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Eric J Topol

Publications and source records attributed to Eric J Topol.

At least 37 records · Page 2Linked to original sources
PubMed2006

Outcomes of patients with acute coronary syndromes who are treated with bivalirudin during percutaneous coronary intervention: an analysis from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial.

BACKGROUND: The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition is not inferior to heparin plus GPIIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. The extent to which this applies to patients with acute coronary syndromes (ACS) is unclear. Therefore, we sought to determine if bivalirudin has similar efficacy in ACS patients as compared with "stable" patients in the REPLACE-2 trial. METHODS: We analyzed the outcomes of ACS patients compared with stable patients and the outcomes of ACS patients according to whether or not they had received bivalirudin, including the economic costs. The trial enrolled 1351 ACS patients (myocardial infarction within 7 days or unstable angina within 48 hours, but not on ongoing GPIIb/IIIa or heparin therapy) and 4554 stable patients. RESULTS: Patients with ACS had a similar rate of death or myocardial infarction at 30 days compared to stable patients (7.2% vs 6.7%, P = .51) and death at 1 year (1.6% vs 2.2%, P = .169), but a higher rate of urgent coronary artery bypass graft at 30 days (1.0% vs 0.3%, P = .002). Patients with ACS treated with bivalirudin had a similar rate of 30-day death, myocardial infarction, or urgent revascularization compared with ACS patients treated with heparin and GPIIb/IIIa inhibitors (8.7% vs 8.0%, P = .616) and death at 1 year (1.5% vs 1.8%, P = .701), but a higher rate of revascularization at 6 months (12% vs 8.4%, P = .04). Patients with ACS treated with bivalirudin had less major bleeding than ACS patients treated with heparin and GPIIb/IIIa inhibitors, although this was not statistically significant (2.7% vs 4.5%, P = .07). Mean 30-day costs for patients with ACS were dollar 12415 for those treated with bivalirudin and dollar 12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022). CONCLUSION: Bivalirudin with provisional GPIIb/IIIa inhibitor use in low-risk ACS patients (not receiving preprocedural GPIIb/IIIa blockade) appears to provide similar protection against death and myocardial infarction as the combination of heparin and GPIIb/IIIa inhibitors, although we observed a higher rate of revascularization at 6 months.

Aged↗
PubMed2006

Coronary artery imaging with multidetector computed tomography: a call for an evidence-based, multidisciplinary approach.

Modern multidetector computed tomography systems are capable of a comprehensive assessment of the cardiovascular system, including noninvasive assessment of coronary anatomy. Multidetector computed tomography is expected to advance the role of noninvasive imaging for coronary artery disease, but clinical experience is still limited. Clinical guidelines are necessary to standardize scanner technology and appropriate clinical applications for coronary computed tomographic angiography. Further evaluation of this evolving technology will benefit from cooperation between different medical specialties, imaging scientists, and manufacturers of multidetector computed tomography systems, supporting multidisciplinary teams focused on the diagnosis and treatment of early and advanced stages of coronary artery disease. This cooperation will provide the necessary education, training, and guidelines for physicians and technologists assuring standard of care for their patients.

Coronary Angiography↗
PubMed2006

The prognostic value of the admission and predischarge electrocardiogram in acute coronary syndromes: the GUSTO-IIb ECG Core Laboratory experience.

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.

Aged↗
PubMed2006

Ischemic and bleeding outcomes in women treated with bivalirudin during percutaneous coronary intervention: a subgroup analysis of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial.

