849 results on '"Eric J Topol"'
Search Results
2. Identification of paroxysmal atrial fibrillation subtypes in over 13,000 individuals
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Steven R. Steinhubl, Evan D. Muse, Nathan E. Wineinger, Yunyue Zhang, Eric J. Topol, Ikram Irfanullah, and Paddy M. Barrett
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Adult ,Male ,medicine.medical_specialty ,Paroxysmal atrial fibrillation ,Staccato ,Disease ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Heart Conduction System ,Heart Rate ,Physiology (medical) ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,030212 general & internal medicine ,Stroke ,Aged ,Retrospective Studies ,business.industry ,Middle Aged ,medicine.disease ,Pathophysiology ,Ambulatory ,Cardiology ,Disease Progression ,Electrocardiography, Ambulatory ,Maximum duration ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Background Paroxysmal atrial fibrillation (PAF) is broadly defined despite high variability in the occurrence and duration of PAF episodes. Objective The purpose of this study was to identify rhythm patterns in a large cohort of individuals with PAF who wore an ambulatory single-lead electrocardiogram (ECG) patch sensor as part of standard clinical care. Methods We performed a retrospective analysis of longitudinal rhythm data obtained from 13,293 individuals with PAF. Results In this study, 7934 men and 5359 women with PAF wore an ambulatory single-lead ECG patch sensor for 11.4 days on average, experiencing 1,041,504 PAF episodes. The median daily rate of PAF was 1.21 episodes per day (interquartile range [IQR] 0.31–4.99), and the median maximum duration per individual was 7.5 hours (IQR 2.4–18.6 hours). There was an inverse relationship between the duration of PAF episodes and the frequency in which they occurred, which became pronounced at moderate and high overall burdens of AF. This produced a spectrum of PAF flanked by 2 distinct subtypes of the disease: the staccato subtype, characterized by many, short AF episodes; and the legato subtype, characterized by fewer, longer episodes. Longer but less frequent episodes became more common with increasing age. Only 49.4% of individuals experienced an episode in the first 24 hours of monitoring, increasing to 89.7% after 1 week of monitoring. Conclusion We identified subtypes of the disease that we labeled staccato and legato. Although further study is required, these subtypes may result from differing elements of pathophysiology and disease progression, and may confer differing stroke risks.
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- 2018
3. Corrigendum: Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?
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Glenn N. Wagner, Eric J. Topol, Evan D. Muse, Tierney Phillips, Jennifer L. Wagner, Jonathan R. Lucas, Manuel Rueda, Sarah E. Topol, and Ali Torkamani
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lcsh:Diseases of the circulatory (Cardiovascular) system ,Mitochondrial DNA ,business.industry ,mitochondrial DNA ,Bioinformatics ,medicine.disease ,Sudden death ,sudden cardiac death ,whole exome sequencing ,Sudden cardiac death ,gene panel ,lcsh:RC666-701 ,Gene panel ,molecular autopsy ,Molecular autopsy ,medicine ,business ,Cardiology and Cardiovascular Medicine ,Exome sequencing - Published
- 2018
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4. Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?
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Evan D. Muse, Jonathan R. Lucas, Jennifer L. Wagner, Glenn N. Wagner, Eric J. Topol, Sarah E. Topol, Ali Torkamani, Tierney Phillips, and Manuel Rueda
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Genomics ,Disease ,mitochondrial DNA ,030204 cardiovascular system & hematology ,Biology ,Cardiovascular Medicine ,Sudden death ,sudden cardiac death ,Sudden cardiac death ,whole exome sequencing ,03 medical and health sciences ,0302 clinical medicine ,gene panel ,medicine ,Allele frequency ,Exome sequencing ,Genetic testing ,Original Research ,Genetics ,medicine.diagnostic_test ,Correction ,Sudden infant death syndrome ,medicine.disease ,3. Good health ,030104 developmental biology ,lcsh:RC666-701 ,molecular autopsy ,Cardiology and Cardiovascular Medicine - Abstract
The Scripps Molecular Autopsy (MA) study seeks to incorporate genetic testing into the postmortem examination of cases of sudden death in the young (< 45 years old). Here we describe the results from the first two years of the study, which consisted of whole exome sequencing (WES) of a cohort of 50 cases predominantly from San Diego County. Apart from the individual description of cases, we analyzed the data at the cohort-level, which brought new perspectives on the genetic causes of sudden death. We investigated the advantages and disadvantages of using WES compared to a gene panel for cardiac disease (usually the first genetic test used by medical examiners). In an attempt to connect complex clinical phenotypes with genotypes, we classified samples by their genetic fingerprint. Finally, we studied the benefits of analyzing the mitochondrial DNA genome. In this regard, we found that half of the cases clinically diagnosed as sudden infant death syndrome had an increased ratio of heteroplasmic variants, and that the variants were also present in the mothers. We believe that community-based data aggregation and sharing will eventually lead to an improved classification of variants. Allele frequencies for the all cases can be accessed via our genomics browser at https://genomics.scripps.edu/browser.
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- 2017
5. Moving From Digitalization to Digitization in Cardiovascular Care
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Eric J. Topol and Steven R. Steinhubl
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medicine.diagnostic_test ,business.industry ,Medical record ,Counterintuitive ,Wearable computer ,Cardiovascular care ,030204 cardiovascular system & hematology ,Precision medicine ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Health care ,medicine ,030212 general & internal medicine ,Medical emergency ,business ,Cardiology and Cardiovascular Medicine ,Digitization ,Genetic testing - Abstract
So far, the digitization of health care is best exemplified by electronic medical records, which have been far from favorably or uniformly accepted. However, properly implemented digitization can enable better patient outcomes, improve convenience, potentially lower healthcare costs, and possibly lead to much greater physician satisfaction. Precision (also known as personalized or individualized) medicine is frequently discussed today, but, in reality, it is what physicians have attempted to do as best they could for millennia. But now we have new tools that can begin to give us a much more high-definition view of our patients; from affordable and rapid genetic testing to wearable sensors that track a wide range of important physiologic parameters continuously. Although seemingly counterintuitive, the digitization of health care can also markedly improve the physician-patient relationship, allowing more time for human interaction when care is bolstered by digital technologies that better individualize diagnostics and treatments.
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- 2015
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6. HEALTHCARE RESOURCE UTILIZATION ASSOCIATED WITH ELECTROCARDIOGRAPH (ECG) SENSOR PATCH SCREENING FOR ATRIAL FIBRILLATION (AF): RESULTS FROM THE MHEALTH SCREENING TO PREVENT STROKES (MSTOPS) TRIAL
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Steven R. Steinhubl, Troy Sarich, Chureen Carter, Robert Zambon, Rajesh Mehta, Eric J. Topol, Elise Felicione, Lauren Ariniello, Jill Waalen, Gail S. Ebner, Alison M. Edwards, and Katie Baca-Motes
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medicine.medical_specialty ,business.industry ,Atrial fibrillation ,030204 cardiovascular system & hematology ,medicine.disease ,Asymptomatic ,03 medical and health sciences ,0302 clinical medicine ,Healthcare utilization ,Emergency medicine ,Health care ,Medicine ,cardiovascular diseases ,030212 general & internal medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,mHealth ,Resource utilization - Abstract
Routine ECG screening for AF is not recommended due in part to a lack of healthcare utilization data. In the mSToPS trial asymptomatic individuals underwent screening with an ECG sensor patch. Healthcare utilization was evaluated following monitoring & compared to matched controls. 1738 Aetna
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- 2019
7. Abstract 288: Novel Mechanisms of Non-coding Genomic Regulation Identified in Cardiac Disease-in-a-dish Models
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Eric J. Topol, Kevin Tenerelli, Valentina Lo Sardo, Adam J. Engler, Stephanie Thomas, Aditya Kumar, William Ferguson, Kristin Baldwin, and Kirsten C. Wong
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Genetics ,Physiology ,Genotype ,Connexin ,Single-nucleotide polymorphism ,Genome-wide association study ,Locus (genetics) ,Biology ,Cardiology and Cardiovascular Medicine ,Gap junction assembly ,Phenotype ,Gene ,Molecular biology - Abstract
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at gene loci that affect cardiovascular function, and while mechanisms in protein-coding loci are obvious, those in non-coding loci are difficult to determine. 9p21 is a recently identified locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction. Associations have implicated SNPs in altering smooth muscle and endothelial cell properties but have not identified adverse effects in cardiomyocytes (CMs) despite enhanced disease risk. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs and either CAD positive or negative, we assessed CM function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. “heart attack-in-a-dish” stiffening from 11 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype and disease beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions and had significantly lower correlation coefficients versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 gene locus from a R/R patient using TALEN-mediated gene editing, i.e. R/R KO. Deletion of the 9p21 locus restored synchronous contractility and organized connexin 43 junctions. As a non-coding locus, 9p21 appears to repress connexin transcription, leading to the phenotypes we observe, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling, e.g. a “heart attack-in-a-dish” model, can differentially affect CM function depending on SNPs within a non-coding locus.
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- 2016
8. A gender-specific blood-based gene expression score for assessing obstructive coronary artery disease in nondiabetic patients: Results of the Personalized Risk Evaluation and Diagnosis in the Coronary Tree (PREDICT) Trial
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Robert S. Schwartz, Eric J. Topol, Dana Lazar, Michael Elashoff, William E. Kraus, Vivian G. Ng, John A. McPherson, Alexandra J. Lansky, and Szilard Voros
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Coronary Artery Disease ,Coronary Angiography ,Chest pain ,Risk Assessment ,Cohort Studies ,Coronary artery disease ,Myocardial perfusion imaging ,Sex Factors ,Predictive Value of Tests ,Internal medicine ,Prevalence ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Aged ,Cardiac catheterization ,medicine.diagnostic_test ,business.industry ,Gene Expression Profiling ,Age Factors ,Myocardial Perfusion Imaging ,Middle Aged ,medicine.disease ,United States ,Clinical trial ,Predictive value of tests ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Cohort study - Abstract
Currently available noninvasive tests to risk stratify patients for obstructive coronary disease result in many unnecessary cardiac catheterizations, especially in women. We sought to compare the diagnostic accuracy of presenting symptoms, noninvasive test results, and a gene expression score (GES) in identifying obstructive coronary artery disease (CAD) according to gender, using quantitative coronary angiography as the criterion standard.The PREDICT trial is a prospective multicenter observational study designed to develop and validate gene expression algorithms to assess obstructive CAD, defined as at least one ≥50% diameter stenosis measured by quantitative coronary angiography. Patients referred for diagnostic cardiac catheterization with suspected but previously unknown CAD were enrolled. Noninvasive myocardial perfusion imaging (MPI) was available in 60% of patients. The GES, comprising gender-specific age functions and 6 gene expression terms containing 23 genes, was performed for all patients.A total of 1,160 consecutive patients (57.6% men and 42.4% women) were enrolled in PREDICT. The prevalence of obstructive CAD was 46.7% in men and 22.0% in women. Chest pain symptoms were a discriminator of obstructive CAD in men (P.001) but not in women. The positive predictive value of MPI was significantly higher in men (45%) than in women (22%). An abnormal site-read MPI was not significantly associated with obstructive or severity of CAD. The GES was significantly associated with a 2-fold increase in the odds of obstructive CAD for every 10-point increment in the GES and had a significant association with all measures of severity and burden of CAD. By multivariable analysis, GES was an independent predictor of obstructive CAD in the overall population (odds ratio [OR] 2.53, P = .001) and in the male (OR 1.99, P = .001) and female (OR 3.45, P = .001) subgroups separately, whereas MPI was not.Commonly used diagnostic approaches including symptom evaluation and MPI performed less well in women than in men for identifying significant CAD. In contrast, gender-specific GES performed similarly in women and men. Gene expression score offers a reliable diagnostic approach for the assessment of nondiabetic patients and, in particular, women with suspected obstructive CAD.
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- 2012
9. Influence of Genetic Polymorphisms on the Effect of High- and Standard-Dose Clopidogrel After Percutaneous Coronary Intervention
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Gift Investigators, Paul S. Teirstein, Sarah S. Murray, Nicholas J. Schork, Erin N. Smith, Matthew J. Price, Rebecca L. Tisch, Elizabeth O. Lillie, Dominick J. Angiolillo, and Eric J. Topol
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Percutaneous coronary intervention ,Single-nucleotide polymorphism ,CYP2C19 ,Clopidogrel ,Surgery ,Pharmacodynamics ,Internal medicine ,Genotype ,Conventional PCI ,medicine ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,Prospective cohort study ,business ,medicine.drug - Abstract
Objectives This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). Background There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. Methods The GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. Results CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R2 = 0.07, p = 2.2 × 10−15), 30 days (R2 = 0.10, p = 1.3 × 10−7), and 6 months after PCI (R2 = 0.07, p = 1.9 × 10−11), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. Conclusions CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420)
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- 2012
10. Whole Blood Gene Expression Testing for Coronary Artery Disease in Nondiabetic Patients: Major Adverse Cardiovascular Events and Interventions in the PREDICT Trial
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Eric J. Topol, Robert S. Schwartz, Alexandra J. Lansky, Bradley O. Brown, Stephen G. Ellis, Ron Waksman, Michael Elashoff, John A. McPherson, Hsiao D. Lieu, Steven A. Rosenberg, William E. Kraus, and Szilard Voros
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Male ,Time Factors ,medicine.medical_treatment ,Myocardial Infarction ,Pharmaceutical Science ,Coronary Artery Disease ,Coronary Angiography ,Coronary artery disease ,Peripheral blood gene expression ,Risk Factors ,Odds Ratio ,Genetics(clinical) ,Myocardial infarction ,Prospective Studies ,Angioplasty, Balloon, Coronary ,Coronary Artery Bypass ,Prospective cohort study ,Genetics (clinical) ,Aged, 80 and over ,Angiography ,Genomics ,Middle Aged ,Prognosis ,Stroke ,Coronary interventions ,Phenotype ,Ischemic Attack, Transient ,Predictive value of tests ,Cardiology ,Molecular Medicine ,Female ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,MACE ,Revascularization ,Risk Assessment ,Article ,Predictive Value of Tests ,Angioplasty ,Internal medicine ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Genetic Testing ,Aged ,business.industry ,Reproducibility of Results ,Odds ratio ,medicine.disease ,United States ,Logistic Models ,Gene Expression Regulation ,business ,Mace - Abstract
The majority of first-time angiography patients are without obstructive coronary artery disease (CAD). A blood gene expression score (GES) for obstructive CAD likelihood was validated in the PREDICT study, but its relation to major adverse cardiovascular events (MACE) and revascularization was not assessed. Patients (N = 1,160) were followed up for MACE and revascularization 1 year post-index angiography and GES, with 1,116 completing follow-up. The 30-day event rate was 23% and a further 2.2% at 12 months. The GES was associated with MACE/revascularizations (p 15 trended towards increased >30 days MACE/revascularization likelihood (odds ratio = 2.59, 95% confidence interval = 0.89–9.14, p = 0.082). MACE incidence overall was 1.5% (17 of 1,116) and 3 of 17 patients had GES ≤15. For the total low GES group (N = 396), negative predictive value was 90% for MACE/revascularization and >99% for MACE alone, identifying a group of patients without obstructive CAD and highly unlikely to suffer MACE within 12 months. Electronic supplementary material The online version of this article (doi:10.1007/s12265-012-9353-z) contains supplementary material, which is available to authorized users.
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- 2012
11. Comparison of Incidence of Bleeding and Mortality of Men Versus Women With ST-Elevation Myocardial Infarction Treated With Fibrinolysis
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Karen S. Pieper, Eric J. Topol, Paul W. Armstrong, Harvey D. White, Robert M. Califf, Christopher B. Granger, Frans Van de Werf, Renato D. Lopes, A. Stebbins, Judith S. Hochman, John H. Alexander, and Rajendra H. Mehta
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Myocardial Infarction ,Hemorrhage ,Lower risk ,Electrocardiography ,Sex Factors ,Fibrinolytic Agents ,Risk Factors ,Internal medicine ,Fibrinolysis ,Odds Ratio ,medicine ,Humans ,Thrombolytic Therapy ,Prospective Studies ,Myocardial infarction ,Sex Distribution ,Prospective cohort study ,Aged ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Odds ratio ,Middle Aged ,Prognosis ,medicine.disease ,Confidence interval ,Surgery ,Survival Rate ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Gender-related differences in the incidence of bleeding and its relation to subsequent mortality in patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolysis are not well understood. We studied patients with STEMI receiving fibrinolysis enrolled in 6 clinical trials. Outcomes included moderate or severe bleeding defined using Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria and adjusted 1-year mortality (excluding deaths in first 24 hours). Moderate or severe bleeding was 1.9-fold higher in women compared to men (13.3% vs 7.1%, p
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- 2012
12. Emerging Genomic Applications in Coronary Artery Disease
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Eric J. Topol and Samir Damani
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medicine.medical_specialty ,Genome-wide association study ,Bioinformatics ,Risk Assessment ,Article ,Sudden cardiac death ,Coronary artery disease ,Apolipoproteins E ,Risk Factors ,cardiovascular disease ,Internal medicine ,genomics ,Medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Epigenetics ,Myocardial infarction ,Precision Medicine ,pharmacogenomics ,Polymorphism, Genetic ,business.industry ,Gene Expression Profiling ,medicine.disease ,Clopidogrel ,Cytochrome P-450 CYP2C19 ,Phenotype ,Pharmacogenetics ,DNA methylation ,Cardiology ,Human genome ,Aryl Hydrocarbon Hydroxylases ,business ,Cardiology and Cardiovascular Medicine ,Platelet Aggregation Inhibitors ,coronary artery disease ,medicine.drug ,Lipoprotein(a) - 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.
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- 2011
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13. High-sensitivity C-reactive protein and clopidogrel treatment in patients at high risk of cardiovascular events: a substudy from the CHARISMA trial
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Koon Hou Mak, Graeme J. Hankey, Keith A.A. Fox, Eric J. Topol, S. Claiborne Johnston, Donald J. Easton, Michael Weber, Steven R. Steinhubl, Gilles Montalescot, Deepak L. Bhatt, Christian W. Hamm, and Danielle M. Brennan
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Male ,medicine.medical_specialty ,Ticlopidine ,Population ,Placebo ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,cardiovascular diseases ,Myocardial infarction ,education ,Stroke ,Aged ,education.field_of_study ,Aspirin ,biology ,business.industry ,C-reactive protein ,nutritional and metabolic diseases ,Middle Aged ,Atherosclerosis ,medicine.disease ,Clopidogrel ,Surgery ,C-Reactive Protein ,Treatment Outcome ,Cardiovascular Diseases ,biology.protein ,Cardiology ,Drug Therapy, Combination ,Female ,Epidemiologic Methods ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
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.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 28emsp14;months). The predefined primary composite endpoint was myocardial infarction, stroke, or death from cardiovascular causes.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 (3 mg/l) clopidogrel treatment was associated with a lower event rate compared with placebo (4.0% vs 6.0%, log rank p=0.005). In contrast no treatment effect was observed in patients with high hsCRP levels (8.1% vs 8.0%, ns).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.
- Published
- 2011
14. Association of Mortality With Years of Education in Patients With ST-Segment Elevation Myocardial Infarction Treated With Fibrinolysis
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Rajendra H. Mehta, Amanda Stebbins, Paul W. Armstrong, Harvey D. White, Robert M. Califf, Eric J. Topol, Christopher B. Granger, E. Magnus Ohman, and J.Conor O’Shea
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Male ,medicine.medical_specialty ,Time Factors ,Myocardial Infarction ,acute myocardial infarction ,outcomes ,Alberta ,law.invention ,socioeconomic status ,Electrocardiography ,Fibrinolytic Agents ,Patient Education as Topic ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,ST segment ,Thrombolytic Therapy ,Myocardial infarction ,Socioeconomic status ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,United States ,Survival Rate ,Coronary arteries ,Clinical trial ,medicine.anatomical_structure ,Physical therapy ,fibrinolysis ,Female ,Cardiology and Cardiovascular Medicine ,business ,Ireland ,Follow-Up Studies ,New Zealand - Abstract
ObjectivesThe purpose of this study was to examine the association between lower socioeconomic status (SES), as ascertained by years of education, and outcomes in patients with acute ST-segment elevation myocardial infarction (STEMI).BackgroundPrevious studies have shown an inverse relationship between SES and coronary heart disease and mortality. Whether a similar association between SES and mortality exists in STEMI patients is unknown.MethodsWe evaluated 11,326 patients with STEMI in the GUSTO-III (Global Use of Strategies to Open Occluded Coronary Arteries) trial study from countries that enrolled >500 patients. We evaluated clinical outcomes (adjusted using multivariate regression analysis) according to the number of years of education completed.ResultsOne-year mortality was inversely related to years of education and was 5-fold higher in patients with 16 years of education (17.5% vs. 3.5%, p < 0.0001). The strength of the relationship between education and mortality varied among different countries. Nonetheless, years of education remained an independent correlate of mortality at day 7 (hazard ratio per year of increase in education: 0.86; 95% confidence interval: 0.83 to 0.88) and also between day 8 and 1 year (hazard ratio per year of increase in education: 0.96; 95% confidence interval: 0.94 to 0.98), even after adjustment for baseline characteristics and country of enrollment.ConclusionsWhen the number of years of education was used as a measure of SES, there was an inverse relationship such that significantly higher short-term and 1-year mortality existed beyond that accounted for by baseline clinical variables and country of enrollment. Future studies should account for and investigate the mechanisms underlying this link between SES and cardiovascular disease outcomes.
