Presentation on theme: "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,"— Presentation transcript:
1CHARISMA GenomicsDeepak 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
2Disclosure 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.
3Variability in Clopidogrel Responsiveness in a Diverse Population of 544 Serebruany VL, Steinhubl SR, Berger PB, et al. JACC 2005; 45:246 –51.
4Genetic Variations and Clopidogrel Response Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:
5Genetic 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 registrySimon T, et al. N Engl J Med. 2009;360:
6Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p valueQualifying CAD, CVD or PAD * (0.77, 0.998)(n=12,153)Multiple Risk Factors * (0.91, 1.59) (n=3,284)Overall Population† (0.83, 1.05) (n=15,603)The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of cardiovascular death (including haemorrhagic death), fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause)There was no statistical difference in the primary endpoint between the two treatment arms.Analysis of symptomatic (documented atherothrombotic disease) and asymptomatic (multiple atherothrombotic risk factors) groups was pre-specified in the CHARISMA statistical analysis plan.Among 3284 asymptomatic patients, there was a 20% increase in primary events with clopidogrel (RR 1.20 [0.91, 1.59], p=0.20), while among 12,153 symptomatic patients, there was a marginally significant reduction in the primary end point with clopidogrel (6.9% versus 7.9% in the placebo group, RR 0.88, p=0.046, 95% CI: 0.77, 0.998).The interaction term for this analysis, examining the differential treatment response in asymptomatic and symptomatic patients, was marginally significant (p=0.045). Of note, there was an increase in all cause mortality (5.4% versus 3.8%, p=0.04), and an increase in cardiovascular death (3.9% versus 2.2%, p=0.01), among the asymptomatic patients assigned to clopidogrel compared with placebo, respectively.There were 166 patients originally randomized which were found later to have not met any of the inlclusion criteria.Bhatt DL, Fox KA, Hacke W, et al. 2006, in press..0.40.60.81.21.41.6Clopidogrel + ASABetterPlacebo + ASABetter* 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 criteriaBhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:
7Cumulative event rate (%) Months since randomization§ Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†Placebo + ASA*17.9%Cumulative event rate (%)5101520Months since randomization§612182430Clopidogrel + ASA*16.7%RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04The secondary efficacy endpoint in CHARISMA was a cluster of the first occurrence of MI, stroke, cardiovascular death (including haemorrhagic death), (of any cause), hospitalization for unstable angina, TIA, or a revascularization procedure.There was a statistically significant risk reduction in the clopidogrel plus ASA arm in the rate of the principal secondary efficacy end point. The rate of the secondary efficacy outcome was 16.7% in the clopidogrel arm versus 17.9% in the placebo arm (p=0.037, RR 0.92, 95% CI: 0.86, 0.995)The yearly secondary events rates were 8.07% vs. 8.76% for clopidogrel plus ASA vs. placebo plus ASAThe secondary endpoint result was driven by the statistically significant relative risk reduction in hospitalization for unstable angina, TIA, or a revascularization procedure (see next slide)Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.†First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization*All patients received ASA mg/day§The number of patients followed beyond 30 months decreases rapidly to zeroBhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:
8Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD* “CAPRIE-like Cohort” A post-hoc analysis of patients (n=9478) with a previous MI, stroke, or PAD (similar to the entry criteria for the CAPRIE trial) showed a significant 17.1% RRR in favor of clopidogrel plus ASA over ASA alone* Post hoc analysis.Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:
9AimsTo determine the effect of CYP2C19 polymorphisms on CV death, MI, stroke in patients randomized to clopidogrel versus placebo in a stable CV populationTo assess the impact on severe or moderate GUSTO bleedingTo assess the impact on CV death, MI, stroke, or hospitalization for ischemic events (more events)To examine effects in higher risk subgroupsTo assess the impact on any GUSTO bleeding (more events)
10MethodsA subset (N=4862) of the 15,603 patients enrolled into CHARISMA who consented were genotyped for CYP2C19*2, *3, and *17 allelesGenotyping details*2 and *17 were genotyped by Restriction Fragment Length Polymorphism*3 was genotyped by Taqman allelic discrimination assayAccuracy: 11% of samples were genotyped in duplicate; no errors were identified in the replicatesStatistical methods:A Cox model of time to primary event, with treatment, genotype, and treatment by genotype interaction terms, was used to elucidate the genotype effectCovariates used in the genetic analyses were: inclusion criterion (symptomatic versus asymptomatic), prior use of statins, prior use of calcium channel blockers, and smokingBleeding events were analyzed with logistic regression using the same terms
12K-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: 0.166Uncorrected p-value for testing the difference of time to primary event between genotype groups, from the log-rank test: 0.162Subjects with genotype frequencies < 5 were excluded from the analysis.Survival curves are truncated at 30 months.
