Showing papers by "Eric J. Topol published in 2007"

Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial.

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 <0.05). Mortality rates were higher in patients with than without major hemorrhage at 30 days (5.1% vs 0.2%), 6 months (6.7% vs 1.0%), and 1 year (8.7% vs 1.9%; p <0.001 for all). Furthermore, major hemorrhage was an independent predictor of 1-year mortality (odds ratio 2.66, 95% confidence interval 1.44 to 4.92, p = 0.002). In conclusion, in patients undergoing elective or urgent PCI, major hemorrhage was an independent predictor of 1-year mortality. A number of baseline and periprocedural factors independently predicted major hemorrhage, including treatment with heparin plus GPI.

A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease

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.

The genomics gold rush.

Abstract: IN RECENT WEEKS THERE HAS BEEN AN UNPRECEDENTED chain of discoveries in the genomics of complex traits. The studies identified DNA markers associated with susceptibility to many of the most common diseases, ranging from acute lymphoblastic leukemia, the most important pediatric cancer, to obesity, type 2 diabetes mellitus, and coronary heart disease, which collectively affect nearly a billion individuals worldwide. The breakneck pace of discovery will be continuing in the months ahead, with anticipated findings for many cancers, cardiovascular diseases, and neurological diseases. In aggregate, these studies have the potential to radically change medicine. This Commentary is intended to provide perspective for the medical community, to understand the limitations of the work that has thus far been completed, and to outline the challenges that lie ahead.

An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial

Abstract: Aims To examine the unanticipated, excess mortality observed in patients randomized to clopidogrel and aspirin vs. aspirin alone in the prespecified ‘asymptomatic’ subgroup of CHARISMA, we investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular (CV) events in a primary prevention population. Methods and results Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior CV event, leaving 2289 patients to represent the primary prevention cohort. This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding. A multivariate analysis analysed predictors of CV death in this group. No post mortem data were available. Compared with aspirin alone, a significant increase in CV death (P ¼ 0.01) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population. Within the primary prevention cohort, this excess CV death was not significant (P ¼ 0.07). Multivariate analysis of the primary prevention group showed a trend towards excess CV death (P ¼ 0.054; HR 1.72; CI 0.99–2.97) with dual-antiplatelet therapy (aspirin plus clopidogrel). Other independent predictors of CV death included increasing age, hypertension, atrial fibrillation, and a history of heart failure. There was a non-significant increase in moderate or severe bleeding (P ¼ 0.218) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate. Conclusion These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation.

Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V

Abstract: Background: Women with acute myocardial infarction are more likely than men to experience reinfarction, bleeding, or death. This difference has been hypothesized to be due to older age, treatment d ...

Thrombospondins, Their Polymorphisms, and Cardiovascular Disease

Abstract: The thrombospondins are a 5-member gene family that mediate cell-cell and cell-matrix interactions. The thrombospondins are either trimers or pentamers, and their functions depend on their abilities to interact with numerous extracellular ligands and cell surface receptors through the multiple domains that compose each subunit. Recent genetic studies have indicated associations of particular single nucleotide polymorphisms in 3 of the 5 thrombospondins with cardiovascular disease. This observation has stimulated efforts to understand how the thrombospondins influence cardiovascular pathology, to dissect how the individual polymorphisms alter the structure and function of the parent thrombospondin molecules, and to replicate the genetic data in different patient populations. This review seeks to summarize current information that has emerged on each of these fronts.

The resequencing imperative

Abstract: The possibility of deep population resequencing of genes has generated excitement over its potentially promising role in understanding complex human traits. A new study has now demonstrated the utility of this approach, reporting the resequencing of a lipid metabolism gene in a large multiethnic population and definitively showing that coding variants in the gene are associated with plasma triglyceride levels.

The impact of anthropomorphic indices on clinical outcomes in patients with acute ST-elevation myocardial infarction.

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 (<1% of total prognostic information) making it of limited clinical relevance for predicting 30-day death and cardiogenic shock. In contrast, weight accounted for 8.4% and 4.3% of the prognostic information in the logistic regression models for major bleeding and for stroke. BMI or BSA added little incremental value over simple measure of weight. Conclusion Although statistically significantly related to most outcomes in patients with STEMI including death and shock, body weight provided clinically relevant prognostic information only for the risk of major bleeding and of stroke. Furthermore, BMI or BSA contributed little incremental prognostic information beyond that provided by weight alone. Thus, the existing large body of information concerning the strong prognostic importance of anthropometric measures with outcomes after STEMI should be interpreted in the context of other more important risk factors.

