Showing papers by "Eric J. Topol published in 2008"

Facilitated PCI in patients with ST-elevation myocardial infarction.

Abstract: In this international, double-blind, placebo-controlled study, we randomly assigned patients with ST-segment elevation myocardial infarction who presented 6 hours or less after the onset of symptoms to receive combination-facilitated PCI, abciximabfacilitated PCI, or primary PCI. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary end point was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. Results A total of 2452 patients were randomly assigned to a treatment group. Significantly more patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; P = 0.01 and P = 0.003, respectively). The primary end point occurred in 9.8%, 10.5%, and 10.7% of the patients in the combination-facilitated PCI group, abciximab-facilitated PCI group, and primary-PCI group, respectively (P = 0.55); 90-day mortality rates were 5.2%, 5.5%, and 4.5%, respectively (P = 0.49). Conclusions Neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab alone significantly improved the clinical outcomes, as compared with abciximab given at the time of PCI, in patients with ST-segment elevation myocardial infarction. (ClinicalTrials.gov number, NCT00046228.)

Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

Abstract: Context Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated. Objective To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans. Design, Setting, and Participants The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity. Main Outcome Measures Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD. Results The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P Conclusion This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.

Patients with peripheral arterial disease in the CHARISMA trial

Abstract: Aims The aim of this study was to determine whether clopidogrel plus aspirin provides greater protection against major cardiovascular events than aspirin alone in patients with peripheral arterial disease (PAD). Methods and results This is a post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHARISMA trial. The rate of cardiovascular death, myocardial infarction (MI), or stroke (primary endpoint) was higher in patients with PAD than in those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25; 95% CI 1.08, 1.44; P = 0.002]. Among the patients with PAD, the primary endpoint occurred in 7.6% in the clopidogrel plus aspirin group and 8.9% in the placebo plus aspirin group (HR, 0.85; 95% CI, 0.66–1.08; P = 0.18). In these patients, the rate of MI was lower in the dual antiplatelet arm than the aspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42–0.96; P = 0.029), as was the rate of hospitalization for ischaemic events: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68–0.95; P = 0.011). The rates of severe, fatal, or moderate bleeding did not differ between the groups, whereas minor bleeding was increased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99; 95% CI, 1.69–2.34; P < 0.001). Conclusion Dual therapy provided some benefit over aspirin alone in PAD patients for the rate of MI and the rate of hospitalization for ischaemic events, at the cost of an increase in minor bleeding.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk.

Abstract: Background—Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B2 concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B2 concentrations that could thereby reduce cardiovascular risk. Methods and Results—Urinary 11-dehydro thromboxane B2 concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B2 concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B2, whereas aspirin dose 150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B2 levels. Conclusions—In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events. (Circulation. 2008;118:1705-1712.)

Abstract 3999: Baseline Proton Pump Inhibitor Use is Associated with Increased Cardiovascular Events With and Without the Use of Clopidogrel in the CREDO Trial

Abstract: Ex vivo data suggest that a pharmacokinetic interaction may exist between proton pump inhibitors (PPIs) and clopidogrel, decreasing the antiplatelet effect of the latter. We assessed that baseline ...

The use of high-sensitivity assays for C-reactive protein in clinical practice.

Abstract: High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD.

Four SNPS on chromosome 9p21 confer risk to premature, familial CAD and MI in an American Caucasian population (GeneQuest).

Abstract: Genome-wide association studies have separately identified four single nucleotide polymorphisms (SNPs) on chromosome 9p21 that confer susceptibility to coronary artery disease (CAD) and myocardial infarction (MI). This study presents the first analysis of these SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) in a premature, familial CAD/MI population (GeneQuest). We performed a case-control analysis of the GeneQuest Caucasian population with 310 cases with premature CAD and MI (average age at onset of 40.3 +/- 5.1) and 560 non-CAD controls to determine if these SNPs are associated with risk of CAD using both the population-based and family-based association study designs. The four SNPs are significantly associated with premature and familial MI and CAD in the GeneQuest Caucasian population (allelic P= 6.61 x 10(-7) to 1.87 x 10(-8)). Sib-TDT analysis showed that three of the four SNPs could confer significant susceptibility to premature CAD and MI. These results indicate that the four SNPs on chromosome 9p21 are also associated with premature, familial CAD.

