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Biomedical subjects

Eric J Topol

Publications and source records attributed to Eric J Topol.

At least 73 records · Page 4Linked to original sources
PubMed2005

Effectiveness and safety of bivalirudin during percutaneous coronary intervention in a single medical center.

A recent large-scale, randomized trial demonstrated the noninferiority of a strategy of bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. There is a paucity of outcome data with bivalirudin use in the setting of real-world experience. We evaluated 6,996 patients who underwent percutaneous coronary intervention between January 2001 and December 2004 to compare early and late outcomes with a bivalirudin-based antithrombotic regimen with those with a heparin-based regimen. Propensity adjustment was performed to correct for baseline differences in patient characteristics. Bivalirudin-based therapy was used in 1,070 patients, heparin only in 801 patients, and heparin plus GP IIb/IIIa inhibitors in 5,125 patients. Compared with patients who received heparin or those who received heparin plus GP IIb/IIIa inhibitors, patients who received bivalirudin had lower incidences of bleeding (blood transfusion rate 1.7% vs 4.0%, p <0.001) and periprocedural myonecrosis (creatine kinase-MB >5 times the upper limit of normal 2.7% vs 4.3%, p = 0.016). Differences in bleeding end points remained significant after adjusting for the propensity to receive bivalirudin, but there was no difference in ischemic events. There was no difference in unadjusted long-term survival rate (log-rank test p = 0.46, total number of deaths 412, mean follow-up 17 months) or in propensity-adjusted long-term survival rate (hazard ratio 1.37, 95% confidence interval 0.90 to 2.08, p = 0.14). Compared with heparin with or without GP IIb/IIIa inhibition, the use of bivalirudin in a large consecutive patient registry at a tertiary care center was associated with fewer bleeding events and no evident increase in the incidence of ischemic complications.

Aged↗
PubMed2005

Comparison of the safety and efficacy of emboli prevention devices versus platelet glycoprotein IIb/IIIa inhibition during carotid stenting.

Distal embolization is the main potential risk of carotid stenting, and techniques to minimize this risk are evolving. Between July 1998 and March 2002, 305 consecutive patients who underwent elective or urgent percutaneous carotid intervention at The Cleveland Clinic were prospectively followed. During this period, the clinical practice of carotid stenting evolved from the routine use of glycoprotein IIb/IIIa inhibitors (GPIs) to routine emboli-prevention device (EPD) placement. A total of 199 patients received adjunctive GPIs (91% abciximab), and 106 patients underwent the procedure with an EPD (85% filter design, 15% occlusive balloon). At 30 days, the composite end point of neurologic death, nonfatal stroke, and major bleeding, including intracranial hemorrhage, was significantly lower among patients treated with EPDs compared with those treated with GPIs (0% vs 5.1%, p = 0.02). EPDs may provide an overall safer and more effective means of neuroprotection during carotid stenting than GPIs.

Abciximab↗
PubMed2005

Aspirin resistance and a single gene.

This study examined the association of single nucleotide polymorphisms in 4 candidate genes in a cohort of subjects with aspirin resistance. Aspirin resistance was significantly associated with genetic variation in the platelet surface adenosine 5-diphosphate receptor gene P2Y1.

Alleles↗
PubMed2005

Comparison of ST-segment resolution with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy versus fibrinolytic alone (data from four clinical trials).

We compared combination fibrinolytic plus glycoprotein IIb/IIIa inhibitor therapy with stand-alone fibrinolysis with respect to speed and stability of reperfusion in patients who had acute ST-segment elevation myocardial infarction; data were obtained from 654 patients in 4 trials (Integrilin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction, Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction, Integrilin and Tenecteplase in Acute Myocardial Infarction, and the Fifth Global Use of Strategies to Open Occluded Coronary Arteries) that compared thrombolytics plus lamifiban, eptifibatide, or abciximab with standard thrombolysis. We found significantly faster and more stable ST-segment recovery with combination therapy starting at 60 minutes (56.7% vs 48.0% with >/=50% ST-segment resolution, p = 0.03) and sustained over 180 minutes after drug administration; this transient benefit may suggest a time frame when more optimal percutaneous coronary intervention can be performed.