- Published
- 2011
15. Pilot Study of the Antiplatelet Effect of Increased Clopidogrel Maintenance Dosing and Its Relationship to CYP2C19 Genotype in Patients With High On-Treatment Reactivity
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Paul S. Teirstein, David E. Kandzari, Matthew J. Price, Colin MacLeod Barker, Sarah S. Murray, and Eric J. Topol
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Male ,Platelet Aggregation ,medicine.medical_treatment ,Pilot Projects ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Gastroenterology ,California ,Body Mass Index ,0302 clinical medicine ,P2Y12 ,Risk Factors ,Platelet ,Longitudinal Studies ,030212 general & internal medicine ,platelet ,thienopyridine ,Middle Aged ,Clopidogrel ,Receptors, Purinergic P2Y12 ,3. Good health ,Phenotype ,Female ,Aryl Hydrocarbon Hydroxylases ,Cardiology and Cardiovascular Medicine ,medicine.drug ,medicine.medical_specialty ,Ticlopidine ,Genotype ,Platelet Function Tests ,Thienopyridine ,CYP2C19 ,Risk Assessment ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Dosing ,Aged ,clopidogrel ,Chi-Square Distribution ,Polymorphism, Genetic ,business.industry ,Percutaneous coronary intervention ,Surgery ,Cytochrome P-450 CYP2C19 ,Regimen ,Logistic Models ,business ,Platelet Aggregation Inhibitors - Abstract
ObjectivesThe objective of this study was to evaluate the antiplatelet effect of clopidogrel 150 mg/day in patients with high on-treatment reactivity (OTR) and to further assess this effect according to CYP2C19 genotype.BackgroundHigh OTR is associated with ischemic events in clopidogrel-treated patients after percutaneous coronary intervention. Alternative dosing regimens might enhance platelet inhibition.MethodsPatients with high OTR receiving a standard clopidogrel regimen were identified with the VerifyNow P2Y12 assay and administered clopidogrel 150 mg daily for 7 days, after which OTR was reassessed. Comprehensive CYP2C19 genotyping was performed with the BeadXpress platform (Illumina, San Diego, California) for the *2, *3, *4, *5, *6, *7, *8, and *17 variants.ResultsA total of 41 subjects were enrolled, 20 of whom were carriers of a CYP2C19 loss-of-function (LoF) allele. High-dose clopidogrel significantly reduced OTR from 285 ± 47 P2Y12 reaction units (PRU) to 220 ± 91 PRU (p < 0.001). There were no significant differences in antiplatelet effect according to CYP2C19 status, although the reduction in reactivity was minimal in the small number of patients homozygous for LoF alleles (n = 3, 28 ± 31 PRU, p = NS). Increasing body mass index was independently and negatively associated with the reduction in OTR (p = 0.009).ConclusionsIn patients with high OTR, clopidogrel 150 mg/day results in a significant reduction in platelet reactivity. Carriage of an LoF CYP2C19 polymorphism does not seem to have a major influence on dose effect. The observed lack of effect in patients with 2 copies of a CYP2C19 LoF allele must be confirmed by larger studies.
- Published
- 2010
16. KICKBOXING A CARDIOMYOPATHY: A CASE WHERE MITOCHONDRIAL SEQUENCING PROVIDES NOVEL ANSWER FOR YOUNG ATHLETE AND HER FAMILY
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Elizabeth Hill, Ali Torkamani, Eric J. Topol, and Evan D. Muse
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business.industry ,Cardiomyopathy ,medicine ,Cardiology and Cardiovascular Medicine ,Bioinformatics ,medicine.disease ,business - Published
- 2018
17. Enoxaparin in Primary and Facilitated Percutaneous Coronary Intervention
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Michal Tendera, Howard C. Herrmann, Ad J. van Boven, Stephen G. Ellis, Luc Janssens, Mark A. de Belder, Gilles Montalescot, Olivier Katz, Eric J. Topol, Mark B. Effron, Paul W. Armstrong, Petr Widimsky, Patrick Ecollan, Elliot S. Barnathan, Bruce R. Brodie, Franz-Josef Neumann, Wladyslaw Pluta, Amadeo Betriu, Jiandong Lu, and H. R. Andersen
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Percutaneous coronary intervention ,Reteplase ,Thrombolysis ,medicine.disease ,Lower risk ,Internal medicine ,Conventional PCI ,medicine ,Abciximab ,Cardiology ,cardiovascular diseases ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,TIMI ,medicine.drug - Abstract
Objectives The aim of this study was to assess the risk-benefit of enoxaparin (Sanofi-Aventis, Paris, France) in primary percutaneous coronary intervention (PCI). Background Randomized studies have demonstrated the superiority of enoxaparin over unfractionated heparin (UFH) in acute ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytics. Methods In the FINESSE (Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events) trial—a double-blind, placebo-controlled study—2,452 patients with STEMI were randomized to primary PCI or facilitated PCI with abciximab alone or with half-dose reteplase. In this prospective FINESSE substudy, centers pre-specified use of either enoxaparin (0.5 mg/kg intravenous [IV], 0.3 mg/kg subcutaneous [SC]) or UFH (40 U/kg IV, 3,000 U maximum) with PCI. A logistic-regression model and a propensity multivariate model, both adjusted for baseline variables, were used to evaluate primary safety and secondary efficacy end points for enoxaparin versus UFH. Results Enoxaparin was administered to 759 patients and UFH to 1,693 patients. Nonintracranial Thrombolysis In Myocardial Infarction (TIMI) major/minor bleeding was not significantly different, but lower nonintracranial TIMI major bleeding was found with enoxaparin (2.6% vs. UFH 4.4%, logistic-regression adjusted odds ratio [OR]: 0.55; 95% confidence interval [CI]: 0.31 to 0.99, p = 0.045), whereas intracranial hemorrhage was similar (0.27% vs. 0.24%, adjusted OR: 1.03; 95% CI: 0.11 to 9.68, p = 0.980). Lower death, myocardial infarction, urgent revascularization, or refractory ischemia through 30 days was also associated with enoxaparin (5.3%) versus UFH (8.0%, adjusted OR: 0.47, 95% CI: 0.31 to 0.72, p = 0.0005) as was all-cause mortality through 90 days (3.8% vs. 5.6%, respectively, adjusted OR: 0.59, 95% CI: 0.35 to 0.99, p = 0.046). End points evaluating the net clinical benefit also significantly favored enoxaparin over UFH. Conclusions Enoxaparin seems to be associated with a lower risk of cardiovascular outcomes compared with UFH in patients with STEMI undergoing primary PCI. Confirmation of these findings in a randomized study is warranted. (A Study of Abciximab and Reteplase When Administered Prior to Catheterization After a Myocardial Infarction [Finesse]; NCT00046228)
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- 2010
18. Relationship Between Baseline Inflammatory Markers, Antiplatelet Therapy, and Adverse Cardiac Events After Percutaneous Coronary Intervention
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Kristofer Dosh, Eric J. Topol, Fredrick Van Lente, Danielle M. Brennan, Steven R. Steinhubl, Richard Charnigo, Peter B. Berger, and Steven P. Marso
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medicine.medical_specialty ,Aspirin ,Randomization ,business.industry ,medicine.medical_treatment ,Percutaneous coronary intervention ,medicine.disease ,Placebo ,Clopidogrel ,Internal medicine ,Clinical endpoint ,medicine ,Cardiology ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,medicine.drug - Abstract
Background— We evaluated patients undergoing percutaneous coronary intervention to assess the predictive value of high-sensitivity C-reactive protein (hs-CRP) and pregnancy-associated plasma protein-A (PAPP-A) on adverse cardiac outcomes and the effect of antiplatelet therapy on these outcomes. Methods and Results— Baseline blood samples were available on 1468 CREDO (Clopidogrel for the Reduction of Events During Observation) patients for hs-CRP testing and 1096 patients for PAPP-A testing. The 1-year primary end point was the composite incidence of death, myocardial infarction, or stroke. Patients in the highest 2 tertiles of hs-CRP had more events compared with the lowest tertile (11.4% versus 6.4%, P =0.003). Treatment with clopidogrel reduced the 1-year composite end point for patients in the highest 2 tertiles of hs-CRP (9.1% clopidogrel versus 13.5% placebo, P =0.04) but not in the lowest tertile. Elevated PAPP-A levels were associated with a trend toward more events at 1 year that did not reach statistical significance. Patients in the highest 2 tertiles of PAPP-A randomized to clopidogrel had fewer events (7.3% clopidogrel versus 13.1% placebo, P =0.01), but no benefit was seen in the lowest tertile. A 46% risk reduction with randomization to clopidogrel was seen in patients in the highest 2 tertiles of both biomarkers (8.7% versus 16.2%, P =0.02). Conclusions— Patients undergoing nonurgent percutaneous coronary intervention who have elevated hs-CRP and PAPP-A have an increased incidence of adverse cardiovascular events. The clinical benefit of adding clopidogrel to aspirin seems greater in those with increased levels of these inflammatory biomarkers.
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- 2009
19. The Relative Efficacy and Safety of Clopidogrel in Women and Men
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Peter B. Berger, Steven R. Steinhubl, Zhengming Chen, Eric J. Topol, Lixin Jiang, Deepak L. Bhatt, Jeffrey S. Berger, J.B. Jones, Christopher P. Cannon, Marc S. Sabatine, and Shamir R. Mehta
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medicine.medical_specialty ,Unstable angina ,business.industry ,Odds ratio ,Placebo ,medicine.disease ,Clopidogrel ,law.invention ,Randomized controlled trial ,law ,Anesthesia ,Internal medicine ,medicine ,cardiovascular diseases ,Myocardial infarction ,business ,Cardiology and Cardiovascular Medicine ,Stroke ,circulatory and respiratory physiology ,medicine.drug ,Metoprolol - Abstract
Objectives This study sought to investigate the efficacy and safety of clopidogrel in women and men. Background Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men. Methods This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY–TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling. Results Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42). Conclusions Clopidogrel reduces the risk of cardiovascular events in both women and men.
