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Charisma Genomics

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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)1.11

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