Abciximab↗
PubMed2005

Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial).

Among patients who undergo percutaneous coronary intervention, renal impairment is associated with an excessive risk of bleeding and ischemic events. Bivalirudin provides comparable suppression of ischemic events with a decrease in bleeding events compared with heparin and glycoprotein IIb/IIIa inhibition. We examined the relation between adverse events, renal impairment, and antithrombotic therapy within a randomized comparison. The Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events per-protocol study population was assessed. Renal function was defined as calculated creatinine clearance <60 ml/min. Events within the overall study population and within each study arm were assessed. Thirty-day events by renal function were compared by chi-square test and logistic regression. Late mortality was compared by log-rank test. Interaction analyses were performed. Among 5,710 patients, renal impairment was associated with increased ischemic events (hazard ratio 1.45, 95% confidence interval 1.13 to 1.88, p = 0.004), bleeding complications (hazard ratio 1.72, 95% confidence interval 1.06 to 2.80, p = 0.028), and excessive 12-month mortality (hazard ratio 3.85, 95% confidence interval 2.67 to 5.54, p <0.001). Bivalirudin provided suppression of ischemic events that was comparable to heparin and glycoprotein IIb/IIIa inhibition regardless of renal impairment. Fewer bleeding events with bivalirudin were also evident irrespective of renal dysfunction. No interaction between treatment assignment, bleeding or ischemic complications, and renal impairment was observed. The safety and efficacy of bivalirudin compared with heparin and planned glycoprotein IIb/IIIa inhibition in this high-risk group are comparable and consistent with the results of the overall trial.

Abciximab↗
PubMed2005

Variability in platelet responsiveness to clopidogrel among 544 individuals.

OBJECTIVES: We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population. BACKGROUND: Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of "non-responders" and a majority of "responders." Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications. METHODS: We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n = 94) and patients after coronary stenting (n = 405), with heart failure (n = 25), and after stroke (n = 20). RESULTS: The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 +/- 20.8% when aggregation was induced by 5 mumol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel. CONCLUSIONS: Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events.

Aged↗
PubMed2005

The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: the do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial.

BACKGROUND: Renal function significantly impacts morbidity and mortality after a percutaneous coronary intervention. Platelet glycoprotein (GP) IIb/IIIa inhibitors reduce ischemic complications during percutaneous coronary intervention; little is known of whether their safety and efficacy are influenced by renal function. In particular, whether outcome differences exist between agents that are renally excreted (tirofiban) or not (abciximab) in patients with mild renal impairment is not known. METHODS: The TARGET trial randomized 4623 patients to tirofiban or abciximab. In this analysis, patients were grouped in creatinine clearance quartiles (<70, 70-90, 90-114, >114 mL/min) and analyzed for efficacy and bleeding risk. Univariate and multivariate analyses were performed to identify interactions between GP IIb/IIIa inhibitor used and creatinine clearance with respect to ischemic outcomes and bleeding. RESULTS: Using unadjusted logistic regression tests for trend, 30-day death/myocardial infarction/urgent target vessel revascularization was greater in patients with lower creatinine clearances (7.3%, 8.5%, 5.1%, and 5.8%, P = .005), as were both major and minor bleeding. There was no interaction between assigned GP IIb/IIIa inhibitor, creatinine clearance and ischemic outcome, major bleeding or minor bleeding. CONCLUSIONS: Both ischemic and bleeding complications are highest in the lowest creatinine clearance quartile of patients treated with GP IIb/IIIa inhibitors. Although tirofiban is renally cleared and abciximab is not, there was no interaction between these GP IIb/IIIa inhibitors and creatinine clearance regarding ischemic or bleeding events.