Mortality, kidney disease and cardiac procedures following acute coronary syndrome

Abstract: Background. Cardiac interventions are underutilized in patients with chronic kidney disease (CKD) following acute coronary syndrome (ACS) partly due to nephrotoxicity concerns. Methods. We analyzed outcomes of 4631 subjects with ACS enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial, including time to death, time to reduced renal function (50% reduction in estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD)) and percent change in eGFR from baseline. Results. Subjects with a lower baseline eGFR were more likely to be older, female and have diabetes, hypertension, congestive heart failure or peripheral vascular disease (all P < 0.0001); they were less likely to be taking aspirin ≥162 mg or to have undergone a percutaneous coronary intervention (PCI) prior to enrollment (P < 0.0001). As eGFR declined, the proportion of subjects experiencing death versus reduced eGFR or ESRD qualitatively increased. In adjusted analyses, every 10 ml/min/1.73 m 2 decrease in eGFR ≤ 90 was associated with a 15% increased hazard of death (HR 1.15, P = 0.01). In adjusted analyses of predictors of percent change in eGFR, catheterization (cath) with or without PCI compared to medical therapy during follow-up was not associated with significant differences in long-term eGFR (P = 0.09). Conclusions. Among CKD subjects in this study, the risk of death greatly outweighed the risk of reduced eGFR or development of ESRD following ACS and the occurrence of cath ± PCI was not associated with significant differences in long-term renal function. The presence of CKD should not preclude potentially beneficial interventions and research should focus on reducing the high cardiovascular burden in this population.

Impact of sex, metabolic syndrome, and diabetes mellitus on cardiovascular events

Abstract: Although cardiovascular events occur more frequently among patients with metabolic syndrome (MS) or diabetes mellitus (DM), the impact of gender is unclear. We aimed to determine the relation of MS and DM on cardiovascular events between men and women. The National Health Survey of 1992 provided information on outcomes for 3,414 Singaporeans aged 18 to 69 years without cardiovascular diseases. Definition of MS was based on the National Cholesterol Education Program criteria. Cardiovascular events included hospital admissions for coronary heart disease, stroke, and cardiovascular mortality. The proportion of subjects with MS was 12.4%. After 10 years, the annual cardiovascular event rates (per 1,000 person-years) for men without DM were 3.0 and 15.9 among subjects without and with MS, respectively, and the respective rates for men with DM were 22.5 and 21.4. The corresponding rates for women were 0.9, 3.7, 5.3, and 21.5, respectively. Among nondiabetic subjects, cardiovascular events occurred more frequently among men than women among subjects with MS (adjusted hazard ratios [HRs] 4.71, 95% confidence interval [CI] 1.56 to 14.2) and those without MS (HR 3.35, 95% CI 1.78 to 6.31). Among patients with DM, cardiovascular events occurred more commonly among men than women without MS (HR 6.04, 95% CI 1.43 to 25.6). Rates for cardiovascular events were comparable between men and women with DM and MS (HR 0.98, 95% CI 0.48 to 1.99). In conclusion, the adverse impact of MS or DM was greater among men, and the presence of both conditions increases the risk substantially for cardiovascular events among women.

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

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.

Prolonged dual antiplatelet therapy after percutaneous coronary intervention reduces ischemic events without affecting the need for repeat revascularization : Insights from the CREDO trial