BACKGROUND: Outcomes in women undergoing percutaneous coronary intervention (PCI) in the contemporary era are poorly defined. The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GpIIb-IIIa) blockade is noninferior to heparin with planned GpIIb-IIIa blockade during PCI, with regard to ischemic and bleeding end points. OBJECTIVES: The aim of this study was to define sex-based clinical ischemic and bleeding outcomes from the REPLACE-2 trial. METHODS: A retrospective sex-based subgroup analysis of the REPLACE-2 trial comparing clinical ischemic and inhospital bleeding end points was conducted. RESULTS: Compared with men in REPLACE-2, women were older, had more diabetes, congestive heart failure and hypertension, and less prior revascularization and myocardial infarction. Female sex was a univariate predictor of death and bleeding complications. Among women treated with either bivalirudin or heparin, there was no significant difference in the individual or composite ischemic end points of death, myocardial infarction, or urgent revascularization at 30 days or 6 months. Protocol-defined major bleeding, minor bleeding, and access site bleeding were less frequent with bivalirudin compared with heparin. Multivariable modeling found no significant interactions between sexes, with the composite ischemic end point, major bleeding, or 1-year mortality. CONCLUSIONS: Women remain at higher risk for poorer outcomes with contemporary PCI, likely because of comorbidities. Bivalirudin with provisional GpIIb-IIIa confers similar protection against ischemic end points compared with heparin and planned GpIIb-IIIa blockade and significantly reduces the inherent bleeding risk of women undergoing contemporary PCI.

Aged↗
PubMed2006

Granulocyte colony stimulating factor in patients with large acute myocardial infarction: results of a pilot dose-escalation randomized trial.

BACKGROUND: Preclinical studies suggest that administration of cytokines to mobilize stem cells and alter the postinfarction inflammatory cardiac milieu may enhance left ventricular function and survival. METHODS: Eighteen patients were randomized in a 2:1 double-blind fashion to granulocyte colony stimulating factor (G-CSF) (at 5 escalating to 10 microg/kg per day subcutaneously for 5 days [6 patients in each group]) or matching placebo. Principal safety and efficacy end points were rupture-free survival and recovery of left ventricular function, respectively. Mobilization into the systemic circulation of precursor CD34+ and CD117+ stem cells at 30 days were also assessed. RESULTS: Baseline characteristics of the 3 groups were well matched. Mean +/- SD creatine kinase-MB maximum was 349 (169) IU. Follow-up averaged 30 +/- 6, 21 +/- 11, and 11 +/- 6 months in the 3 groups, respectively. Precursor cell mobilization increased by a factor of 5 to 7 in the G-CSF-treated patients. There were no deaths or myocardial ruptures leading to tamponade through 30 days. Baseline and 30-day left ventricular ejection fraction in the placebo, 5-microg, and 10-microg dose groups were 33.7% (1.6) and 41.7% (8.2), 36.8% (7.5) and 41.3% (10.3), and 33.5% (4.8) and 38.7% (7.3), respectively (P = NS for all between-group comparisons). No differences between the G-CSF and placebo groups were noted in any other measure of left ventricular systolic or diastolic function 30 days after infarction. CONCLUSIONS: Despite demonstrated mobilization of precursor stem cells in a timely fashion, in this small, pilot-scale randomized trial involving patients with large myocardial infarction, we were unable to demonstrate improvement in left ventricular function at 30 days.

Aged↗
PubMed2006

Differences in the clinical features and outcomes in African Americans and whites with myocardial infarction.

PURPOSE: Less is known about the differences in clinical and angiographic features and the outcomes of African Americans with ST-elevation myocardial infarction compared with whites with ST-elevation myocardial infarction. Accordingly, the current study examines the relationship of African American race to patient-related clinical factors, angiographic findings, and clinical events. METHODS: We evaluated data from 32419 patients with ST-elevation myocardial infarction who received fibrinolysis. The primary outcomes of interest were 30-day and 5-year mortality. RESULTS: African Americans comprised 5.1% of the study population (1664/32419). Compared with white patients, black patients were younger, were more likely female, had a higher prevalence of coronary risk factors, and were more likely to have higher presenting heart rate, blood pressure, and Killip Class. Coronary angiography rates were similar in the two groups, but blacks were less likely to undergo coronary revascularization. The patency of the infarct-related artery after thrombolysis or mechanical reperfusion was higher in blacks, who were more likely to have no significant coronary artery disease and less likely to have disease in two or more vessels. In-hospital stroke (adjusted odds ratio 1.75, 95% confidence interval [CI] 1.19-2.59) and major bleeding (adjusted odds ratio 1.32, 95% CI 1.13-1.55) were higher among African Americans. Although no differences were observed in the 30-day mortality between the two groups, African Americans who survived to 30 days had higher 5-year mortality than whites (17% vs 12.5%, adjusted hazard ratio 1.63, 95% CI 1.41-1.90). CONCLUSIONS: Although 30-day survival was similar between African Americans and whites with ST-elevation myocardial infarction, in-hospital stroke and bleeding and 5-year mortality among 30-day survivors were significantly higher among blacks despite their younger age.

Black or African American↗
PubMed2006

Meta-analysis: cardiovascular events associated with nonsteroidal anti-inflammatory drugs.

PURPOSE: We performed a meta-analysis of randomized controlled trials to assess the effect of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) on cardiovascular events in trials of joint disease and Alzheimer's disease. METHODS: We performed comprehensive searches of MEDLINE, EMBASE, CINAHL and Cochrane databases from 1966 to July 2005, and references of identified articles and reviews. We included randomized placebo-controlled trials of at least 6 weeks duration that evaluated nonselective NSAIDs in trials of joint disease or Alzheimer's disease, and reported at least one cardiovascular event or death. The outcome measured was the composite of death, myocardial infarction or cerebrovascular accident, with the pooled results reported as odds ratios (OR). Subgroup analyses evaluated the difference between trials of joint disease and Alzheimer's disease, and for naproxen and non-naproxen NSAIDs. RESULTS: Pooled data from 13 trials with 7718 participants showed that nonselective NSAIDs had no significant effect on cardiovascular events (OR 1.3; 95% confidence interval [CI], 0.8 to 2.1). No significant effect was seen for joint disease trials (OR 0.6; 95% CI, 0.2 to 1.7) or Alzheimer disease trials (OR 1.6; 95% CI, 0.9 to 2.7). There was no significant difference in results for naproxen and non-naproxen NSAIDs. CONCLUSION: Nonselective NSAIDs have no significant effect on cardiovascular events or death in trials of joint disease and Alzheimer disease, but a small adverse effect could not be excluded. An indication for risk was present in trials of Alzheimer's disease but not in joint disease trials. There was no significant adverse or cardioprotective effect of naproxen.

Alzheimer Disease↗
PubMed2006

The genetics of health.

Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health.

Biological Evolution↗
PubMed2006

Identification of atherosclerosis-modifying genes: pathogenic insights and therapeutic potential.

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.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor gamma down-regulates receptor for advanced glycation end products and inhibits smooth muscle cell proliferation in a diabetic and nondiabetic rat carotid artery injury model.

Diabetes is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE binding through the administration of soluble RAGE (sRAGE) has been shown to decrease neointimal hyperplasia. Peroxisome proliferator-activated receptor gamma (PPARgamma), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPARgamma agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPARgamma agonist rosiglitazone significantly down-regulated RAGE expression and inhibited SMC proliferation in response to the RAGE agonist S100/calgranulins. In vivo studies showed that rosiglitazone decreased RAGE expression and SMC proliferation at 7 days following carotid arterial injury in both diabetic and nondiabetic rats. At 21 days following injury, neointimal formation was significantly decreased in both diabetic and nondiabetic animals that received rosiglitazone. To determine whether inhibition of neointimal formation by PPARgamma activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPARgamma activator, and sRAGE + PPARgamma activator. Consistent with PPARgamma working through its effects on RAGE, we found that the addition of PPARgamma activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPARgamma agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPARgamma activation inhibits neointimal formation in response to arterial injury.

Animals↗
PubMed2005

Aspirin and clopidogrel resistance: an emerging clinical entity.

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.

Aged↗
PubMed2005

A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction.

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

Black or African American↗
PubMed2005

Predictors of revascularization method and long-term outcome of percutaneous coronary intervention or repeat coronary bypass surgery in patients with multivessel coronary disease and previous coronary bypass surgery.

