
300 mg–325 mg from Day 2 to 30
ASA 300 mg Day 1
75–100 mg from Day 2 to 30
ASA 300 mg Day 1
300 mg–325 mg from Day 2 to 30
1o Outcome: Death / MI /stroke, 30 Days; 2o outcome: bleeding 5

5. 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

6. GRAVITAS Study Design R Elective or Urgent PCI with DES* (83 sites)
VerifyNow P2Y12 Test hours post-PCI
PRU ≥ 230 R
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel protocol-mandated to ensure steady-state at hrs
†Placebo-controlled
All patients received aspirin (81-162mg daily) 7

7. Pharmacodynamics: Effect of SD vs HD Clopidogrel
Standard-Dose
High-Dose
500
P = 0.98
P < 0.001
400
Persistently high 30 days: 62% vs 40%, p<0.001
PRU
value
300
200
100
N=1105
N=1013
N=940
N=1109
N=1012
N=944
Post-PCI
30 d
6 mo
Post-PCI
30 d
6 mo
ITT population 8

8. Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test. 9

9. Prior Drug-Drug Interaction Studies
Many studies (CURRENT-OASIS 7, GRAVITAS, CILON-t, etc.) have now shown that letting platelet function tests guide clinical decision making-choice of drug, dose of drug, etc- is misleading, and would be a mistake

10. Prior Drug-Drug Interaction Studies
Virtually all studies have indicated a reduction in inhibition of aggregability when clopidogrel is administered with certain statins (ie, atorvastatin), and calcium channel blockers
The existence of a negative interaction between atorvastatin and clopidogrel, has been thoroughly debunked; between calcium channel blockers and clopidogrel also appears to be false
But what about PPIs?

11. Treatment Effect of Clopidogrel
Reduction in 1o endpoint:
20% among ACS pts in CURE
20% among STEMI pts in CLARITY
9% among AMI pts in COMMIT
27% among elective PCI pts in CREDO
13% among pts with vascular disease in CHARISMA
Therefore, if a polymorphism rendered clopidogrel completely ineffective, would expect ~20% increase in events

12. Registry Analysis of a PPI-Clopidogrel Interaction Methods
All pts with ACS (MI or unstable angina) discharged from any VA Medical Center from 10/1/2003 through 1/31/2006 and prescribed clopidogrel at discharge
Primary outcome: Death/re-hospitalization for ACS
Secondary outcomes:
1. ACS hospitalization
2. Revascularization procedures: PCI or CABG
3. All-cause mortality
Follow-up through 9/30/2006
Median follow-up was 521 days (IQ range )
Ho P et al. JAMA. 2009;301:937-44

13. Clopidogrel with or without PPI at any point in time (n=8,205)
Variable
Clopidogrel with or without PPI at any point in time (n=8,205)
Clopidogrel only
(n=2,961)
Clopidogrel + PPI
(n=5,244)
p-value
Age, mean (SD)
65.7 (11.7)
67.7 (11.4)
<0.001
Diabetes
38.0
45.5
Prior MI
20.1
26.4
CABG
19.8
26.3
Heart failure
16.1
26.2
Cerebrovascular disease
7.6
9.1
0.02
Peripheral vascular disease
16.2
25.7
Prior clopidogrel use
17.5
Cancer
5.6
7.3
<0.01
Chronic obstructive pulmonary disease
17.0
Renal disease
9.9
17.4
Liver disease
2.4
3.5
Dementia
10.2
13.8
Ho P et al. JAMA. 2009;301:937-44

14. Clopidogrel with or without PPI at any point in time (n=8,205)
Variable
Clopidogrel with or without PPI at any point in time (n=8,205)
Clopidogrel only
(n=2,961)
Clopidogrel + PPI
(n=5,244)
p-value
TIMI risk score, mean (SD)
2.8(1.2)
2.9(1.2)
<0.001
LVEF<0.40
24.3
26.6
0.02
ACS presentation
STEMI
NSTEMI
21.7
68.8
16.7
70.5
PCI performed
55.5
46.3
CABG performed
2.5
2.6
0.83
Discharge medications
Aspirin
Β-blocker
ACE-inhibitor
Statin
91.2
92.7
79.0
95.4
89.4
93.3
78.4
95.9
0.01
0.64
0.09
0.25
Ho P et al. JAMA. 2009;301:937-44

15. Adverse Outcomes Following Hospital Discharge for Acute Coronary Syndrome
Freq. of events
Unadjusted OR
(95 CI)
Adjusted
OR*
Clopidogrel only
(n=2961)
Clopidogrel + PPI
(n=5244)
Death/ACS hospitalization
20.8
29.8
1.62
( )
1.25
( )
ACS hospitalization
6.9
14.6
2.29
( )
1.86
( )
Revascularization procedures
11.9
15.5
1.36
( )
1.49
( )
Death
16.6
19.9
1.24
( )
0.91
( )
Ho P et al. JAMA. 2009;301:937-44
* Adjusted for all important variables

