Combined Use of Oral Antiplatelet Agents and Gastroprotective Agents: Focus on PPIs and Clopidogrel

1
Combined Use of Oral Antiplatelet Agents and
Gastroprotective AgentsFocus on PPIs and
Clopidogrel 
Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of
Cardiology, VA Boston Healthcare System Director,
Integrated Interventional Cardiovascular Program
at Brigham and Womens Hospital and the VA Boston
Healthcare System Senior Investigator, TIMI Study
Group Harvard Medical School
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ADP Receptors
Bhatt DL et al. Nature Reviews Drug Discovery
2003 215-28.
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CREDO Long-Term (1 Year) Benefits of Clopidogrel
in PCI Patients
MI, stroke, or death ITT population
15
Placebo Clopidogrel
11.5
27 RRR P0.02
10
8.5
Combined endpoint occurrence ()
5
0
0
3
6
9
12
Months from randomization
Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al.
JAMA. 2002Vol 288,No 192411-2420.
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Multivariable Predictors of Bleeding
EventsDischarge to 1 Year (n1816)
Variable Hazard Ratio (95 CI) X2 P value
Clopidogrel 1.04 (0.75-1.44) 0.05 0.82
Age (per 10 years) 1.26 (1.07-1.48) 8.1 0.005
CABG discharge-1 year 32.15 (23.10-44.74) 423.6 lt0.0001
Aronow HD, et al. Am Heart J 2008 (published
online Nov 2008)
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Kaplan Meier Estimates of Bleeding RiskDischarge
to 1 Year (n1816)
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Timing of Severe or Moderate Bleeding
0.00008
Placebo ASA Clopidogrel ASA
0.00007
0.00006
0.00005
0.00004
Hazard Function/d
0.00003
0.00002
0.00001
0
15
60
135
270
450
630
810
Days Since Randomization
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll
Cardiol. 2007491982-1988.
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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
therapyConcomitant anticoagulant
Test for H pylori treat if infected
Yes
Yes
No
PPI
More than one risk factor Aged 60 years or
more Corticosteroid use Dyspepsia or GERD symptoms
Yes
Bhatt DL, Scheiman J, Abraham NS, et al.
Circulation 2008.
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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)
plt0.0001
Gilard et al. J Am Coll Cardiol 200851256-60.
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Intake of PPIs 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 diphosphateinduced platelet
aggregation in patients on clopidogrel with or
without PPI pantoprazole or esomeprazole.
Data are presented as mean and 95 CI. PPI,
proton pump inhibitor VASP, vasodilator-stimulat
ed phosphoprotein.
Siller-Matula JM, et al. Am Heart J.
2009157(1)148.e1-148.e5.
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Variability in Clopidogrel Responsiveness in a
Diverse Population of 544
D 5mM ADP Platelet Aggregation
Serebruany V, Steinhubl S et al. JACC 2005.
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Genetic Variations and Clopidogrel Response
Gene Percent Difference in AUC0-t P Value
CYP2C19 -32.4 ?.001
CYP2C9 -6.8 .59
CYP2B6 -15.7 .03
CYP3A5 5.6 .59
CYP1A2 11.2 .45
Pharmacokinetic Response
-50
-40
-30
-20
-10
0
10
20
30
Relative Percent Difference
Gene Percent Difference in ?MPA P Value
CYP2C19 -9.0 ?.001
CYP2C9 -0.6 .86
CYP2B6 -5.7 .012
CYP3A5 7.5 .012
CYP1A2 0.5 .90
Pharmacodynamic Response
-15
-10
-5
0
5
10
25
Absolute Difference
Mega JL, Close SL, Wiviott SD, et al. N Engl J
Med. 2009360354-362.
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Risk of All-Cause Mortality and Recurrent ACS in
Patients Taking Clopidogrel and PPI
Ho PM, et al. JAMA. 2009301(9)937-944.
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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)
With PPI
Without PPI
With PPI
Without PPI
Ho PM, et al. JAMA. 2009301(9)937-944.
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Results 1 Year Endpoint from CREDO Unadjusted
Data
Primary 1-Year Endpoint Death, MI or Stroke
20
P0.45
PPI at baseline (N374)
P0.001
16.2
15
No PPI at baseline (N1742)
14.8
13.2
10
10.8
9.2
7.7
5
0
All N2116
Placebo N1063
Clopidogrel N1053
Dunn S.P. et al AHA 2008. Slide courtesy of Steve
Steinhubl MD
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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 (n179) 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 (n874) 47/874 (5.4) 1.8 (0.99, 3.23) 0.051 66/874 (7.7) 1.6 (1.02, 2.63) 0.043
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 2008. Slide courtesy of Steve
Steinhubl MD
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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 (n195) 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 (n868) 64/868 (7.4) 1.4 (0.81, 2.41) 0.221 91/868 (10.8) 1.6 (1.03, 2.34) 0.035
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 2008. Slide courtesy of Steve
Steinhubl MD
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Results 1 Year Primary Endpoint
PPI at Baseline
Randomized Therapy Death, MI or Stroke Adjusted HR (95 CI) P-value
Placebo (N195) 16.2 0.77 (0.45, 1.33) 0.35
Clopidogrel (N179) 13.2 0.77 (0.45, 1.33) 0.35
P-value for interaction between randomized
therapy and baseline PPI P0.69
No PPI at Baseline
Randomized Therapy Death, MI or Stroke Adjusted HR (95 CI) P-value
Placebo (N868) 10.8 0.75 (0.55, 1.03) 0.08
Clopidogrel (N874) 7.7 0.75 (0.55, 1.03) 0.08
Dunn S.P. et al AHA 2008. Slide courtesy of Steve
Steinhubl MD
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THE LANCET
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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 0.80-1.11
PRASUGREL PPI vs no PPI Adj HR 1.00, 95 CI
0.84-1.20
Days
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Risk of CV Events with Different Types of PPIs
Type of PPI Clopidogrel HR (95 CI) CV death, MI or stroke Prasugrel HR (95 CI) CV death, MI or stroke
Omeprazole (n1675) 0.91 (0.72-1.15) 1.04 (0.81-1.34)
Pantoprazole (n1844) 0.94 (0.74-1.18) 1.09 (0.86-1.39)
Esomeprazole (n613) 1.07 (0.75-1.52) 0.86 (0.55-1.33)
Lansoprazole (n441) 1.00 (0.63-1.59) 0.98 (0.61-1.57)
Rabeprazole not included due to small sample size
(n66)
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Clopidogrel and the Optimization of GI Events
Trial COGENT
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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