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The importance of spatially-localized and quantified image interpretation in cancer management

The importance of spatially-localized and quantified image interpretation in cancer management

Writer & reporter: Dror Nir, PhD

I became involved in the development of quantified imaging-based tissue characterization more than a decade ago. From the start, it was clear to me that what clinicians needs will not be answered by just identifying whether a certain organ harbors cancer. If imaging devices are to play a significant role in future medicine, as a complementary source of information to bio-markers and gene sequencing the minimum value expected of them is accurate directing of biopsy needles and treatment tools to the malignant locations in the organ. Therefore, the design goal of the first Prostate-HistoScanning (“PHS”) version I went into the trouble of characterizing localized volume of tissue at the level of approximately 0.1cc (1x1x1 mm). Thanks to that, the imaging-interpretation overlay of PHS localizes the suspicious lesions with accuracy of 5mm within the prostate gland; Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(™).

I then started a more ambitious research aiming to explore the feasibility of identifying sub-structures within the cancer lesion itself. The preliminary results of this exploration were so promising that it surprised not only the clinicians I was working with but also myself. It seems, that using quality ultrasound, one can find Imaging-Biomarkers that allows differentiation of inside structures of a cancerous lesions. Unfortunately, for everyone involved in this work, including me, this scientific effort was interrupted by financial constrains before reaching maturity.

My short introduction was made to explain why I find the publication below important enough to post and bring to your attention.

I hope for your agreement on the matter.

Quantitative Imaging in Cancer Evolution and Ecology

Robert A. Gatenby, MD, Olya Grove, PhD and Robert J. Gillies, PhD

From the Departments of Radiology and Cancer Imaging and Metabolism, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612. Address correspondence to R.A.G. (e-mail: Robert.Gatenby@Moffitt.org).

Abstract

Cancer therapy, even when highly targeted, typically fails because of the remarkable capacity of malignant cells to evolve effective adaptations. These evolutionary dynamics are both a cause and a consequence of cancer system heterogeneity at many scales, ranging from genetic properties of individual cells to large-scale imaging features. Tumors of the same organ and cell type can have remarkably diverse appearances in different patients. Furthermore, even within a single tumor, marked variations in imaging features, such as necrosis or contrast enhancement, are common. Similar spatial variations recently have been reported in genetic profiles. Radiologic heterogeneity within tumors is usually governed by variations in blood flow, whereas genetic heterogeneity is typically ascribed to random mutations. However, evolution within tumors, as in all living systems, is subject to Darwinian principles; thus, it is governed by predictable and reproducible interactions between environmental selection forces and cell phenotype (not genotype). This link between regional variations in environmental properties and cellular adaptive strategies may permit clinical imaging to be used to assess and monitor intratumoral evolution in individual patients. This approach is enabled by new methods that extract, report, and analyze quantitative, reproducible, and mineable clinical imaging data. However, most current quantitative metrics lack spatialness, expressing quantitative radiologic features as a single value for a region of interest encompassing the whole tumor. In contrast, spatially explicit image analysis recognizes that tumors are heterogeneous but not well mixed and defines regionally distinct habitats, some of which appear to harbor tumor populations that are more aggressive and less treatable than others. By identifying regional variations in key environmental selection forces and evidence of cellular adaptation, clinical imaging can enable us to define intratumoral Darwinian dynamics before and during therapy. Advances in image analysis will place clinical imaging in an increasingly central role in the development of evolution-based patient-specific cancer therapy.

Introduction

Cancers are heterogeneous across a wide range of temporal and spatial scales. Morphologic heterogeneity between and within cancers is readily apparent in clinical imaging, and subjective descriptors of these differences, such as necrotic, spiculated, and enhancing, are common in the radiology lexicon. In the past several years, radiology research has increasingly focused on quantifying these imaging variations in an effort to understand their clinical and biologic implications (1,2). In parallel, technical advances now permit extensive molecular characterization of tumor cells in individual patients. This has led to increasing emphasis on personalized cancer therapy, in which treatment is based on the presence of specific molecular targets (3). However, recent studies (4,5) have shown that multiple genetic subpopulations coexist within cancers, reflecting extensive intratumoral somatic evolution. This heterogeneity is a clear barrier to therapy based on molecular targets, since the identified targets do not always represent the entire population of tumor cells in a patient (6,7). It is ironic that cancer, a disease extensively and primarily analyzed genetically, is also the most genetically flexible of all diseases and, therefore, least amenable to such an approach.

Genetic variations in tumors are typically ascribed to a mutator phenotype that generates new clones, some of which expand into large populations (8). However, although identification of genotypes is of substantial interest, it is insufficient for complete characterization of tumor dynamics because evolution is governed by the interactions of environmental selection forces with the phenotypic, not genotypic, properties of populations as shown, for example, by evolutionary convergence to identical phenotypes among cave fish even when they are from different species (9–11). This connection between tissue selection forces and cellular properties has the potential to provide a strong bridge between medical imaging and the cellular and molecular properties of cancers.

We postulate that differences within tumors at different spatial scales (ie, at the radiologic, cellular, and molecular [genetic] levels) are related. Tumor characteristics observable at clinical imaging reflect molecular-, cellular-, and tissue-level dynamics; thus, they may be useful in understanding the underlying evolving biology in individual patients. A challenge is that such mapping across spatial and temporal scales requires not only objective reproducible metrics for imaging features but also a theoretical construct that bridges those scales (Fig 1).

Figure 1a: Computed tomographic (CT) scan of right upper lobe lung cancer in a 50-year-old woman.

Figure 1b: Isoattenuation map shows regional heterogeneity at the tissue scale (measured in centimeters).

Figure 1c & 1d: (c, d)Whole-slide digital images (original magnification, ×3) of a histologic slice of the same tumor at the mesoscopic scale (measured in millimeters) (c) coupled with a masked image of regional morphologic differences showing spatial heterogeneity (d).

Figure 1e: Subsegment of the whole slide image shows the microscopic scale (measured in micrometers) (original magnification, ×50).

Figure 1f: Pattern recognition masked image shows regional heterogeneity. In a, the CT image of non–small cell lung cancer can be analyzed to display gradients of attenuation, which reveals heterogeneous and spatially distinct environments (b). Histologic images in the same patient (c, e) reveal heterogeneities in tissue structure and density on the same scale as seen in the CT images. These images can be analyzed at much higher definition to identify differences in morphologies of individual cells (3), and these analyses reveal clusters of cells with similar morphologic features (d, f). An important goal of radiomics is to bridge radiologic data with cellular and molecular characteristics observed microscopically.

To promote the development and implementation of quantitative imaging methods, protocols, and software tools, the National Cancer Institute has established the Quantitative Imaging Network. One goal of this program is to identify reproducible quantifiable imaging features of tumors that will permit data mining and explicit examination of links between the imaging findings and the underlying molecular and cellular characteristics of the tumors. In the quest for more personalized cancer treatments, these quantitative radiologic features potentially represent nondestructive temporally and spatially variable predictive and prognostic biomarkers that readily can be obtained in each patient before, during, and after therapy.

Quantitative imaging requires computational technologies that can be used to reliably extract mineable data from radiographic images. This feature information can then be correlated with molecular and cellular properties by using bioinformatics methods. Most existing methods are agnostic and focus on statistical descriptions of existing data, without presupposing the existence of specific relationships. Although this is a valid approach, a more profound understanding of quantitative imaging information may be obtained with a theoretical hypothesis-driven framework. Such models use links between observable tumor characteristics and microenvironmental selection factors to make testable predictions about emergent phenotypes. One such theoretical framework is the developing paradigm of cancer as an ecologic and evolutionary process.

For decades, landscape ecologists have studied the effects of heterogeneity in physical features on interactions between populations of organisms and their environments, often by using observation and quantification of images at various scales (12–14). We propose that analytic models of this type can easily be applied to radiologic studies of cancer to uncover underlying molecular, cellular, and microenvironmental drivers of tumor behavior and specifically, tumor adaptations and responses to therapy (15).

In this article, we review recent developments in quantitative imaging metrics and discuss how they correlate with underlying genetic data and clinical outcomes. We then introduce the concept of using ecology and evolutionary models for spatially explicit image analysis as an exciting potential avenue of investigation.

Quantitative Imaging and Radiomics

In patients with cancer, quantitative measurements are commonly limited to measurement of tumor size with one-dimensional (Response Evaluation Criteria in Solid Tumors [or RECIST]) or two-dimensional (World Health Organization) long-axis measurements (16). These measures do not reflect the complexity of tumor morphology or behavior, and in many cases, changes in these measures are not predictive of therapeutic benefit (17). In contrast, radiomics (18) is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form (Figs 1, 2). Once transformed into a quantitative form, radiologic tumor properties can be linked to underlying genetic alterations (the field is called radiogenomics) (19–21) and to medical outcomes (22–27). Researchers are currently working to develop both a standardized lexicon to describe tumor features (28,29) and a standard method to convert these descriptors into quantitative mineable data (30,31) (Fig 3).

Figure 2: Contrast-enhanced CT scans show non–small cell lung cancer (left) and corresponding cluster map (right). Subregions within the tumor are identified by clustering pixels based on the attenuation of pixels and their cumulative standard deviation across the region. While the entire region of interest of the tumor, lacking the spatial information, yields a weighted mean attenuation of 859.5 HU with a large and skewed standard deviation of 243.64 HU, the identified subregions have vastly different statistics. Mean attenuation was 438.9 HU ± 45 in the blue subregion, 210.91 HU ± 79 in the yellow subregion, and 1077.6 HU ± 18 in the red subregion.

Figure 3: Chart shows the five processes in radiomics.

Several recent articles underscore the potential power of feature analysis. After manually extracting more than 100 CT image features, Segal and colleagues found that a subset of 14 features predicted 80% of the gene expression pattern in patients with hepatocellular carcinoma (21). A similar extraction of features from contrast agent–enhanced magnetic resonance (MR) images of glioblastoma was used to predict immunohistochemically identified protein expression patterns (22). Other radiomic features, such as texture, can be used to predict response to therapy in patients with renal cancer (32) and prognosis in those with metastatic colon cancer (33).

These pioneering studies were relatively small because the image analysis was performed manually, and the studies were consequently underpowered. Thus, recent work in radiomics has focused on technical developments that permit automated extraction of image features with the potential for high throughput. Such methods, which rely heavily on novel machine learning algorithms, can more completely cover the range of quantitative features that can describe tumor heterogeneity, such as texture, shape, or margin gradients or, importantly, different environments, or niches, within the tumors.

Generally speaking, texture in a biomedical image is quantified by identifying repeating patterns. Texture analyses fall into two broad categories based on the concepts of first- and second-order spatial statistics. First-order statistics are computed by using individual pixel values, and no relationships between neighboring pixels are assumed or evaluated. Texture analysis methods based on first-order statistics usually involve calculating cumulative statistics of pixel values and their histograms across the region of interest. Second-order statistics, on the other hand, are used to evaluate the likelihood of observing spatially correlated pixels (34). Hence, second-order texture analyses focus on the detection and quantification of nonrandom distributions of pixels throughout the region of interest.

The technical developments that permit second-order texture analysis in tumors by using regional enhancement patterns on dynamic contrast-enhanced MR images were reviewed recently (35). One such technique that is used to measure heterogeneity of contrast enhancement uses the Factor Analysis of Medical Image Sequences (or FAMIS) algorithm, which divides tumors into regions based on their patterns of enhancement (36). Factor Analysis of Medical Image Sequences–based analyses yielded better prognostic information when compared with region of interest–based methods in numerous cancer types (19–21,37–39), and they were a precursor to the Food and Drug Administration–approved three-time-point method (40). A number of additional promising methods have been developed. Rose and colleagues showed that a structured fractal-based approach to texture analysis improved differentiation between low- and high-grade brain cancers by orders of magnitude (41). Ahmed and colleagues used gray level co-occurrence matrix analyses of dynamic contrast-enhanced images to distinguish benign from malignant breast masses with high diagnostic accuracy (area under the receiver operating characteristic curve, 0.92) (26). Others have shown that Minkowski functional structured methods that convolve images with differently kernelled masks can be used to distinguish subtle differences in contrast enhancement patterns and can enable significant differentiation between treatment groups (42).

