Transcript Slide 1

Influence of CYP2C19 Polymorphism on Antiplatelet
Effects of Clopidogrel and Long-term Recurrent
Ischemic Event Occurrence
Paul A. Gurbel, Kevin P. Bliden, Kathleen Ryan, William Herzog,
Mark J. Antonino, Udaya S. Tantry, Alan R. Shuldiner,
Sinai Center for Thrombosis Research, Baltimore, MD,
University of Maryland School of Medicine, Baltimore, MD
Disclosures
Research Grants
Honoraria/Consultant
- Schering Plough
- Schering Plough
- Astra Zeneca
- Astra Zeneca
- Sanofi/Aventis
- Sanofi/Aventis
- Bayer
- Bayer
- Portola
- Portola
- Daiichi Sankyo
- Daiichi Sankyo
- Lilly
- Lilly
- Pozen
Background
Limitations of Clopidogrel
Turbidometric aggregation revealed:
(i) unpredictable pharmacodynamic response
(ii) delayed onset
(iii) modest platelet inhibition (30%-50%)
(iv) wide response variability and non-responsiveness
(v) association of high on-treatment platelet reactivity with post-PCI ischemic
event occurrence
(Gurbel PA et al. J Am Coll Cadriol. 2008; 51:261-3)
Mechanism of Clopidogrel Response Variability
Intestinal
Absorption
?
P-glycoprotein
(ABCB1 gene polymorphism)
Limited
Absorption
Esterases 85%
15%
2C19
1A2
Gene polymorphisms, PPI’s
Smoking
2B6
Hepatic Cytochromes
P450 Isoenzymes
2C19
Gene polymorphisms, PPI’s
3A4/5
Lipophilic statins, Calcium antagonists,
Genetic polymorphisms
2B6
P2Y12 Receptor
Wide and Unpredictable Pharmacodynamic Response
High On-treatment Platelet Reactivity and Recurrent Ischemic Events
Gene Polymorphisms and Platelet Reactivity on Clopidogrel Therapy
Study
Patients (n)
Gene Variants
Studied
High Platelet Reactivity
Gene Variant
1. Taubert et al (2006)
PCI (60)
ABCB1 3435T
 CLP absorption/active metabolite
2. Suh et al (2006)
Healthy (16)
CYP3A5
Nonexpressor more drug-drug interactions
Nonexpressor-  CV events
PCI (348)
3. Giusti et al (2007)
PCI (1419)
P2Y12, CYP3A4, CYP2C19*2
CYP2C19*2
4. Hulot et al (2006)
Healthy (29)
CYP2C19, CYP3A5, CYP2B6
CYP2C19*2
CYP1A2
5. Fontana et al (2007)
Healthy (94)
CYP2C19*2, CYP3A4
CYP2C19*2
6. Brandt et al (2007)
Healthy (74)
CYP2C19, CYP2C9, CYP3A4,
CYP2C19*2/3, CYP2C9*11
CYP3A5, CYP2B6, CYP1A2
7. Geisler et al (2008)
PCI (235)
CYP2C19, CYP3A4, CYP3A5
CYP2C19*2
8. Kim et al (2008)
Healthy (24)
CYP2C19
CYP2C19*2
9. Trenk et al. (2008)
PCI (797)
CYP2C19*2
CYP2C19*20
10. Gladding et al (2008)
PCI (60)
CYP2C19, CYP2C9, CYP3A4,
CYP2C19*2/3, CYP2C9*11
CYP3A5, CYP2B6, P2Y12, ABCB1 CYP2C19*2,*4,*17
11. Frere et al (2008)
NSTE-ACS
CYP2C19, CYP3A4, CYP3A5
CYP2C19*2
12. Mega et al (2008)
Healthy (162)
CYP2C19, CYP3A4, CYP2B6,
CYP2C19*2
ACS (1477)
CYP3A5, CYP1A2
CYP2C19*-  1.53x- MACE, 3x- ST
Acute MI (2009)
CYP2C19, CYP3A5, ABCB1,
ABCB1, CYP2C19*2,*3, *4,*5 -HPR
13. Simon et al (2008)
P2Y12
14. Collet et al (2009)
MI (259)
CYP2C19
 CV events
Aim
To study the link between:
- Platelet reactivity to ADP
- CYP2C19*2 (rs4244285) gene
- Post-discharge cardiovascular outcome
in patients undergoing non-emergent coronary arterial stenting
Methods
Patients
- Enrolled in prior studies (CLEAR PLATELETS 1 and 2)
- Genetic and 1 year F/U data available in 227 patients
- Ages >18 years
- non-emergent PCI
- no differences in age, sex, or other baseline characteristics in stratified
analyses of clopidogrel loading dose, and thus these groups were combined
for further analyses
Exclusion Criteria:
- Bleeding diathesis, gastrointestinal bleeding, hemorrhagic stroke, MI <48 h,
non-hemorrhagic CVA < 3 mo, major surgery < 6 wk, illicit drug or alcohol
abuse, coagulopathy, platelets <100,000/mm3, hematocrit <25%,
creatinine >2 mg/dL
Methods
Patients n=227
Aspirin 75-325mg/day for >1 wk
Clopidogrel Naïve (n=137)
600mg Load
n=112
300mg LD
n=25
Clopidogrel Maintenance (n=90)
No Load
- All patients treated with Heparin or Bivalirudin
- Eptifibatide n =107
- Discharge Treatment – 325 mg/day aspirin and 75mg/day clopidogrel
Methods
Platelet Function Analysis
- Turbidometric aggregation (20 μM ADP)
- 3.2% trisodium citrate
- Pretreatment in clopidogrel naïve patients
- On-treatment measured on the day of hospital discharge in patients not treated
with eptifibatide
- On-treatment measured 5 days post-discharge in patients treated with
eptifibatide
Methods
Genotyping
• CYP2C19*2 variant (rs4244285) determined by TaqMan® SNP genotyping assays
(Applied Biosystems, Foster City, CA).
