Juan Gaztanaga

Antithrombotic effects of factor Xa inhibition with DU-176b : Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber

Direct and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.

Usefulness of Cardiac Computed Tomographic Delayed Contrast Enhancement of the Left Atrial Appendage Before Pulmonary Vein Ablation

Left atrial appendage (LAA) contrast filling defects are commonly found in patients undergoing multidetector cardiac computed tomography (CCT) before catheter ablation of atrial fibrillation. Delayed CCT allows quantification of the LAA delayed/initial attenuation ratio and improves accuracy for LAA thrombus detection, which may obviate routine transesophageal echocardiography (TEE) before ablation. CCT with contrast-enhanced scans (initial CCT) and with noncontrast-enhanced scans (delayed CCT) was performed in 176 patients. LAA was evaluated for filling defects. LAA apex, left atrial (LA) body, and ascending aorta (AA) attenuations (Hounsfield units) were measured on initial and delayed cardiac computed tomograms to calculate LAA, LA, LAA/LA, and LAA/AA attenuation ratios. LAA, initial LAA/LA, and initial LAA/AA attenuation ratios differed significantly in patients with versus without filling defects on cardiac computed tomogram, those with atrial fibrillation versus normal sinus rhythm, and those with abnormal left ventricular ejection fraction versus larger LA volumes (p <0.05). In 70 patients (40%) who underwent TEE, 13 LAA filling defects were seen on initial cardiac computed tomogram. Two defects persisted on delayed cardiac computed tomogram and thrombus was confirmed on transesophageal echocardiogram. Sensitivity, specificity, and positive and negative predictive values of initial CCT for LAA thrombi detection were 100%, 84%, 15%, and 100%, respectively. With delayed CCT these values increased to 100%. Intraobserver and interobserver reproducibilities for cardiac computed tomographic measurements were good (intraclass correlation 0.72 to 0.97, kappa coefficients 0.93 to 1.00). In conclusion, delayed CCT provided an increase in diagnostic accuracy of CCT for detection of LAA thrombus in patients with atrial fibrillation before ablation, which may decrease the need for routine TEE before the procedure.

A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome

OBJECTIVE Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET. METHODS A Phase II, randomized, double-blind, parallel-group study was conducted in 52 patients with recent ACS assigned 1:1 to either 100 mg VIA-2291 or placebo for 24 weeks. The primary outcome was the effect of VIA-2291 relative to placebo on arterial inflammation detected by (18)fluorodeoxyglucose positron emission tomography (FDG-PET) within the index vessel after 24 weeks of daily treatment, compared to baseline. RESULTS VIA-2291 was relatively well tolerated and was associated with a significant inhibition of the potent chemo-attractant LTB4, with a mean inhibition of activity of 92.8% (p<0.0001) at 6 weeks in the VIA-2291 group, without further significant change in inhibition at 24 weeks. However, for VIA-2291 was not associated with significant difference in inflammation (target-to-background ratio) compared to placebo at 24 weeks or 6 weeks of treatment. Further, VIA-2291 was not associated with a significant reduction in hsCRP from baseline after either 6 or 24 weeks of treatment. CONCLUSIONS VIA-2291 is well-tolerated and effectively reduces leukotriene production. However, inhibition of 5-LO with VIA-2291 is not associated with significant reductions in vascular inflammation (by FDG-PET) or in blood inflammatory markers. Accordingly, this study does not provide evidence to support a significant anti-inflammatory effect of VIA-2291 in patients with recent ACS.

Clinical and Experimental Experience with Factor Xa Inhibitors

Cardiovascular disease is the major cause of mortality in the industrial world today. We are constantly moving towards new and better ways of fighting this epidemic. Advances have been made in various fields such as patient education, imaging techniques, interventional cardiology, and novel therapeutic agents. In particular, antithrombotics are being studied with great interest and hope. Amid this class of agents, factor Xa inhibitors have already begun to show promising results in trials involving patients with acute coronary syndromes. Whereas DX-9065a is in late stage clinical trials, fondaparinux sodium is available for clinical use. Promising results have been obtained with fondaparinux sodium in patients with coronary artery disease in the PENTUA (Pentasaccharide in Unstable Angina) and PENTALYSE (Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction) trials. Besides having a direct effect on the coagulation cascade, they have shown properties that indirectly influence the remodeling of plaques in the coronary circulation. Available evidence on factor Xa inhibitors does not ensure a remedy to acute coronary syndromes but it gives hope of improving current treatments and reducing the morbidity and mortality of cardiovascular disease.The efficacy and tolerability of fondaparinux sodium in the prevention and treatment of deep vein thrombosis (with or without pulmonary embolism) has been established in several large trials such as PENTATHLON (Pentasaccharide in Total Hip Replacement Surgery), PENTAMAKS (Pentasaccharide in Major Knee Surgery), EPHESUS (European Pentasaccharide Hip Elective Surgery), PENTHIFRA (Pentasaccharide in Hip-Fracture Surgery), and PENTHIFRA-Plus. Whereas fondaparinux sodium offers benefits over low molecular weight heparins and unfractionated heparin, the incidence of bleeding complications was greater with fondaparinux sodium than with unfractionated heparin. Treatment with factor VIIa can reverse the anticoagulant effect of fondaparinux sodium and this may be particularly important in patients who need to undergo emergency surgical procedures. Fondaparinux sodium has been recently approved for use, in conjunction with warfarin, in patients with symptomatic deep vein thrombosis or acute pulmonary embolism based on the results of two large trials conducted by the Matisse investigators. In conclusion, these observations strongly suggest the clinical potential of this class of agents in preventing arterial and venous thrombosis.

Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial

Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher‐risk patients who otherwise may not be candidates for such a therapeutic approach. In this double‐blind, randomized, placebo‐controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4‐week period). The co‐primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24‐hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA‐IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event‐based trials.

Is intra‐procedure three‐dimensional transesophageal echocardiogram an alternative to preprocedure multidetector computed tomography for the measurement of the aortic annulus in patients undergoing transcatheter aortic valve replacement?

The role of three‐dimensional transesophageal echocardiography (3DTEE) vs multidetector computed tomography (MDCT) in aortic annular sizing has been poorly defined in patients undergoing transcatheter aortic valve replacements (TAVR). We set to determine the correlation between 3DTEE and MDCT in measuring the aortic annulus prior to TAVR.

Cardiac MRI in Diagnosis and Management

Cardiac magnetic resonance imaging (CMR) is an essential tool in the diagnosis, risk stratification and treatment of patients with hypertrophic cardiomyopathy (HCM). CMR works by manipulating protons found in myocytes and contrast agents such as Gadolinium, using magnetic pull to create and then detect energy differences and thus obtain images. CMR is ideal for detecting the location and extent of hypertrophy, presence or absence of membranes, the distribution of fibrosis and the anatomy and physiology of the mitral valve, all of which are crucial for diagnosis of HCM, which can be missed on standard echocardiography. This is especially true for hard to see areas of the heart such as the apical area as well as atypical presentations such as focal segmental hypertrophy or mass-like HCM. Additionally, extremely accurate assessments of the left ventricular volumes, mass and function are prognostic as well as diagnostic. Magnetic resonance tagging and delayed-enhancement with Gadolinium allow for strain and perfusion analysis, further increasing the utility of CMR to detect regional function and cardiac microvascular ischemia, of which HCM patients are particularly susceptible. Delayed enhancement distribution and extent may also impact risk stratification for sudden cardiac death. Limitations of CMR include assessment of the left ventricular outflow tract gradient and highly mobile structures on the mitral valve, although newer protocols and improved technology may be able to compensate for these deficits in the future.

INCREASED CARDIAC READMISSIONS IN PATIENTS WITH LEFT VENTRICULAR NONCOMPACTION COMPARED TO NONISCHEMIC CARDIOMYOPATHY

Left ventricular noncompaction (LVNC) is an incompletely understood form of cardiomyopathy that can lead to heart failure, ventricular arrhythmias, and sudden cardiac death; however, outcome studies in this disease are lacking. Therefore we examined patients found to have cardiomyopathy by cardiac

ASSESSMENT OF CHANGE IN CLINICAL PRACTICE USING THE UPDATED 2009 AMERICAN COLLEGE OF CARDIOLOGY/ AMERICAN SOCIETY OF NUCLEAR CARDIOLOGY FOR APPROPRIATENESS CRITERIA SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY MYOCARDIAL PERFUSION IMAGING

In 2009 the American College of Cardiology/ American Society of Nuclear Cardiology (ACC/ASNC) updated the 2005 appropriateness criteria categorizing the various indications for the performance of Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT MPI). We sought to

IMPACT OF THE UPDATED 2009 AMERICAN COLLEGE OF CARDIOLOGY/ AMERICAN SOCIETY OF NUCLEAR CARDIOLOGY APPROPRIATENESS CRITERIA FOR SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY MYOCARDIAL PERFUSION IMAGING

In 2009 the American College of Cardiology/ American Society of Nuclear Cardiology (ACC/ASNC) updated the 2005 appropriateness criteria categorizing the various indications for the performance of Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT MPI). We sought to