Showing papers by "Eric J. Topol published in 2011"

Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.

Abstract: Context High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined. Objective To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI. Design, Setting, and Patients Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. Interventions High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months. Main Outcome Measures The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days. Results At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P Conclusions Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Trial Registration clinicaltrials.gov Identifier: NCT00645918

Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention

Abstract: Matthew J. Price, MDPeter B. Berger, MDPaul S. Teirstein, MDJean-Franc¸ois Tanguay, MDDominick J. Angiolillo, MDDouglas Spriggs, MDSanjeev Puri, MDMark Robbins, MDKirk N. Garratt, MDOlivier F. Bertrand, MDMichael E. Stillablower, MDJoseph R. Aragon, MDDavid E. Kandzari, MDCurtiss T. Stinis, MDMichael S. Lee, MDSteven V. Manoukian, MDChristopher P. Cannon, MDNicholas J. Schork, PhDEric J. Topol, MDfor the GRAVITAS Investigators

9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response

Abstract: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) and type 2 diabetes. Despite evidence for a role of the associated interval in neighbouring gene regulation, the biological underpinnings of these genetic associations with CAD or type 2 diabetes have not yet been explained. Here we identify 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and six times denser than the whole genome (P < 6.55 × 10(-33)). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1. Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD non-risk haplotype, binding of STAT1 inhibits CDKN2BAS (also known as CDKN2B-AS1) expression, which is reversed by short interfering RNA knockdown of STAT1. Using a new, open-ended approach to detect long-distance interactions, we find that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21. In human vascular endothelial cells, interferon-γ activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1-binding, long-range enhancer interactions and altered expression of neighbouring genes. Our findings establish a link between CAD genetic susceptibility and the response to inflammatory signalling in a vascular cell type and thus demonstrate the utility of genome-wide association study findings in directing studies to novel genomic loci and biological processes important for disease aetiology.

Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk

Abstract: Background The use of direct-to-consumer genomewide profiling to assess disease risk is controversial, and little is known about the effect of this technology on consumers. We examined the psychological, behavioral, and clinical effects of risk scanning with the Navigenics Health Compass, a commercially available test of uncertain clinical validity and utility. Methods We recruited subjects from health and technology companies who elected to purchase the Health Compass at a discounted rate. Subjects reported any changes in symptoms of anxiety, intake of dietary fat, and exercise behavior at a mean (±SD) of 5.6±2.4 months after testing, as compared with baseline, along with any test-related distress and the use of health-screening tests. Results From a cohort of 3639 enrolled subjects, 2037 completed follow-up. Primary analyses showed no significant differences between baseline and follow-up in anxiety symptoms (P=0.80), dietary fat intake (P=0.89), or exercise behavior (P=0.61). Secondary analyses reveale...

The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?

Abstract: N-of-1 or single subject clinical trials consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions. The ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria. Such trials can leverage study design and statistical techniques associated with standard population-based clinical trials, including randomization, washout and crossover periods, as well as placebo controls. Despite their obvious appeal and wide use in educational settings, n-of-1 trials have been used sparingly in medical and general clinical settings. We briefly review the history, motivation and design of n-of-1 trials and emphasize the great utility of modern wireless medical monitoring devices in their execution. We ultimately argue that n-of-1 trials demand serious attention among the health research and clinical care communities given the contemporary focus on individualized medicine.

Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial.

Abstract: Background—In the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial, 6 months of high-dose clopidogrel did not reduce cardiovascular events compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity (OTR) after percutaneous coronary intervention, defined as OTR ≥230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test. The aim of this analysis was to examine the relationship between outcomes and OTR over the course of the trial. Methods and Results—OTR was measured at 12 to 24 hours and 30±7 days after percutaneous coronary intervention. Cox proportional hazards models with OTR as a time-varying covariate were used to determine the association between OTR and the primary end point of cardiovascular death, myocardial infarction, and stent thrombosis. Of the 2800 enrolled patients, 2796 (99.98%) had evaluable platelet function data. OTR <208 P2Y12 reaction units was significantly associated with a...

The importance of phase information for human genomics.

