Showing papers by "Eric J. Topol published in 2006"

Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events

Abstract: Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P = 0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P = 0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P = 0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P = 0.046). Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.)

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

Abstract: 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 1 . 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.

Aspirin and clopidogrel resistance: an emerging clinical entity

Abstract: Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.

Genetic susceptibility to myocardial infarction and coronary artery disease

Abstract: Atherosclerotic involvement in the coronary arteries, which can result in heart attack and sudden death, is a common disease and prototypic of a complex human trait. To understand its genomic basis, eight linkage studies of sibling pairs have been performed. Although there was limited inter-study concordance of important loci, two gene variants in the leukotriene pathway (ALOX5AP and LTA4) have emerged as susceptibility factors for myocardial infarction (MI). Genome-wide association studies have also been undertaken, and the pro-inflammatory cytokine lymphotoxin-alpha (LTA), and its key ligand galectin-2 (LGALS2) have been identified as genes implicated in predisposition for heart attack. By cueing into the genomic basis for low serum LDL cholesterol levels, much work has been done to advance the importance of the serine protease PCSK9, which modulates LDL receptor function. Lifelong lowered LDL cholesterol associated with PCSK9 point mutations in 2-3% of individuals have been shown to provide marked protection from coronary artery disease (CAD). Most of the success in this field has been with the phenotype of MI, which is considerably more restrictive than CAD. Four principal and interdependent processes--lipoprotein handling, endothelial integrity, arterial inflammation, and thrombosis--have been supported as important via the clustering of genes, thus far implicated in CAD susceptibility. Of note, connecting genes in a single pathway (leukotriene), of a protein and its ligand (LTAalpha) or from one disease to another [age-related macular degeneration (AMD); complement factor H (CFH)], or even three disease characterized by inflammation (MHC2) have now been reported. Although the population attributable risk for any of the genes identified to date is limited, such discovery is likely to be accelerated in the future.

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

Abstract: 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 ¼ 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 ¼ 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.

Gene Variants of VAMP8 and HNRPUL1 Are Associated With Early-Onset Myocardial Infarction

Abstract: Objectives— Identify gene variants associated with early-onset myocardial infarction (MI). Methods and Results— We tested 11 647 single-nucleotide polymorphisms (SNPs) for association with early-onset MI in a case-control study (study 1 200 cases, 262 controls). To reduce the number of false positives among the 666 SNPs that were nominally associated with early-onset MI ( P P P =0.025; odds ratio [OR], 1.75; CI, 1.17 to 2.62) and an HNRPUL1 variant ( P =0.0043; OR, 1.92; CI, 1.28 to 2.86) were associated with early-onset MI (nominal P Conclusions— Variants in 2 genes were associated with early-onset MI: VAMP8, which is involved in platelet degranulation, and HNRPUL1, which encodes a ribonuclear protein. The identification of these variants could improve understanding of disease mechanisms and suggest novel drug targets.

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.

Abstract: 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 γ (PPARγ), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPARγ agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPARγ 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 PPARγ activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPARγ activator, and sRAGE + PPARγ activator. Consistent with PPARγ working through its effects on RAGE, we found that the addition of PPARγ activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPARγ agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPARγ activation inhibits neointimal formation in response to arterial injury.

Statin Use and Sex-Specific Stroke Outcomes in Patients With Vascular Disease

Abstract: Background and Purpose— Although statins reduce the risk of stroke in patients with coronary heart disease, possible differing effects of statins on stroke outcomes based on sex remain uncertain. W...

The genetics of health

Abstract: 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.

Clinical end point definitions after percutaneous coronary intervention and their relationship to late mortality: an assessment by attributable risk

Abstract: Objectives: To explore the relative and absolute risks associated with various definitions for myocardial infarction, bleeding and revascularisation within the context of percutaneous coronary intervention (PCI). Methods: The REPLACE-2 (randomised evaluation of PCI linking Angiomax to reduced clinical events) database of patients undergoing PCI was used. Various definitions of myocardial infarction, bleeding and revascularisation were modelled by logistic regression assessing their relationship with 12-month mortality. Estimates from these models were used to calculate the “attributable fraction” for late mortality associated with each definition. Results: The most liberal definition of myocardial infarction was associated with an attributable risk of 13.7% (95% CI 3.4% to 23.0%). The most stringent definition was associated with an attributable risk of 4.6% (95% CI 0.6% to 8.6%). Restrictive definitions of bleeding such as TIMI (thrombolysis in myocardial infarction) major bleeding are associated with a high odds ratio of risk (6.1, 95% CI 2.1 to 17.7, p = 0.001) but low attributable fraction (3.5%, 95% CI 0.9% to 6.8%). Conclusions: Stringent end point definitions may under-represent the clinical significance of adverse outcomes after PCI. Considering both the proportional and absolute risk associated with definitions may be a more useful method for evaluating clinical trial end points. This analysis supports the current definitions of ischaemic events but suggests that more liberal definitions of bleeding events may also be relevant to late mortality.

