First Analysis of Relation Between
CYP2C19 Genotype and Platelet Function in
Ticagrelor Versus Clopidogrel Treated Patients:
::
Results from the ONSET/OFFSET and RESPOND Studies
Gurbel PA1, Bliden K1, Storey RF2, Wei C3, Armstrong M3, Butler K3, Tantry US1
1Sinai
Center for Thrombosis Research, Baltimore, Maryland, USA
2Univ
of Sheffield, Sheffield, United Kingdom
3AstraZeneca,
Wilmington, Delaware, USA
Disclosures
Research Grants/Support
Pozen
Astra Zeneca
Nanosphere
Accumetrics
Helena
Multiplate
Portola
Daiichi
Honoraria/Consulting
Pozen
Novartis
Bayer
Astra Zeneca
Eli Lilly
Accumetrics
Nanosphere
Sanofi Aventis
Boehringer
Merck
Medtronic
Background
• Variable and insufficient active metabolite generation by hepatic CYP P450 isoenzymes
result in clopidogrel response variability and resistance.1
• LOF SNPs of CYP isoenzyme genes, particularly 2C19, linked to:
- diminished clopidogrel PK and PD effects
- increased ischemic events in PCI patients
- highlighted by FDA, EMEA, ACCF/AHA.1
• Ticagrelor is a reversibly-binding, noncompetitive, direct-acting, oral P2Y12 antagonist.2
• Ticagrelor therapy was associated with:
- less MACE in ACS patients in PLATO trial.3
- more rapid onset, offset, and greater level of inhibition in ONSET/OFFSET Study.4
- greater platelet inhibition in both clopidogrel responders and non-responders in
RESPOND Study.5
• Unknown facts:
- influence of CYP2C19 genotype on ticagrelor PD
- comparative PD effects of clopidogrel and ticagrelor in relation to 2C19 genotype
- whether ticagrelor treated patients have greater inhibition than clopidogrel treated
patients with “clopidogrel responder” genotype.
1. Bonello et al. J Am Coll Cardiol. 2010;56:1024-31.
3. Wallentin L et al. N Engl J Med. 2009;361:1045-57.
5. Gurbel PA et al. Circulation. 2010;121:1188-99.
2. Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9.
4. Gurbel PA et al. Circulation. 2009;120:2577-85.
Objectives
In stable CAD patients taking either ticagrelor or clopidogrel
in the ONSET/OFFSET and RESPOND studies:
1) compare platelet function between genetic categories
(CYP2C19 and ABCB1)
for each treatment:
Kruskal-Wallis test
2) compare platelet function between treatment groups
for each genetic category:
Wilcoxon rank-sum test
ONSET/OFFSET Study Design
- 21
days
Visit 1
Screening/Washout Period (n=154)
Screen Failures (n=31)
6 weeks ± 3
days
10 days
Offset
Maintenance
1 day
Onset
Visits 2-3
Randomization (n=123)
Platelet Function Testing
(Pre-dose and 0.5,1,2,4,8,24 hours post-dose)
180 mg Ticagrelor (n=57)
PM: 90 mg Ticagrelor
600 mg Clopidogrel (n=54)
Placebo (n=12)
90 mg Ticagrelor bid
75 mg Clopidogrel qd
Placebo
Visit 4
Last Dose
Platelet Function Testing
(0,2, 4,8 hours post last dose)
Visits 5-10
Platelet Function Testing
Day 1-3,5, 7 and 10 after last dose
RESPOND Study Design: Nonresponders
Screening * Randomization
Visit 1
Period 2
Crossover
14 ± 2 days
(n=144)
Nonresponders
(n=41)
Period 1
14 ± 2 days
Treatment C (n=20)
Clopidogrel 600 mg/75 mg
Treatment T (n=17)
Ticagrelor 180mg/90 mg
Treatment T (n=21)
Ticagrelor 180mg/90 mg
Treatment C (n=17)
Clopidogrel 600 mg/75 mg
Visit 2
Visit 3
PK/PD:
Predose,
0.5,1,2,4,8
hours
postdose
PK/PD:
Predose,
2,4,8 hours
postdose
Visit 4=
Visit 3+1 day
PK/PD:
Predose,
0.5,1,2,4,8
hours
postdose
*patients were dosed with study drug >14 days after screening
Visit 5
PK/PD:
Predose,
2,4,8 hours
postdose
RESPOND Study Design: Responders
Period 2
Screening * Randomization Period 1
14 ± 2 days
(n=144)
14 ± 2 days
Treatment C (n=13)
Clopidogrel 75 mg
Treatment C (n=29)
Clopidogrel 600 mg/75 mg
Treatment T (n=15)
Ticagrelor 180mg/90 mg
Responders
(n=57)
Treatment C (n=13)
Clopidogrel 600 mg/75 mg
Treatment T (n=28)
Ticagrelor 180mg/90 mg
Visit 1
Treatment T (n=13)
Ticagrelor 90 mg
Visit 2
Visit 3
PK/PD:
Predose,
0.5,1,2,4,8
hours
postdose
PK/PD:
Predose,
2,4,8 hours
postdose
Visit 4=
Visit 3+1 day
PK/PD:
Predose,
0.5,1,2,4,8
hours
postdose
*patients were dosed with study drug >14 days after screening
Visit 5
PK/PD:
Predose,
2,4,8 hours
postdose
Demographics
Methods
Platelet Function Assessments:
- Light Transmittance Aggregometry (5 and 20 M ADP, maximal)
(Chronolog, Havertown, PA)
- VASP-P Assay (Biocytex, Marseille, FR)
- VerifyNow P2Y12 Assay (Accumetrics, San Diego, CA)
Genotyping:
TaqMan® Drug Metabolism Genotyping Assays
(Life Technologies; Pleasanton, CA)
- loss of function CYP2C19*2 variant (rs4244285)
- other functional variants of CYP2C19 [*3 (rs4986893),*4 (rs28399504),
*5 (rs56337013),*6 (rs72558184), *7 (rs72558186),*8 (rs41291556)
*17 (rs12248560)] and ABCB1 (rs1045642)
CYP2C19 Genotype/Predicted Phenotype Relationships
Genotype
Phenotype
*1/*1
*1/*2-*8
*2-8/*2-*8
*17/*17
*1/*17
*2-8/*17
WT/WT
WT/LOF
LOF/LOF
GOF/GOF
WT/GOF
LOF/GOF
Extensive
Intermediate
Poor
Ultra-rapid
Rapid heterozygous
Poor/rapid
Group I- Metabolizer Status
Ultra-rapid Metabolizer
(UM)
Extensive Metabolizer
(EM)
Intermediate Metabolizer (IM)
Poor Metabolizer
(PM)
[Ultra-rapid] +[Rapid Het]
Extensive
[Intermediate] + [Poor/rapid]
Poor
Group II- LOF Carrier Status
LOF carriers
[Intermediate] + [Poor/rapid ] + [Poor]
LOF non-carriers
[Extensive] + [Ultra-rapid] + [Rapid het]
Group III- GOF Carrier Status
GOF Carriers
Extensive Metabolizer
LOF carriers
(EM)
[Ultra-rapid] + [Rapid het]
Extensive
[Intermediate] + [Poor/rapid] + [Poor]
CYP2C19 Genotype Frequencies, n (%)
Ticagrelor
(n=92)
Ultra-rapid Metabolizer
Extensive Metabolizer
Intermediate Metabolizer
Poor Metabolizer
LOF carrier
LOF non-carrier
GOF carrier
Extensive Metabolizer
*1/*1
*1/*2
*1/*3
*1/*17
*2/*2
*2/*17
*8/*17
*17/*17
Clopidogrel
(n=82)
Total
(n=174)
28 (24)
31 (38)
55 (32)
59 (34)
55 (32)
Group 1
27 (30)
28 (30)
35 (38)
2 (2)
Group II
37 (40)
55 (60)
Group III
27 (29)
28 (30)
CYP2C19 Diplotype
28 (30)
20 (22)
1 (1)
22 (24)
2 (2)
13 (14)
1 (1)
5 (5)
20 (24)*
3 (4)
5 (3)
23 (28)
59 (72)
60 (35)