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- 2009
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20. Benefit of Facilitated Percutaneous Coronary Intervention in High-Risk ST-Segment Elevation Myocardial Infarction Patients Presenting to Nonpercutaneous Coronary Intervention Hospitals
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Stephen G. Ellis, Eric J. Topol, Paul W. Armstrong, Franz Joseph Neuman, Mark B. Effron, Bruce R. Brodie, Howard C. Herrmann, Gilles Montalescot, Amadeo Betriu, Jiandong Lu, and Elliot S. Barnathan
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Patient Transfer ,medicine.medical_specialty ,Time Factors ,Abciximab ,medicine.medical_treatment ,Myocardial Infarction ,Hemorrhage ,Reteplase ,Kaplan-Meier Estimate ,Risk Assessment ,Health Services Accessibility ,Immunoglobulin Fab Fragments ,Double-Blind Method ,Fibrinolytic Agents ,Risk Factors ,Internal medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Thrombolytic Therapy ,Myocardial infarction ,cardiovascular diseases ,Angioplasty, Balloon, Coronary ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Framingham Risk Score ,business.industry ,Cardiogenic shock ,percutaneous coronary intervention ,Antibodies, Monoclonal ,Percutaneous coronary intervention ,medicine.disease ,Combined Modality Therapy ,Recombinant Proteins ,STEMI facilitation ,Treatment Outcome ,Tissue Plasminogen Activator ,Conventional PCI ,Cardiology ,business ,Cardiology and Cardiovascular Medicine ,Platelet Aggregation Inhibitors ,TIMI ,medicine.drug - Abstract
ObjectivesWe hypothesized that patients most likely to benefit would be those at high risk with a shorter duration of acute ischemia and who required transfer for percutaneous coronary intervention (PCI).BackgroundThe FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) study failed to demonstrate an improvement in the 90-day composite clinical end point of early treatment with abciximab plus half-dose reteplase (combination-facilitated PCI) or abciximab alone.MethodsWe performed a retrospective analysis of 2,452 patients in this double-blind, placebo-controlled study. Patients were stratified by Thrombolysis In Myocardial Infarction (TIMI) risk score for ST-segment elevation myocardial infarction (STEMI), presentation to a spoke (no PCI available) or hub site, and symptom-to-randomization time. Outcomes included the primary composite end point of death, ventricular fibrillation after 48 h, cardiogenic shock, and congestive heart failure through day 90 as well as 1-year mortality.ResultsMortality for all patients at 1 year was directly related to TIMI risk score (23 of 1,223 = 1.9% in patients with score
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- 2009
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21. 1-Year Survival in a Randomized Trial of Facilitated Reperfusion
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Stefano Savonitto, Ad J. van Boven, Michal Tendera, Jerzy Adamus, Luc Janssens, Waladyslaw Pluta, Keith G. Oldroyd, Finesse Investigators, Gilles Montalescot, Howard C. Herrmann, Eric J. Topol, Mark B. Effron, Amadeo Betriu, Paul W. Armstrong, Franz-Josef Neumann, Maciej Hamankiewicz, Petr Widimsky, Mark A. de Belder, Patrick Ecollan, Barnathan Elliot, Bruce R. Brodie, Stephen G. Ellis, Jan Z. Peruga, and H. R. Andersen
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medicine.medical_specialty ,Cath lab ,business.industry ,medicine.medical_treatment ,Percutaneous coronary intervention ,Reteplase ,medicine.disease ,Surgery ,law.invention ,Reperfusion therapy ,Randomized controlled trial ,law ,Internal medicine ,Conventional PCI ,medicine ,Abciximab ,Cardiology ,Myocardial infarction ,business ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Objectives The aim of this report was to evaluate 12-month outcomes of facilitated percutaneous coronary intervention (PCI) in the FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) trial. Background Treatment delays remain common for patients with primary PCI leading to studies evaluating possible benefit of “facilitated” PCI. In the FINESSE trial, no reduction in the 90-day primary ischemic end point and an increase in bleeding were observed with both facilitated approaches, although modest favorable trends were seen for some patient subgroups. Methods A total of 2,452 patients with ST-segment elevation myocardial infarction (MI) and anticipated 1 to 4 h delay until catheterization were randomized to reduced-dose reteplase + abciximab, abciximab alone, or placebo, followed by expedited primary PCI. Placebo-treated patients received abciximab in the cath lab. One-year mortality was a pre-specified secondary end point. Results One-year mortalities in the 3 groups noted in the preceding text were 6.3%, 7.4%, and 7.0%, respectively (p = NS), representing 1.1%, 1.9%, and 2.5% increments since the 90-day outcome (p = 0.053 for combination treatment vs. primary PCI). A favorable trend with combination treatment was seen for patients with anterior MI (p = 0.09), but no other specified groups benefited or tended to benefit. Independent baseline correlates of 1-year mortality were systolic blood pressure 1, anterior MI, body mass index ≤25 kg/m2, heart rate >100 beats/min, and no statin use. Conclusions These results suggest that widespread utilization of the facilitated approaches tested cannot be justified, but that high-risk patient groups such as patients with anterior MI may deserve further study. (The FINESSE trial; NCT00046228 )
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- 2009
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22. Impact of Blood Transfusion on Short- and Long-Term Mortality in Patients With ST-Segment Elevation Myocardial Infarction
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Eric J. Topol, Vivek Rajagopal, Mehdi H. Shishehbor, Samir R. Kapadia, Hitinder S. Gurm, Amy Hsu, Surabhi Madhwal, Michael S. Lauer, and Peter Kelly
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Male ,long-term outcome ,medicine.medical_specialty ,Blood transfusion ,Time Factors ,medicine.medical_treatment ,Myocardial Infarction ,propensity analysis ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,blood transfusion ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Confidence Intervals ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Prospective Studies ,Acute Coronary Syndrome ,Prospective cohort study ,Survival analysis ,Aged ,Proportional Hazards Models ,Proportional hazards model ,business.industry ,Hazard ratio ,Transfusion Reaction ,Anemia ,Middle Aged ,medicine.disease ,Confidence interval ,United States ,3. Good health ,Surgery ,ST-segment elevation myocardial infarction ,Logistic Models ,Treatment Outcome ,Propensity score matching ,Multivariate Analysis ,Cardiology ,Female ,business ,Cardiology and Cardiovascular Medicine - Abstract
ObjectivesWe sought to examine the short- and long-term outcomes of blood transfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI).BackgroundThe short- and long-term consequences of blood transfusion in anemic patients with recent STEMI remain controversial.MethodsWe evaluated 30-day, 6-month, and 1-year all-cause mortality among 4,131 STEMI patients enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial. Patients were categorized according to whether they received a blood transfusion during hospitalization. Cox proportional hazards survival models with transfusion as a time-dependent covariate were conducted for the whole and for the propensity-matched groups. Additionally, a series of sensitivity analyses assessed the magnitude of hidden bias that would need to be present to explain the associations actually observed.ResultsDeath at 30 days (13.7% vs. 5.5%), 6 months (19.7% vs. 6.9%), and 1 year (21.8% vs. 8.7%) was significantly higher for transfused patients than for nontransfused patients, respectively. After adjusting for over 25 baseline characteristics, nadir hemoglobin, and propensity score for transfusion, and using transfusion as a time-dependent covariate, transfusion remained significantly associated with increased risk of mortality at 30 days (hazard ratio [HR]: 3.89, 95% confidence interval [CI]: 2.66 to 5.68, p < 0.001), 6 months (HR: 3.63, 95% CI: 2.67 to 4.95, p < 0.001), and 1 year (HR: 3.03, 95% CI: 2.25 to 4.08, p < 0.001). Similar results were observed in the propensity-matched patients.ConclusionsBlood transfusion is associated with increased short- and long-term mortality in the setting of STEMI.
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- 2009
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23. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease
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Graeme J. Hankey, Mingyuan Shao, Philippe Gabriel Steg, Keith A.A. Fox, Koon Hou Mak, Gilles Montalescot, Steven R. Steinhubl, S. Claiborne Johnston, Steven M. Haffner, Christian W. Hamm, Deepak L. Bhatt, and Eric J. Topol
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Male ,medicine.medical_specialty ,Ticlopidine ,Coronary Disease ,Hemorrhage ,Body Mass Index ,Fibrinolytic Agents ,Risk Factors ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Prospective Studies ,Stroke ,Aged ,Aspirin ,business.industry ,Vascular disease ,Thrombosis ,medicine.disease ,Clopidogrel ,Surgery ,Quartile ,Cardiovascular agent ,Female ,Cardiology and Cardiovascular Medicine ,business ,Body mass index ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Aims We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease. Methods and results This was a prospective observational study of 15 532 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who were randomly assigned to clopidogrel or placebo, and followed-up for a median of 28 months for the occurrence of the primary endpoint (cardiovascular death, myocardial infarction, or stroke), all-cause mortality, and bleeding complications. Compared with the highest BMI quartile, the primary endpoint, cardiovascular, and all-cause mortality all occurred more frequently among patients in the lowest BMI quartile (about a third lower). The relationship between continuous BMI and adverse cardiovascular outcomes were presented as two linear spline terms with 29 kg/m2 as the cut-point for all-cause mortality. Lower BMI was associated with an increase in moderate and severe bleeding complications, largely accounted for by those receiving dual-antiplatelet agents with the highest tertile aspirin dose. Conclusion Adverse cardiovascular events and bleeding complications occurred more frequently among individuals with or at-risk for atherothrombotic disease and low BMI. Further studies should be directed to these patients to improve outcomes. The CHARISMA trial is registered with ClinicalTrials.gov, NCT00050817.
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- 2008
24. Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid
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J. Thom, Tingfei Hu, P. Gabriel Steg, Eric J. Topol, J. Donald Easton, Koon Hou Mak, S. Claiborne Johnston, Christian W. Hamm, Graeme J. Hankey, John W. Eikelboom, Keith A.A. Fox, Deepak L. Bhatt, Steven R. Steinhubl, and Gilles Montalescot
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Male ,medicine.medical_specialty ,Internationality ,Thromboxane ,Urinary system ,chemistry.chemical_compound ,Double-Blind Method ,Risk Factors ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Cyclooxygenase Inhibitors ,Myocardial infarction ,Stroke ,Aged ,Aspirin ,business.industry ,Hazard ratio ,Thromboxanes ,Middle Aged ,Clopidogrel ,medicine.disease ,Survival Rate ,Thromboxane B2 ,Endocrinology ,chemistry ,Cardiovascular Diseases ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background— Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B 2 concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B 2 concentrations that could thereby reduce cardiovascular risk. Methods and Results— Urinary 11-dehydro thromboxane B 2 concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B 2 concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P =0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B 2 , whereas aspirin dose ≥150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B 2 levels. Conclusions— In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B 2 are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.