Abstract: Contemporary sequencing studies often ignore the diploid nature of the human genome because they do not routinely separate or 'phase' maternally and paternally derived sequence information. However, many findings - both from recent studies and in the more established medical genetics literature - indicate that relationships between human DNA sequence and phenotype, including disease, can be more fully understood with phase information. Thus, the existing technological impediments to obtaining phase information must be overcome if human genomics is to reach its full potential.

The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care

Abstract: PART I: Setting the Foundation 1. The Digital Landscape: Cultivating a Data-Driven, Participatory Culture 2. The Orientation of Medicine Today: Population Versus Individual 3. To What Extent Are Consumers Empowered? Clicks and Tricks PART II: Capturing the Data 4. Physiology: Wireless Sensors 5. Biology: Sequencing the Genome 6. Anatomy: From Imaging to Printing Organs 7. Electronic Health Records and Health Information Technology 8. The Convergence of Human Data Capture PART III: The Impact of Homo Digitus 9. Doctors with Plasticity? 10. Rebooting the Life Science Industry 11. Homo Digitus and the Individual

Is pocket mobile echocardiography the next-generation stethoscope? A cross-sectional comparison of rapidly acquired images with standard transthoracic echocardiography.

Abstract: Background A pocket mobile echocardiography (PME) device is commercially available for clinical use, but public data documenting its accuracy compared with standard transthoracic echocardiography (TTE) are not available. Objective To compare the accuracy of rapidly acquired PME images with those acquired by standard TTE. Design Cross-sectional study. At the time of referral for TTE, ultrasonographers acquired PME images first in 5 minutes or less. Ultrasonographers were not blinded to the clinical indication for imaging or to the PME image results when obtaining standard TTE images. Two experienced echocardiographers and 2 cardiology fellows who were blinded to the indication for the study and TTE results but not to the device source interpreted the PME images. Setting Scripps Clinic Torrey Pines and Scripps Green Hospital, La Jolla, California. Patients Convenience sample of 97 patients consecutively referred for echocardiography. Measurements Visualizability and accuracy (the sum of proportions of true-positive and true-negative readings and observer variability) for ejection fraction, wall-motion abnormalities, left ventricular end-diastolic dimension, inferior vena cava size, aortic and mitral valve pathology, and pericardial effusion. Results Physician-readers could visualize some but not all echocardiographic measurements obtained with the PME device in every patient (highest proportions were for ejection fraction and left ventricular end-diastolic dimension [95% each]; the lowest proportion was for inferior vena cava size [75%]). Accuracy also varied by measurement (aortic valve was 96% [highest] and inferior vena cava size was 78% [lowest]) and decreased when nonvisualizability was accounted for (aortic valve was 91% and inferior vena cava size was 58%). Observer agreement was fair to moderate for some measurements among less-experienced readers. Limitation The study was conducted at a single setting, there was no formal estimate of accuracy given the small convenience sample of patients, and few abnormal echocardiographic measurements occurred. Conclusion The rapid acquisition of images by skilled ultrasonographers who use PME yields accurate assessments of ejection fraction and some but not all cardiac structures in many patients. Further testing of the device in larger patient cohorts with diverse cardiac abnormalities and with untrained clinicians obtaining and interpreting images is required before wide dissemination of its use can be recommended. Primary funding source National Institutes of Health.

Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients.

Abstract: Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility. Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes. RT-PCR analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI 0.73-0.81) in ROC analysis. We have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography. PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, http://www.clinicaltrials.gov , NCT00500617

Direct-to-consumer personalized genomic testing

Abstract: Over the past 18 months, there have been notable developments in the direct-to-consumer (DTC) genomic testing arena, in particular with regard to issues surrounding governmental regulation in the USA. While commentaries continue to proliferate on this topic, actual empirical research remains relatively scant. In terms of DTC genomic testing for disease susceptibility, most of the research has centered on uptake, perceptions and attitudes toward testing among health care professionals and consumers. Only a few available studies have examined actual behavioral response among consumers, and we are not aware of any studies that have examined response to DTC genetic testing for ancestry or for drug response. We propose that further research in this area is desperately needed, despite challenges in designing appropriate studies given the rapid pace at which the field is evolving. Ultimately, DTC genomic testing for common markers and conditions is only a precursor to the eventual cost-effectiveness and wide availability of whole genome sequencing of individuals, although it remains unclear whether DTC genomic information will still be attainable. Either way, however, current knowledge needs to be extended and enhanced with respect to the delivery, impact and use of increasingly accurate and comprehensive individualized genomic data.

Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial.

Abstract: BackgroundThe Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel t...

Genomic information as a behavioral health intervention: can it work?

Abstract: Individuals can now obtain their personal genomic information via direct-to-consumer genetic testing, but what, if any, impact will this have on their lifestyle and health? A recent longitudinal cohort study of individuals who underwent consumer genome scanning found minimal impacts of testing on risk-reducing lifestyle behaviors, such as diet and exercise. These results raise an important question: is personal genomic information likely to beneficially impact public health through motivation of lifestyle behavioral change? In this article, we review the literature on lifestyle behavioral change in response to genetic testing for common disease susceptibility variants. We find that only a few studies have been carried out, and that those that have been done have yielded little evidence to suggest that the mere provision of genetic information alone results in widespread changes in lifestyle health behaviors. We suggest that further study of this issue is needed, in particular studies that examine response to multiplex testing for multiple genetic markers and conditions. This will be critical as we anticipate the wide availability of whole-genome sequencing and more comprehensive phenotyping of individuals. We also note that while simple communication of genomic information and disease susceptibility may be sufficient to catalyze lifestyle changes in some highly motivated groups of individuals, for others, additional strategies may be required to prompt changes, including more sophisticated means of risk communication (e.g., in the context of social norm feedback) either alone or in combination with other promising interventions (e.g., real-time wireless health monitoring devices).

Emerging genomic applications in coronary artery disease.

Abstract: Over the last 4 years, an unprecedented number of studies illuminating the genomic underpinnings of common “polygenic” diseases including coronary artery disease have been published. Notably, these studies have established numerous deoxyribonucleic acid (DNA) variants within or near chromosome 9p21.3, the LPA, CXADR, and APOE genes, to name a few, as key coronary artery disease and sudden cardiac death susceptibility markers. Most importantly, many of these DNA variants confer over a 2-fold increase in risk for coronary artery disease, myocardial infarction, and ventricular fibrillation. Additionally, loss-of-function variants in the hepatic cytochrome 2C19 system have now been found to be the predominant genetic mediators of clopidogrel antiplatelet response, with variant carriers having a >3-fold increase in risk for stent thrombosis. In the near future, many additional rare polymorphisms, structural variants, and tissue-specific epigenetic features of the human genome including DNA methylation, histone modifications, and chromatin state will emerge as significant contributors to disease pathogenesis and drug response. In aggregate, these findings will have the potential to radically change the practice of cardiovascular medicine. However, only the individual clinician can ultimately enable the translation of these important discoveries to systematic implementation in clinical practice.

Catapulting clopidogrel pharmacogenomics forward.

Abstract: The antiplatelet drug clopidogrel helps prevent stent-associated thrombosis, but the antiplatelet effects are quite variable and the clinical consequences can be serious. New findings show that the variability in clopidogrel efficacy is affected by the enzyme paraoxonase-1 (PON1), which is required for clopidogrel bioactivation (pages 110–116 ).

The Lost Decade of Nesiritide

Abstract: The concept of the “lost decade” is typically attributed to the Japanese economy in the 1990s, when there was exceptionally little or weak economic growth, amid unprofitable zombie firms and liquidity traps.1 With the financial collapse in the United States in 2008, some economists have forecast the potential for a similar circumstance in this country.2 But there are other places to find lost decades. Unfortunately, the “lost decade” can now also be applied to the deficient clinical development of certain pharmaceutical agents. In this issue of the Journal, O'Connor and colleagues3 report the results of a large, randomized, placebo-controlled trial . . .

High-sensitivity C-reactive protein and clopidogrel treatment in patients at high risk of cardiovascular events: a substudy from the CHARISMA trial

Abstract: Aims This study investigated the effect of clopidogrel treatment on inflammatory activity as evidenced by the change in high-sensitivity C-reactive protein (hsCRP) levels in a broad population of patients who are at high risk of atherothrombotic events. The predictive value of hsCRP levels for a treatment benefit of clopidogrel was also explored. Methods The study included 8021 patients with established atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomly assigned either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28 months). The predefined primary composite endpoint was myocardial infarction, stroke, or death from cardiovascular causes. Results There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP at baseline (4.0%, 6.1%, 7.4% and 8.7% for the highest quartile). In both treatment groups the changes in hsCRP levels over time were identical. In patients with low hsCRP levels ( Conclusions In this broad population, hsCRP is a powerful predictor of ischaemic events. Compared with placebo, clopidogrel was without effect on inflammatory markers. The reduction in cardiovascular events by antiplatelet treatment with clopidogrel was isolated to patients with low levels of hsCRP.

Direct-to-consumer genetic testing: Reliable or risky?

Abstract: In recent years there has been a dramatic increase in the discovery of information related to the genetic risk of disease, as well as in the technical ability to accurately measure an individual's genotype. These advances underlie the promise of personalized medicine, in which a patient's genotype informs the medical care they receive. Private companies are attempting to capitalize on these advances by providing direct-to-consumer (DTC)6 genetic testing that estimates the risk of disease for a customer, given their genotype. Because these tests make claims about medical conditions, they have come under scrutiny by regulatory agencies. We ask experts in the field to comment on several issues relevant to DTC genetic testing. DTC genetic testing is based primarily on associations between common genetic variants and disease. Do we have enough evidence about these associations to use them as genetic tests? Eric Topol: Yes, without question, in select circumstances. For several pharmacogenomic interactions, the information can be especially valuable for an individual to avoid a major adverse side effect (as with carbamazepine) or to ensure efficacy (clopidogrel). Also, when there is clear evidence of heightened risk (e.g., 2-fold or greater) for a common disease, such as diabetes, heart attack, colon, melanoma, or other cancers, there can be actionable information to get appropriate screening (e.g., colonoscopy) or potential preventive steps (e.g., protection from the sun). As we move toward sequencing and identification of rare or low-frequency variants that have high penetrance, it is unlikely that the heightened risk from the previously identified common variants will go away. James Evans: We clearly do not. This is best demonstrated by several straightforward studies in which the same sample was sent to leading DTC companies for analysis. The results included wildly divergent risk estimates, with companies reporting “above average,” “below average,” and “average” risks …

The next phase in human genetics

Abstract: Experimental haplotyping of whole genomes is now feasible, enabling new studies aimed at linking sequence variation to human phenotypes and disease susceptibility.

Emerging clinical applications in cardiovascular pharmacogenomics

Abstract: Over one-fourth of the 36 million annual outpatient prescriptions filled in the United States are known to have human genomic biomarker information available that predicts drug safety and efficacy, or both. However, to date, we have not systematically implemented strategies to effectively use this data in clinical practice to improve patient outcomes. Part of the difficulty has stemmed from the only modest predictive capacity of previously identified gene variants, lack of replication of data in multiple studies, and the hesitancy of the clinical community to translate data gleaned from basic and translational research to routine clinical practice. Now, additional key variants that strongly impact drug absorption, metabolism, and excretion are rapidly surfacing through the use of genome-wide association technology. Most importantly, these variants are being validated in independent cohorts of thousands of cases and controls. In the near future, the dramatic reduction in the cost of DNA sequencing will lead to further insight into the common and rare genetic variants that strongly predict our individual response to commonly used medications. The clinical community will need to be prepared to utilize this vital data in aiding their selection of the right drug for the right patient if we expect to significantly reduce the ever increasing burden of societies' most common diseases. Herein, we detail the most clinically compelling and robust examples of pharmacogenomics emerging in the field of cardiovascular disease and hopefully foretell how cardiovascular disease might be treated in the era of genomic medicine. WIREs Syst Biol Med 2011 3 206–215 DOI: 10.1002/wsbm.113 For further resources related to this article, please visit the WIREs website

Methods for Healthy Aging

Abstract: Genome-wide association studies have been used to elucidate genes and/or pathways related to diseases; however, this methodology has yet to be used to understand the phenotype of healthy aging and/or healthspan in humans.