• Effect of CYP2C19*2 genotype on pre- and on-treatment ADP- induced platelet
aggregation under an additive genetic model by classifying subjects according
to whether they had 0, 1, or 2 risk alleles.
• Constructed survival curves to compare 1 year cardiovascular event-free
survival between subjects with and without a CYP2C19*2 risk allele.
Patient Demographics
Patients Without
Ischemic Events
Patients With
Ischemic Events
(p-Value)
64 ± 12
64 ± 10
NS
Gender (Male)
61%
53%
NS
Race, Caucasian (%)
61%
53%
NS
31 ± 7
28 ± 6
0.04
Systolic BP (mm Hg)
141 ± 20
137 ± 20
NS
Diastolic BP (mm Hg)
73 ± 14
70 ± 13
NS
Current Smoking (%)
26%
23%
NS
Family History of CAD (%)
41%
50%
NS
Hypertension (%)
81%
70%
NS
Hyperlipidemia (%)
81%
80%
NS
Diabetes (%)
38%
50%
0.05
Prior MI (%)
31%
33%
NS
Prior CABG (%)
21%
27%
NS
Prior PTCA (%)
38%
37%
NS
Prior CVA (%)
5%
3%
NS
Age (years)
Body Mass Index (kg/m2)
Risk Factors/ Medical Hx
Patient Demographics
Patients
Without
Ischemic
Events
Patients
With
Ischemic
Events
(p-Value)
67%
72%
NS
26%
17%
NS
Statins
75%
86%
NS
PPI
27%
40%
0.05
WBC (x 1000/mm3)
9.0 ± 2.4
6.9 ± 2.2
NS
Hemoglobin (g/dl)
13.6 ± 2.1
13.3 ± 1.7
NS
Hematocrit (%)
40%
40%
NS
Creatinine (g/dl)
1.1 ± .3
1.6 ± .3
0.009
Baseline Medications
Beta-blockers
Calcium-channel
Blockers
Laboratory Data
Procedural Characteristics
Patients
without ischemic
Events
Patients with
Ischemic Events
(p-Value)
Length of Procedure (min)
44 ± 24
47± 34
NS
Ejection Fraction (%)
51 ± 9
48 ± 14
NS
Total Contrast (mL)
170 ± 76
176 ± 55
NS
Number of vessels treated
1.5 ± 4.0
1.2 ± 0.4
NS
Calcified lesions
12%
7%
NS
Restenosis
11%
7%
NS
RCA
35%
20%
0.05
LAD
29%
47%
NS
CX
23%
27%
NS
SVG
3%
6%
NS
Drug-eluting
82%
85%
NS
Lesion Diameter (mm)
3.0 ± 0.5
2.9 ± 0.4
NS
Total Stent Length (mm)
24 ± 16
17± 8
0.02
58%
53%
NS
Lesion Morphology
Lesion Location (TVR)
Stent post- dilation
Results
CYP2C19*2 Frequency
Patients (n)
120
160
80
64
40
3
0
-/-
-/*2
*2/*2
Patients With Events (%)
(Frequency = 30%)
160
CYP2C19*2 Frequency and Events
25
p=0.02
20
15
21%
10
10%
5
0
+ CYP2C19*2
(n=14/67)
- CYP2C19*2
(n=16/160)
Results
Relation of Race to CYP2C19*2
40
30
20
28%
30%
10
0
African American
Caucasian
Results
Relation of CYP2C19*2 to Event Occurrence
Results
Relation of Pre-Treatment Aggregation to
CYP2C19*2 and Event Occurrence
p=0.86
20 µM ADP-Induced
Aggregation (%)
p=0.58
75
75
60
60
45
45
30
30
15
15
0
0
-/-
-/*2
*2/*2
CYP2C19*2
Without
Events
With
Events
Results
Relation of On-Treatment Aggregation to
p=0.58
CYP2C19*2
and Event Occurrence
p=0.004
20 µM ADP-Induced
Aggregation (%)
p=0.02
75
75
60
60
45
45
30
30
15
15
0
0
-/-
-/*2
CYP2C19*2
*2/*2
Without
Events
With
Events
Conclusions
• The CYP2C19*2 allele is frequent in the PCI population.
• CYP2C19*2 has no effect on pre-clopidogrel treatment platelet
reactivity.
• Patients with the CYP2C19*2 allele have higher on-treatment platelet
reactivity than the wild type.
• This common variant encodes a defective enzyme that likely fails to
adequately convert clopidogrel to its activate metabolite, leading to
lesser inhibition of platelet function and diminished cardiovascular
protection.
• Larger prospective studies are needed to confirm our observations
linking CYP2C19*2 to high on-treatment platelet reactivity and
ischemic events post-stenting.