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- 2008
25. The use of high-sensitivity assays for C-reactive protein in clinical practice
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Richard A. Lange, Milind Y. Desai, Ty J. Gluckman, Valentin Fuster, Brian G. Kral, James T. Willerson, Roger S. Blumenthal, Samia Mora, Kiran Musunuru, Catherine Y. Campbell, Michael H. Davidson, and Eric J. Topol
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Male ,Oncology ,medicine.medical_specialty ,Cost-Benefit Analysis ,Disease ,Risk Assessment ,Sensitivity and Specificity ,Asymptomatic ,Article ,Diabetes Complications ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Secondary Prevention ,Humans ,Medicine ,cardiovascular diseases ,Aged ,Metabolic Syndrome ,Aspirin ,biology ,business.industry ,C-reactive protein ,nutritional and metabolic diseases ,Cholesterol, LDL ,General Medicine ,Middle Aged ,Clinical Practice ,C-Reactive Protein ,Cardiovascular Diseases ,Predictive value of tests ,Hypertension ,biology.protein ,Physical therapy ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Inflammatory biomarker ,Risk assessment ,Risk Reduction Behavior ,Biomarkers ,medicine.drug - Abstract
Measurement of the inflammatory biomarker high sensitivity C-reaction protein (hsCRP) has been proposed for assessment of risk for cardiovascular disease (CVD). It remains unclear which patient populations would benefit from and should be targeted for hsCRP testing. Current data indicate that hsCRP levels are independently associated with risk of CVD, including both coronary events and stroke, in various asymptomatic populations; add predictive power to current coronary risk scores for some intermediate risk individuals; and are associated with clinical outcomes in high risk individuals treated with statin therapy. HsCRP levels are also associated with incident diabetes and CVD outcomes in patients with the metabolic syndrome. There is a growing body of evidence to support recommendations for measurement of hsCRP in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk factor assessment and who do not already warrant treatment with chronic aspirin and statin therapy, and selected secondary CVD prevention patients for further risk stratification in combination with LDL cholesterol.
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- 2008
26. Efficacy and safety of clopidogrel pretreatment before percutaneous coronary intervention with and without glycoprotein IIb/IIIa inhibitor use
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Marc S. Sabatine, Eric J. Topol, Christopher P. Cannon, Shamir R. Mehta, Keith A.A. Fox, Steven R. Steinhubl, and Hussam Hamdalla
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Male ,medicine.medical_specialty ,Ticlopidine ,medicine.medical_treatment ,Coronary Artery Disease ,Platelet Glycoprotein GPIIb-IIIa Complex ,Internal medicine ,Angioplasty ,medicine ,Humans ,cardiovascular diseases ,Myocardial infarction ,Angioplasty, Balloon, Coronary ,Stroke ,Aged ,Randomized Controlled Trials as Topic ,business.industry ,Percutaneous coronary intervention ,Middle Aged ,medicine.disease ,Clopidogrel ,Combined Modality Therapy ,Treatment Outcome ,Anesthesia ,Conventional PCI ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,Glycoprotein IIb/IIIa ,business ,Platelet Aggregation Inhibitors ,TIMI ,medicine.drug - Abstract
Background Clopidogrel pretreatment before percutaneous coronary intervention (PCI) has been shown to reduce the risk of death and ischemic complications after PCI. However, the need for clopidogrel pretreatment is debated in patients receiving a glycoprotein IIb/IIIa inhibitor (GPI). Methods We performed a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment: PCI-CURE, CREDO, and PCI-CLARITY. Patients were stratified based on GPI use at the time of PCI (a postrandomization subgroup analysis). Odds ratios (ORs) and 95% CIs for the effect of clopidogrel pretreatment versus placebo pretreatment on the incidence of cardiovascular death, myocardial infarction (MI), or stroke for up to 30 days after PCI were calculated for each trial within each GPI stratum and were combined using a random effects model. Results Six thousand three hundred twenty-five patients were included, 32.4% of whom received a GPI. There was a consistent benefit of clopidogrel pretreatment in reducing the incidence of cardiovascular death, MI, or stroke after PCI both in patients who did not receive a GPI (OR 0.72, 95% CI 0.53-0.98, P = .03) and in those who did (OR 0.69, 95% CI 0.47-1.00, P = .05). There was no evidence of heterogeneity in the benefit of clopidogrel pretreatment between GPI use strata ( P = .85 for heterogeneity). Clopidogrel pretreatment was not associated with a significant excess of TIMI major or minor bleeding, either in those who did not receive a GPI (OR 1.20, 95% CI 0.76-1.92) or in those who did (OR 1.22, 95% CI 0.71-2.09) ( P = .97 for heterogeneity). Conclusion Clopidogrel pretreatment before PCI is beneficial and safe regardless of whether a GPI is used at the time of PCI.
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- 2008
27. Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial)
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Hans-Christoph Diener, Robert A. Harrington, Carmelo Graffagnino, Pierre Théroux, Desmond J. Fitzgerald, Pierre Amarenco, Ashfaq Shuaib, Stephen M. Davis, Robert M. Califf, Marc Vallee, Peter J. Koudstaal, James J. Ferguson, J. Donald Easton, Herbert D. Aronow, Frans Van de Werf, Eric J. Topol, Neurosciences, and Neurology
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Male ,medicine.medical_specialty ,Coronary Disease ,Hemorrhage ,Fibrinolytic Agents ,Cause of Death ,Internal medicine ,medicine ,Humans ,Myocardial infarction ,Dosing ,Stroke ,Aged ,Retrospective Studies ,Cause of death ,Aspirin ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Clopidogrel ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Fibrinolytic agent ,medicine.drug - Abstract
Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (< 162 mg vs >= 162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, cl nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of >= 162 mg/day may be more beneficial than those
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- 2008
28. Predictors and Impact of Major Hemorrhage on Mortality Following Percutaneous Coronary Intervention from the REPLACE-2 Trial
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Michele D. Voeltz, Frederick Feit, Eric J. Topol, Derek P. Chew, Steven V. Manoukian, A. Michael Lincoff, Michael J. Attubato, and John A. Bittl
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Coronary Disease ,Hemorrhage ,Antithrombins ,law.invention ,Fibrinolytic Agents ,law ,Internal medicine ,Angioplasty ,medicine ,Humans ,Bivalirudin ,Prospective Studies ,Angioplasty, Balloon, Coronary ,Prospective cohort study ,Aged ,business.industry ,Mortality rate ,Percutaneous coronary intervention ,Odds ratio ,Hirudins ,Middle Aged ,Intensive care unit ,Peptide Fragments ,Recombinant Proteins ,Logistic Models ,Multivariate Analysis ,Conventional PCI ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Patients undergoing percutaneous coronary intervention (PCI) have a significant risk of hemorrhagic complications. Predictors of major hemorrhage and its relation to mortality in PCI are not well defined. Baseline and periprocedural predictors of major hemorrhage and its impact on mortality in patients undergoing elective or urgent PCI randomly assigned to heparin plus planned glycoprotein IIb/IIIa inhibitor (GPI) versus bivalirudin plus provisional GPIs in the REPLACE-2 Trial were determined. Of 6,001 patients, 3.2% experienced a major hemorrhage. Independent baseline predictors of major hemorrhage included advanced age, female gender, impaired creatinine clearance, and anemia. Independent periprocedural predictors of major hemorrhage included treatment with heparin plus GPI, increased procedural duration, provisional use of GPI, increased time to sheath removal, length of intensive care unit stay, and use of an intra-aortic balloon pump (all p
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- 2007
29. Long-Term Outcome and its Predictors Among Patients With ST-Segment Elevation Myocardial Infarction Complicated by Shock
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Mandeep Singh, Eric J. Topol, Peter B. Berger, David R. Holmes, David Hasdai, Robert M. Califf, Jennifer A. White, and Patricia K. Hodgson
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medicine.medical_specialty ,Heart disease ,business.industry ,Proportional hazards model ,Cardiogenic shock ,Streptokinase ,ST elevation ,Mortality rate ,medicine.disease ,Surgery ,Internal medicine ,Cardiology ,Medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Killip class ,medicine.drug - Abstract
Objectives This study sought to assess long-term outcome and determine its predictors among 30-day survivors of cardiogenic shock. Background Patients with cardiogenic shock have high in-hospital and 30-day mortality, but there are little data about those who survive beyond 30 days. Methods We analyzed baseline, in-hospital, and survival data from patients in the U.S. with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock enrolled in the GUSTO (Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries)-I trial and compared them with patients in the same trial who did not have shock. Results Of 22,883 patients enrolled in the U.S., shock occurred in 1,891 (8.3%); 953 (50.4%) survived 30 days and 527 (27.8%) survived 11 years. Of 20,992 U.S. patients without shock, 20,360 (96.9%) survived 30 days and 14,131 (67.3%) survived 11 years. After the first year, 2% to 4% of patients died each year regardless of whether they had cardiogenic shock. Using Cox proportional hazards models, we were able to predict long-term mortality in all U.S. GUSTO-I 30-day survivors from their baseline demographics and in-hospital complications. The strongest predictors were diabetes mellitus, cardiogenic shock, hypertension, previous myocardial infarction, current smoking, anterior infarct, higher Killip class, higher heart rate, and older age; patients >75 years were at highest risk. Percutaneous revascularization during the index hospitalization was associated with a reduced risk of death. Conclusions Among patients with cardiogenic shock who survive 30 days after STEMI, annual mortality rates of 2% to 4% approximate those of patients without shock.
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- 2007
30. A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease
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Eric J. Topol, Dongming Liu, John P. Kane, Mary J. Malloy, Stephen G. Ellis, Clive R. Pullinger, Charles M. Rowland, Irina Movsesyan, Carmen H. Tong, Dov Shiffman, Josephina Naya-Vigne, Marlys L. Koschinsky, Diane U. Leong, Curtis Noordhof, Joseph J. Catanese, Nicole T. Feric, Andre R. Arellano, May M. Luke, James J. Devlin, and June Cassano
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Male ,medicine.medical_specialty ,Apolipoprotein B ,Single-nucleotide polymorphism ,Coronary Artery Disease ,Apoprotein(a) ,Polymorphism, Single Nucleotide ,Gastroenterology ,Coronary artery disease ,Gene Frequency ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Risk factor ,Aged ,biology ,Odds ratio ,Lipoprotein(a) ,Middle Aged ,medicine.disease ,Endocrinology ,Case-Control Studies ,biology.protein ,Female ,Cardiology and Cardiovascular Medicine ,Lipoprotein - Abstract
Objectives— The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD). Methods and Results— We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA , CALM1 , HAP1 , AP3B1 , and ABCG2 ) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels ( P =0.003). Conclusions— The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.