It is not surprising that analyses of heterogeneity in enhancement patterns can improve diagnosis and prognosis, as this heterogeneity is fundamentally based on perfusion deficits, which generate significant microenvironmental selection pressures. However, texture analysis is not limited to enhancement patterns. For example, measures of heterogeneity in diffusion-weighted MR images can reveal differences in cellular density in tumors, which can be matched to histologic findings (43). Measures of heterogeneity in T1- and T2-weighted images can be used to distinguish benign from malignant soft-tissue masses (23). CT-based texture features have been shown to be highly significant independent predictors of survival in patients with non–small cell lung cancer (24).

Texture analyses can also be applied to positron emission tomographic (PET) data, where they can provide information about metabolic heterogeneity (25,26). In a recent study, Nair and colleagues identified 14 quantitative PET imaging features that correlated with gene expression (19). This led to an association of metagene clusters to imaging features and yielded prognostic models with hazard ratios near 6. In a study of esophageal cancer, in which 38 quantitative features describing fluorodeoxyglucose uptake were extracted, measures of metabolic heterogeneity at baseline enabled prediction of response with significantly higher sensitivity than any whole region of interest standardized uptake value measurement (22). It is also notable that these extensive texture-based features are generally more reproducible than simple measures of the standardized uptake value (27), which can be highly variable in a clinical setting (44).

Spatially Explicit Analysis of Tumor Heterogeneity

Although radiomic analyses have shown high prognostic power, they are not inherently spatially explicit. Quantitative border, shape, and texture features are typically generated over a region of interest that comprises the entire tumor (45). This approach implicitly assumes that tumors are heterogeneous but well mixed. However, spatially explicit subregions of cancers are readily apparent on contrast-enhanced MR or CT images, as perfusion can vary markedly within the tumor, even over short distances, with changes in tumor cell density and necrosis.

An example is shown in Figure 2, which shows a contrast-enhanced CT scan of non–small cell lung cancer. Note that there are many subregions within this tumor that can be identified with attenuation gradient (attenuation per centimeter) edge detection algorithms. Each subregion has a characteristic quantitative attenuation, with a narrow standard deviation, whereas the mean attenuation over the entire region of interest is a weighted average of the values across all subregions, with a correspondingly large and skewed distribution. We contend that these subregions represent distinct habitats within the tumor, each with a distinct set of environmental selection forces.

These observations, along with the recent identification of regional variations in the genetic properties of tumor cells, indicate the need to abandon the conceptual model of cancers as bounded organlike structures. Rather than a single self-organized system, cancers represent a patchwork of habitats, each with a unique set of environmental selection forces and cellular evolution strategies. For example, regions of the tumor that are poorly perfused can be populated by only those cells that are well adapted to low-oxygen, low-glucose, and high-acid environmental conditions. Such adaptive responses to regional heterogeneity result in microenvironmental selection and hence, emergence of genetic variations within tumors. The concept of adaptive response is an important departure from the traditional view that genetic heterogeneity is the product of increased random mutations, which implies that molecular heterogeneity is fundamentally unpredictable and, therefore, chaotic. The Darwinian model proposes that genetic heterogeneity is the result of a predictable and reproducible selection of successful adaptive strategies to local microenvironmental conditions.

Current cross-sectional imaging modalities can be used to identify regional variations in selection forces by using contrast-enhanced, cell density–based, or metabolic features. Clinical imaging can also be used to identify evidence of cellular adaptation. For example, if a region of low perfusion on a contrast-enhanced study is necrotic, then an adaptive population is absent or minimal. However, if the poorly perfused area is cellular, then there is presumptive evidence of an adapted proliferating population. While the specific genetic properties of this population cannot be determined, the phenotype of the adaptive strategy is predictable since the environmental conditions are more or less known. Thus, standard medical images can be used to infer specific emergent phenotypes and, with ongoing research, these phenotypes can be associated with underlying genetic changes.

This area of investigation will likely be challenging. As noted earlier, the most obvious spatially heterogeneous imaging feature in tumors is perfusion heterogeneity on contrast-enhanced CT or MR images. It generally has been assumed that the links between contrast enhancement, blood flow, perfusion, and tumor cell characteristics are straightforward. That is, tumor regions with decreased blood flow will exhibit low perfusion, low cell density, and high necrosis. In reality, however, the dynamics are actually much more complex. As shown in Figure 4, when using multiple superimposed sequences from MR imaging of malignant gliomas, regions of tumor that are poorly perfused on contrast-enhanced T1-weighted images may exhibit areas of low or high water content on T2-weighted images and low or high diffusion on diffusion-weighted images. Thus, high or low cell densities can coexist in poorly perfused volumes, creating perfusion-diffusion mismatches. Regions with poor perfusion with high cell density are of particular clinical interest because they represent a cell population that is apparently adapted to microenvironmental conditions associated with poor perfusion. The associated hypoxia, acidosis, and nutrient deprivation select for cells that are resistant to apoptosis and thus are likely to be resistant to therapy (46,47).

Figure 4: Left: Contrast-enhanced T1 image from subject TCGA-02-0034 in The Cancer Genome Atlas–Glioblastoma Multiforme repository of MR volumes of glioblastoma multiforme cases. Right: Spatial distribution of MR imaging–defined habitats within the tumor. The blue region (low T1 postgadolinium, low fluid-attenuated inversion recovery) is particularly notable because it presumably represents a habitat with low blood flow but high cell density, indicating a population presumably adapted to hypoxic acidic conditions.

Furthermore, other selection forces not related to perfusion are likely to be present within tumors. For example, evolutionary models suggest that cancer cells, even in stable microenvironments, tend to speciate into “engineers” that maximize tumor cell growth by promoting angiogenesis and “pioneers” that proliferate by invading normal issue and co-opting the blood supply. These invasive tumor phenotypes can exist only at the tumor edge, where movement into a normal tissue microenvironment can be rewarded by increased proliferation. This evolutionary dynamic may contribute to distinct differences between the tumor edges and the tumor cores, which frequently can be seen at analysis of cross-sectional images (Fig 5).

Figure 5a: CT images obtained with conventional entropy filtering in two patients with non–small cell lung cancer with no apparent textural differences show similar entropy values across all sections.