Abstract: Background. Dual antiplatelet therapy reduces ischemic events after percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes. The relationship between target vessel revascularization (TVR) and ischemic events in patients treated with aspirin and clopidogrel or aspirin alone from 1 month to 1 year after PCI has not been studied. Methods. Patients enrolled in the CREDO trial were treated with aspirin and clopidogrel or aspirin and placebo for up to 1 year. We compared the rates of TVR and ischemic events (cardiac death, myocardial infarction or stroke) in the two groups, and modeled the effect of clopidogrel treatment on ischemic events after adjusting for relevant parameters. Results. One month after PCI, 1,955 patients have remained asymptomatic. By 1 year, ischemic events occurred in 5.3% of placebo- and 3.1% of clopidogrel-treated patients; p = 0.02. The rate of TVR was 11.9% and 12.2%, respectively; p = 0.82. Only 7 patients (clopidogrel: 3 and placebo: 4) experienced TVR within 7 days of an ischemic event. After adjustment, long-term dual antiplatelet therapy was associated with a 48% reduction in events; p = 0.01. Patients who experienced TVR had a significantly higher rate of ischemic events than those without TVR, regardless of treatment assignment: 12.3% vs. 3.1%, respectively; p < 0.001. Conclusion. Thus, after successful PCI, prolonged dual antiplatelet therapy reduces ischemic events without affecting TVR. Overall, patients with TVR experienced an ischemic event much more often that was not related to the PCI vessel. This suggests that the benefit of antiplatelet therapy after coronary revascularization is indexed to the patient's underlying atherothrombotic process, rather than the artery that underwent intervention.

Risk for Cardiovascular Outcomes among Subjects with Atherosclerotic Cardiovascular Disease and Greater-than-Normal Estimated Glomerular Filtration Rate

Abstract: Background and objectives: Estimating equations for calculating glomerular filtration rate (eGFR) occasionally identify patients with elevated eGFR, yet the prognostic significance remains to be determined. This study sought to define the association of an elevated eGFR on the risk for death and cardiovascular outcomes among subjects with atherosclerotic cardiovascular disease. Design, setting, participants, & measurements: Data from 8941 subjects who had a history of atherosclerotic vascular disease and were enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial were analyzed. Time to the composite end point of death, congestive heart failure, myocardial infarction, or stroke was modeled using Cox proportion hazards regression. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease and Cockcroft-Gault formulas. Results: Compared with subjects with eGFR of 100 to 125 ml/min per 1.73 m 2 , subjects with eGFR >125 (n 462) were younger, female, and nonwhite. In addition, subjects with an elevated eGFR were more likely to have diabetes and congestive heart failure. In adjusted analyses, every 10-ml/min per 1.73 m 2 decrease in eGFR 100 was associated with a 9% increased hazard for the composite end point. Conclusions: In individuals with a history of vascular disease, the relationship between eGFR and cardiovascular outcomes may be parabolic, with increased risk among patients with both reduced and elevated eGFR. Clin J Am Soc Nephrol 2: 1215–1222, 2007. doi: 10.2215/CJN.00930207

CHAPTER 62 – αIIbβ3 (GPIIb-IIIa) Antagonists

Abstract: The discovery of coronary thrombosis as the underlying cause of myocardial infarction (MI) was first reported by Parkinson and Bedford in 1928.1 However, it was not for another 50 years that the broad acceptance of this notion led to the treatment of patients with acute MI and unstable angina by directly targeting the thrombotic process. With better understanding of the molecular mechanisms of thrombosis, therapeutic targets to inhibit this process have emerged, including thrombin inhibitors, fibrinolytics, and platelet antagonists (Fig. 62-1). Among the latter class of agents, aspirin was the first to show significant clinical benefit in treatment of patients with acute MI (see Chapter 60). A remarkable 19% reduction in mortality was observed with aspirin in the International Study of Infarct Survival-2 trial.2 This significant benefit from aspirin, a relatively weak antiplatelet agent, provided a clear impetus to target platelets with more potent and specific drugs to treat patients with coronary syndromes. Advancement in the basic understanding of platelet aggregation provided the field with such targets. Although many agonists are able to activate platelets and induce their aggregation, the final common pathway underlying platelet aggregation is binding of an adhesive protein set, primarily fibrinogen or von Willebrand factor (VWF), to the platelet surface.3-5 The demonstration that integrin αIIbβ3 (glycoprotein [GP] IIb-IIIa) served as the fibrinogen receptor on the platelet surface and blockade of this interaction inhibited platelet aggregation6 defined this specific membrane protein as a target of antithrombotic therapy. However, complete abrogation of platelet aggregation, although attractive in the treatment of the thrombotic state, raised major safety concerns. Would such blockade lead to major, and ultimately unacceptable, bleeding complications? The reports that natural mutations in αIIbβ3 in patients with Glanzmann thrombasthenia7-9 (see Chapter 57) lead to only sporadic and minor bleeding tendencies and rarely to major internal bleeding provided some comfort, and efforts proceeded throughout the pharmaceutical and biotechnology sectors to develop potent, specific, and safe αIIbβ3 antagonists. These efforts led to development of the first clinically acceptable antagonist of αIIbβ3, abciximab (ReoPro), for clinical use.10 After extensive animal studies,11-14 including in primates,15 to establish efficacy and safety, the clinical benefit of abciximab was first tested in preventing thrombotic complications in patients undergoing percutaneous coronary intervention (PCI) in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) trial.16 In 1994, the results of the EPIC trial demonstrated the efficacy of αIIbβ3 blockade in reducing thrombotic complications. Within the next 5 years, more than 40,000 patients were randomized in studies, which demonstrated the clinical efficacy, and ultimately U.S. Food and Drug Administration (FDA) approval, of three intravenous αIIbβ3 antagonists in the reduction of thrombotic complications in patients undergoing PCI or in the medical management of patients with acute coronary syndromes (ACS).

