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 Honoraria/Consulting
Pozen Pozen
Astra Zeneca Novartis
Nanosphere Bayer
Accumetrics Astra Zeneca
Helena Eli Lilly
Accumetrics
Multiplate
Nanosphere
Portola
Sanofi Aventis
Daiichi 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. 2. Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9.
3. Wallentin L et al. N Engl J Med. 2009;361:1045-57. 4. Gurbel PA et al. Circulation. 2009;120:2577-85.
5. Gurbel PA et al. Circulation. 2010;121:1188-99.
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
Visit 1
Screening/Washout Period (n=154)
days
- 21
Screen Failures (n=31)
Visits 2-3
Onset
Randomization (n=123)
Platelet Function Testing
(Pre-dose and 0.5,1,2,4,8,24 hours post-dose)
1 day
180 mg Ticagrelor (n=57)
600 mg Clopidogrel (n=54) Placebo (n=12)
PM: 90 mg Ticagrelor
Maintenance
6 weeks ± 3
days
90 mg Ticagrelor bid 75 mg Clopidogrel qd Placebo
Visit 4
Offset
Last Dose
Platelet Function Testing
10 days
(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 Period 1 Crossover Period 2
14 ± 2 days 14 ± 2 days
(n=144)
Treatment C (n=20) Treatment T (n=17)
Clopidogrel 600 mg/75 mg Ticagrelor 180mg/90 mg
Nonresponders
(n=41) Treatment T (n=21) Treatment C (n=17)
Ticagrelor 180mg/90 mg Clopidogrel 600 mg/75 mg
Visit 1 Visit 2 Visit 3 Visit 4= Visit 5
Visit 3+1 day
PK/PD: PK/PD: PK/PD: PK/PD:
Predose, Predose, Predose, Predose,
0.5,1,2,4,8 2,4,8 hours 0.5,1,2,4,8 2,4,8 hours
hours postdose hours postdose
postdose postdose
*patients were dosed with study drug >14 days after screening
RESPOND Study Design: Responders
Screening * Randomization Period 1 Period 2
14 ± 2 days 14 ± 2 days
(n=144)
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 Treatment C (n=13)
(n=57) Clopidogrel 600 mg/75 mg
Treatment T (n=28)
Ticagrelor 180mg/90 mg
Treatment T (n=13)
Ticagrelor 90 mg
Visit 1 Visit 2 Visit 3 Visit 4= Visit 5
Visit 3+1 day
PK/PD: PK/PD: PK/PD: PK/PD:
Predose, Predose, Predose, Predose,
0.5,1,2,4,8 2,4,8 hours 0.5,1,2,4,8 2,4,8 hours
hours hours
postdose postdose
postdose
postdose
*patients were dosed with study drug >14 days after screening
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 WT/WT Extensive
*1/*2-*8 WT/LOF Intermediate
*2-8/*2-*8 LOF/LOF Poor
*17/*17 GOF/GOF Ultra-rapid
*1/*17 WT/GOF Rapid heterozygous
*2-8/*17 LOF/GOF Poor/rapid
Group I- Metabolizer Status
Ultra-rapid Metabolizer (UM) [Ultra-rapid] +[Rapid Het]
Extensive Metabolizer (EM) Extensive
Intermediate Metabolizer (IM) [Intermediate] + [Poor/rapid]
Poor Metabolizer (PM) 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 [Ultra-rapid] + [Rapid het]
Extensive Metabolizer (EM) Extensive
LOF carriers [Intermediate] + [Poor/rapid] + [Poor]
CYP2C19 Genotype Frequencies, n (%)
Ticagrelor Clopidogrel Total
(n=92) (n=82) (n=174)
Group 1
Ultra-rapid Metabolizer 27 (30) 28 (24) 55 (32)
Extensive Metabolizer 28 (30) 31 (38) 59 (34)
Intermediate Metabolizer 35 (38) 20 (24)* 55 (32)
Poor Metabolizer 2 (2) 3 (4) 5 (3)
Group II
LOF carrier 37 (40) 23 (28) 60 (35)
LOF non-carrier 55 (60) 59 (72) 114 (66)
Group III
GOF carrier 27 (29) 28 (34) 55 (32)
Extensive Metabolizer 28 (30) 31 (38) 59 (34)
CYP2C19 Diplotype
*1/*1 28 (30) 31 (38) 59 (34)
*1/*2 20 (22) 13 (16) 33 (19)
*1/*3 1 (1) 1 (1) 2 (1)
*1/*17 22 (24) 28 (34) 50 (29)
*2/*2 2 (2) 3 (4) 5 (3)
*2/*17 13 (14) 6 (7) 19 (11)
*8/*17 1 (1) 0 (0) 1 (0)
*17/*17 5 (5) 0 (0)** 5 (3)
* p=0.05, **p=0.04;Ticagrelor vs. Clopidogrel
ABCB1 Genotype/Predicted Phenotype Relationships
and Frequencies, n (%)
Genotype Phenotype
C/C High Expression
Intermediate
C/T
Expression
T/T Low Expression
Ticagrelor Clopidogrel Total
(n=92) (n=82) (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
p-values between genotypes p-values between genotypes p-values between genotypes
80 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.152, CLP=0.289 TIG=0.518, CLP=0.078 TIG=0.117, CLP=0.168
p=0.387
p=0.0006
p<0.0001
p=0.0006
Aggregation (%)
60 p<0.0001 p=0.0006
p<0.0001
40
20
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
5 M ADP-Induced Aggregation
8 hrs After Last Maintenance Dose
p-values between genotypes p-values between genotypes p-values between genotypes
80 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.95, CLP=0.33 TIG=0.88, CLP=0.097 TIG=0.12, CLP=0.17
p=0.149
Aggregation (%)
p=0.0016 p<0.0001
60 p<0.0001 p<0.0001 p=0.0016
p=0.0004
40
20
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
20 M ADP-Induced Aggregation
8 hrs After Loading Dose
p-values between genotypes p-values between genotypes p-values between genotypes
80 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.159, CLP=0.306 TIG=0.525, CLP=0.079 TIG=0.209, CLP=0.165
p<0.0001
p=0.0001 p<0.0001
p<0.0001 p=0.149 p=0.0001
p<0.0001
Aggregation (%)
60
40
20
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
20 M ADP-Induced Aggregation
8 hrs After Last Maintenance Dose
P-values between genotypes P-values between genotypes P-values between genotypes
80 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.864, CLP=0.056 TIG=0.803, CLP 0.049 TIG=0.936, CLP=0.080
p=0.001
p=0.0001 p=0.001
p<0.0001
p=0.139 p<0.0001
60
Aggregation (%)
p=0.0001
40
20
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
VerifyNow-PRU
8 hrs After Loading Dose
p-values between genotypes p-values between genotypes p-values between genotypes
400 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.552, CLP=0.019 TIG=0.301, CLP=0.010 TIG=0.360, CLP=0.028
p<0.0001 p<0.0001
p<0.0001
p<0.0001
300 p=0.149 p<0.0001
p<0.0001
PRU
200
100
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
VerifyNow-PRU
8 hrs After Last Maintenance Dose
p-values between genotypes p-values between genotypes p-values between genotypes
400 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.535, CLP=0.006 TIG=0.898, CLP=0.002 TIG=0.905, CLP=0.007
p<0.0001 p<0.0001 p<0.0001
p<0.0001
300 p=0.138
p<0.0001 p<0.0001
PRU
200
100
0
UM EM IM PM LOF LOF GOF
Non-carrier
Ticagrelor Clopidogrel
VASP-PRI:
8 hrs After Loading Dose
p-values between genotypes p-values between genotypes p-values between genotypes
100 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.601, CLP=0.153 TIG=0.616, CLP=0.036 TIG=0.498, CLP=0.109
p<0.0001
p<0.0001 p<0.0001 p<0.0001
p<0.0001
80 p<0.0001
p=0.148
VASP-PRI
60
40
20
0
UM EM IM PM LOF LOF GOF
Non-Carrier
Ticagrelor Clopidogrel
VASP-PRI
8 hrs After Last Maintenance Dose
p-values between genotypes p-values between genotypes p-values between genotypes
100 (UM,EM,IM,PM) (LOF,Non-LOF) (GOF,LOF,EM)
TIG=0.635, CLP=0.069 TIG=0.878, CLP=0.010 TIG=0.828, CLP=0.034
p<0.0001
p<0.0001
p<0.0001
80 p<0.0001
p<0.0001 p<0.0001
p=0.148
VASP-PRI
60
40
20
0
UM EM IM PM LOF LOF GOF
Non-Carrier
Ticagrelor Clopidogrel
Influence of Diplotype on Platelet Function During Maintenance Therapy:
5 M ADP-Induced Aggregation
75
5M ADP-Induced Platelet Aggregation (%)
p=0.004 p<0.0001 p=0.005 p=0.009
60
45
30
15
N/A N/A
0
*1/*1 *1/*2 *1/*3 *1/*17 *2/*2 *2/*17 *8/*17 *17/*17
Ticagrelor Clopidogrel
Influence of Diplotype on Platelet Function During Maintenance Therapy :
20 M ADP-Induced Aggregation
75
20M ADP-Induced Platelet Aggregation (%)
p=0.0001 p<0.0001 p=0.003 p=0.003
60
45
30
15
N/A N/A
0
*1/*1 *1/*2 *1/*3 *1/*17 *2/*2 *2/*17 *8/*17 *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
320 p<0.0001 p<0.0001
P2Y12 Reaction Units
240
160
80
N/A N/A
0
*1/*1 *1/*2 *1/*3 *1/*17 *2/*2 *2/*17 *8/*17 *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
p<0.0001 p<0.0001 p=0.007
80
VASP–PRI (%)
60
40
20
N/A N/A
0
*1/*1 *1/*2 *1/*3 *1/*17 *2/*2 *2/*17 *8/*17 *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