Figure 5b: Contour plots obtained after the CT scans were convolved with the entropy filter. Further subdividing each section in the tumor stack into tumor edge and core regions (dotted black contour) reveals varying textural behavior across sections. Two distinct patterns have emerged, and preliminary analysis shows that the change of mean entropy value between core and edge regions correlates negatively with survival.

Interpretation of the subsegmentation of tumors will require computational models to understand and predict the complex nonlinear dynamics that lead to heterogeneous combinations of radiographic features. We have exploited ecologic methods and models to investigate regional variations in cancer environmental and cellular properties that lead to specific imaging characteristics. Conceptually, this approach assumes that regional variations in tumors can be viewed as a coalition of distinct ecologic communities or habitats of cells in which the environment is governed, at least to first order, by variations in vascular density and blood flow. The environmental conditions that result from alterations in blood flow, such as hypoxia, acidosis, immune response, growth factors, and glucose, represent evolutionary selection forces that give rise to local-regional phenotypic adaptations. Phenotypic alterations can result from epigenetic, genetic, or chromosomal rearrangements, and these in turn will affect prognosis and response to therapy. Changes in habitats or the relative abundance of specific ecologic communities over time and in response to therapy may be a valuable metric with which to measure treatment efficacy and emergence of resistant populations.

Emerging Strategies for Tumor Habitat Characterization

A method for converting images to spatially explicit tumor habitats is shown in Figure 4. Here, three-dimensional MR imaging data sets from a glioblastoma are segmented. Each voxel in the tumor is defined by a scale that includes its image intensity in different sequences. In this case, the imaging sets are from (a) a contrast-enhanced T1 sequence, (b) a fast spin-echo T2 sequence, and (c) a fluid-attenuated inversion-recovery (or FLAIR) sequence. Voxels in each sequence can be defined as high or low based on their value compared with the mean signal value. By using just two sequences, a contrast-enhanced T1 sequence and a fluid-attenuated inversion-recovery sequence, we can define four habitats: high or low postgadolinium T1 divided into high or low fluid-attenuated inversion recovery. When these voxel habitats are projected into the tumor volume, we find they cluster into spatially distinct regions. These habitats can be evaluated both in terms of their relative contributions to the total tumor volume and in terms of their interactions with each other, based on the imaging characteristics at the interfaces between regions. Similar spatially explicit analysis can be performed with CT scans (Fig 5).

Analysis of spatial patterns in cross-sectional images will ultimately require methods that bridge spatial scales from microns to millimeters. One possible method is a general class of numeric tools that is already widely used in terrestrial and marine ecology research to link species occurrence or abundance with environmental parameters. Species distribution models (48–51) are used to gain ecologic and evolutionary insights and to predict distributions of species or morphs across landscapes, sometimes extrapolating in space and time. They can easily be used to link the environmental selection forces in MR imaging-defined habitats to the evolutionary dynamics of cancer cells.

Summary

Imaging can have an enormous role in the development and implementation of patient-specific therapies in cancer. The achievement of this goal will require new methods that expand and ultimately replace the current subjective qualitative assessments of tumor characteristics. The need for quantitative imaging has been clearly recognized by the National Cancer Institute and has resulted in formation of the Quantitative Imaging Network. A critical objective of this imaging consortium is to use objective, reproducible, and quantitative feature metrics extracted from clinical images to develop patient-specific imaging-based prognostic models and personalized cancer therapies.

It is increasingly clear that tumors are not homogeneous organlike systems. Rather, they contain regional coalitions of ecologic communities that consist of evolving cancer, stroma, and immune cell populations. The clinical consequence of such niche variations is that spatial and temporal variations of tumor phenotypes will inevitably evolve and present substantial challenges to targeted therapies. Hence, future research in cancer imaging will likely focus on spatially explicit analysis of tumor regions.

Clinical imaging can readily characterize regional variations in blood flow, cell density, and necrosis. When viewed in a Darwinian evolutionary context, these features reflect regional variations in environmental selection forces and can, at least in principle, be used to predict the likely adaptive strategies of the local cancer population. Hence, analyses of radiologic data can be used to inform evolutionary models and then can be mapped to regional population dynamics. Ecologic and evolutionary principles may provide a theoretical framework to link imaging to the cellular and molecular features of cancer cells and ultimately lead to a more comprehensive understanding of specific cancer biology in individual patients.

Essentials

• Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution.
• Evolution within tumors is governed by Darwinian dynamics, with identifiable environmental selection forces that interact with phenotypic (not genotypic) properties of tumor cells in a predictable and reproducible manner; clinical imaging is uniquely suited to measure temporal and spatial heterogeneity within tumors that is both a cause and a consequence of this evolution.
• Subjective radiologic descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties.
• Spatially explicit mapping of tumor regions, for example by superimposing multiple imaging sequences, may permit patient-specific characterization of intratumoral evolution and ecology, leading to patient- and tumor-specific therapies.
• We summarize current information on quantitative analysis of radiologic images and propose future quantitative imaging must become spatially explicit to identify intratumoral habitats before and during therapy.

Disclosures of Conflicts of Interest: R.A.G. No relevant conflicts of interest to disclose. O.G. No relevant conflicts of interest to disclose.R.J.G. No relevant conflicts of interest to disclose.

Acknowledgments

The authors thank Mark Lloyd, MS; Joel Brown, PhD; Dmitry Goldgoff, PhD; and Larry Hall, PhD, for their input to image analysis and for their lively and informative discussions.

Footnotes

Received December 18, 2012; revision requested February 5, 2013; revision received March 11; accepted April 9; final version accepted April 29.
Funding: This research was supported by the National Institutes of Health (grants U54CA143970-01, U01CA143062; R01CA077575, andR01CA170595).

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http://www.dicardiology.com/article/reva-completes-drug-eluting-bioresorbable-stent-trial-enrollment?goback=%2Egde_675087_member_5837136244068360192

New Data Dispute Calcium Cardiovascular Risk in Both Sexes

Posted in Atherogenic Processes & Pathology, Biomarkers & Medical Diagnostics, Calcium, Interviews with Scientific Leaders, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged American Society for Bone and Mineral Research, Calcium, Cardiovascular disease, Joshua Lewis, Mark Bolland, Stanford University, University of Western Australia on October 11, 2013| Leave a Comment »

Medscape Update on Calcium and Cardiovascular Risk

Curator and Reporter: Larry H. Bernstein, MD, FCAP

New Data Dispute Calcium Cardiovascular Risk in Both Sexes

Article ID #82: New Data Dispute Calcium Cardiovascular Risk in Both Sexes. Published on 10/11/2013

WordCloud Image Produced by Adam Tubman

Nancy A. Melville Oct 08, 2013

Medscape Medical News from the American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting

BALTIMORE — Two new studies contribute further to the debate over the cardiovascular risk associated with supplementary or dietary calcium, each decidedly coming down on the side of no significant risk — to men or women.

“[Based on these findings], clinicians should continue to evaluate calcium intake, encourage adequate dietary intake, and if necessary, use supplements to reach but not exceed recommended intakes,” Douglas C. Bauer, MD, from the University of California, San Francisco, the lead author of the first study, told Medscape Medical News.

Results of both studies were reported at the recent American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting.

Dr. Bauer’s observational trial is one of few contemporary studies to evaluate the level of risk among men, who are often poorly represented in calcium studies, he noted. The results showed no association between calcium dietary intake or supplementation and total or cardiovascular mortality. The second study was an updated meta-analysis of calcium supplementation among women and similarly demonstrated no increased risk for ischemic heart disease (with adjudicated outcomes) or total mortality in elderly women. It did draw some criticism for potential bias and contamination, however.

Nevertheless, says Robert Marcus, MD, a retired Stanford University bone specialist, the 2 studies are “powerful. The one involving men had very elegant, accurate reports of death and validated diagnosis of myocardial infarction, and the [study involving women] was also excellent work,” he commented.

“This field has been the subject of an enormous amount of controversy, ambiguity, and confusion for the past several years, and I think the most important thing is to help us come up with what is true,” he said. The quality of data to suggest an adverse effect of calcium is “very poor,” and there is now compelling evidence that there is little to substantiate this, he noted. But despite these reassuring new findings, public anxiety over a potential risk with calcium is unlikely to go away, he believes.

In recommendations issued in 2010, the ASBMR said that most adults 19 years of age and older require about 600 to 800 IUs of vitamin D daily and 1000 to 1200 mg of calcium daily through food and with supplements, if needed.

Contemporary Data on Calcium Intake in Men

The use of calcium supplements, predominantly with vitamin D, is an important therapy for the prevention of osteoporosis and its clinical consequences. But concerns about the cardiovascular safety of calcium have emerged periodically; in 2 alarming meta-analyses published in 2010 and 2011 by Dr. Mark Bolland and colleagues, for example, there was a 27% increase in MI among individuals allocated to calcium supplements in the first study and a 24% increased risk in the second.

More recently, a 40% increase in total mortality and up to a 50% increase in cardiovascular mortality was seen among women from a Swedish mammography cohort with a calcium intake exceeding 1400 mg per day. In that study, the effect on mortality appeared to be especially strong if a high dietary intake of calcium was combined with calcium supplements.

In their new study, Dr. Bauer and his colleagues set out to assess rates of dietary calcium intake, use of supplements, and mortality in a prospective cohort of 5967 men over the age of 65 years in the Osteoporotic Fractures in Men (MrOS) study.

The participants completed extensive surveys at baseline on their dietary calcium intake, and supplementation was verified by a review of pill bottles by trained staff.

Mean dietary calcium intake was 1142 ± 590 mg/day, with more than half — 65% — of participants reporting use of calcium supplements.

Over the 10-year follow-up, among 2022 men who died, 687 deaths were caused by cardiovascular disease. The highest mortality for CVD was seen in the quartile with the lowest intake from calcium supplementation.

And in models that adjusted for age, energy intake, and calcium use, men in the lowest quartile of total calcium intake (less than 621 mg per day) had higher total mortality compared with those in the highest quartile (more than 1565 mg of calcium per day).

Adjustment for additional confounding factors showed no association between calcium dietary intake and total or cardiovascular mortality (P for trend .51 and .79, respectfully). Likewise, there was no association between calcium supplementation and total or cardiovascular mortality.

The authors also conducted an additional analysis of calcium intake and adjudicated cardiovascular disease events in a subcohort of the study, MrOS Sleep, involving 3120 patients who took part in a 7-year follow-up, and again there was no higher risk for cardiovascular events associated with calcium intake.

The study did have is limitations, Dr. Bauer acknowledged, including the observational design, calcium intake being assessed with a food frequency questionnaire, and cause of death not being formally adjudicated. Nevertheless, the findings are important in demonstrating the level of risk among men in a contemporary setting, he pointed out.

“Contrary to the Swedish study of women, we found no evidence that calcium supplementation is harmful to men, even among those with the highest dietary calcium intake,” he concluded, recommending that future studies should include adjudicated outcomes.

Study in Men as Expected, but Female Research Questioned

In the second study reported at the ASBMR meeting, Joshua Lewis, MD, PhD, from the University of Western Australia, Perth, and colleagues reported a meta-analysis of 19 randomized controlled trials involving women over the age of 50 years who had received calcium supplementation for more than a year.

Importantly, the analysis included reports of adjudicated cardiovascular outcomes, which the researchers note is important because gastrointestinal events can be misreported as cardiac ones. They also assessed all-cause mortality.

Among 59,844 participants in the studies, there were 4646 deaths, and the relative risk for death among those randomized to calcium supplements was 0.96 (P = .18).

The relative risk for 3334 ischemic heart disease events among 46,843 participants was 1.02 (P = .053), and the risk for 1097 MI events among 49,048 participants was 1.09 (P =.21).

“The data from this meta-analysis does not support the concept that calcium supplementation with or without vitamin D increases the risk of ischemic heart disease or total mortality in elderly women,” concluded Dr. Lewis.

But bone specialist Ian Reid, MD, from the University of Auckland, New Zealand, who was a coauthor on some of the Bolland studies, said this analysis essentially repeats previous ones, but with the inclusion of 20,000 patients from the Women’s Health Initiative (WHI), many of whom continued to take their own calcium tablets, regardless of whether they were randomized to calcium or placebo.

These “contaminated” WHI data have the potential to mask the effect of calcium, he told Medscape Medical News. In addition, in a study from Denmark also included in the meta-analysis, subjects were not properly blinded to treatment assignment and the calcium and control groups were not comparable at baseline for cardiovascular risk, which introduced “major potential bias,” he added.