Is there a genetic basis for acute coronary syndrome

Abstract: DESIGN This study combined a literature review with case–control validation. Using a combination of the search terms “myocardial infarction”, “coronary heart disease”, “coronary artery disease”, “atherosclerosis”, “genetic”, “gene”, and “polymorphism”, the authors searched the PubMed database for studies reporting statistically significant (P <0.05) associations between genetic variants and ACS or coronary atherosclerosis. Only studies published before 10 March 2005 were included. Consecutive patients with ACS (myocardial infarction [MI] or unstable angina) who presented as inpatients at the Mid-American Heart Institute or the Truman Medical Center, Kansas City, MO, USA were selected as cases. Controls were enrolled from the outpatient clinic of Saint Luke’s Hospital, Kansas City, and were excluded if they had previous ACS, CABG surgery, or percutaneous coronary intervention. All selected cases and Is there a genetic basis for acute coronary syndrome?

The Challenge for Stem Cell Therapy

Abstract: Ischemic heart disease remains the leading cause of chronic heart failure (CHF). The prevalence of CHF has increased dramatically over the last three decades, with more than 10% of the US population over 65 years of age now carrying the diagnosis. Based on current trends, heart failure is predicted to increase to more than 6 million people in the United States by the year 2030 (1). One cause of the increased prevalence of CHF is our success in the treatment of acute myocardial infarction (MI). Mortality rates of transmural MI in clinical trials has decreased from more than 10% in clinical trials in the late 1980s to less than 5% in recent primary percutaneous coronary intervention trials. These advances, combined with the compelling data that cholesterol-lowering therapy significantly decreases the risk of MI, would lead one to hypothesize that the incidence of CHF should be on the decline. However, we are a population of increasing risk, given the increasing incidence of diabetes, hypertension, obesity, and sedentary lifestyle. Thus, although great advances have been made in the treatment of cardiovascular disease, there is a great need for stem cell therapy to prevent and treat CHF.

CHAPTER 65 – Experimental Antiplatelet Therapy

Abstract: The platelet plays a central role in the pathophysiology of atherosclerosis through its effects on inflammation.1,2 In addition to modulating inflammation, the platelet is directly involved in thrombosis and subsequent acute vascular events (including acute coronary syndromes, ischemic strokes, and symptomatic peripheral arterial disease).3 Together, this spectrum of disease is termed atherothrombosis, and the goal of antiplatelet therapy is to reduce the development and clinical expression of atherothrombotic disease.

Local Gene and Cell Delivery Devices

Abstract: The concept of locally delivering therapy for the prevention of neointimal hyperplasia after arterial injury has received robust validation by the dramatic reduction in restenosis reported with the use of drug-eluting stents (DES) (1,2). Interest in local delivery initially arose as a result of early studies in which therapeutic concentrations of systemically delivered antirestenotic therapies could only be achieved at the expense of unacceptable toxicity profiles. Locally, delivered therapies offer the distinct advantages of lower systemic side effects and toxicities, and enable a higher concentration of the therapeutic agent to be delivered where needed the most, at the site of intimal injury (3, 4, 5, 6, 7, 8, 9, 10, 11). There has been considerable research over the last decade examining the possibility of genetic modulation for the prevention and treatment of restenosis. Local therapy is especially suited for delivering genetic material as systemic distribution can result in the permanent transfection of distant cells with long-term adverse consequences.