The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease

Abstract: Aims We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease. Methods and results This was a prospective observational study of 15 532 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who were randomly assigned to clopidogrel or placebo, and followed-up for a median of 28 months for the occurrence of the primary endpoint (cardiovascular death, myocardial infarction, or stroke), all-cause mortality, and bleeding complications. Compared with the highest BMI quartile, the primary endpoint, cardiovascular, and all-cause mortality all occurred more frequently among patients in the lowest BMI quartile (about a third lower). The relationship between continuous BMI and adverse cardiovascular outcomes were presented as two linear spline terms with 29 kg/m2 as the cut-point for all-cause mortality. Lower BMI was associated with an increase in moderate and severe bleeding complications, largely accounted for by those receiving dual-antiplatelet agents with the highest tertile aspirin dose. Conclusion Adverse cardiovascular events and bleeding complications occurred more frequently among individuals with or at-risk for atherothrombotic disease and low BMI. Further studies should be directed to these patients to improve outcomes. The CHARISMA trial is registered with ClinicalTrials.gov, NCT00050817.

Genetic determinants of phenotypic diversity in humans

Abstract: New technologies for rapidly assaying DNA sequences have revealed that the degree and nature of human genetic variation is far more complex then previously realized. These same technologies have also resulted in the identification of common genetic variants associated with more than 30 human diseases and traits.

Clopidogrel and aspirin versus aspirin alone for the prevention of stroke in patients with a history of atrial fibrillation: subgroup analysis of the CHARISMA randomized trial.

Abstract: Background: Aspirin offers modest reduction in stroke in patients with atrial fibrillation. Whether combination of aspirin with clopidogrel offers additional protection is unclear.

Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial)

Abstract: Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (

Genome scanning and cardiovascular disease

Abstract: At the end of 2007, Science recognised human genetic variation as the “breakthrough of the year”.1 Beginning in April last year and extending through the current year, major advances have been made almost every week to unravel common DNA sequence variants that are incontrovertibly associated with common diseases. More than 50 diseases have now been reported, and many cardiovascular conditions are included in this avalanche of discoveries. There probably has been more progress in understanding the genomics of disease in the past year than for several previous decades in aggregate. The seemingly relentless and extraordinary progress in genomics of complex traits is an outgrowth of three major initiatives. First, the Human Genome Project accomplished its goal of sequencing the 3.1 billion base pairs of man, with the draft first announced in 20002 (fig 1). Second, the International HapMap project studied 271 subjects of diverse ancestry3 to break down the genome into heritable “bins” or “blocks” that made the billions of base pairs eminently more manageable. Instead of three billion base pairs, the genome could be analysed by 250 000–500 000 bins, with each of these bins representing a sequence of DNA that was inherited as a unit. By selecting a single nucleotide polymorphism (SNP), a base-pair substitution, in each bin, a “window” into the whole genome was achieved. Third, genome science technology matured to the extent that 300 000 to 1 million informative, tag SNPs could be assessed in an individual rapidly and at a cost that was relatively affordable. Such ultra-high throughput genotyping platforms set the stage for the genome-wide association studies (GWAS) and a new era of personal, consumer genomics. Of note, one can see that we have been in a 7–8-year “incubation” phase, as depicted in fig 1, during which these three major fronts were progressing. …

Relation between previous lipid-lowering therapy and infarct size (creatine kinase-MB level) in patients presenting with acute myocardial infarction.

Abstract: Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p 3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p 3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.

Timing and correlates of very early major adverse clinical events following percutaneous coronary intervention.

Abstract: We attempted to determine the incidence, timing and correlates of very early ( 50%. These data show a very low and constant risk of adverse events 6 hours following PCI.