AIMS: The optimal revascularization strategy in patients with symptomatic multivessel coronary artery disease (CAD) and previous coronary artery bypass grafting (CABG) remains unknown. METHODS AND RESULTS: We evaluated all patients with previous CABG undergoing isolated, non-emergency multivessel revascularization between 1 January 1995 and 31 December 2000. The analysis concentrated on the independent predictors of the revascularization method, as well as on long-term mortality and its predictors, after calculating a propensity score for the method of revascularization. There were 2191 patients (1487 with reoperation and 704 with percutaneous coronary intervention, PCI) in the study. The most important factors in choosing reoperation were presence of more diseased or occluded grafts, previous infarction, lower ejection fraction (EF), longer interval from first CABG, and more total occlusions of native arteries, as well as absence of a patent mammary graft. The distribution of the propensity score was skewed towards the two extremes. At 5 years, the unadjusted cumulative survival was 79.5% for CABG and 75.3% for PCI, P=0.008. After adjustment for the propensity score for PCI vs. CABG, PCI was associated with a hazard ratio of 1.47 (0.94-2.28), P=0.09. The most powerful predictors of mortality were higher age and lower EF. CONCLUSION: The choice of the revascularization method in patients with previous CABG is dictated mostly by anatomical considerations and less by clinical characteristics. In contrast, clinical characteristics predominantly affect long-term outcome, whereas the method of revascularization has a limited effect. A randomized clinical trial addressing this important segment of the population with ischaemic heart disease is warranted.

Age Distribution↗
PubMed2005

Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction.

BACKGROUND: Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common alpha-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. METHODS AND RESULTS: In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (P<0.001) less LV dilation and a 52.2% (P<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. CONCLUSIONS: The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.

Acrolein↗
PubMed2005

Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.

CONTEXT: Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that modulate gene expression. Therapeutic agents targeting 2 distinct families of PPARs (alpha and gamma) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by a US Food and Drug Administration (FDA) advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes. OBJECTIVE: To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with controls. DESIGN, SETTING, AND PARTICIPANTS: The source material for this analysis consisted of documents about phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting. All reviewed trials were prospective, randomized, double-blind, multicenter studies enrolling patients with type 2 diabetes and hemoglobin A(1c) levels between 7% and 10%. Patients (N = 3725) were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide in trials ranging from 24 to 104 weeks. MAIN OUTCOME MEASURES: The primary outcome was the incidence of death, nonfatal MI, or nonfatal stroke. A more comprehensive composite outcome included these events plus the incidence of CHF and TIA. RESULTS: In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36-5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97-56.8; P = .053). CONCLUSIONS: Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF. This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.

Cardiovascular Diseases↗
PubMed2005

Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention.

AIMS: We evaluated the effect of direct thrombin inhibitors (DTIs) in patients undergoing early percutaneous coronary intervention (PCI), using the DTI Trialists' Collaboration database of 35,970 patients from 11 randomized trials of DTIs vs. heparin. METHODS AND RESULTS: We performed a Cox proportional hazards regression analysis with PCI as a time-dependent covariate to assess the independent impact of DTIs according to the performance of early PCI. PCI was performed in 7049 patients in the first 72 h after randomization. In trials in which PCI was not planned, DTIs were associated with a 10% relative risk reduction in death or myocardial infarction at 30 days (HR=0.90, 95% CI: 0.84-0.97). This benefit was found to be greater in patients undergoing early PCI (HR=0.66, 95% CI: 0.48-0.91) than those undergoing non-early PCI (HR=0.94, 95% CI: 0.86-1.03). After adjustment for baseline characteristics and propensity to undergo PCI, the risk of death or myocardial infarction remained lower with DTI (HR=0.62, 95% CI: 0.44-0.89). CONCLUSION: After adjustment for baseline differences and propensity to undergo early PCI, DTIs appeared to be more effective than heparin in reducing death or re-infarction among patients undergoing early PCI.

Acute Disease↗