Analytic Considerations in Economic Evaluations of Multinational Cardiovascular Clinical Trials

OBJECTIVES: The growing number of economic evaluations that use data collected in multinational clinical trials raises numerous questions regarding their execution and interpretation. Although recommendations for conducting economic evaluations have been widely disseminated, relatively little guidance has been given for conducting economic evaluations alongside clinical trials, particularly multinational trials. METHODS: Building on a literature review that was conducted in preparation for an expert workshop, we evaluated a subset of methodological issues related to conducting economic evaluations alongside multinational clinical trials. RESULTS: We found wide variation in the types of costs included as part of the analyses and in the methods used to assign costs to hospitalization events. Furthermore, we found that the extrapolation of costs and survival outcomes beyond the trial period is an inconsistent practice and is often not dependent on whether a survival benefit was observed in the trial or on the epidemiology or practice patterns in the country to which the findings are directed. CONCLUSIONS: Although the limited sample size precluded a quantitative analysis of trial characteristics and their associations with the methodologies employed, our findings highlight the need for more guidance to analysts regarding the execution of economic evaluations using data from multinational clinical trials. As the research community grapples with the complexities of methodological and logistical issues involved in multinational economic evaluations, the development of a standardized format to report the basic methodological characteristics of such studies would help to improve transparency and comparability for other analysts and decision-makers

Effect of DOX on rat physical parameters and EF measurements (mean ± standard error of the mean.

<p>Number of animals in treatment group at any given time is indicated within the parentheses.</p><p>Average appearance score of animals in study, where 1  =  excellent, active; 2  =  good: active, slight hair loss; 3  =  fair: less active, slight bloating; 4  =  poor: reluctant to move, poor appetite and diarrhea; 5  =  critical: marked pallor, lethargic.</p>*<p>increase in weight relative to baseline <i>p</i><0.0001</p>**<p>decrease in weight relative to baseline <i>p</i>≤0.001</p><p>#increase in appearance score relative to baseline <i>p</i><0.0001</p>†<p>decrease in LVEF relative to baseline <i>p</i> = 0.005</p>‡<p>decrease in LVEF relative to baseline <i>p</i> = 0.01</p

Effect of Doxorubicin (DOX) on coronary artery lumen diameter, medial thickness, adventitial thickness and total wall thickness.

<p>Low Doxorubicin: 1.5 mg/kg to 1.75 mg/kg</p><p>High Doxorubicin: 2.5 mg/kg</p><p>Values are expressed as the unadjusted mean ± SEM. All statistical comparisons shown are between different doxorubicin doses to normal saline (*<i>p</i> = 0.02, **<i>p</i> = 0.005 in comparison to normal saline).</p

Acquisition of histological samples.

<p>Schematic representation that illustrates the location, selection, and analysis method of the histological specimens used to measure arteriolar wall thickness. Sectioned histologic specimens were obtained in a short axis plane located ½ the distance between the mitral annulus and the apex of the left ventricle (top left). In the top right panel, a low resolution image of the rat myocardium at 2x with high resolution is shown with an insert of a coronary arteriolar vessel at 20x (bottom right). Values for individual artery lumen, medial and adventitial circumferences (LC, MC, and AC, respectively) were obtained by tracing the region of interest using the digital imaging analysis program NDP.view (indicated in green, bottom right). The bottom left panel shows how the circumference data were used to find the lumen, medial, and adventitial radii (LR, MR, and AR, respectively) in order to calculate average diameters and wall thickness.</p

Effect of Doxorubicin (DOX) on coronary artery medial thickness, adventitial thickness and total wall thickness: normalized to lumen diameter.

<p>Low Doxorubicin: 1.5 mg/kg to 1.75 mg/kg</p><p>High Doxorubicin: 2.5 mg/kg</p><p>Values are expressed as the unadjusted mean ± SEM. All statistical comparisons shown are between different doxorubicin doses to normal saline (*<i>p</i><0.05, **<i>p</i><0.01, and ***<i>p</i><0.001).</p

Coronary arteriolar histology in saline versus Doxorubicin sample.

<p>Coronary arteriolar histology from an animal treated with normal saline (1cc/week) for 7–10 weeks (left) with a coronary arteriole obtained from an animal treated with 2.5 mg/kg/week of doxorubicin for 10 weeks (right). Compared with the normal saline treated artery, the doxorubicin treated artery has increased medial and adventitial thickness.</p

Non-Invasive Detection of Early Retinal Neuronal Degeneration by Ultrahigh Resolution Optical Coherence Tomography

Optical coherence tomography (OCT) has revolutionises the diagnosis of retinal disease based on the detection of microscopic rather than subcellular changes in retinal anatomy. However, currently the technique is limited to the detection of microscopic rather than subcellular changes in retinal anatomy. However, coherence based imaging is extremely sensitive to both changes in optical contrast and cellular events at the micrometer scale, and can generate subtle changes in the spectral content of the OCT image. Here we test the hypothesis that OCT image speckle (image texture) contains information regarding otherwise unresolvable features such as organelle changes arising in the early stages of neuronal degeneration. Using ultrahigh resolution (UHR) OCT imaging at 800 nm (spectral width 140 nm) we developed a robust method of OCT image analyses, based on spatial wavelet and texture-based parameterisation of the image speckle pattern. For the first time we show that this approach allows the non-invasive detection and quantification of early apoptotic changes in neurons within 30 min of neuronal trauma sufficient to result in apoptosis. We show a positive correlation between immunofluorescent labelling of mitochondria (a potential source of changes in cellular optical contrast) with changes in the texture of the OCT images of cultured neurons. Moreover, similar changes in optical contrast were also seen in the retinal ganglion cell- inner plexiform layer in retinal explants following optic nerve transection. The optical clarity of the explants was maintained throughout in the absence of histologically detectable change. Our data suggest that UHR OCT can be used for the non-invasive quantitative assessment of neuronal health, with a particular application to the assessment of early retinal disease

Iron and Cancer: More Ore To Be Mined

Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy