Antithrombotic properties of rafigrelide: a phase 1, open-label, non-randomised, single-sequence, crossover study.

Platelets play a central role in atherothrombotic events. We investigated the effect of a novel platelet-lowering agent, rafigrelide, on thrombus formation and characteristics. In this phase 1, open-label, non-randomised, single-sequence, crossover study, healthy male volunteers received rafigrelide for 14 days (Period 1). Following a ≥6-week washout period, they then received rafigrelide + acetylsalicylic acid (ASA) for 14 days (Period 2). Thrombus formation was assessed ex vivo using the Badimon perfusion chamber, and thrombus characteristics were assessed using thromboelastography. A total of 15 volunteers were enrolled in the study and were assigned to Panel A or Panel B, which had different schedules of assessments. In Panel A, after treatment with rafigrelide alone (Period 1), mean (± standard deviation) platelet count was reduced from 283 (± 17) × 109/l at Day 1, to 125 (± 47) × 109/l at Day 14 (n=6) and thrombus area reduced under high and low shear conditions. Reductions in thrombus area under high shear conditions correlated with reductions in platelet count (r²=0.11, p=0.022; n=12). Rafigrelide treatment prolonged clot formation time and reduced clot strength. The addition of ASA to rafigrelide (Period 2) had no additional effect on platelet count or thrombus area under high or low shear conditions. Similar results were seen in Panel B for all parameters. The most common adverse events (≥3 participants per period) were thrombocytopenia and headache. While confirming the platelet-lowering effects of rafigrelide, this early phase study also indicates that rafigrelide has antithrombotic properties under both high and low shear conditions.

Non-invasive assessment of saphenous vein graft patency in asymptomatic patients.

The development and progression of atherosclerotic disease in saphenous vein grafts (SVGs) following coronary artery bypass surgery (CABG) are often without symptoms. Four-slice CT is a non-invasive imaging technique reliable for assessing SVG patency. This study utilised CT to assess temporal progression of patency in asymptomatic patients. A four-slice CT scanner was used employing standard techniques. Analysis of the reconstructed images was performed offline by two experienced operators blinded to patient details. The primary aim was vein graft patency. 130 asymptomatic subjects were studied. The mean time from CABG was 7.3 years (range, 15 days to 21 years 9 months; standard deviation (SD), 4.4 years). 294 of the 305 SVGs were suitable for assessment of patency. The overall occlusion rate for assessable grafts was 23.5%. Occlusion rates for grafts <1 year old was 12.5% (2/16), 20.7% (42/203) for grafts 1-10 years old, and 33.3% (25/75) for grafts >10 years old. In conclusion, significant occlusion of SVGs occurs early after CABG in asymptomatic patients. Four-slice CT has the potential for the non-invasive assessment of individuals after surgery.

Guidelines to practice gap in the use of glycoprotein IIb/IIIa inhibitors: from ISAR-REACT to overreact?

UNLABELLED: Adjunctive use of glycoprotein IIb/IIIa inhibitors (GPI) is associated with favorable outcomes following percutaneous coronary intervention (PCI). Guidelines for use of GPI have been published by various national societies including National Institute of Clinical Excellence (NICE), United Kingdom. The latter has not been updated since publication. The impact of contemporary trials such as ISAR-REACT (which showed no benefit of abciximab and 600 mg of clopidogrel compared with 600 mg of clopidogrel alone, in elective patients) on adherence to NICE guidelines is unknown. METHODS: We audited use of GPI against NICE guidelines following publication in May 2002. Data were collected from 1,685 patients between September and November in years 2002, 2003, 2004, and 2007. RESULTS: In 2002 and 2003, only 10.2% and 11.8%, respectively, of patients were noncompliant to NICE guidelines. Over time, there was an increase in patients not given GPI despite meeting NICE criteria. After publication of ISAR-REACT, the comparative figures for noncompliance in 2004 and 2007 were 40.0% and 44.5%. A similar pattern was seen in patients with diabetes; in 2002 and 2003 noncompliance was 16.7% and 11.1%, respectively, and in 2004 and 2007 noncompliance was 38.0% and 44.7%, respectively. Qualitatively, similar findings were recorded in patients with NSTE-ACS. The overall noncompliance to NICE guidelines increased from 11.0% to 42.1% (P < 0.0001) after the ISAR-REACT study. CONCLUSIONS: We found a decline in compliance to NICE guidelines on GPI usage during PCI. This was likely influenced by contemporary trials demonstrating little or no benefit of GPI in patients undergoing elective PCI who are adequately pretreated with clopidogrel. Our findings suggest the need for a mechanism whereby regular updates to guidelines can be disseminated following new trial evidence.

Local vessel injury following percutaneous coronary intervention does not promote early mobilisation of endothelial progenitor cells in the absence of myocardial necrosis.

BACKGROUND/OBJECTIVES: Endothelial progenitor cells (EPCs) are circulating mononuclear cells that are released from the bone marrow in response to injury and participate in vascular repair. Some previous studies have suggested an early mobilisation of EPCs following percutaneous coronary intervention (PCI) that could modulate the subsequent risk of restenosis or stent thrombosis. However, those studies did not discriminate between vascular injury caused by PCI and any associated myocardial injury. Myocardial injury alone can influence EPC mobilisation in a non-specific manner, and could therefore confound any association with risk. We investigated the effect of local endothelial trauma following PCI on EPC mobilisation in the absence of myocyte necrosis. DESIGN: We quantified circulating EPCs from 20 patients immediately before, 6 hours and 24 hours following elective PCI in patients without a 24-hour troponin rise. Absolute counts of EPCs expressing combinations of CD45, CD34, CD133 and kinase domain receptor (KDR) were recorded using flow cytometry. RESULTS: There was a fall of 7-15% in EPC numbers between baseline and 6 hours post procedure and a subsequent rise (5-18%) from 6 hours to 24 hours. At 24 hours EPC levels were similar to baseline. CONCLUSIONS: The specific localised vascular injury induced by PCI did not lead to early mobilisation of EPCs. However, the fall in EPCs 6 hours after PCI was significant and its relation to early post-PCI complications such as stent thrombosis requires further exploration.

Atopic optic neuritis.

PURPOSE: To report a case of optic neuritis associated with atopic dermatitis, which may represent an optic nerve counterpart of atopic myelitis. METHODS: Clinical examination, MRI, blood investigations. RESULTS: A 34-year-old man with severe atopic dermatitis developed a steroid-responsive bilateral optic neuritis. Serum IgE was highly elevated, with high titers of mite-specific IgE. Clinical ophthalmological fluctuations paralleled those of atopic dermatitis. CONCLUSIONS: The clinical features and parallel fluctuations strongly suggest that the patient's optic neuritis was related to atopic dermatitis. This atopic optic neuritis may represent the optic nerve equivalent of atopic myelitis.

Predicting sudden death in patients with mild to moderate chronic heart failure.

OBJECTIVES: To explore the relation between non-invasive measures of cardiac function and sudden cardiac death, as well as the development and utility of an index integrating these variables to identify patients at increased risk of this mode of death. DESIGN: UK-HEART (United Kingdom-heart failure evaluation and assessment of risk trial) was a prospective study conducted between December 1993 and April 2000. The study was specifically designed to identify non-invasive markers of death and mode of death among patients with chronic heart failure. SETTING: 8 UK general hospitals. MAIN OUTCOME MEASURES: Death and mode of death. RESULTS: 553 patients aged a mean (SD) of 63 (10) years, in New York Heart Association functional class 2.3 (0.02), recruited prospectively. After 2365 patient-years' follow up, 201 patients had died (67 suddenly). Predictors of sudden death were greater cardiothoracic ratio, QRS dispersion, QT dispersion corrected for rate (QTc) across leads V1-V6 on the 12 lead ECG, and the presence of non-sustained ventricular tachycardia. The hazard ratio and 95% confidence intervals (CI) of sudden death for a 10% increase in cardiothoracic ratio was 1.43 (95% CI 1.20 to 1.71), for a 10% increase in QRS dispersion 1.11 (95% CI 1.04 to 1.19), for the presence of non-sustained ventricular tachycardia 2.03 (95% CI 1.27 to 3.25), and for a 10% increase in QTc dispersion across leads V1-V6 1.03 (95% CI 1.00 to 1.07) (all p < 0.04). An index derived from these four factors performed well in identifying patients specifically at increased risk of sudden death. CONCLUSIONS: Results show that an index derived from three widely available non-invasive investigations has the potential to identify ambulant patients with chronic heart failure at increased risk of sudden death. This predictive tool could be used to target more sophisticated investigations or interventions aimed at preventing sudden death.

Cardiac gated breath-hold black blood MRI of the coronary artery wall: an in vivo and ex vivo comparison.

BACKGROUND: High resolution magnetic resonance (MR) imaging of the coronary artery wall in vivo has been limited by the cardiac and respiratory motion, flow artifacts as well as the relatively small size of the coronary arteries. We sought to validate in vivo black blood MR imaging of the coronary artery wall using a double inversion recovery fast spin echo MR imaging sequence with limited breath-holding and cardiac gating for suppression of motion artifacts by comparison with ex vivo MR imaging. METHODS: Yorkshire albino swine (n = 6) were used in this study and coronary lesions were induced with balloon angioplasty. Four weeks after balloon injury of the coronary arteries MR imaging of the coronary artery lesions was performed. High resolution in vivo and ex vivo images of the coronary artery wall and lesions were obtained using a double inversion recovery fast spin echo sequence in a 1.5 T MR system. There was a statistically significant agreement (p < 0.0001) between measurements of vessel wall area (r = 0.87, slope = 0.87) and maximal wall thickness (r = 0.84, slope = 0.88) from in vivo and ex vivo MR images of the coronary arteries. The mean differences between in vivo and ex vivo measurements were 0.56 +/- 1.98 mm2 for vessel wall area and 0.02 +/- 0.36 mm for maximal wall thickness. CONCLUSIONS: Using breathholding and cardiac gating, it is possible to perform high resolution MR imaging of the coronary artery wall in vivo with good suppression of motion artifacts with a double inversion recovery fast spin echo black blood imaging sequence.

[Identification of unstable coronary atherosclerotic plaques]. / Identification des plaques d'athérosclérose coronaire instables.

The mechanisms of atherogenesis are better understood and the detection of atherosclerosis has improved with the different diagnostic methods currently available. However, it is almost impossible at present to differentiate high risk, unstable or vulnerable plaques from quiescent or stable plaques of atherosclerosis. This is a crucial problem given the banality of atherosclerosis on the one hand, and, on the other hand, the serious consequences (acute coronary syndromes, cerebrovascular accidents) of thrombotic occlusion at the site of an atherosclerotic plaque. It has now been established that the composition of the plaque is more important than the degree of stenosis, a fundamental concept in the risk of plaque rupture, precipitating the cascade of reactions leading to uncontrolled thrombosis. Consequently, new imaging techniques should address the problem of analysing the composition of atheromatous plaques. Endovascular ultrasonography, fast CT, angioscopy, nuclear imaging techniques and MRI are so many promising tools. However, non-invasive techniques should be distinguished from invasive ones. In all probability, it will be the former which will turn out to be the most useful diagnostic aid in pauci or asymptomatic patients. This article reviews the different imaging techniques under evaluation for the identification of risk of plaque rupture.

Atherosclerotic aortic component quantification by noninvasive magnetic resonance imaging: an in vivo study in rabbits.

OBJECTIVES: We sought to demonstrate the ability that noninvasive in vivo magnetic resonance imaging (MRI) has to quantify the different components within atherosclerotic plaque. BACKGROUND: Atherosclerotic plaque composition plays a critical role in both lesion stability and subsequent thrombogenicity. Noninvasive MRI is a promising tool for the characterization of plaque composition. METHOD: Thoracic and abdominal aortic atherosclerotic lesions were induced in rabbits (n = 5). Nine months later, MRI was performed in a 1.5T system. Fast spin-echo sequences (proton density-weighted and T2-weighted [T2W] images) were obtained (in-plane resolution: 350 x 350 microns, slice thickness: 3 mm). Magnetic resonance images were correlated with matched histopathological sections (n = 108). RESULTS: A significant correlation (p < 0.001) was observed for mean wall thickness and vessel wall area between MRI and histopathology (r = 0.87 and r = 0.85, respectively). The correlation was also present on subanalysis of the thoracic and upper part of the abdominal aorta, susceptible to respiratory motion artifacts. There was a significant correlation for plaque composition (p < 0.05) between MRI and histopathology for the analysis of lipidic (low signal on T2W, r = 0.81) and fibrous (high signal on T2W, r = 0.86) areas with Oil Red O staining. T2-weighted images showed greater contrast than proton density-weighted between these different components of the plaques as assessed by signal intensity ratio analysis with the mean difference in signal ratios of 0.47 (S.E. 0.012, adjusted for clustering of observations within lesions) being significantly different from 0 (t1 = 39.1, p = 0.016). CONCLUSIONS: In vivo noninvasive high resolution MRI accurately quantifies fibrotic and lipidic components of atherosclerosis in this model. This may permit the serial analysis of therapeutic strategies on atherosclerotic plaque stabilization.

Combination thrombolytic therapy and percutaneous coronary intervention: the future for revascularisation for acute myocardial infarction?

It seems theoretically sound to consider rescue percutaneous coronary intervention (PCI) in patients with failed thrombolysis. However, randomised controlled data in this setting are limited. In this brief review we will present those trials analysing the role of rescue PCI in patients with acute myocardial infarction and failed thrombolysis, and consider appropriate management strategies in this setting.

Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.

There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/L) at 2 hours in this front-loaded regimen group (36.1+/-2. 0% and 53.2+/-9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.

Ventricular dilation after anterior ST-elevation myocardial infarction in the thrombolytic era.

BACKGROUND: The aim of this work was to study changes in end-diastolic volume 6 months after Q-wave and non-Q-wave anterior ST-elevation myocardial infarction by echocardiography. Ventricular dilation after anterior Q-wave myocardial infarction is well-recognized. However, there is a dearth of information about the natural history of ventricular volumes after non-Q-wave myocardial infarction. METHODS: One hundred ninety patients receiving thrombolytic therapy after anterior ST-elevation myocardial infarction were studied. All patients had 2D echocardiograms and 12-lead electrocardiograms recorded within 24 hours of symptoms and at 3, 42, and 180 days later. In addition, a further electrocardiogram was recorded on day 7 to assess patients for the presence of Q waves. Peak creatine kinase over the first 3 days of admission was recorded. End-diastolic volume index was the study end point. RESULTS: Peak creatine kinase was strongly associated with ventricular dilation in both groups (P <.001). Mean end-diastolic volume in the Q-wave group increased significantly from day 1 to 6 months (P <.05) but did not alter after non-Q-wave infarction. However, when patients were selected on predefined criteria for significant change in ventricular dilation (>10 mL/m(2)), then 35% of those with and 15% of those without Q waves fell into this category. Within this group, the increase in end-diastolic volume followed a similar pattern, with the maximum percentage increase occurring between day 1 and 6 weeks. CONCLUSIONS: In the postthrombolytic group of anterior ST-elevation myocardial infarction, a minority of patients without Q-wave development also undergo significant ventricular dilation.

High resolution ex vivo magnetic resonance imaging of in situ coronary and aortic atherosclerotic plaque in a porcine model.

