Literature Review
Peter R. McNally, DO, FACP, FACG
University Colorado Denver
School of Medicine
Center for Human Simulation
Aurora, Colorado 80045
1
Gilard M1, Arnaud B2, Cornily JC1, Le Gal G3,
Lacut K3, Le Calvez G2, Mansourati J1, Mottier D2,
Abgrall JF2, Boschat J1.
Influence of omeprazole
on the antiplatelet action of clopidogrel associated with
aspirin: the randomized, double-blind OCLA
(Omeprazole CLopidogrel Aspirin) study.
J Am Coll Cardiol 2008;51:256-60.
1Dept
Cardiology, 2Dept Hematology, INSERM 0502,
3Center for Clinical Investigation EA3878 and Dept
Internal Medicine and Chest Diseases, Brest
University Hospital, Brest, France
2
Introduction
• Platelet activation & aggregation play an important role
in the pathogenesis of arterial thrombosis and can lead
to acute coronary syndrome (ACS) associated with
percutaneous coronary intervention (PCI).
• Clopidogrel (Plavix*) a thienopyridine, inhibits platelet
activation induced by adenosine diphosphate (ADP).
• Clopidogrel metabolites form an inactive disulfide bond
with the platelet P2Y12 ADP receptor, inhibiting platelet
reactivity.
• Clopidogrel is a prodrug, needing hepatic metabolism
to acquire platelet anti-aggregation properties.
Small DS, et al. Effects of PPI Lansoprazole on pharmacodynamics of
Prasugrel and Clopidogrel. J Clin Pharm. 2008;48:475-84.
3
Introduction
• Vasodilator-Stimulated Phosphoprotein
Phosphorylation (VASP) provides an functional
index of platelet reactivity to clopidogrel.
• The higher the platelet reactivity index (PRI) the
more frequently thrombosis occurs with
clopidogrel treatment.
• The hepatic CYP450 isoenzyme CYP2C19 is the
dominant enymatic pathway of prodrug
(clopidogrel) activation.
Gilard M, et al. J Thromb Hemost 2006;4:2508-9
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Introduction
• Omeprazole (OMP) is a racemic compound commonly
used to suppress gastric acid production in the
treatment of peptic ulcer disease and
Gastroesophageal Reflux Disease (GERD).
• OMP is a prodrug, predominantly metabolized by
hepatic CYP450 isoenzyme CYP2C19.
• Competitive inhibition of the CYP2C19 metabolic
pathway by OMP may decrease Clopidogrel activation
thereby decreasing PRI values and increasing risk for
ACS.
Gilard M, et al. J Thromb Hemost 2006;4:2508-9
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Hepatic CYP450 Activation of Prodrugs:
PPIs and Clopidogrel
Active Metabolites
Pro Drugs
Benzimidazole
PPI’s
Clopidogrel
CYP-3A4
CYP-2C19
Competitive Inhibition
↓ Active Metabolites
Ishizaki T, et al. Aliment Pharmacol Ther. 1999;13:Suppl 3:27-36.
Small DS, et al. J Clin Pharmacol. 2008;48:475-484.
Sulfenamide
R-130964
Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Aim
• The authors sought to test the hypothesis that
OMP reduces the biological action of clopidogrel
(platelet reactivity index or PRI) , probably due to
competitive inhibition of the CYP2C19 pathway.
• In a prospective, randomized double-blind study,
Gilard, et al, evaluated the impact of OMP
20mg/day vs. placebo on clopidogrel effect by
measuring platelet phosphorylation-VASP as
expressed as PRI.
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Design:
Prospective, blinded, placebo controlled, randomized trial
• Consecutive patients undergoing elective coronary
stent implantation were considered for inclusion
• All patients gave written informed consent
• Controlled Treatment (all patients received)
– Aspirin 75 mg/day
– Clopidogrel 300 mg loading, followed by 75 mg/day
• Randomization Treatment
– Omperazole 20 mg or Placebo
– Treatment daily for 7 days
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Design
Randomized
N = 140
N=70
Omeprazole
N=70
Placebo
Evaluable n=64
(drop outs, 6)
Evaluable n=60
(drop outs, 9)
Total Assessed for Eligibility, N=354
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Design: Study Population
• Exclusion Criteria
– Previous treatment with Clopidogrel
– Previous treatment with PPI
– History of thrombocytopenia < 150K
– Bleeding disorder
– Liver disease
– Peptic ulcer disease
– Pregnancy
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Design: Study Evaluations
• Conducted on Day 1 (pre-Clopidogrel) and 7
days after (clopidogrel + OMP vs. placebo)
• Platelet Reactivity Evaluation
– Vasodilator-Stimulated Phosphoprotein
(VASP) Biodis-Stago, Asnieres, France.