Regarding the results from the study in men by Dr. Bauer and colleagues, Dr. Reid said they were not surprising to him. “Generally, people who take calcium supplements have more health-conscious behaviors than those who do not and so have a lower baseline risk of heart disease” that can “obscure small adverse effects of drugs such as calcium,” he observed.

An effect has to be “very substantial” before it can be picked up in an observational study, because of the many confounders that can obscure such an effect, he concluded.

Dr. Bauer, Dr. Lewis, Dr. Reid, and Dr. Marcus have reported no financial relationships. MrOS is supported by funding from the National Institutes of Health.

American Society for Bone and Mineral Research 2013 Annual Meeting. Abstracts 1001 and 1002, presented October 4, 2013.

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents

Posted in Atherogenic Processes & Pathology, Cardiac and Cardiovascular Surgical Procedures, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, tagged American College of Cardiology, DES, Drug-eluting stent, Medina, Percutaneous coronary intervention, Ron Waksman, Stent on August 6, 2013| 1 Comment »

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents

Curator: Aviva Lev-Ari, PhD, RN

UPDATED 2/8/2014

Reva Completes Drug-Eluting Bioresorbable Stent Trial Enrollment

January 24, 2014

January 24, 2014 — Reva Medical Inc. has completed enrollment in the clinical trial of the ReZolve2 drug-eluting bioresorbable scaffold. A total of 112 patients from three continents have been enrolled in the trial to provide the data needed to apply for CE marking.

The company anticipates filing a CE mark application before the end of 2014. It plans to report an update on trial data at the Paris Course on Revascularization (EuroPCR) in Paris, France, May 2014.

For more information: http://www.teamreva.com

MORE LIKE THIS

SOURCE

This article has the following SIX Parts:

Part I: Bifurcation Intervention – Stent Design and Thrombosis

Part II: Biodegradable Polymer DES Reduce Stent Thrombosis Rates vs. Durable Polymer DES

Part III: Stent Flexibility versus Stent Concertina Longitudinal Deformation Effect on Outcomes

Part IV: Stent Thrombosis Through the Generations of Stent Design

Part V: Stent Thrombosis in Randomized Trials of Drug-Eluting Stents: Reappraisal of the Synthesis of Evidence!

Part VI. Duration of Dual Antiplatelet Therapy following Zotarolimus-Eluting Stents and A New Strategy for Discontinuation of Dual Antiplatelet Therapy

Conclusions by Larry H Bernstein, MD, FCAP

Part I

Bifurcation Intervention – Stent Design and Thrombosis

The 5 Ts of Bifurcation Intervention: Type, Technique, Two Stents, T-Stenting, Trials

Ron Waksman, MD, FACC; Laurent Bonello, MD

Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.

J Am Coll Cardiol Intv. 2008;1(4):366-368. doi:10.1016/j.jcin.2008.06.006

http://interventions.onlinejacc.org/article.aspx?articleid=1110233

Bifurcation, the division of an artery into 2 branches, is a common anatomy feature of the human coronary tree and is recognized as a common site for atherosclerotic plaque buildup due to the differences in coronary flow, turbulence, and shear stress at the site of the bifurcation. The prevalence of bifurcation stenosis in the human coronary tree is reported to be between 15% to 20% of all interventions and is considered complex and challenging for percutaneous intervention.

Numerous techniques and devices have been proposed to address the treatment of bifurcation lesions: balloon angioplasty, metallic stents, drug-eluting stents (DES), newly designed stents with dedicated access to the side branch, and full bifurcated stents. Clearly, the interest in the treatment of bifurcation stenting has increased with the availability to significantly reduce the recurrence rate, but this was associated with the increasing fear of stent thrombosis. Despite this extensive body of work and the latest innovations of 2008, there is not a “one size fits all” solution to the bifurcation puzzle, while the optimal percutaneous coronary intervention technique remains undetermined.

In this issue of JACC: Cardiovascular Interventions, Routledge et al. (1) present 2-year outcome data of 477 patients treated for bifurcation coronary disease with provisional side branch T-stenting using DES, and claim a systematic approach feasible for 90% of the patients, with acceptable efficacy and safety profiles. This editorial is written in response to this provocative study and will cover the 5 Ts of bifurcation stenting: Type of bifurcation, Techniques, Two stents versus one, T-stenting, and Trial design.

Types Of Bifurcation

Part of the complexity in treating bifurcation lesions and applying technique standardization is in regard to the numerous anatomic patterns of bifurcation stenosis and the lack of consistent, reliable methodology. Further, the variations in anatomy, angulations, and location of the disease within the bifurcation have led to the development of numerous classifications of bifurcation lesions, with differentiation between “true” bifurcation (both the main and the branch are diseased) and “false” bifurcation (either the main or the branch is disease) based on angiography. The most popular and intuitive classification is that of Medina et al. (2), which identifies at least 7 types of bifurcation involving the proximal main branch, the distal main branch, and the side branch, with different variations. If we add this to the classification of the various potential angulations between the main and the side branches, the sizes of the parent vessel and the side branch, and the different potential morphologies of the diseased segment (calcification, fibrosis, and so on), we can identify nearly endless anatomic and morphologic configurations of bifurcations types (3).

Technique

2 stents versus 1

Numerous techniques have been proposed for the treatment of bifurcation lesions. The first decision that the operator must make is whether the procedure will involve 1 or 2 stents. The most important information relates to the size of the side branch and the degree of the disease in this branch. Or do we really care about the side branch? Initially, the thought of using 2 stents for all bifurcated lesions was appealing because this approach usually resulted in an optimal angiographic success rate. Among the most popular techniques that employed the use of 2 stents are the culotte, crush, V-stenting, T-stenting, and simultaneous kissing stents (4). However, after numerous reports of high rates of late complications, including an increase in stent thrombosis and restenosis frequency, systematical use of 2 stents did not live up to expectations (5–8). These poor outcomes were observed regardless of the technique used and thus discouraged the liberal use of 2 stents. Therefore, the provisional strategy gained ground: try 1 stent first, and, if the result is not acceptable (dissection, impaired lumen, or flow of the other branch), use a second stent for the side branch. The superiority of such a provisional approach over a 2-stent technique was confirmed by the Nordic Bifurcation study (9). The results of this study had operators favoring the provisional rather than the 2-stent approach. However, many questions still remain regarding this approach: can we predict which bifurcation will require 2, rather than 1 stent? In how many patients is the provisional approach feasible? If a second stent is required, what then is the optimal technique for implantation of the second stent? Is provisional stenting still superior to the 2-stent approach with the new generation of stents available? And lastly, are the latest technique modifications, including pre- and post-kissing, clinically beneficial?