Abciximab↗
PubMed2005

The relationship between baseline risk and mortality in ST-elevation acute myocardial infarction treated with pharmacological reperfusion: insights from the Global Utilization of Strategies To open Occluded arteries (GUSTO) V trial.

BACKGROUND: We studied the potential interaction between baseline risk of death and treatment with either standard fibrinolytic monotherapy or combination fibrin and platelet lysis with respect to outcome of patients with ST-elevation myocardial infarction (STEMI) enrolled in the Global Utilization of Strategies To open Occluded arteries (GUSTO) V trial. METHODS: Using the Thrombolysis in Myocardial Infarction (TIMI) risk score (0-14 points) for STEMI, we analyzed the 30-day and 1-year mortality according to treatment assignment and risk category. Multivariable analysis was performed to identify the potential interactions between treatment and baseline risk. RESULTS: The TIMI risk score could be calculated in 16256 patients (98% of patients enrolled). The median score was 2 (1-4) in each treatment group (P = .07). The risk score was significantly associated with 30-day mortality (hazard ratio [HR], 1.52; 95% CI 1.47-1.56, P < .001, for each additional 1 point), as well as with 1-year mortality (HR 1.51, CI 1.47-1.55, P < .001). The treatment allocation was not significantly related to mortality, and there was no significant interaction between baseline risk score and treatment with respect to either end point. Although combination therapy significantly reduced death or reinfarction at 7 days (HR 0.69, CI 0.54-0.89, P < .01), independent of the risk score, there was no significant statistical interaction between the two (P = .29). CONCLUSION: The TIMI risk score accurately predicted early and 1-year mortality in patients with STEMI treated with pharmacological reperfusion. We did not identify any heterogeneity in the response of patients to combination therapy according to their TIMI risk score.

Aged↗
PubMed2005

A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

BACKGROUND: The manifestations of atherothrombosis such as myocardial infarction, ischemic stroke, limb ischemia, or cardiovascular death pose a global health care burden. Additional therapies to decrease ischemic events in patients with established vascular disease or at risk for developing vascular disease are necessary. We sought to characterize the risk factors and treatments of a diverse contemporary population of patients with atherothrombosis. METHODS: The CHARISMA trial has enrolled 15,603 patients from around the world. Patients with established coronary, cerebrovascular, or peripheral arterial disease, or those at high risk of developing atherothrombosis due to multiple risk factors, have been randomized to receive either the adenosine diphosphate receptor antagonist clopidogrel or placebo, in addition to background therapy with low- to moderate-dose aspirin. RESULTS: A high percentage of enrolled patients are being treated with statins and angiotensin-converting enzyme inhibitors. In the CHARISMA population, a total of 75.6% of the population had an abnormal body mass index: 42.2% were overweight and 33.4% were obese, with particularly high rates in the United States, especially of morbid obesity. Correspondingly, the prevalence of diabetes was 42%. CONCLUSION: The CHARISMA trial will further characterize atherothrombosis and provide insight into the role of dual antiplatelet therapy in improving outcomes in patients with multiple risk factors or established vascular disease. Of note, the rates of obesity and diabetes in patients with atherothrombosis throughout the world are particularly alarming.

Adult↗
PubMed2005

Creation of a large-scale genetic data bank for cardiovascular association studies.

BACKGROUND: A prerequisite for undertaking genetic association studies is the need for a genetic data bank with adequate DNA samples and a well-described clinical cohort. METHODS: We initiated a prospective single-center study enrolling 6,273 patients referred for cardiac catheterization in a genetic data bank (with eventual goal of 10,000 enrollees). Using a prescreening tool, the patients had comprehensive clinical phenotyping, including angiogram, electrocardiogram, echocardiogram, clinical history, and medication profile (Appendix A). Along with this clinical information, DNA, serum, plasma, basic metabolic panel, inflammation, and lipid panel were collected and stored in the database. RESULTS: Mean age of the patients enrolled was 64 +/- 12 years; 69% are men, 26% have diabetes, 79% have dyslipidemia, and 72% have coronary artery disease (CAD) > or = 50%. We undertook extensive quality-control measures to ensure the validity of both the clinical and DNA samples acquired into our GenBank. As part of this validation, we undertook a genetic association study to discern the effect of the apoE4 polymorphism on the risk for atherosclerosis. We are able to show that the apoE4 polymorphism is an independent risk factor for CAD. CONCLUSIONS: We have been able to create a large-scale genetic data bank as a resource to undertake genetic association studies. Key elements in implementation of this GenBank and baseline characteristics of our patient cohort are summarized. Lastly, as a "proof of concept" for the utility of this resource to discern gene variants associated with disease, we validated apoE4 polymorphism as an independent risk factor for CAD.