114 (66)
28 (34)
31 (38)
55 (32)
59 (34)
31 (38)
13 (16)
1 (1)
28 (34)
3 (4)
6 (7)
0 (0)
59 (34)
33 (19)
2 (1)
50 (29)
5 (3)
19 (11)
1 (0)
5 (3)
0 (0)**
* p=0.05, **p=0.04;Ticagrelor vs. Clopidogrel
ABCB1 Genotype/Predicted Phenotype Relationships
and Frequencies, n (%)
Genotype
Phenotype
C/C
High Expression
Intermediate
Expression
Low Expression
C/T
T/T
Ticagrelor
(n=92)
Clopidogrel
(n=82)
Total
(n=174)
C/C
30 (33)
21 (26)
51 (29)
C/T
43 (47)
40 (49)
83 (48)
T/T
19 (21)
21 (26)
40 (23)
Predose Platelet Function
5 M ADP-Induced Aggregation
8 hrs After Loading Dose
80
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.152, CLP=0.289
p=0.387
p-values between genotypes
(LOF,Non-LOF)
TIG=0.518, CLP=0.078
p-values between genotypes
(GOF,LOF,EM)
TIG=0.117, CLP=0.168
p=0.0006
Aggregation (%)
p<0.0001
60
p=0.0006
p<0.0001
p<0.0001
p=0.0006
40
20
0
UM
EM
IM
PM
Ticagrelor
LOF
LOF
Non-carrier
Clopidogrel
GOF
5 M ADP-Induced Aggregation
8 hrs After Last Maintenance Dose
80
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.95, CLP=0.33
p-values between genotypes
(LOF,Non-LOF)
TIG=0.88, CLP=0.097
p-values between genotypes
(GOF,LOF,EM)
TIG=0.12, CLP=0.17
Aggregation (%)
p=0.149
p=0.0016
p<0.0001
p<0.0001
60
p<0.0001
p=0.0016
p=0.0004
40
20
0
UM
EM
IM
PM
LOF
LOF
Non-carrier
Ticagrelor
Clopidogrel
GOF
20 M ADP-Induced Aggregation
8 hrs After Loading Dose
Aggregation (%)
80
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.159, CLP=0.306
p<0.0001
p=0.0001
p<0.0001
p=0.149
p-values between genotypes
(LOF,Non-LOF)
TIG=0.525, CLP=0.079
p-values between genotypes
(GOF,LOF,EM)
TIG=0.209, CLP=0.165
p<0.0001
p=0.0001
p<0.0001
60
40
20
0
UM
EM
IM
PM
LOF
LOF
Non-carrier
Ticagrelor
Clopidogrel
GOF
20 M ADP-Induced Aggregation
8 hrs After Last Maintenance Dose
80
P-values between genotypes
(UM,EM,IM,PM)
TIG=0.864, CLP=0.056
P-values between genotypes
(LOF,Non-LOF)
TIG=0.803, CLP 0.049
p=0.001
p=0.0001
Aggregation (%)
p<0.0001
60
p=0.139
p=0.0001
P-values between genotypes
(GOF,LOF,EM)
TIG=0.936, CLP=0.080
p=0.001
p<0.0001
40
20
0
UM
EM
IM
PM
LOF
LOF
Non-carrier
Ticagrelor
Clopidogrel
GOF
VerifyNow-PRU
8 hrs After Loading Dose
400
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.552, CLP=0.019
p-values between genotypes
(LOF,Non-LOF)
TIG=0.301, CLP=0.010
p-values between genotypes
(GOF,LOF,EM)
TIG=0.360, CLP=0.028
p<0.0001
p<0.0001
p<0.0001
300
p=0.149
p<0.0001
PRU
p<0.0001
p<0.0001
200
100
0
UM
EM
IM
PM
LOF
LOF
Non-carrier
Ticagrelor
Clopidogrel
GOF
VerifyNow-PRU
8 hrs After Last Maintenance Dose
400
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.535, CLP=0.006
p<0.0001
p-values between genotypes
(LOF,Non-LOF)
TIG=0.898, CLP=0.002
p<0.0001
p-values between genotypes
(GOF,LOF,EM)
TIG=0.905, CLP=0.007
p<0.0001
p<0.0001
PRU
300
p=0.138
p<0.0001
p<0.0001
200
100
0
UM
EM
IM
PM
LOF
LOF
Non-carrier
Ticagrelor
Clopidogrel
GOF
VASP-PRI:
8 hrs After Loading Dose
100