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- 2007
31. Peroxisome proliferator–activated receptor γ agonists for the Prevention of Adverse events following percutaneous coronary Revascularization—results of the PPAR Study
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Deepak L, Bhatt, Derek P, Chew, Cindy, Grines, Debabrata, Mukherjee, Massoud, Leesar, Ian C, Gilchrist, John C, Corbelli, James C, Blankenship, Avichai, Eres, Steven, Steinhubl, Walter A, Tan, Jon R, Resar, Amjad, AlMahameed, Ahmed, Abdel-Latif, W H Wilson, Tang, H Wilson, Tang, Danielle, Brennan, Ellen, McErlean, Stanley L, Hazen, and Eric J, Topol
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Coronary Disease ,Pilot Projects ,Rosiglitazone ,Double-Blind Method ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Humans ,Hypoglycemic Agents ,Myocardial infarction ,Angioplasty, Balloon, Coronary ,education ,Stroke ,Metabolic Syndrome ,education.field_of_study ,business.industry ,Percutaneous coronary intervention ,Middle Aged ,medicine.disease ,Brain natriuretic peptide ,PPAR gamma ,Endocrinology ,Cardiovascular Diseases ,Conventional PCI ,Disease Progression ,Cardiology ,Female ,Thiazolidinediones ,Metabolic syndrome ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,medicine.drug - Abstract
Background Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator–activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). Methods A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. Results There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (−35.4% vs −15.8%, P = .059) and 12 months (−40.0% vs −20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (−13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. Conclusions Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator–activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted.
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- 2007
32. Lack of Evidence of a Clopidogrel–Statin Interaction in the CHARISMA Trial
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Deepak L. Bhatt, Koon-Hou Mak, Jacqueline Saw, Steven R. Steinhubl, Eric J. Topol, Keith A.A. Fox, Charisma Investigators, and Danielle M. Brennan
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Male ,medicine.medical_specialty ,Ticlopidine ,Statin ,medicine.drug_class ,Atorvastatin ,Population ,Hemorrhage ,Placebo ,law.invention ,Cytochrome P-450 Enzyme System ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Drug Interactions ,Pyrroles ,Prospective Studies ,cardiovascular diseases ,education ,Pravastatin ,education.field_of_study ,business.industry ,Middle Aged ,Clopidogrel ,Surgery ,Cardiovascular Diseases ,Heptanoic Acids ,Drug Therapy, Combination ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Cardiology and Cardiovascular Medicine ,Platelet Aggregation Inhibitors ,Follow-Up Studies ,Fluvastatin ,medicine.drug - Abstract
Objectives The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up. Background There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy. Methods The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non–CYP3A4-MET). Results Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non–CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non–CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates. Conclusions Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.
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- 2007
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33. Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial
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Charisma Investigators, J. Donald Easton, Keith A.A. Fox, Tingfei Hu, Koon-Hou Mak, Eric J. Topol, William E. Boden, Graeme J. Hankey, Christian W. Hamm, Patrice Cacoub, Eric A. Cohen, Deepak L. Bhatt, Peter B. Berger, Werner Hacke, P. Gabriel Steg, Marcus Flather, Michael A. Weber, Steven R. Steinhubl, Henry R. Black, S. Claiborne Johnston, Jean-Louis Mas, Liz Fabry-Ribaudo, Mark A. Creager, Thomas A. Pearson, and Gilles Montalescot
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Male ,medicine.medical_specialty ,Ticlopidine ,Heart disease ,Population ,Myocardial Infarction ,Placebo ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Myocardial infarction ,education ,Stroke ,Aged ,Peripheral Vascular Diseases ,Aspirin ,education.field_of_study ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Clopidogrel ,Surgery ,Treatment Outcome ,Cardiology ,Drug Therapy, Combination ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,Follow-Up Studies ,medicine.drug - Abstract
Objectives The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD). Background Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied. Methods We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD. Results A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004). Conclusions In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1 ; NCT00050817 )
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- 2007
34. The impact of anthropomorphic indices on clinical outcomes in patients with acute ST-elevation myocardial infarction
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Christopher B. Granger, Karen S. Pieper, Rajendra H. Mehta, Frans Van de Werf, Jyotsna Garg, Paul W. Armstrong, Harvey D. White, Eric J. Topol, and Robert M. Califf
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Male ,medicine.medical_specialty ,Myocardial Infarction ,Context (language use) ,Body Mass Index ,Internal medicine ,Humans ,Medicine ,Clinical significance ,Myocardial infarction ,Intensive care medicine ,Stroke ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Body surface area ,business.industry ,Cardiogenic shock ,Body Weight ,Middle Aged ,Prognosis ,medicine.disease ,Body Height ,Cardiology ,Regression Analysis ,Female ,Cardiology and Cardiovascular Medicine ,business ,Body mass index ,Obesity paradox - Abstract
Aims Multiple studies have focused on the relationship of body anthropometric measures with clinical events in ST-elevation myocardial infarction (STEMI) patients, highlighting the ‘obesity paradox’. However, the relative prognostic importance of these measures over other baseline variables is less known. Method and results We performed a retrospective analysis of 94 108 STEMI patients from seven clinical trials evaluating various reperfusion strategies to study the relationship and prognostic importance of height, weight, body mass index (BMI), and body surface area (BSA) with 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Main outcome measures of interest included 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Weight, BMI, and BSA were inversely and independently related to all clinical events. Despite being statistically significant ( P < 0.0001), the prognostic information contributed by weight beyond that conferred by baseline clinical factors was minimal (
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- 2007
35. In Unstable Angina or Non–ST-Segment Acute Coronary Syndrome, Should Patients With Multivessel Coronary Artery Disease Undergo Multivessel or Culprit-Only Stenting?
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Stephen G. Ellis, Juhana Karha, Inder M. Singh, Sorin J. Brener, Eric J. Topol, David J. Moliterno, Michael S. Lauer, Mehdi H. Shishehbor, Deepak L. Bhatt, and Derek P. Chew
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Male ,medicine.medical_specialty ,Acute coronary syndrome ,medicine.medical_treatment ,Myocardial Infarction ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Revascularization ,Angina ,Coronary artery disease ,Prosthesis Implantation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Myocardial Revascularization ,Humans ,cardiovascular diseases ,030212 general & internal medicine ,Myocardial infarction ,Angina, Unstable ,Aged ,business.industry ,Unstable angina ,Percutaneous coronary intervention ,Stent ,medicine.disease ,3. Good health ,Surgery ,Treatment Outcome ,Multivariate Analysis ,Cardiology ,Female ,Stents ,business ,Cardiology and Cardiovascular Medicine ,Follow-Up Studies - Abstract
Objectives We examined the safety and efficacy of nonculprit multivessel compared with culprit-only stenting in patients with multivessel disease presenting with unstable angina or non–ST-segment elevation myocardial infarction (non–ST-segment elevation acute coronary syndromes [NSTE-ACS]). Background In patients presenting with NSTE-ACS, multivessel coronary artery disease (CAD) is associated with adverse outcome. Methods Patients with multivessel CAD and NSTE-ACS that underwent percutaneous coronary intervention were included. The culprit lesion was defined by reviewing each patient’s angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. All patients had at least 2 vessels with ≥50% stenosis, and the angiographic severity of CAD was assessed using the Duke Prognostic Angiographic Score. Patients with coronary bypass grafts, chronic total occlusions, and those with uncertain culprit lesions were excluded. Our end point was the composite of death, myocardial infarction, or any target vessel revascularization. Results From January 1995 to June 2005, 1,240 patients with ACS and multivessel CAD underwent percutaneous coronary intervention with bare-metal stenting and met our study criteria. Of these, 479 underwent multivessel and 761 underwent culprit-only stenting. There were 442 events during a median follow-up of 2.3 years. Multivessel intervention was associated with lower death, myocardial infarction, or revascularization after both adjusting for baseline and angiographic characteristics (hazard ratio 0.80; 95% confidence interval 0.64 to 0.99; p = 0.04) and propensity matched analysis (hazard ratio 0.67; 95% confidence interval 0.51 to 0.88; p = 0.004). Conclusions In patients with multivessel CAD presenting with NSTE-ACS, multivessel intervention was significantly associated with a lower revascularization rate, which translated to a lower incidence of the composite end point compared with culprit-only stenting.
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- 2007
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36. Risk stratification for patients undergoing nonurgent percutaneous coronary intervention using N-terminal pro–B-type natriuretic peptide: A Clopidogrel for the Reduction of Events During Observation (CREDO) substudy
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Anjli Maroo, Danielle M. Brennan, Gary S. Francis, W.H. Wilson Tang, Eric J. Topol, Steven R. Steinhubl, Ellen McErlean, and Frederick Van Lente
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Male ,medicine.medical_specialty ,Ticlopidine ,medicine.medical_treatment ,Myocardial Infarction ,Coronary Disease ,Risk Assessment ,Angioplasty ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Humans ,Multicenter Studies as Topic ,cardiovascular diseases ,Myocardial infarction ,Angioplasty, Balloon, Coronary ,Stroke ,Aged ,Randomized Controlled Trials as Topic ,Ejection fraction ,business.industry ,Percutaneous coronary intervention ,Stroke Volume ,Middle Aged ,Prognosis ,medicine.disease ,Brain natriuretic peptide ,Clopidogrel ,Survival Analysis ,Peptide Fragments ,Multivariate Analysis ,Conventional PCI ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,hormones, hormone substitutes, and hormone antagonists ,circulatory and respiratory physiology ,medicine.drug - Abstract
The utility of N-terminal pro-BNP (NT-proBNP) measurement as a prognostic marker during nonurgent percutaneous coronary intervention (PCI) has been suggested in several studies. The comparative prognostic values between NT-proBNP levels and left ventricular ejection fraction (LVEF) in the nonurgent PCI setting are unclear.CREDO was a double blind, placebo-controlled, randomized trial comparing 2 clopidogrel regimens before and after nonurgent PCI. Baseline NT-proBNP levels and LVEF were measured in 1468 subjects using the Roche Elecsys proBNP assay (Roche Diagnostics, Indianapolis, IN), and the 1-year combined end point of death/myocardial infarction (MI)/stroke was analyzed according to NT-proBNP quartiles in impaired and preserved LVEF.In this patient cohort (mean age 61.6 +/- 10 years, 22% with LVEF50%), the median NT-proBNP level was 131 pg/mL. Increasing quartiles of NT-proBNP were associated with a higher rate of death, MI, and the combined end point (but not stroke) at 1 year, including those with LVEFor = 50% (P.001 for trend). This prognostic power for death and MI remained robust even when adjusted for other clinical or biochemical markers including cardiac troponin, creatinine clearance, and high-sensitive C-reactive protein (hazard ratio 1.249, P = .006). Despite its robust prognostic value, baseline NT-proBNP levels did not identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy.In patients undergoing a nonurgent PCI, NT-proBNP levels may provide important prognostic value for death and MI, even in patients with preserved cardiac function, However, NT-proBNP levels were unable to identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy.