The present study demonstrated that provisional stenting is feasible in 90% of all patients, and those who received a second stent in the side branch, 28%, had similar long-term outcomes as those treated with 1 stent. The outcome of this study is similar to that of the Nordic Bifurcation study, which observed no difference in outcomes at 6 months’ follow-up between 1 and 2 stents (9). Finally, the latest Nordic Bifurcation Stent Technique study, comparing the culotte and crush techniques, reported low rates of angiographic restenosis and major adverse cardiac events for both techniques (10), with similar angiographic and clinical outcomes as the provisional approach with T-stenting reported in the Routledge et al. study (1). This leaves us with the question of whether, in 2008, provisional stenting is still superior to 2 stents when an improved technique is applied and new-generation stents are used?

T-stenting

Use of the provisional T-stenting technique is gaining interest because of its simplicity and subsequent reports of good mid-term outcomes (11–13). As illustrated in the present report by Routledge et al. (1), it is feasible in a large majority of patients and is associated with low rates of recurrent events during long-term follow-up. In the past, the technique was described to resolve dissections of a side branch (8) or as a new technique for the use of 2 stents for the treatment of bifurcation lesions (11). In the present study, the authors used provisional T-stenting as the default technique. From a technical point of view, provisional T-stenting offers several advantages compared with other bifurcation techniques: it is simple to perform in most cases, and it limits the need for a second stent, as illustrated by the low rate of stenting in the side branch in the present study. One technical aspect of the procedure remains in question: is kissing post-procedure mandatory in the provisional T-stenting approach with 1 or 2 stents? Bench testing observed that the final kissing balloon may have several interesting advantages: it opens the stent cells to the side branch, it allows the side branch ostium to be at least partially covered by stent struts, and it prevents the main branch stent from becoming deformed by side branch dilation. Further, in previous studies involving crush stenting, kissing balloon was shown to be critical in preventing restenosis (14). Nevertheless, the clinical impact of a final kissing balloon in provisional T-stenting must be established in future trials. Several limitations should be considered with T-stenting: it is not applicable for all lesions, it is dependent on the bifurcation angle and cannot be applied to angles <40°; the second stent, if needed, may not be able to fully cover the ostium, which will result in switching to a mini-crush technique, and like other techniques, there is a learning curve. Nevertheless, among today’s available options, the provisional T-stenting technique seems to be the simplest and is associated with favorable long-term outcomes.

Table 1 Comparison of Bifurcation Studies in the DES Era

Bifurcation stenting continues to challenge the interventional cardiologist. Despite the recent literature, including the present manuscript, there is a lack of consensus on an array of important issues, such as: Which branches deserve protection? Should provisional stenting be the default strategy of bifurcation stenting? Should we always pre-dilate the side branch? And if 2 stents are required, which technique would be the best? Is kissing always mandatory for both branches? Are DES more thrombogenic? And finally, how will the special dedicated bifurcated stents be integrated into current practice? With further trials and perhaps the sixth T in bifurcation stenting (Time), the answers to these important questions will be answered.

References

1 Routledge H.C., Morice M.-C., Lefèvre T.; 2-year outcome of patients treated for bifurcation coronary disease with provisional side branch T-stenting using drug-eluting stents. J Am Coll Cardiol Intv. 1 2008:358-365.

2 Medina A., Suárez de Lezo J., Pan M.; A new classification of coronary bifurcation lesions. Rev Esp Cardiol. 59 2006:183

3 Thomas M., Hildick-Smith D., Louvard Y.; Percutaneous coronary intervention for bifurcation disease. A consensus view from the first meeting of the European bifurcation club. Euro Intervention. 2 2006:149-153.

4 Louvard I., Lefevre T., Morice M.C.; Percutaneous coronary intervention for bifurcation coronary disease. Heart. 90 2004:713-722.

5 Iakovou I., Schmidt T., Bonizzoni E.; Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 293 2005:2126-2130.

6 Finn A.V., Kolodgie F.D., Harnek J.; Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 112 2005:270-278.

7 Daemen J., Wenaweser P., Tsuchida K.; Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 369 2007:667-678.

8 Carrie D., Karouny E., Chouairi S., Puel J.; “T” shaped stent placement: a technique for the treatment of dissected bifurcation lesions. Cathet Cardiovasc Diagn. 37 1996:311-313.

9 Steigen T.K., Maeng M., Wiseth R.; Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic Bifurcation study. Circulation. 114 2006:1955-1961.

10 Gunnes P, Niemela M, Kervinen K, et al, for the Nordic-Baltic PCI Study Group. Eight months angiographic follow-up in patients randomized to crush or culotte stenting of coronary artery bifurcation lesions. The Nordic Bifurcation Stent Technique study. Paper presented at: ACC 2008 Late Breaking Trials; April 1, 2008; Chicago, IL.

11 Palvakis G., de Man F., Hamer B., Doevendas P., Stella P.R.; Registry of new technique on coronary bifurcation lesions: the Utrech-“T” experience. Euro Intervention. 3 2007:262-268.

12 Pan M., Suárez de Lezo J., Medina A.; Drug-eluting stents for the treatment of bifurcation lesions: a randomized comparison between paclitaxel and sirolimus stents. Am Heart J. 153 2007:15-17.

13 Ormiston J.A., Webster M.W., El Jack S.; Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv. 67 2006:49-55.

14 Ge L., Airoldi F., Iakovou I.; Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon post-dilation. J Am Coll Cardiol. 46 2005:613-620.

15 Hoye A., Iakovou I., Ge L.; Long-term outcomes after stenting of bifurcation lesions with the “crush” technique: predictors of an adverse outcome. J Am Coll Cardiol. 47 2006:1949-1958.