– Platelet mean fluorescence intensity (MFI)
– Platelet Reactivity Index (PRI)
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Design: Study Evaluations
Platelet Reactivity Index (PRI) calculation:
% PRI = (MFI[PGE1] - MF1[PGE1+ADP] X 100
MFI (PGE1)
Established Criteria for Clopidogrel response:
Good % PRI < 50%
Poor
% PRI > 50%
Barragan P et al. Catheter Cardiovasc Interv. 2003;107:32-7
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Results: Demographics
Placebo
N=60
Age
63
♂ gender
75%
Smoker
71%
HTN
47%
FHx CAD
43%
DM
18%
BMI
27
Dyslipidemia 71%
Omeprazole
N=64
62
81%
64%
53%
34%
9%
27
66%
P-value
ns
ns
ns
ns
ns
ns
ns
ns
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Results: Demographics
Table 1.
Placebo
N=60
Previous MI 8%
Beta-blocker 91%
ACE
50%
inhibitor
Atorvastatin 68%
Other statin 28%
Omeprazole
N=64
11%
83%
48%
P-value
67%
23%
ns
ns
ns
ns
ns
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Results: Platelet Reactivity Index (PRI)
PRI (%)
Figure 1.
100
90
80
70
60
50
40
30
20
10
0
P = NS
83.9
83.2
51.4
P < 0.0001
39.8
Omp D1
Plac D1
Omp D7
Plac D7
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Results: Variation of PRI
Figure 2.
0
PRI Variation (%)
-10
-20
-30
-40
-32
-43
P < 0.0001
-50
-60
-70
Placebo
Omp
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Study Results: Summary
• Baseline demographic characteristics between the Omp and
placebo treated groups were statistically similar, Table 1.
• Day 1, mean PRI was similar in both groups (83.9% vs. 83.2%),
but PRI on Day 7 was significantly higher in the Omp group
(51.4% vs.. 39.8%), (p< 0.0001) Figure 1.
• Clopidogrel “poor” responders (defined as PRI >50%) were
more common in the Omp group 60.9% vs. 26.7% in the
placebo group (p < 0.0001).
• The odds ratio of being a clopidogrel “poor” responder when
treated with Omp was 4.31 (95% CI 2.0 to 9.2).
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Conclusions:
1.
Omp significantly decreased the effect of clopidogrel on
platelet activation as tested by VASP phosphorylation.
2.
Clinical implications of this study suggest that 1/3 of
patients on clopidogrel alone are unprotected against
ACS (PRI > 50%) and that patients co-treated with Omp
have double the risk of ACS (60.9% have PRI > 50%).
3.
The empiric prescription of Omp to prevent the potential
of gastrointestinal bleeding caused by aspirinclopidogrel antiplatelet therapy should be stopped. Risk
stratification for GI complications should guide Omp use
in these patients.
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Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Reviewer Comments
Gilard, et al, do not answer the following questions?
1.
Although all of the PPIs are prodrugs with some metabolism through the
CYP450. Each PPI has unique CYP450 metabolic pathways. This study
does not determine if all PPIs convey the same negative effect on
clopidogrel (PRI > 50%) as shown with Omp.
PPI
a.
b.
c.
d.
e.
f.
2.
Omperazole
Esomperazole
Lansoprazole
Dexlansoprazole
Rabeprazole
Pantoprazole
conjugation)
Primary Pathway (Secondary pathway)
CYP2C19
CYP3A4
CYP3A4
CYP2C19
CYP2C19 + CYP3A4
CYP2C9
(CYP3A4)
(CYP2C19)
(CYP2C19,CYP1A)
(CYP3A4)
(CYP2C19sulfate
The investigators did not evaluate for CYP2C19 polymorphisms or other
confounding variables that may have influenced clopidogrel hepatic
metabolism and explained high PRI (>50%) seen in 30% of the placebo
group.
Gilard M, et al. J Am Coll Cardiol 2008;51:256-60.
Reviewer Comments
1.
Dr. Gilard and colleagues are commended for using a readily available
clinical assay (VASP phosphorylation) to demonstrate the effects of
Omp on clopidogrel inhibition of the ACS marker, PRI.
2.
The study is well designed, the results striking and with important
negative clinical implication for the coadministration of omp and
clopidogrel among patients at risk for ACS.
3.
This study design should be applied in a similar fashion to evaluate
the effect of other PPIs on clopidogrel and the ACS risk measured by
PRI > 50%.
4.
For now, we should all use restraint in the prescription of PPI among
patients on clopidogrel and follow the current recommendation of the
FDA until further studies are available.
http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm
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The identification of increased risk for Acute Coronary Syndrome when at risk
cardiac patients receiving clopidogrel are concomitantly given PPIs has lead to
the Food & Drug Administration to issue the following warning:



“Healthcare providers should continue to prescribe and patients should
continue to take clopidogrel as directed, because clopidogrel has
demonstrated benefits in preventing blood clots that could lead to a heart
attack or stroke.”
“Healthcare providers should re-evaluate the need for starting or continuing
treatment with a PPI, including Prilosec OTC, in patients taking
clopidogrel.”
“Patients taking clopidogrel should consult with their healthcare provider if
they are currently taking or considering taking PPI, including Prilosec
OTC.”
http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm
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