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- 2007
37. Creatine kinase-MB elevation after coronary artery bypass grafting surgery in patients with non-ST-segment elevation acute coronary syndromes predict worse outcomes: results from four large clinical trials
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Maarten L. Simoons, Matthew T. Roe, Frans Van de Werf, Kenneth W. Mahaffey, Rakhi Kilaru, Eric J. Topol, Robert A. Harrington, John H. Alexander, Robert M. Califf, Neurosciences, and Cardiology
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Male ,medicine.medical_specialty ,Acute coronary syndrome ,Shock, Cardiogenic ,Infarction ,Coronary Disease ,Postoperative Hemorrhage ,Disease-Free Survival ,Angina ,Coronary artery bypass surgery ,Internal medicine ,Creatine Kinase, MB Form ,Humans ,Medicine ,Myocardial infarction ,Coronary Artery Bypass ,Aged ,Randomized Controlled Trials as Topic ,business.industry ,ST elevation ,Anticoagulants ,medicine.disease ,Surgery ,Stroke ,Treatment Outcome ,Blood pressure ,Heart failure ,Cardiology ,Regression Analysis ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery. Methods and results This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0–1, > 1–3, > 3–5, > 5–10, and > 10 × the upper limit of normal measured at the local lab ( P < 0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure. Conclusion CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.
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- 2007
38. Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine
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Eric J. Topol, Saif Anwaruddin, and Arman T. Askari
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Genetic Markers ,Male ,medicine.medical_specialty ,Acute coronary syndrome ,CD40 Ligand ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Risk Assessment ,Sensitivity and Specificity ,Smoking history ,03 medical and health sciences ,0302 clinical medicine ,Troponin T ,Internal medicine ,Diabetes mellitus ,medicine ,Myocardial Revascularization ,Humans ,Genetic Predisposition to Disease ,Angina, Unstable ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,medicine.disease ,Tailored Intervention ,Prognosis ,Molecular medicine ,3. Good health ,Electrocardiographic Finding ,P-Selectin ,C-Reactive Protein ,Cardiology ,Female ,Serum creatine phosphokinase ,business ,Cardiology and Cardiovascular Medicine - Abstract
Acute coronary syndromes represent a complex phenotype involving the interplay of many elements. The risk of developing an acute coronary syndrome and related complications has been defined by variables such as age, diabetes, smoking history, serum creatine phosphokinase, or electrocardiographic findings. However, in the past 5 years the wide-scale acceptance of a protein--troponin--has changed the diagnostic profile. With advances in molecular medicine, this protein is a segue to a panel of molecular assays that will improve screening and tailored intervention. We expound upon some of these factors and the potential they may carry in changing clinical medicine.
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- 2007
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39. Rationale and design of a home-based trial using wearable sensors to detect asymptomatic atrial fibrillation in a targeted population: The mHealth Screening To Prevent Strokes (mSToPS) trial
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Rajesh R. Mehta, Gines Diego Miralles, Dimitri Talantov, Joseph P. Honcz, Marissa M. Ballesteros, Gregory R. Steinberg, Eric J. Topol, Elise Felicione, Shawn Edmonds, Gail S. Ebner, Jill Waalen, C Carter, Percy Van Crocker, Steven R. Steinhubl, and Troy C. Sarich
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Male ,medicine.medical_specialty ,Telemedicine ,Population ,030204 cardiovascular system & hematology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Cost Savings ,Risk Factors ,Atrial Fibrillation ,Clinical endpoint ,Medicine ,Humans ,Mass Screening ,030212 general & internal medicine ,education ,mHealth ,Mass screening ,Aged ,education.field_of_study ,business.industry ,Medical record ,Incidence ,Middle Aged ,medicine.disease ,United States ,3. Good health ,Stroke ,Outcome and Process Assessment, Health Care ,Emergency medicine ,Asymptomatic Diseases ,Electrocardiography, Ambulatory ,Observational study ,Female ,Medical emergency ,business ,Cardiology and Cardiovascular Medicine - Abstract
Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF.
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- 2015
40. Prediction of Causal Candidate Genes in Coronary Artery Disease Loci
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Aldons J. Lusis, Mete Civelek, Eric J. Topol, Nilesh J. Samani, Ingrid Braenne, Johan Björkegren, Tom R. Webb, Jeanette Erdmann, Stephen E. Hamby, Hassan Foroughi Asl, Baiba Vilne, Xia Yang, Heribert Schunkert, Veronica Codoni, Benedikt Reiz, David-Alexandre Trégouët, Ke Hao, Antonio Fabio Di Narzo, Yuqi Zhao, Andrew D. Johnson, Eric E. Schadt, and Lingyao Zeng
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Genetics ,Male ,Candidate gene ,Genetic Variation ,Genome-wide association study ,Single-nucleotide polymorphism ,MiRNA binding ,Coronary Artery Disease ,Biology ,Polymorphism, Single Nucleotide ,Article ,MicroRNAs ,Genetic Loci ,Predictive Value of Tests ,Expression quantitative trait loci ,Genetic variation ,Humans ,Female ,Genetic Predisposition to Disease ,Cardiology and Cardiovascular Medicine ,Promoter Regions, Genetic ,Gene ,Genetic association ,Genome-Wide Association Study - Abstract
Objective— Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. Approach and Results— All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously. Conclusions— Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses.
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- 2015
41. The Influence of Peripheral Arterial Disease on Outcomes
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Maarten L. Simoons, Dean J. Kereiakes, James E. Tcheng, Tingfei Hu, Eric J. Topol, Mobeen A. Sheikh, Sorin J. Brener, Deepak L. Bhatt, A. Michael Lincoff, Jacqueline Saw, Steven R. Steinhubl, Robert A. Harrington, and David J. Moliterno
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medicine.medical_specialty ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Percutaneous coronary intervention ,medicine.disease ,Confidence interval ,Surgery ,Coronary artery disease ,Internal medicine ,Angioplasty ,Conventional PCI ,Medicine ,Myocardial infarction ,business ,Cardiology and Cardiovascular Medicine - Abstract
OBJECTIVES We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI). BACKGROUND A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes. METHODS We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events. RESULTS In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013). CONCLUSIONS The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.
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- 2006
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42. Identification of atherosclerosis-modifying genes: pathogenic insights and therapeutic potential
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Jonathan D. Smith and Eric J. Topol
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Genetic Linkage ,Quantitative Trait Loci ,Genomics ,Coronary Artery Disease ,Disease ,Quantitative trait locus ,Bioinformatics ,Genetic linkage ,Genetic variation ,Internal Medicine ,Animals ,Humans ,Medicine ,Genetic Predisposition to Disease ,Genetic Testing ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Chromosome Mapping ,Genetic Variation ,General Medicine ,Atherosclerosis ,Disease Models, Animal ,Polygene ,Identification (biology) ,Cardiology and Cardiovascular Medicine ,business - Abstract
Atherosclerosis is a common, complex trait, with genetic variation in many genes and the environment contributing to risk for this condition, which has multiple and highly variable phenotypic manifestations. Progress has been made in the identification of atherosclerosis-modifying genes in both human studies and through the use of animal models. In the future, it may be possible to administer a genetic test for variation in a handful of the most common atherosclerosis-modifier genes, and thus predict if a patient is likely to develop atherosclerosis and ischemic heart disease. These patients could then be treated aggressively to lower their low-density lipoprotein cholesterol levels and other risk factors, including counseling to make adjustments in their lifestyle. This review will summarize the methods and results thus far in the identification of atherosclerosis-modifier genes.
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- 2006
43. The prognostic value of the admission and predischarge electrocardiogram in acute coronary syndromes: The GUSTO-IIb ECG Core Laboratory experience
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Anatoly Langer, Galen S. Wagner, Shaun G. Goodman, Frans Van de Werf, Elena B. Sgarbossa, Mary Tan, Aiala Barr, Robert M. Califf, Yochai Birnbaum, Paul W. Armstrong, Christopher B. Granger, Eric J. Topol, Alejandro Barbagelata, and Yuling Fu
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Male ,medicine.medical_specialty ,Myocardial Infarction ,law.invention ,Electrocardiography ,Randomized controlled trial ,law ,Internal medicine ,Humans ,Medicine ,Angina, Unstable ,Myocardial infarction ,Case report form ,Aged ,Randomized Controlled Trials as Topic ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,ST elevation ,Mortality rate ,Retrospective cohort study ,Syndrome ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Hospitalization ,Clinical trial ,Multivariate Analysis ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Prior research suggests that patients may be entered into clinical trials with different electrocardiographic (ECG) findings than specified by study protocol criteria; the extent and impact of this variability in a large-scale trial have not been previously described. Methods We evaluated the relationship between case report form (CRF) categorization of the admission ECG and a Core Laboratory and subsequent outcome in a retrospective analysis of a trial of patients with acute ischemia and a broad spectrum of ECG changes (the GUSTO-IIb trial). Results In 11 037 patients with CRF information and an interpretable ECG, there was agreement in 89.1% of ST-elevation and 81.9% of non–ST-elevation cases. Among patients designated as having no ST elevation on the CRF, 1-year mortality rates were significantly higher in the subgroup of patients with Core Laboratory–determined ST elevation as compared with those where both the CRF and Core Laboratory classification were in agreement (8.8% vs 6.8%, P = .0093). Among patients designated as having ST elevation by the CRF, 1-year mortality rates were similar in both the subgroup of patients with and without Core Laboratory agreement (7.7% vs 8.2%, P = .72). Conclusions These findings have important implications for clinicians in routine practice because even a simple evaluation (presence or absence of ST elevation) on the admission ECG was often discordant and was associated with adverse clinical outcome.