Atherosclerotic plaque composition is central to the pathogenesis of plaque disruption and acute thrombosis. Thus, there is a need for accurate imaging and characterization of atherosclerotic lesions. Even though there is no ideal animal model of atherosclerosis, the porcine model is considered to most closely resemble human atherosclerosis. We report the feasibility of MR imaging and characterizing of atherosclerotic lesions from in situ coronary arteries and aortas in an ex vivo setting and validate this with histopathology. Coronary and aortic atherosclerosis was induced in Yucatan mini-swine (n=4) by a combination of atherogenic diet (6 months) and balloon injury. All coronary arteries were imaged ex vivo on the intact heart, preserving the curvature of their course. The aorta also underwent MR imaging. The MR images were correlated with the matched histopathology sections for both the coronary arteries (n=54) and the aortas (n=43). MR imaging accurately characterized complex atherosclerotic lesions, including calcified, lipid rich, fibrocellular and hemorrhagic regions. Mean wall thickness for the coronary arteries (r=0.94, slope: 0.81) and aortas (r=0.94, slope: 0.81) as well as aortic plaque area (r=0.97, slope: 0.90) was accurately determined by MR imaging (P<0.0001). Coronary artery MR imaging is not limited by the curvature of the coronary arteries in the heart. MR imaging accurately quantifies and characterizes coronary and aortic atherosclerotic lesions, including the vessel wall, in this experimental porcine model of complex atherosclerosis. This model may be useful for future study of MR imaging of atherosclerosis in vivo.

Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model.

BACKGROUND: The ability to characterize and quantify coronary artery atherosclerotic lesions accurately, reproducibly, and noninvasively may allow the stratification of risk for future acute coronary syndromes and help direct therapeutic management. MRI has been shown to accurately characterize and quantify atherosclerosis; however, because of the combination of cardiac and respiratory motion artifacts, nonlinear course, and relatively small size of the coronary arteries, these techniques have not been able to be translated to the coronary system in vivo. METHODS AND RESULTS: Coronary lesions were induced in Yorkshire albino swine (n=6) with balloon angioplasty, and 4 weeks later MRI of the coronary artery lesions was performed. High-resolution in vivo images of the coronary artery wall and lesions were obtained with a double-inversion-recovery fast-spin-echo sequence in a 1.5-T MR system. There was good agreement between measurements of vessel wall thickness and area from MR images of the coronary arteries and the matched histopathology sections (n=43). The mean difference (MRI minus histopathology +/- SD) for mean wall thickness was 0.26+/-0.18 mm, and for vessel wall area, 5.65+/-3.51 mm(2). MRI was also able to visualize intralesion hematoma (sensitivity 82%, specificity 84%). CONCLUSIONS: Using a clinical MR system, we were able to image coronary artery lesions in vivo in an experimental porcine model. Further studies are needed to assess the ability of MRI to characterize coronary atherosclerotic lesions in vivo.

Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification.

BACKGROUND: Atrial fibrillation (AF) occurs in 20% to 40% of patients after CABG. Identification of patients vulnerable for arrhythmia will allow targeting of those most likely to benefit from prophylactic therapy. The aim of the present study was to evaluate accuracy of a prospectively defined signal-averaged P-wave duration (SAPD) cutoff and additional preoperative characteristics for the prediction of AF after CABG. METHODS AND RESULTS: Patients undergoing elective isolated CABG were recruited to the present prospective study. SAPD was recorded in all patients. Filtered signals from 3 orthogonal leads were combined in a vector analysis, and total SAPD was measured preoperatively. Postoperative in-hospital AF occurred in 92 (28.2%) of 326 patients. Patients who developed AF were older (65.9 versus 61.7 years of age; P<0.0005) and had longer SAPD (158 versus 145 ms; P<0.0005) than non-AF patients. Incidence of AF increased in patients > or =75 years of age and increased progressively throughout the range of SAPD. Stepwise logistic regression analysis of preoperative variables identified that SAPD >155 ms (odds ratio, 5.37; 95% CI, 3.10 to 9.30; P<0.0005), advanced age (odds ratio, 1. 53; 95% CI, 1.26 to 1.86 per 5-year increase in age; P<0.0005), and male sex (odds ratio, 2.88; 95% CI, 1.30 to 6.40; P<0.01) independently predicted AF. Prospectively defined SAPD >155 ms predicted AF with positive and negative predictive accuracy of 49% and 84%, respectively. CONCLUSIONS: A combination of prolonged SAPD, advanced age, and male sex identifies patients at high risk for development of AF after CABG.