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.601, CLP=0.153
p<0.0001
p<0.0001
p<0.0001
p-values between genotypes p-values between genotypes
(GOF,LOF,EM)
(LOF,Non-LOF)
TIG=0.498, CLP=0.109
TIG=0.616, CLP=0.036
p<0.0001
80
VASP-PRI
p=0.148
p<0.0001
p<0.0001
60
40
20
0
UM
EM
IM
PM
Ticagrelor
LOF
LOF
Non-Carrier
Clopidogrel
GOF
VASP-PRI
8 hrs After Last Maintenance Dose
100
p-values between genotypes
(UM,EM,IM,PM)
TIG=0.635, CLP=0.069
p-values between genotypes
(LOF,Non-LOF)
TIG=0.878, CLP=0.010
p-values between genotypes
(GOF,LOF,EM)
TIG=0.828, CLP=0.034
p<0.0001
80
p<0.0001
p<0.0001
p<0.0001
p<0.0001
p<0.0001
VASP-PRI
p=0.148
60
40
20
0
UM
EM
IM
PM
Ticagrelor
LOF
LOF
Non-Carrier
Clopidogrel
GOF
5M ADP-Induced Platelet Aggregation (%)
Influence of Diplotype on Platelet Function During Maintenance Therapy:
5 M ADP-Induced Aggregation
75
p=0.004
p<0.0001
p=0.005
p=0.009
60
45
30
15
0
*1/*1
*1/*2
*1/*3
*1/*17
Ticagrelor
*2/*2
*2/*17
Clopidogrel
N/A
N/A
*8/*17
*17/*17
20M ADP-Induced Platelet Aggregation (%)
Influence of Diplotype on Platelet Function During Maintenance Therapy :
20 M ADP-Induced Aggregation
75
p=0.0001
p<0.0001
p=0.003
p=0.003
60
45
30
15
0
N/A
*1/*1
*1/*2
*1/*3
*1/*17
*2/*2
*2/*17
*8/*17
N/A
*17/*17
Within the clopidogrel group, there was an influence of diplotype on platelet function, p=0.09
Ticagrelor
Clopidogrel
Influence of Diplotype on Platelet Function During Maintenance Therapy:
VerifyNow P2Y12 Assay
400
p=0.0011
p<0.0001
P2Y12 Reaction Units
320
p<0.0001
p<0.0001
240
160
80
0
N/A
*1/*1
*1/*2
*1/*3
*1/*17
*2/*2
*2/*17
*8/*17
N/A
*17/*17
Within the clopidogrel group, there was a significant influence of diplotype on platelet function, p=0.006
Ticagrelor
Clopidogrel
Influence of Diplotype on Platelet Function During Maintenance Therapy:
VASP-P Assay
100
p<0.0001
VASP–PRI (%)
80
p<0.0001
p<0.0001
p=0.007
60
40
20
N/A
0
*1/*1
*1/*2
*1/*3
*1/*17
*2/*2
*2/*17
*8/*17
N/A
*17/*17
Within the clopidogrel group, there was an influence of diplotype on platelet function, p=0.09
Ticagrelor
Clopidogrel
Influence of ABCB1 Genotype on Platelet Function
• No influence of ABCB1 genotype on
platelet reactivity to ADP before treatment or during
treatment in either group by all measurements.
Conclusions
• First report demonstrating the superior antiplatelet effect of
ticagrelor compared to clopidogrel irrespective of CYP2C19 genotype.
• Whereas CYP2C19 genotype influenced the antiplatelet effect of
clopidogrel, there was no effect during ticagrelor therapy.
• Influence of CYP2C19 genotype in clopidogrel-treated patients most
evident during maintenance and by the VerifyNow P2Y12 assay.
• Larger studies needed to examine the relative influences *2 and *17 on
clopidogrel antiplatelet effects.
• Results consistent with:
- overall PLATO trial clinical outcomes
- PLATO genetic substudy:
ticagrelor was more clinically effective than clopidogrel
irrespective of CYP2C19 genotype.
Published online November 15, 2010