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- 2006
44. Gene Variants of VAMP8 and HNRPUL1 Are Associated With Early-Onset Myocardial Infarction
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Charles F. Stiggins, John P. Kane, Eric J. Topol, Joel I. Bolonick, Joseph J. Catanese, Clive R. Pullinger, James J. Devlin, Judy Z. Louie, Bradford A. Young, Charles M. Rowland, May M. Luke, Mary J. Malloy, Lance A. Bare, Dov Shiffman, and Stephen G. Ellis
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Adult ,Male ,Oncology ,Pathology ,medicine.medical_specialty ,Myocardial Infarction ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Heterogeneous-Nuclear Ribonucleoproteins ,R-SNARE Proteins ,Platelet degranulation ,Polymorphism (computer science) ,Internal medicine ,Odds Ratio ,Humans ,Medicine ,Genetic Predisposition to Disease ,Myocardial infarction ,Age of Onset ,Risk factor ,Alleles ,business.industry ,Case-control study ,Genetic Variation ,Nuclear Proteins ,Odds ratio ,Middle Aged ,medicine.disease ,Case-Control Studies ,Female ,Age of onset ,Cardiology and Cardiovascular Medicine ,business ,Transcription Factors - Abstract
Objectives— Identify gene variants associated with early-onset myocardial infarction (MI). Methods and Results— We tested 11 647 single-nucleotide polymorphisms (SNPs) for association with early-onset MI in a case-control study (study 1 200 cases, 262 controls). To reduce the number of false positives among the 666 SNPs that were nominally associated with early-onset MI ( P P P =0.025; odds ratio [OR], 1.75; CI, 1.17 to 2.62) and an HNRPUL1 variant ( P =0.0043; OR, 1.92; CI, 1.28 to 2.86) were associated with early-onset MI (nominal P Conclusions— Variants in 2 genes were associated with early-onset MI: VAMP8, which is involved in platelet degranulation, and HNRPUL1, which encodes a ribonuclear protein. The identification of these variants could improve understanding of disease mechanisms and suggest novel drug targets.
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- 2006
45. Outcome of Multivessel Coronary Intervention in the Contemporary Percutaneous Revascularization Era
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Tingfei Hu, Rick R. McClure, Debabrata Mukherjee, David J. Moliterno, Marco Roffi, Mehdi H. Shishehbor, David J. Cohen, Eric J. Topol, and Gregg W. Stone
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Male ,medicine.medical_specialty ,Acute coronary syndrome ,Abciximab ,medicine.medical_treatment ,Coronary Disease ,Platelet Glycoprotein GPIIb-IIIa Complex ,Revascularization ,Blood Vessel Prosthesis Implantation ,Immunoglobulin Fab Fragments ,Coated Materials, Biocompatible ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Myocardial infarction ,Angioplasty, Balloon, Coronary ,business.industry ,Hazard ratio ,Antibodies, Monoclonal ,Percutaneous coronary intervention ,Tirofiban ,Middle Aged ,medicine.disease ,Clopidogrel ,Surgery ,Survival Rate ,Treatment Outcome ,Conventional PCI ,Cardiology ,Tyrosine ,Female ,Stents ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,Follow-Up Studies ,medicine.drug - Abstract
Clinical outcomes after multivessel versus single-vessel percutaneous coronary intervention (PCI) in the era of stents, glycoprotein IIb/IIIa inhibitors, and clopidogrel pretreatment have not been well studied. Thus, we compared outcomes from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET) for patients who underwent multivessel versus single-vessel PCI and separately considered the effect of acute coronary syndromes on the results. Composite clinical outcomes (death, myocardial infarction, and target vessel revascularization) were evaluated at 30 days and 6 months and mortality at 1 year. Safety analysis included in-patient major and minor bleeding. Despite similar baseline characteristics, patients who underwent multivessel PCI (n = 775) had significantly higher 30-day and 6-month composite event rates than did those who were treated in a single coronary artery territory (n = 3,969). This association remained significant at 30 days (hazard ratio 1.57, 95% confidence interval 1.06 to 2.33, p = 0.025) after using propensity matching to minimize confounding factors. The higher event rate was primarily due to an increase in periprocedural myocardial infarction. However, there were no significant differences in propensity-matched ischemic outcomes at 6 months and 1 year or in bleeding. In addition, in a propensity-matched analysis that included 810 patients with acute coronary syndrome, multivessel stenting resulted in numerically more ischemic events than did single-vessel stenting, although this did not reach statistical significance (hazard ratio 1.32, 95% confidence interval 0.85 to 2.05, p = 0.221). In conclusion, multivessel PCI was more often associated with periprocedural myocardial infarction than single-vessel intervention, although this did not translate into higher 1-year mortality. A randomized trial comparing multivessel PCI with staged or surgical revascularization is warranted.
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- 2006
46. Aspirin and clopidogrel resistance: an emerging clinical entity
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Eric J. Topol, Thomas H. Wang, and Deepak L. Bhatt
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Blood Platelets ,Male ,medicine.medical_specialty ,Ticlopidine ,Platelet Aggregation ,Drug Resistance ,Drug resistance ,Disease ,medicine ,Humans ,cardiovascular diseases ,Myocardial infarction ,Platelet activation ,Intensive care medicine ,Stroke ,Aged ,Aged, 80 and over ,Aspirin ,business.industry ,medicine.disease ,Clopidogrel ,Surgery ,Blood pressure ,Cardiovascular Diseases ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.
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- 2005
47. The genetics of heart attack
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Eric J. Topol
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Genetics ,Genetic Linkage ,Genome, Human ,business.industry ,Myocardial Infarction ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Education in Heart ,Genome ,Pedigree ,symbols.namesake ,Phenotype ,Genetic linkage ,Mendelian inheritance ,symbols ,Humans ,Medicine ,Genetic Predisposition to Disease ,Human genome ,Allele ,Cardiology and Cardiovascular Medicine ,business ,Gene ,Forecasting ,Genetic association - Abstract
Although it has been more than five years since the draft of the human genome was first announced,w1 only in recent months has there been substantial progress in the identification of genes that are implicated in susceptibility or cause of myocardial infarction (MI). There are many reasons for this lag, particularly related to the point that myocardial infarction is a “complex” trait. As opposed to “simple” Mendelian traits which are infrequent, deterministic and inherited in an autosomal dominant, recessive, or X-linked mode, complex traits are relatively common, probabilistic, and involve gene–gene and gene–environmental interactions. The technology and methodology to identify complex traits have rapidly evolved, and still can be considered to be in flux, with a progression from linkage studies using genome wide scanning to whole genome single nucleotide polymorphism (SNP) association studies. With this refinement in approaches, several genes are now implicated for susceptibility for myocardial infarction and one is already the subject of a dedicated randomised pharmacologic intervention trial for “personalised” medicine. This paper will review the progress in this burgeoning and important field, to provide the reader with a perspective on how genetic information will someday radically alter our approach and facilitate the prevention of heart attacks. With a human genome that consists of 3.1 billion base pairs, finding the particular alleles that are promoting or protecting an individual to have an MI appears, on the surface, to be especially daunting. But the number of genes that comprise the genome is just over 25 000 and although the function of many has yet to be determined, the chromosomal map of the location of these genes is virtually complete. With 3.1 billion nucleotide pairs (cytosine, adenine, guanine, thymine), fortunately the inter-subject variability is rather limited to only 10 million SNPs—or 0.3% of the base pairs that are …
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- 2005
48. The Genomic Basis of Myocardial Infarction
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Eric J. Topol
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medicine.medical_specialty ,Heart disease ,business.industry ,Heritability ,medicine.disease ,Internal medicine ,medicine ,Cardiology ,Trait ,SNP ,Myocardial infarction ,Myocardial disease ,Family history ,business ,Cardiology and Cardiovascular Medicine - Abstract
The evidence for heritability of myocardial infarction (MI) is striking, with a positive family history being one of the most important risk factors for this complex trait ([1][1]). The term “complex trait” implies both gene-environment and gene-gene interaction, along with the complexity of
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- 2005
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49. Long-Term Cost Effectiveness of Early and Sustained Dual Oral Antiplatelet Therapy With Clopidogrel Given for Up to One Year After Percutaneous Coronary Intervention
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Eric J. Topol, Elizabeth M. Mahoney, Sean C. Beinart, Steven R. Steinhubl, Emir Veledar, Sylvie Gabriel, Joseph Jackson, Olivier Bouin, William S. Weintraub, Roland Chen, Zefeng Zhang, Paul Kolm, and J. Jaime Caro
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Relative risk reduction ,medicine.medical_specialty ,Framingham Risk Score ,Cost effectiveness ,business.industry ,medicine.medical_treatment ,Percutaneous coronary intervention ,Clopidogrel ,Placebo ,Surgery ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Conventional PCI ,Medicine ,cardiovascular diseases ,business ,Cardiology and Cardiovascular Medicine ,health care economics and organizations ,medicine.drug - Abstract
Objectives This study sought to evaluate the long-term cost effectiveness of a clopidogrel loading strategy before percutaneous coronary intervention (PCI) followed by continued treatment for one year. Background The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized trial of 2,116 patients, showed the effectiveness of antiplatelet therapy with clopidogrel 300 mg before PCI and 75 mg daily for one year afterward compared with placebo load and placebo days 29 to 365 in reducing the combined risk of death, myocardial infarction, and stroke. All patients received clopidogrel on days 1 to 28 and aspirin on days 1 to 365. Methods All hospitalizations were assigned a diagnosis-related group. Associated costs were estimated three ways (including professional costs): 1) Medicare costs, 2) MEDSTAT costs, and 3) blend with Medicare for those age ≥65 years and MEDSTAT for those age Results The primary composite end point occurred in 89 (8.45%) clopidogrel patients and in 122 (11.48%) placebo patients (relative risk reduction [RRR] 26.9%; 95% confidence interval [CI] 3.9% to 44.4%). The number of life-years gained (LYG) with clopidogrel was 0.1526 (95% CI 0.0263 to 0.2838) using Framingham data and 0.1920 (95% CI 0.054 to 0.337) using Saskatchewan data. Average total costs were $664 higher for the clopidogrel arm (95% CI −$461 to $1,784). The incremental cost-effectiveness ratios (ICERs) based on Framingham data ranged from $3,685/LYG to $4,353/LYG, with over 97% of bootstrap-derived ICER estimates below $50,000/LYG. The ICERs based on Saskatchewan data were $2,929/LYG to $3,460/LYG, with over 98% of estimates below $50,000/LYG. Conclusions Platelet inhibition with clopidogrel loading before PCI followed by therapy for one year is highly cost effective.
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- 2005
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50. Periprocedural Cardiac Enzyme Elevation Predicts Adverse Outcomes
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Deepak L. Bhatt and Eric J. Topol
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medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Elevation ,Percutaneous coronary intervention ,Physiology (medical) ,Internal medicine ,medicine ,biology.protein ,Cardiology ,Creatine kinase ,Cardiology and Cardiovascular Medicine ,business - Published
- 2005
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