13Cox Model HRs by Treatment Arm Effectp valueHR95% CI for HRTreatment vs Placebo0.331.209(0.83, 1.77)Effect of Genotype in Placebo Group*2/WT vs WT/WT0.540.852(0.51, 1.42)*2/*2 vs WT/WT0.191.852(0.74, 4.65)*2/*17 vs WT/WT0.471.285(0.65, 2.54)*17/WT vs WT/WT0.0521.486(1.00, 2.21)*17/*17 vs WT/WT0.710.841(0.33, 2.11)Effect of Genotype in Clopidogrel Group0.631.112(0.72, 1.71)0.0222.383(1.14, 5.00)0.361.322(0.72, 2.42)0.720.927(0.61, 1.40)0.440.696(0.28, 1.74)*2/*2 has increased risk in clopidogrel arm, but much of this risk is also present in placebo arm
15Caveat: Small Number of Primary Events PlaceboGenotypeNumber (%) of Subjects with Primary EventTotalWT/WT49 (5.05%)971*2/WT21 (4.29%)489*2/*25 (8.77%)57*2/*1710 (6.29%)159*17/WT48 (7.48%)642*17/*175 (4.42%)113*3/WT0 (0%)1*2/*32ClopidogrelGenotypeNumber (%) of Subjects with Primary EventTotalWT/WT57 (6%)950*2/WT33 (6.73%)490*2/*28 (13.79%)58*2/*1713 (7.65%)170*17/WT37 (5.75%)643*17/*175 (4.42%)113*3/WT0 (0%)2*2/*3
19GUSTO moderate and severe: Logistic Regression ORs by Treatment Arm Effectp valueOR95% CI for ORTreatment vs Placebo0.4071.228(0.756, 2.007)Effect of Genotype in Placebo Group*2/WT vs WT/WT0.0070.313(0.106, 0.742)*2/*2 vs WT/WT0.4201.707(0.400, 4.985)*2/*17 vs WT/WT0.6440.785(0.231, 2.018)*17/WT vs WT/WT0.3020.723(0.377, 1.330)*17/*17 vs WT/WT0.7090.801(0.190, 2.291)Effect of Genotype in Clopidogrel Group0.2971.322(0.777, 2.214)0.0330.000–0.8230.905(0.339, 2.029)0.9061.031(0.619, 1.714)0.0540.217(0.012, 1.018)Significantly decreased bleeding risk for *2/wt compared with wt/wt on placeboResult is based on very few eventsNo conclusions for *2/*2 (3 vs 0 events)
20All GUSTO bleeding events: Logistic Regression ORs by Treatment Arm Effectp valueOR95% CI for ORTreatment vs Placebo<0.00012.4110(1.978, 2.943)Effect of Genotype in Placebo Group*2/WT vs WT/WT0.63921.0640(0.821, 1.374)*2/*2 vs WT/WT0.35280.7250(0.340, 1.400)*2/*17 vs WT/WT0.58031.1180(0.748, 1.641)*17/WT vs WT/WT0.86180.9790(0.769, 1.243)*17/*17 vs WT/WT0.34770.7910(0.469, 1.278)Effect of Genotype in Clopidogrel Group0.17120.8550(0.683, 1.070)4 x 10-40.3290(0.160, 0.619)0.06520.7270(0.513, 1.020)0.92221.0100(0.824, 1.238)0.22361.2770(0.860, 1.891)Significantly more bleeding events in wt/wt subjects on clopidogrel compared with placeboSignificantly reduced risk of bleeding events for the *2/*2 genotype vs wt/wt on clopidogrelRisk in *2/*2 is not significantly different between treatments
21Limitations Genotyped patients differed from non-genotyped patients Overall trial was negative for the primary endpoint, so power is somewhat limitedSecondary endpoint was positive and more than doubles events, but still no relationship with heterozygotes and outcomesHigher risk subgroups also did not find relationship with heterozygotes and outcomesStill, more events in a placebo controlled trial than any other study to dateStable population, so results seen here may not apply to ACSBut perhaps more relevant for chronic therapy
22ConclusionsNo relationship seen between CYP2C19*2 heterozygotes and outcomesSmall % of homozygotes may have worse outcome, though this is noted to an extent in the placebo arm as wellFirst large study to establish potential relationship between less bleeding and genotypeFurther 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
23AcknowledgementsBristol-Myers Squibb Human Genetics Group for the genotypingTerrye A. DelMonte, B.S.Lester E. Hui, B.S.Bristol-Myers Squibb Statistical Genetics and Biomarkers Group for statistical analysesOksana Mokliatchouk, Ph.D.Lisa R. Denogean, Ph.D.Lionel Thevathasan, M.D., sanofi aventis, for reviewingStuart Wakelin, Ph.D. and George Clarkson, Ph.D. from Alpha-Plus Medical Communications Ltd for graphical support (funded by sanofi aventis)
26GUSTO moderate and severe: Counts and Interactions by Treatment Arm GenotypeTreatmentNo. (%) with Mod / severe bleedsTotalp-valueRel to wtinteractionWT/WTClopidogrel37(3.89%)9500.407Placebo31(3.19%)971*2/WT25(5.10%)4900.2970.0055(1.02%)4890.007*2/*2(0%)580.0330.0273(5.26%)570.420*2/*176(3.53%)1700.8230.8394(2.52%)1590.644*17/WT26(4.04%)6430.9060.38815(2.34%)6420.302*17/*171(0.88%)1130.0540.239(2.65%)0.709*3/WT2*2/*3Significantly decreased bleeding risk for *2/wt compared with wt/wt on placeboResult is based on very few eventsNo conclusions for *2/*2 (3 vs 0 events)
27All GUSTO bleeding events: Counts and Interactions by Treatment Arm GenotypeTreatmentNo. (%) with bleeding eventTotalp-valueRel to wtinteractionWT/WTClopidogrel392(41.3%)950<0.0001Placebo220(22.7%)971*2/WT184(37.6%)4900.1710.211116(23.7%)4890.639*2/*211(19.0%)580.00040.11310(17.5%)570.353*2/*17(34.1%)1700.0650.10739(24.5%)1590.580*17/WT266(41.4%)6430.9220.845143(22.3%)6420.862*17/*1753(46.9%)1130.2240.13421(18.6%)0.348*3/WT(0%)21(100%)*2/*3(50%)Significantly more bleeding events in wt/wt subjects on clopidogrel compared with placeboSignificantly reduced risk of bleeding events for the *2/*2 genotype vs wt/wt on clopidogrelRisk in *2/*2 is not significantly different between treatments