Transcript Plaque Rupture

CHARISMA Genomics
Deepak L. Bhatt MD, MPH, Katy L. Simonsen PhD, Eileen S.
Emison PhD, Keith A. A. Fox MBChB, P. Gabriel Steg MD,
Gilles Montalescot MD, PhD, Nihar Bhakta MD, Werner Hacke
MD, Marcus D. Flather MD, Patrice Cacoub MD, Mark A.
Creager MD, Peter B. Berger MD, Steven R. Steinhubl MD,
Gurunathan Murugesan PhD, Kandice Kottke-Marchant MD,
PhD, A. Michael Lincoff MD, Eric J. Topol MD, on Behalf of
the CHARISMA Executive Committee and Investigators
Disclosure for Dr. Bhatt
Dr. Bhatt has served as a consultant to: Arena, Astra Zeneca, Bristol-Myers
Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith
Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL,
Philips, Portola, sanofi aventis, Schering Plough, Takeda, The Medicines
Company, Vertex.
Principal Investigator for several potentially related studies. His institution
has received funding from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape,
Sanofi Aventis, The Medicines Company.
This presentation discusses off-label and/or investigational uses of various
drugs and devices.
This CHARISMA study was funded by sanofi aventis and Bristol-Myers
Squibb. The genetic analyses were done by Bristol-Myers Squibb’s Human
Genetics and Statistical Genetics Groups.
Variability in Clopidogrel Responsiveness in a
Diverse Population of 544
Serebruany VL, Steinhubl SR, Berger PB, et al. JACC 2005; 45:246 –51.
Genetic Variations and Clopidogrel Response
Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.
Genetic Variations and Clopidogrel Response
Heterozygotes vs Homozygotes
•
Probability of all-cause death, recurrent myocardial infarction, and stroke (%)
according to CYP2C19 loss of function variant allele polymorphisms in the FAST MI
registry
Simon T, et al. N Engl J Med. 2009;360:363-375.
Primary Efficacy Results (MI/Stroke/CV
Death) by Pre-Specified Entry Category
Population
RR (95% CI)
p value
Qualifying CAD, CVD or PAD *
0.88 (0.77, 0.998) 0.046
(n=12,153)
Multiple Risk Factors *
1.20 (0.91, 1.59)
0.20
0.93 (0.83, 1.05)
0.22
(n=3,284)
Overall Population†
(n=15,603)
0.4
0.6 0.8
Clopidogrel + ASA
Better
1.2
1.4 1.6
Placebo + ASA
Better
* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these prespecified subgroups of patients
† 166 patients did not meet any of the main inclusion criteria
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:1706-17.
Cumulative event rate (%)
Overall Population: Principal Secondary Efficacy
Outcome (MI/Stroke/CV Death/Hospitalization)†
20
Placebo + ASA*
17.9%
15
Clopidogrel + ASA*
16.7%
10
RRR: 7.7% [95% CI: 0.5%, 14.4%]
p = 0.04
5
0
0
6
12
18
24
Months since randomization§
†First
30
Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization
*All patients received ASA 75-162 mg/day
§The number of patients followed beyond 30 months decreases rapidly to zero
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:1706-17.
Primary Endpoint (MI/Stroke/CV Death) in
Patients With Previous MI, IS, or PAD*
“CAPRIE-like Cohort”
* Post hoc analysis.
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.
Aims
•
To determine the effect of CYP2C19 polymorphisms on CV death, MI,
stroke in patients randomized to clopidogrel versus placebo in a stable CV
population
•
To assess the impact on severe or moderate GUSTO bleeding
•
To assess the impact on CV death, MI, stroke, or hospitalization for
ischemic events (more events)
•
To examine effects in higher risk subgroups
•
To assess the impact on any GUSTO bleeding (more events)
Methods
•
A subset (N=4862) of the 15,603 patients enrolled into CHARISMA who consented were
genotyped for CYP2C19*2, *3, and *17 alleles
•
Genotyping details
–
*2 and *17 were genotyped by Restriction Fragment Length Polymorphism
–
*3 was genotyped by Taqman allelic discrimination assay
–
Accuracy: 11% of samples were genotyped in duplicate; no errors were identified in the
replicates
•
Statistical methods:
–
A Cox model of time to primary event, with treatment, genotype, and treatment by genotype
interaction terms, was used to elucidate the genotype effect
–
Covariates used in the genetic analyses were: inclusion criterion (symptomatic versus
asymptomatic), prior use of statins, prior use of calcium channel blockers, and smoking
–
Bleeding events were analyzed with logistic regression using the same terms
Genotype Frequencies
n = 4862
K-M Survival Curves by Genotype
Uncorrected p-value for testing the difference of time to
primary event between genotype groups, from the log-rank
test: 0.166
Uncorrected p-value for testing the difference of time to
primary event between genotype groups, from the log-rank
test: 0.162
Subjects with genotype frequencies < 5 were excluded from the analysis.
Survival curves are truncated at 30 months.
Cox Model HRs by Treatment Arm
Effect
Treatment vs Placebo
p value
0.33
HR
95% CI for HR
1.209
(0.83, 1.77)
Effect of Genotype in Placebo Group
*2/WT vs WT/WT
0.54
0.852
(0.51, 1.42)
*2/*2 vs WT/WT
0.19
1.852
(0.74, 4.65)
*2/*17 vs WT/WT
0.47
1.285
(0.65, 2.54)
*17/WT vs WT/WT
0.052
1.486
(1.00, 2.21)
*17/*17 vs WT/WT
0.71
0.841
(0.33, 2.11)
Effect of Genotype in Clopidogrel Group
*2/WT vs WT/WT
0.63
1.112
(0.72, 1.71)
*2/*2 vs WT/WT
0.022
2.383
(1.14, 5.00)
*2/*17 vs WT/WT
0.36
1.322
(0.72, 2.42)
*17/WT vs WT/WT
0.72
0.927
(0.61, 1.40)
*17/*17 vs WT/WT
0.44
0.696
(0.28, 1.74)
*2/*2 has increased
risk in clopidogrel
arm, but much of this
risk is also present in
placebo arm
Hazard Ratios
* Primary Analysis
Caveat: Small Number of Primary Events
Placebo
Genotype
Number (%) of
Subjects with
Primary Event
Clopidogrel
Total
Genotype
Number (%) of
Subjects with
Primary Event
Total
WT/WT
49 (5.05%)
971
WT/WT
57 (6%)
950
*2/WT
21 (4.29%)
489
*2/WT
33 (6.73%)
490
*2/*2
5 (8.77%)
57
*2/*2
8 (13.79%)
58
*2/*17
10 (6.29%)
159
*2/*17
13 (7.65%)
170
*17/WT
48 (7.48%)
642
*17/WT
37 (5.75%)
643
*17/*17
5 (4.42%)
113
*17/*17
5 (4.42%)
113
*3/WT
0 (0%)
1
*3/WT
0 (0%)
2
*2/*3
0 (0%)
2
*2/*3
0 (0%)
2
Secondary Endpoint: Hazard Ratios
Symptomatic Subpopulation (N=3666):
Hazard Ratios
CAPRIE-like Subpopulation (N=2773):
Hazard Ratios
GUSTO moderate and severe:
Logistic Regression ORs by Treatment Arm
Effect
Treatment vs Placebo
p value
OR
95% CI for OR
0.407
1.228
(0.756, 2.007)
Effect of Genotype in Placebo Group
*2/WT vs WT/WT
0.007
0.313
(0.106, 0.742)
*2/*2 vs WT/WT
0.420
1.707
(0.400, 4.985)
*2/*17 vs WT/WT
0.644
0.785
(0.231, 2.018)
*17/WT vs WT/WT
0.302
0.723
(0.377, 1.330)
*17/*17 vs WT/WT
0.709
0.801
(0.190, 2.291)
Effect of Genotype in Clopidogrel Group
*2/WT vs WT/WT
0.297
1.322
(0.777, 2.214)
*2/*2 vs WT/WT
0.033
0.000
–
*2/*17 vs WT/WT
0.823
0.905
(0.339, 2.029)
*17/WT vs WT/WT
0.906
1.031
(0.619, 1.714)
*17/*17 vs WT/WT
0.054
0.217
(0.012, 1.018)
• Significantly decreased
bleeding risk for *2/wt
compared with wt/wt on
placebo
• Result is based on very
few events
• No conclusions for *2/*2
(3 vs 0 events)
All GUSTO bleeding events:
Logistic Regression ORs by Treatment Arm
Effect
p value
OR
95% CI for OR
Treatment vs Placebo
<0.0001
2.4110
(1.978, 2.943)
Effect of Genotype in Placebo Group
*2/WT vs WT/WT
0.6392
1.0640
(0.821, 1.374)
*2/*2 vs WT/WT
0.3528
0.7250
(0.340, 1.400)
*2/*17 vs WT/WT
0.5803
1.1180
(0.748, 1.641)
*17/WT vs WT/WT
0.8618
0.9790
(0.769, 1.243)
*17/*17 vs WT/WT
0.3477
0.7910
(0.469, 1.278)
Effect of Genotype in Clopidogrel Group
*2/WT vs WT/WT
0.1712
0.8550
(0.683, 1.070)
*2/*2 vs WT/WT
4 x 10-4
0.3290
(0.160, 0.619)
*2/*17 vs WT/WT
0.0652
0.7270
(0.513, 1.020)
*17/WT vs WT/WT
0.9222
1.0100
(0.824, 1.238)
*17/*17 vs WT/WT
0.2236
1.2770
(0.860, 1.891)
• Significantly more
bleeding events in wt/wt
subjects on clopidogrel
compared with placebo
• Significantly reduced
risk of bleeding events for
the *2/*2 genotype vs
wt/wt on clopidogrel
• Risk in *2/*2 is not
significantly different
between treatments
Limitations
•
Genotyped patients differed from non-genotyped patients
•
Overall trial was negative for the primary endpoint, so power is somewhat limited
– Secondary endpoint was positive and more than doubles events, but still no
relationship with heterozygotes and outcomes
– Higher risk subgroups also did not find relationship with heterozygotes and
outcomes
– Still, more events in a placebo controlled trial than any other study to date
•
Stable population, so results seen here may not apply to ACS
– But perhaps more relevant for chronic therapy
Conclusions
•
No relationship seen between CYP2C19*2 heterozygotes and outcomes
•
Small % of homozygotes may have worse outcome, though this is noted
to an extent in the placebo arm as well
•
First large study to establish potential relationship between less bleeding
and genotype
•
Further prospective study needed to determine clinical relevance of
CYP2C19 polymorphisms on efficacy/bleeding - and appropriate clinical
action to take - before routine testing can be recommended
Acknowledgements
• Bristol-Myers Squibb Human Genetics Group for the genotyping
– Terrye A. DelMonte, B.S.
– Lester E. Hui, B.S.
• Bristol-Myers Squibb Statistical Genetics and Biomarkers Group
for statistical analyses
– Oksana Mokliatchouk, Ph.D.
– Lisa R. Denogean, Ph.D.
• Lionel Thevathasan, M.D., sanofi aventis, for reviewing
• Stuart Wakelin, Ph.D. and George Clarkson, Ph.D. from Alpha-Plus
Medical Communications Ltd for graphical support (funded by
sanofi aventis)
Q+A
Backup Slides
GUSTO moderate and severe:
Counts and Interactions by Treatment Arm
Genotype
Treatment
No. (%) with Mod /
severe bleeds
Total
p-value
Rel to wt
Clopidogrel
37
(3.89%)
950
Placebo
31
(3.19%)
971
Clopidogrel
25
(5.10%)
490
0.297
Placebo
5
(1.02%)
489
0.007
Clopidogrel
0
(0%)
58
0.033
Placebo
3
(5.26%)
57
0.420
Clopidogrel
6
(3.53%)
170
0.823
Placebo
4
(2.52%)
159
0.644
Clopidogrel
26
(4.04%)
643
0.906
Placebo
15
(2.34%)
642
0.302
Clopidogrel
1
(0.88%)
113
0.054
Placebo
3
(2.65%)
113
0.709
Clopidogrel
0
(0%)
2
Placebo
0
(0%)
1
Clopidogrel
0
(0%)
2
Placebo
0
(0%)
2
WT/WT
*2/WT
*2/*2
*2/*17
*17/WT
*17/*17
p-value
interaction
0.407
*3/WT
*2/*3
0.005
0.027
0.839
0.388
0.239
• Significantly decreased
bleeding risk for *2/wt
compared with wt/wt on
placebo
• Result is based on very
few events
• No conclusions for *2/*2
(3 vs 0 events)
All GUSTO bleeding events:
Counts and Interactions by Treatment Arm
Genotype
WT/WT
*2/WT
*2/*2
*2/*17
*17/WT
*17/*17
*3/WT
*2/*3
Treatment
No. (%) with
bleeding event
Total
p-value
Rel to wt
Clopidogrel
392
(41.3%)
950
Placebo
220
(22.7%)
971
Clopidogrel
184
(37.6%)
490
0.171
Placebo
116
(23.7%)
489
0.639
Clopidogrel
11
(19.0%)
58
0.0004
Placebo
10
(17.5%)
57
0.353
Clopidogrel
58
(34.1%)
170
0.065
Placebo
39
(24.5%)
159
0.580
Clopidogrel
266
(41.4%)
643
0.922
Placebo
143
(22.3%)
642
0.862
Clopidogrel
53
(46.9%)
113
0.224
Placebo
21
(18.6%)
113
0.348
Clopidogrel
0
(0%)
2
Placebo
1
(100%)
1
Clopidogrel
1
(50%)
2
Placebo
1
(50%)
2
p-value
interaction
<0.0001
0.211
• Significantly more
bleeding events in wt/wt
subjects on clopidogrel
compared with placebo
0.113
0.107
0.845
• Significantly reduced
risk of bleeding events for
the *2/*2 genotype vs
wt/wt on clopidogrel
0.134
• Risk in *2/*2 is not
significantly different
between treatments