Eric J. Topol

Bio: Eric J. Topol is an academic researcher from Scripps Health. The author has contributed to research in topics: Myocardial infarction & Angioplasty. The author has an hindex of 193, co-authored 1373 publications receiving 151025 citations. Previous affiliations of Eric J. Topol include Loyola University Chicago & Cleveland Clinic.

Arthritis medicines and cardiovascular events house of coxibs

Abstract: PHYSICIANS, PATIENTS, AND THE GENERAL PUBLIC ARE confronted with an acute confusional state regarding the cardiovascular safety of medicines for arthritis. Since September 30, 2004, the day that rofecoxib was precipitously withdrawn, there has hardly been a day without significant news on the general topic of cyclooxygenase 2 (COX-2) inhibitors. On December 9, 2004, the US Food and Drug Administration (FDA) issued a black box warning for valdecoxib for life-threatening skin reactions and cardiovascular risk. Just over a week later, on December 17, 2004, the National Cancer Institute announced the premature cessation of a trial of celecoxib known as Adenoma Prevention with Celecoxib (APC) due to a significant excess of cardiovascular death, myocardial infarction (MI), and stroke. The principal cardiovascular event data for APC are summarized in the FIGURE. This was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer. A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo) (Figure). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib. However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials, lumiracoxib is the most selective. A trial of 18325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen. Importantly, there have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs. Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors. In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke. But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present. As my colleagues and I described in a 2001 review of the Celecoxib Long-term Arthritis Safety Study (CLASS), the MI rate was 1.6% in the celecoxib group (at a dosage of 400 mg twice per day) and 1.2% in the diclofenac or ibuprofen group for the 1739 patients taking low-dose aspirin. This numerical excess, albeit not statistically significant, was also found in the 6229 Figure. Event Rates of Cardiovascular Death, Myocardial Infarction, and Stroke in the Adenoma Prevention With Celecoxib (APC) Trial

Variations in patient management and outcomes for acute myocardial infarction in the United States and other countries. Results from the GUSTO trial. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

Abstract: OBJECTIVE To examine differences in outcomes and patient management between patients in the United States and outside the United States undergoing thrombolysis for acute myocardial infarction. DESIGN, SETTING, AND PATIENTS Patients in the United States (n = 23,105) and 14 other countries (n = 17,916) were randomized to receive streptokinase plus either subcutaneous or intravenous (IV) heparin, accelerated recombinant tissue-type plasminogen activator (rt-PA) plus IV heparin, or combined streptokinase and rt-PA plus IV heparin. OUTCOME MEASURES Differences in 30-day mortality and patient management were compared among treatments and between US and non-US patients. Treatment-by-country interactions were assessed by logistic regression analyses. Expected mortality of US and non-US patients was estimated using a predictive model and was compared with observed mortality. RESULTS Mortality reduction with accelerated rt-PA vs streptokinase was greater in the United States (1.2% absolute decrease vs 0.7% elsewhere), but the test for treatment-by-country interaction against streptokinase was not significant (P = .30). Benefits of accelerated rt-PA over combination therapy were observed in the United States, but not in other countries (P = .02). Despite differences in base-line characteristics and patient management, 30-day mortality was not significantly different: 6.8% in the United States vs 7.2% elsewhere (P = .09). After adjustment for baseline differences, observed vs predicted outcomes were slightly better in the United States (6.8% vs 7.0%) than elsewhere (7.2% vs 7.0%), indicating that enrollment in the United States was a marginally significant predictor of better survival (P = .047). CONCLUSIONS No significant evidence for a differentially greater benefit of accelerated rt-PA over streptokinase was found in US vs non-US patients. However, increased procedure and treatment use in the United States was associated with only a small decrease in short-term mortality. Long-term follow-up is required to clarify the relationship between survival and the more intensive US management approach.

Attainment and Maintenance of Platelet Inhibition Through Standard Dosing of Abciximab in Diabetic and Nondiabetic Patients Undergoing Percutaneous Coronary Intervention

Abstract: Background —Although the effectiveness of abciximab (c7E3 Fab; ReoPro) in large populations of patients undergoing a percutaneous coronary intervention has been consistently proved in clinical trials, it is unknown whether all patients achieve and maintain target inhibition during treatment. Diabetic patients in particular are a subgroup of patients with known underlying platelet abnormalities whose long-term response to abciximab has been shown to vary from that of nondiabetic patients. Methods and Results —Forty-nine diabetic and 51 nondiabetic patients who received adjunctive abciximab therapy during percutaneous coronary interventions were evaluated prospectively. The degree of platelet function inhibition was determined immediately after the abciximab bolus, 8 hours after the bolus (during the 12-hour abciximab infusion), and the next morning (13 to 26 hours after the bolus) with the use of a rapid platelet function assay (Accumetrics). After the abciximab bolus, platelet function was inhibited by 95±4% (mean±SD). By 8 hours, the average percent inhibition had decreased to 88±9%, with 13% of patients with Conclusions —Although the majority of patients achieve and maintain ≥80% platelet inhibition during the 12-hour infusion with standard-dose abciximab, there is substantial variability among patients. Diabetic status does not appear to influence this variability.

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication

Abstract: Context Little is known about lifetime prevalence or age of onset of DSM-IV disorders. Objective To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Main Outcome Measures Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders. Results Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups. Conclusions About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

Abstract: ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle–brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute Candesartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : CAndesartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease—EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy Candesartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries INVEST : INternational VErapamil SR/T Trandolapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : randomized controlled trials RF : risk factor ROADMAP : Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly: Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospective Diabetes Study VADT : Veterans' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization ### 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

An integrated encyclopedia of DNA elements in the human genome

Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.