16. Cumulative Hazard for Death/ACS, Re-Hospitalization
Ho P et al. JAMA. 2009;301:937-44
Days Since Discharge

17. MEDCO Analysis: Baseline Characteristics
No PPI
(N=9862)
PPI*
(N=6828)
Age - yrs; mean±SD
65.2±10.6
67.5±10.4
Age ≥65 years - no. (%)
4903 (49.7)
4076 (59.7)
Female - no. (%)
2572 (26.1)
2596 (38.0)
Prior cardiovascular event - no. (%)
2226 (22.6)
1845 (27.0)
Congestive heart failure - no. (%)
1831 (18.6)
1719 (25.2)
Diabetes mellitus - no. (%)
2238 (22.7)
1767 (25.9)
Hypertension - no. (%)
4581 (46.5)
3454 (50.6)
Dyslipidemia treatment - no. (%)
5190 (52.6)
3991 (58.5)
Dyslipidemia diagnosis or treatment - no. (%)
6254 (63.4)
4630 (67.8)
Chronic kidney disease - no. (%)
265 (2.7)
312 (4.6)
Any upper gastrointestinal disease - no. (%)
474 (4.8)
1649 (24.2)
Prior upper gastrointestinal bleeding - no. (%)
13 (0.1)
122 (1.8)
Drug-eluting stent – no. (%)
3124 (31.7)
1964 (28.9)
*all p<0.01
Stanek EJ et al SCAI LBCT 09

18. MEDCO Database (N=14,383 on Clopidogrel Post Stent) Association Between PPI Use and Clinical Outcomes
Adjusted OR 1.79
( )
MACE ,
1 Year
(%)
PPI
No PPI
(n=4321)
(n=9862)
Aubert RE et al. Circulation 2008;118:S-815

19. Clopidogrel And PPIs: Interaction?
Several other registries reveal the same
Possible Explanations:
PPIs (at least some PPIs) do inhibit the conversion of clopidogrel to its active metabolite
PPIs directly cause CV events
Confounding

20. Clopidogrel and Proton Pump Inhibitors Competition at CYP 2C19?
VASP-P
(%)
PPI
(N=24)
No PPI
(N=81)
Gilard M et al, J Thromb Hem. 2006:4:2508 21

21. VASP Before and After 7 Days of Clopidogrel in Pts on and Not On Omeprazole (Prilosec)
Gilard M et al JACC 2008;51:

22. The Issue of Those Drug-Drug Interaction Studies
But is there a clinical interaction between PPIs and clopidogrel?
Proper subgroup analyses from every randomized trial examining the issue (CREDO, CHARISMA, PLATO, TRITON) indicate that there is not a clinically significant reduction in clinical efficacy (or increase in bleeding) among patients on clopidogrel taking these other drugs

23. CREDO Death, MI, and Stroke at 1 Yr And PPIs
RRR= 0.77
(0.45, 1.33)
RRR=0.75
(0.55, 1.03)
CV Death, MI, Stroke (%)
PPI (N=366)
No PPI (N=1750)
Placebo n=1063
Clopidogrel n=1053
Steinhubl S et al Circulation 2008 Abstract

24. CREDO Death, MI, and Stroke at 1 Yr And PPIs
RRR= 0.77
(0.45, 1.33)
RRR=0.75
(0.55, 1.03)
CV Death, MI, Stroke (%)
P-value for interaction between randomized therapy and baseline PPI P=0.69
PPI (N=366)
No PPI (N=1750)
Placebo n=1063
Clopidogrel n=1053
Steinhubl S et al Circulation 2008 Abstract

25. TRITON CV Death, Nonfatal MI, Nonfatal Stroke And PPIs
RRR=0.82
(0.72, 0.95)
RRR=0.82
0.68, 0.93
CV Death, MI, Stroke ()
PPI
No PPI
Prasugrel
Clopidogrel
FDA Website

26. TRITON Major Non-Cardiac Bleeding and PPIs
PPI Inhibitor?
H2 Blocker?
1.19 (0.70, 2.02)
1.11 (0.79, 1.56)
1.35 (0.94, 1.94)
1.23 (0.93, 1.63)
Prasugrel
Clopidogrel
FDA Website

27. COGENT Aspirin Non-STEMI, STEMI, or Elective Stent n=3627
Clopidogrel 75 mg
and Placebo
Clopidogrel 75 mg
and
Omeprazole (Prilosec) 20 mg
Planned enrollment: 5000; stopped due to bankruptcy
Mean follow-up 133 days (maximum, 362 days)

28. Composite Cardiovascular Events
COGENT Trial
1.00
N=3627
Placebo: 67 events; 1821 at risk Treated: 69 events; 1806 at risk
0.98
HR= % CI=0.70;1.51
0.96
Survival Probability
0.94
Placebo
0.92
Omeprazole (Prilosec)
0.90 30 60 90
120
150
180
210
240
270
300
330
360
390
Time (Days)
Adjusted with Cox proportional hazards model for
NSAID use and H. pylori status.
Bhatt D, et al. NEJM 2010

29. COGENT No. of Events Clopidogrel with: Placebo Omeprazole N=3627
Mean follow-up 133 days (maximum, 362 days)
Omeprazole
N=3627
No. of
Events
Bhatt D et al NEJM 2010

30. Conclusion
“There is no good evidence that the differences in surrogate markers resulting from concomitant PPI administration to pts on clopidogrel translate into meaningful differences in clinical outcomes.”
ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010: