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CHARISMA GenomicsCHARISMA 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
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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 drugsand devices.
This CHARISMA study was funded by sanofi aventis and Bristol-Myers Squibb.
The genetic analyses were done by Bristol-Myers Squibbs Human Genetics and
Statistical Genetics Groups.
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Variability in Clopidogrel Responsiveness in a
Diverse Population of 544
Serebruany VL, Steinhubl SR, Berger PB, et al. JACC 2005; 45:246 51.
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Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response
Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.
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Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response
Heterozygotes vs HomozygotesHeterozygotes vs Homozygotes
Simon T, et al. N Engl J Med. 2009;360:363-375.
Probability of all-cause death, recurrent myocardial infarction, and stroke (%) according to
CYP2C19 loss of function variant allele polymorphisms in the FAST MI registry
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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
(n=3,284)
Overall Population 0.93 (0.83, 1.05) 0.22(n=15,603)
Primary Efficacy Results (MI/Stroke/CV
Death) by Pre-Specified Entry Category
0.6 0.8 1.41.2
Clopidogrel + ASA
Better
Placebo + ASA
Better
1.60.4
* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-
specified 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.
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Overall Population: Principal Secondary Efficacy
Outcome (MI/Stroke/CV Death/Hospitalization)
First 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
Placebo + ASA*
17.9%
Clopidogrel + ASA*
16.7%
RRR: 7.7% [95% CI: 0.5%, 14.4%]
p = 0.04Cumulativee
ventrate(%)
0
5
10
15
20
Months since randomization0 6 12 18 24 30
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:1706-17.
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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.
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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)
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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
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Genotype Frequencies
n = 4862
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K-M Survival Curves by Genotype
Subjects with genotype frequencies < 5 were excluded from the analysis.
Survival curves are truncated at 30 months.
Uncorrectedp-value for testing the difference of time to
primary event between genotype groups, from the log-rank
test: 0.166
Uncorrectedp-value for testing the difference of time to
primary event between genotype groups, from the log-rank
test: 0.162
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Cox Model HRs by Treatment Arm
*2/*2 has
increased risk in
clopidogrel arm,
but much of this
risk is alsopresent in
placebo arm
(0.28, 1.74)0.6960.44*17/*17 vs WT/WT
(0.61, 1.40)0.9270.72*17/WT vs WT/WT(0.72, 2.42)1.3220.36*2/*17 vs WT/WT
(1.14, 5.00)2.3830.022*2/*2 vs WT/WT
(0.72, 1.71)1.1120.63*2/WT vs WT/WT
Effect of Genotype in Clopidogrel Group
(0.33, 2.11)0.8410.71*17/*17 vs WT/WT
(1.00, 2.21)1.4860.052*17/WT vs WT/WT
(0.65, 2.54)1.2850.47*2/*17 vs WT/WT
(0.74, 4.65)1.8520.19*2/*2 vs WT/WT
(0.51, 1.42)0.8520.54*2/WT vs WT/WT
Effect of Genotype in Placebo Group
(0.83, 1.77)1.2090.33Treatment vs Placebo
95% CI for HRHRp valueEffect
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Hazard Ratios
* Primary Analysis
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Caveat: Small Number of Primary Events
Clopidogrel
20 (0%)*2/*3
20 (0%)*3/WT
1135 (4.42%)*17/*17
64337 (5.75%)*17/WT
17013 (7.65%)*2/*17
588 (13.79%)*2/*2
49033 (6.73%)*2/WT
95057 (6%)WT/WT
TotalNumber (%) of
Subjects with
Primary Event
Genotype
Placebo
20 (0%)*2/*3
10 (0%)*3/WT
1135 (4.42%)*17/*17
64248 (7.48%)*17/WT
15910 (6.29%)*2/*17
575 (8.77%)*2/*2
48921 (4.29%)*2/WT
97149 (5.05%)WT/WT
TotalNumber (%) of
Subjects with
Primary Event
Genotype
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Secondary Endpoint: Hazard Ratios
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Symptomatic Subpopulation (N=3666):
Hazard Ratios
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CAPRIE-like Subpopulation (N=2773):
Hazard Ratios
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GUSTO moderate and severe:
Logistic Regression ORs by Treatment Arm
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)
(0.012, 1.018)0.2170.054*17/*17 vs WT/WT
(0.619, 1.714)1.0310.906*17/WT vs WT/WT
(0.339, 2.029)0.9050.823*2/*17 vs WT/WT
0.0000.033*2/*2 vs WT/WT
(0.777, 2.214)1.3220.297*2/WT vs WT/WT
Effect of Genotype in Clopidogrel Group
(0.190, 2.291)0.8010.709*17/*17 vs WT/WT
(0.377, 1.330)0.7230.302*17/WT vs WT/WT
(0.231, 2.018)0.7850.644*2/*17 vs WT/WT
(0.400, 4.985)1.7070.420*2/*2 vs WT/WT
(0.106, 0.742)0.3130.007*2/WT vs WT/WT
Effect of Genotype in Placebo Group
(0.756, 2.007)1.2280.407Treatment vs Placebo
95% CI for ORORp valueEffect
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All GUSTO bleeding events:
Logistic Regression ORs by Treatment Arm
Significantly more
bleeding events in
wt/wt subjects on
clopidogrel
compared with
placebo
Significantly
reduced risk of
bleeding events for
the *2/*2 genotypevs wt/wt on
clopidogrel
Risk in *2/*2 is not
significantlydifferent between
(0.860, 1.891)1.27700.2236*17/*17 vs WT/WT
(0.824, 1.238)1.01000.9222*17/WT vs WT/WT
(0.513, 1.020)0.72700.0652*2/*17 vs WT/WT
(0.160, 0.619)0.32904 x 10-4*2/*2 vs WT/WT
(0.683, 1.070)0.85500.1712*2/WT vs WT/WT
Effect of Genotype in Clopidogrel Group
(0.469, 1.278)0.79100.3477*17/*17 vs WT/WT
(0.769, 1.243)0.97900.8618*17/WT vs WT/WT
(0.748, 1.641)1.11800.5803*2/*17 vs WT/WT
(0.340, 1.400)0.72500.3528*2/*2 vs WT/WT
(0.821, 1.374)1.06400.6392*2/WT vs WT/WT
Effect of Genotype in Placebo Group
(1.978, 2.943)2.4110
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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
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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
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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)
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Q+A
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Backup Slides
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All GUSTO bleeding events:
Counts and Interactions by Treatment Arm
Significantly more
bleeding events in
wt/wt subjects on
clopidogrel
compared withplacebo
Significantly
reduced risk of
bleeding events forthe *2/*2 genotype
vs wt/wt on
clopidogrel
Risk in *2/*2 is notsignificantly
2(50%)1Placebo
2(50%)1Clopidogrel*2/*3
1(100%)1Placebo
2(0%)0Clopidogrel*3/WT
0.348113(18.6%)21Placebo0.134
0.224113(46.9%)53Clopidogrel
*17/*17
0.862642(22.3%)143Placebo0.845
0.922643(41.4%)266Clopidogrel*17/WT
0.580159(24.5%)39Placebo0.107
0.065170(34.1%)58Clopidogrel*2/*17
0.35357(17.5%)10Placebo0.1130.000458(19.0%)11Clopidogrel*2/*2
0.639489(23.7%)116Placebo0.211
0.171490(37.6%)184Clopidogrel*2/WT
971(22.7%)220Placebo