Outcome of Multivessel Coronary Intervention in the Contemporary Percutaneous Revascularization Era

Abstract: Clinical outcomes after multivessel versus single-vessel percutaneous coronary intervention (PCI) in the era of stents, glycoprotein IIb/IIIa inhibitors, and clopidogrel pretreatment have not been well studied. Thus, we compared outcomes from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET) for patients who underwent multivessel versus single-vessel PCI and separately considered the effect of acute coronary syndromes on the results. Composite clinical outcomes (death, myocardial infarction, and target vessel revascularization) were evaluated at 30 days and 6 months and mortality at 1 year. Safety analysis included in-patient major and minor bleeding. Despite similar baseline characteristics, patients who underwent multivessel PCI (n = 775) had significantly higher 30-day and 6-month composite event rates than did those who were treated in a single coronary artery territory (n = 3,969). This association remained significant at 30 days (hazard ratio 1.57, 95% confidence interval 1.06 to 2.33, p = 0.025) after using propensity matching to minimize confounding factors. The higher event rate was primarily due to an increase in periprocedural myocardial infarction. However, there were no significant differences in propensity-matched ischemic outcomes at 6 months and 1 year or in bleeding. In addition, in a propensity-matched analysis that included 810 patients with acute coronary syndrome, multivessel stenting resulted in numerically more ischemic events than did single-vessel stenting, although this did not reach statistical significance (hazard ratio 1.32, 95% confidence interval 0.85 to 2.05, p = 0.221). In conclusion, multivessel PCI was more often associated with periprocedural myocardial infarction than single-vessel intervention, although this did not translate into higher 1-year mortality. A randomized trial comparing multivessel PCI with staged or surgical revascularization is warranted.

Angiographic adverse events, creatine kinase-MB elevation, and ischemic end points complicating percutaneous coronary intervention (a REPLACE-2 substudy).

Abstract: Several angiographic adverse events during coronary balloon angioplasty have been associated with increased creatine kinase-MB (CK-MB) enzymes and adverse clinical outcomes. The significance of angiographic adverse events in the stent era has not been widely studied. We analyzed 10 types of angiographic adverse events that were reported in the 6,010-patient Second Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial to determine their relation to CK-MB elevation and clinical ischemic end points after percutaneous coronary intervention (PCI). Angiographic adverse events occurred in 9.1% of REPLACE-2 patients. Most (8 of 10) types of angiographic adverse events were associated with an increased risk of increased CK-MB (p <0.001 for each), and 47% of all patients with an angiographic adverse event developed increased CK-MB. Logistic regression analysis showed that the strongest predictor of death, myocardial infarction, or revascularization at 6 months was the occurrence of an angiographic adverse event during PCI (odds ratio 1.9, 95% confidence interval 1.6 to 2.4, p <0.001). Side branch closure, abrupt closure, any decreased flow during the procedure, angiographic distal embolization, and perforation or tamponade were individual predictors of the occurrence of the combined clinical ischemic end point at 6-month follow-up (p <0.005 for each). In conclusion, most angiographic adverse events during PCI are associated with increased CK-MB and are powerful predictors of adverse clinical events within 6 months.

The influence of body mass index on outcomes and the benefit of antiplatelet therapy following percutaneous coronary intervention.

Abstract: UNLABELLED In general, obesity is associated with better outcome in patients undergoing percutaneous coronary interventions (PCI). One small study has suggested that these patients do not achieve adequate platelet inhibition with clopidogrel and that this may shape clinical outcomes. We evaluated the relationship between body mass index (BMI) and clinical outcomes at 1 year following PCI in patients randomized to clopidogrel or placebo in the CREDO trial. METHODS AND RESULTS BMI, baseline clinical characteristics and clopidogrel regimen were assessed in 2,116 patients. The primary study endpoint was the 1-year composite of death, MI or stroke. A total of 342 patients had low or normal BMI (< 25 kg per m2), 847 were overweight (25-29.9 kg per m2), 810 were obese (30-39.9 kg per m2) and 113 were very obese (greater than or equal to 40 kg per m2). Obese patients were more likely to be young males with diabetes, hypertension and hyperlipidemia (p < 0.01). Bleeding complications occurred in 38% of low BMI, 32% of overweight/obese, and 25% of very obese patients (p = 0.03). Randomization to clopidogrel was associated with a 25% risk reduction in 1-year death, MI or stroke events, as BMI increased by every 5 kg per m2 (p = 0.009). CONCLUSION In general, increasing BMI was associated with better efficacy and bleeding outcomes at 1 year in this nonurgent PCI population. Randomization to early- and long-term clopidogrel was associated with even further improvements in those with increasing BMI.