Aged↗
PubMed2005

Outcomes in African Americans and whites after percutaneous coronary intervention.

PURPOSE: We aimed to determine whether African Americans and whites have different outcomes after percutaneous coronary intervention (PCI). METHODS: We prospectively selected 8832 patients (707 African Americans) for long-term follow-up after PCI at our institution from 1992 to 2002. The primary outcome studied was death or myocardial infarction at 1 year. Propensity adjustment was performed to account for baseline differences between African Americans and whites. RESULTS: African Americans had higher rates of diabetes and less prior revascularization. Percutaneous coronary interventions in African Americans were more often urgent. Stent use was similar. Procedural success rates were similar, as were periprocedural and 30-day composite rates of death or myocardial infarction. In 1-year unadjusted outcomes, African Americans had a higher rate of death or myocardial infarction (18.0% vs 14.5%; hazard ratio (HR) = 1.25; 95% confidence interval (CI): 1.04 to 1.50; P = 0.017), but the difference was no longer significant after propensity adjustment (HR = 1.18; 95% CI: 0.98 to 1.43, P = 0.087). African Americans had a higher risk for periprocedural bleeding that persisted after propensity adjustment (adjusted odds ratio = 1.45; 95% CI: 1.14 to 1.84, P = 0.002). CONCLUSIONS: After PCI, African Americans have similar short-term rates of death or myocardial infarction when compared with whites but have a nonsignificant trend toward worse long-term outcomes. Our findings, when interpreted in the context of reportedly lower revascularization rates among African Americans, suggest that continued efforts to optimize the appropriate use of coronary revascularization among African Americans are warranted.

Black or African American↗
PubMed2005

Molecular mechanisms of myocardial infarction.

Despite an increased knowledge of risk factors for atherosclerotic heart disease, it remains nearly endemic in Western society. Despite the high penetrance, only a fraction of those with the disease progress to develop a frank myocardial infarction (MI). Over the past decade, it has become clear that inflammation plays an important role in the pathogenesis of MI. Inflammatory arterial disease therefore may be a better term for the subset of patients that develop the serious adverse consequences related to the rupture of the intracoronary plaque. Using newer molecular techniques such as high-throughput SNP analysis, genome-wide scanning, and enriched pedigree analysis, many of the specific mechanisms underlying the inflammatory milieu involved in this transition have been elucidated and may help identify those at risk for the adverse events associated with atherosclerotic disease.

Arteriosclerosis↗
PubMed2005

A robust hybrid between genetic algorithm and support vector machine for extracting an optimal feature gene subset.

Development of a robust and efficient approach for extracting useful information from microarray data continues to be a significant and challenging task. Microarray data are characterized by a high dimension, high signal-to-noise ratio, and high correlations between genes, but with a relatively small sample size. Current methods for dimensional reduction can further be improved for the scenario of the presence of a single (or a few) high influential gene(s) in which its effect in the feature subset would prohibit inclusion of other important genes. We have formalized a robust gene selection approach based on a hybrid between genetic algorithm and support vector machine. The major goal of this hybridization was to exploit fully their respective merits (e.g., robustness to the size of solution space and capability of handling a very large dimension of feature genes) for identification of key feature genes (or molecular signatures) for a complex biological phenotype. We have applied the approach to the microarray data of diffuse large B cell lymphoma to demonstrate its behaviors and properties for mining the high-dimension data of genome-wide gene expression profiles. The resulting classifier(s) (the optimal gene subset(s)) has achieved the highest accuracy (99%) for prediction of independent microarray samples in comparisons with marginal filters and a hybrid between genetic algorithm and K nearest neighbors.

