charisma genomics deepak l. bhatt md, mph, katy l. simonsen phd, eileen s. emison phd, keith a. a....
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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
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 ResponseGenetic Variations and Clopidogrel Response
Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.
Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel ResponseHeterozygotes 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
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.
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 = 0.04
Cu
mu
lati
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ven
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te (
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0
5
10
15
20
Months since randomization§
0 6 12 18 24 30
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 Frequenciesn = 4862
K-M Survival Curves by Genotype
Subjects with genotype frequencies < 5 were excluded from the analysis.Survival curves are truncated at 30 months.
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
Cox Model HRs by Treatment Arm
*2/*2 has increased risk in clopidogrel arm, but much of this risk is also present in placebo arm
Effect p value HR 95% CI for HR
Treatment vs Placebo 0.33 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)
Hazard Ratios
* Primary Analysis
Caveat: Small Number of Primary Events
Clopidogrel
Genotype Number (%) of Subjects with Primary Event
Total
WT/WT 57 (6%) 950
*2/WT 33 (6.73%) 490
*2/*2 8 (13.79%) 58
*2/*17 13 (7.65%) 170
*17/WT 37 (5.75%) 643
*17/*17 5 (4.42%) 113
*3/WT 0 (0%) 2
*2/*3 0 (0%) 2
Placebo
Genotype Number (%) of Subjects with Primary Event
Total
WT/WT 49 (5.05%) 971
*2/WT 21 (4.29%) 489
*2/*2 5 (8.77%) 57
*2/*17 10 (6.29%) 159
*17/WT 48 (7.48%) 642
*17/*17 5 (4.42%) 113
*3/WT 0 (0%) 1
*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
• 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)
Effect p value OR 95% CI for OR
Treatment vs Placebo 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)
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 genotype vs wt/wt on clopidogrel
• Risk in *2/*2 is not significantly different between treatments
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)
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
• 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)
Genotype Treatment No. (%) with Mod / severe bleeds
Total p-valueRel to wt
p-value interaction
WT/WTClopidogrel 37 (3.89%) 950
0.407Placebo 31 (3.19%) 971
*2/WT Clopidogrel 25 (5.10%) 490 0.297
0.005Placebo 5 (1.02%) 489 0.007
*2/*2 Clopidogrel 0 (0%) 58 0.033
0.027Placebo 3 (5.26%) 57 0.420
*2/*17 Clopidogrel 6 (3.53%) 170 0.823
0.839Placebo 4 (2.52%) 159 0.644
*17/WT Clopidogrel 26 (4.04%) 643 0.906
0.388Placebo 15 (2.34%) 642 0.302
*17/*17Clopidogrel 1 (0.88%) 113 0.054
0.239Placebo 3 (2.65%) 113 0.709
*3/WTClopidogrel 0 (0%) 2
Placebo 0 (0%) 1
*2/*3 Clopidogrel 0 (0%) 2
Placebo 0 (0%) 2
All GUSTO bleeding events: Counts and Interactions 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 genotype vs wt/wt on clopidogrel
• Risk in *2/*2 is not significantly different between treatments
Genotype Treatment No. (%) with bleeding event
Total p-valueRel to
wt
p-value interaction
WT/WTClopidogrel 392 (41.3%) 950
<0.0001Placebo 220 (22.7%) 971
*2/WT Clopidogrel 184 (37.6%) 490 0.171
0.211Placebo 116 (23.7%) 489 0.639
*2/*2 Clopidogrel 11 (19.0%) 58 0.0004
0.113Placebo 10 (17.5%) 57 0.353
*2/*17 Clopidogrel 58 (34.1%) 170 0.065
0.107Placebo 39 (24.5%) 159 0.580
*17/WT Clopidogrel 266 (41.4%) 643 0.922
0.845Placebo 143 (22.3%) 642 0.862
*17/*17Clopidogrel 53 (46.9%) 113 0.224
0.134Placebo 21 (18.6%) 113 0.348
*3/WTClopidogrel 0 (0%) 2
Placebo 1 (100%) 1
*2/*3 Clopidogrel 1 (50%) 2
Placebo 1 (50%) 2