Challenges in the phenotypic characterisation of patients in genetic studies of coronary artery disease

Abstract: Coronary artery disease and acute myocardial infarction are complex traits in which there has been recent research to identify the principal genes that engender susceptibility or provide protection Although there has been exceptional progress in the technology, which now allows genotyping of hundreds of thousands of single-nucleotide polymorphisms in each individual, there remains a pattern of inconsistency in the studies performed to date, in part owing to the difficulties in defining cases and controls In this paper, salient issues to facilitate research in this important field are reviewed

The relationship of obesity to ischemic outcomes following coronary stent placement in contemporary practice.

Abstract: Objectives: We analyzed the relationship of obesity, determined by body mass index (BMI), to short- and long-term outcomes in the TARGET trial. BACKGROUND: Previous studies have conflicting findings regarding the relationship of BMI to outcomes following percutaneous coronary intervention (PCI). Methods: The TARGET trial studied the use of glycoprotein (GP) IIb/IIIa inhibition in patients undergoing planned coronary stent placement. Results: Eighty-one percent of all patients were overweight (BMI > 25), 36% were obese (BMI > 30), and United States patients were more frequently obese (38.7% vs. 25.8%, P 35) obese (12.4% vs 8.7%, P 32) obese patients, this relationship was more significant (TVR 11.3% vs. 8.5%, P = 0.007), particularly in patients <65 years of age (TVR 12.3% vs. 8.4%, P = 0.003). Conclusion: The majority of patients undergoing PCI are overweight, especially in the United States. Extreme obesity is associated with a significant increase in TVR following intent-to-stent PCI, especially in patients <65 years of age. With routine use of GP IIb/IIIa inhibitors, other long- and short-term ischemic events are similar in obese and nonobese patients. However, obese patients have significantly less major bleeding. © 2006 Wiley-Liss, Inc.

Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment

Abstract: Objective: To assess the effectiveness of long term treatment with clopidogrel of patients with extracardiac vascular disease (ECVD) (a history of either peripheral arterial disease or cerebrovascular disease). Design: Subgroup analysis of a prospective randomised clinical trial. Setting: The CREDO (clopidogrel for the reduction of events during observation) trial was a randomised, double blind, placebo controlled trial conducted at 99 centres in North America from June 1999 through April 2001. Patients: 2116 patients who were to undergo elective coronary intervention or were deemed at high likelihood of undergoing percutaneous coronary intervention were enrolled in the CREDO trial. The current study sample consisted of 272 patients with ECVD. Main outcome measure: One year incidence of the composite of death, myocardial infarction, or stroke in the intent to treat population. Results: Patients with ECVD had a more than twofold greater relative risk reduction with clopidogrel for the primary end point compared with patients without ECVD (47.9%, 95% confidence interval (CI) −4.2% to 73.9%, v 18.2%, 95% CI −10.5 % to 39.5%, respectively). Conclusions: Longer term clopidogrel treatment provides added protection against thrombotic events throughout the arterial vasculature, not limited to the coronary arteries, and may be especially effective for patients with more diffuse atherosclerosis such as ECVD.

Direct thrombin inhibition appears to be a safe and effective anticoagulant for percutaneous bypass graft interventions

Abstract: Background: Percutaneous coronary interventions (PCI) of coronary artery bypass grafts (CABG) are associated with worse outcomes compared with those of native coronary PCI. Little is known concerning the use of direct thrombin inhibition during CABG intervention. The objective of this report is to examine the safety and efficacy of bivalirudin with GPIIb/IIIa blockade inhibition in patients undergoing CABG PCI. GP IIb/IIIa use was provisional in REPLACE-2 and planned in REPLACE-1. Methods and Results: A post hoc analysis of patients undergoing CABG PCI in the REPLACE-1 and -2 trials was performed. In REPLACE-1, patients were randomized to either heparin or bivalirudin, with GP IIb/IIIa inhibitor use at the operator's discretion. In REPLACE-2, patients were randomized to heparin plus GP IIb/IIIa inhibition versus bivalirudin with provisional GP IIb/IIIa blockade. In both studies, randomized treatment groups were well matched. In unadjusted and logistic regression analysis, there were no significant differences in the combined endpoint of death, myocardial infarction, urgent revascularization, or major bleeding when patients were treated with either heparin or bivalirudin. Individual safety and efficacy endpoints were also similar. Minor bleeding was significantly reduced in patients treated with bivalirudin (14.8% vs. 22.7%, P = 0.037). Follow-up data available from the REPLACE-2 trial at 12 months found similar efficacy between groups with a trend towards decreased 12 month mortality in the bivalirudin vs. heparin groups (4.2% vs. 7.8%, P = 0.16).CONCLUSION: CABG PCI using bivalirudin with provisional GPIIb/IIIa inhibition appears to provide similar safety and efficacy to heparin with GPIIb/IIIa inhibition. © 2006 Wiley-Liss, Inc.