Algorithms↗
PubMed2005

Celecoxib, a selective cyclooxygenase-2 inhibitor, decreases monocyte chemoattractant protein-1 expression and neointimal hyperplasia in the rabbit atherosclerotic balloon injury model.

The inflammation in response to vascular injury is becoming increasingly recognized as a potential contributor to restenosis. Cyclooxygenase-2 (COX-2) is the inducible form of cyclooxygenase and has been shown to be involved in the proinflammatory response of vascular tissue. Bilateral femoral artery lesions were induced by air desiccation in New Zealand White rabbits followed by high cholesterol diet feeding for 28 days. Balloon injury and stent implantation were performed at the preinjured vessel segments. Immunostaining showed that uninjured vessel segments stained positive only for COX-1 but not for COX-2. Injured vessel segments showed, in addition to COX-1, significant positive staining for COX-2. In the efficacy study, celecoxib (75 mg/kg/d) was administered orally beginning 3 hours before balloon injury or stent implantation on day 28 and daily for 21 days. Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 and -9 (MMPs) expression were quantified in arterial extracts 4 days after balloon injury by Western blot and gelatin zymography. Morphometric analysis and immunostaining for macrophages were performed 21 days after balloon injury. Celecoxib treatment significantly decreased MCP-1 expression (P < 0.01). Neointimal hyperplasia was significantly inhibited by celecoxib in both balloon injury and stent models (0.49 +/- 0.20 versus 0.70 +/- 0.35 mm2 from balloon injury model, P < 0.05, and 0.81 +/- 0.25 versus 1.69 +/- 0.43 mm2 from stent model, P < 0.05), accompanied by reduced macrophage infiltration. We conclude that celecoxib decreases the inflammatory response and intimal hyperplasia following vascular injury, possibly through inhibition of MCP-1 expression, implying a pivotal role of inflammation in the pathogenesis of restenosis.

Angioplasty, Balloon↗
PubMed2005

Bivalirudin vs heparin in percutaneous coronary intervention: a pooled analysis.

OBJECTIVE: This study evaluates outcomes with bivalirudin vs heparin in various patient subgroups and the overall population during percutaneous coronary interventions (PCI). BACKGROUND: Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, provides ischemic protection superior to heparin and comparable to heparin plus glycoprotein (GP) IIb/IIIa inhibitors but with significantly fewer bleeding complications. Whether this advantage persists in different subgroups has not been fully defined. To our knowledge, this is the largest pooled analysis of bivalirudin to date. METHODS: Four randomized controlled trials were identified that compared bivalirudin to heparin (with or without GP IIb/IIIa inhibitors) in PCI. The incidence of death, myocardial infarction (MI), revascularization, and major bleeding at 48 hours was compared between these two agents overall and in patients with and without diabetes mellitus, hypertension, renal insufficiency, and advanced age. RESULTS: The trials consisted of 11,638 patients (bivalirudin, 5,861; heparin, 5,777). There were no significant differences in patient characteristics between the two groups. At 48 hours, the incidence of death, MI, revascularization, and major bleeding was significantly reduced in the bivalirudin group (7.8% vs 1.08%, P < .001); individual ischemic end points were significantly reduced for death (0.01% vs 0.02%, P = .049) and revascularization (2.0% vs 2.7%, P = .02), with similar reductions for major bleeding (2.7% vs 5.8%, P < .001). Subgroup analysis was generally consistent with the overall findings. CONCLUSION: This analysis further supports the superiority of bivalirudin compared with heparin. Bivalirudin provides excellent ischemic protection with a significant reduction of bleeding complications, even in high-risk subgroups.

Angioplasty, Balloon, Coronary↗