16 Sharma S.K.; Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels. Catheter Cardiovasc Interv. 65 2005:10-16.

17 Moussa I., Costa R.A., Leon M.B.; A prospective registry to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions using the “crush technique”. Am J Cardiol. 97 2006:1317-1321.

18 Yanagi D., Shirai K., Takamiya Y.; Results of provisional stenting with a sirolimus-eluting stent for bifurcation lesion: multicenter study in Japan. J Cardiol. 51 2008:89-94.

19 Di Mario C., Morici N., Godino C.; Predictors of restenosis after treatment of bifurcational lesions with paclitaxel eluting stents: a multicenter prospective registry of 150 consecutive patients. Catheter Cardiovasc Interv. 69 2007:416-424.

20 Tsuchida K., Colombo A., Lefèvre T.; The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II). Eur Heart J. 28 2007:433-442.

SOURCE

J Am Coll Cardiol Intv. 2008;1(4):366-368. doi:10.1016/j.jcin.2008.06.006

http://interventions.onlinejacc.org/article.aspx?articleid=1110233

Bifurcation Stenting

David Hildick-Smith, MD

Consultant Cardiologist and Director of Cardiac Research

Brighton-Sussex University Hospital NHS Trust

Brighton, UK

Slide 1

Bifurcation stenting and its various ramifications in the modern cardiology world. The objectives of this presentation are to talk about some of the difficulties of bifurcation stenting, to summarize the recent study data, and to talk a little bit about dedicated stent systems, as well.

Dedicated Bifurcation Stent Systems – Main types:

• Side branch facilitation

• Side branch stenting incorporated

• Main branch stenting with enhanced access

• True dedicated systems

Slide 32

So we then have the issue of dedicated stent systems. Are they the answer to some of these questions? Are they going to bail us out of these difficult geometric issues of bifurcations? There are a number of dedicated stent systems in development and available at the moment, and they fall into a few different groups. There are systems which simply facilitate side branch access. There are systems which actually incorporate side branch stenting as the primary philosophy. There are those which are essentially a main branch stent with enhanced access. And then there are the truly dedicated systems.

Bifurcation Stenting: Should You Keep it Simple

You Keep it Simple

Facilitation

Increasing success of provisional T

Slide 33

If we look at the facilitation group, there are stent systems available where there’s a wire that is integral to the balloon system, and will perhaps then facilitate getting into the side branch, and may certainly facilitate making sure that you are,

Side Branch Ostial Coverage Stents:

• Scaffold side branch ostium

• Allow subsequent main vessel stenting

The side branch ostial coverage stents are intended to scaffold the side branch and retain main vessel stenting capabilities. There are a couple of stents of this nature on the market at the moment which are undergoing clinical trials to see their general applicability.

Main Vessel Enhanced Access Stents

•Pop-up/expand into side vessel

•Improve subsequent or immediate access to side branch

Slide 35

The next group is the main vessel enhanced access stents, which, either through a pop-up mechanism with mechanical scaffolding of the side branch ostium, or with a proximal stent which is self-expanding, enhance the access to the side branch, so that you have both immediate access and subsequent access. Which is one of the things that people worry about in this situation, which is, what happens if you have to come back to that side branch vessel a few months later? Will you be able to gain access to it? So these tools may have a role there.

True Dedicated Bifurcation Stent

Stenting of both branches

Slide 36

The fourth group is the true dedicated bifurcation stent. These are clearly the most useful, but of course, mechanically and from an engineering point of view, the most difficult to create and make work. They will certainly have a potential role in bifurcation stenting, but there’s a little way to go before they could be used in a wide manner.

Slide 37

The dedicated systems, while most are quite ingenious, unfortunately most will not survive in their current format. But the true dedicated bifurcation stent will certainly have a role in the left main. And, as we come back increasingly from these bifurcations to the left main and get a mandate to be able to treat that, this is an area where there will be a significant place for dedicated bifurcation stent systems.

Conclusions

• Bifurcations remain troublesome

• Provisional T stenting is the gold standard

• Subsets of bifurcations require complex strategies

• Large side branches

• Longer ostial disease

• Current complex strategies fail us

• Crush fails more than culotte

• Dedicated devices will have a role

• Large bifurcations in main coronary tree

• Left main

Slide 38

In conclusion, bifurcation stenting is still a troublesome area. Provisional T stenting is the gold standard approach across the board, but we mustn’t forget that there may well be, and I believe there are, subsets of bifurcations which do require a complex strategy. These are the ones with large side branches and significant length of disease at the ostium of that side branch. The current complex strategies do fail from a mechanical point of view, and in that respect crush fails more than culotte. Although it’s a difficult time for dedicated devices at the moment, I think they will have a role, particularly in large bifurcations in the main coronary tree and, most particularly of all, in the left main stem.

SOURCE

http://www.theheart.org/documents/satellite_programs/intervsurgery/913801/BifurcationStenting_REVISED_FINAL.pdf

Part II

Biodegradable Polymer DES Reduce Stent Thrombosis Rates vs. Durable Polymer DES

March 27, 2012 — Biodegradable polymer drug-eluting stents (DES) provide better long-term safety and efficacy than durable polymer DES, according to findings from an analysis of three major clinical trials —

ISAR-TEST 3,
ISAR-TEST 4 and
LEADERS.

The data were presented at at the American College of Cardiology’s 61st Annual Scientific Session. The findings provide the first combined long-term data on the comparison between biodegradable polymer DES and durable polymer DES. Designed to improve long-term clinical outcomes while also shortening healing time, biodegradable polymer DES are a new generation of DES that have undergone little research and thus have yet to substantiate its claims. The three analyzed studies showed that after four years, use of biodegradable polymer DES resulted in

lower rates of target lesion revascularization,
definite stent thrombosis and
cardiac death and
heart attack than durable polymer DES.

“Because it is often difficult to design individual trials to test for differences in rarely occurring adverse events [like stent clotting], we pooled the data from the three largest trials to see if any differences between the two stent types could be seen,” said co-lead investigator Robert A. Byrne, M.B., B.Ch., Ph.D., a cardiologist at Deutsches Herzzentrum in Munich, Germany. “In addition, by including surveillance out to four years, this helped us better capture the differences between the two stents, as benefit was expected to first emerge with long-term follow-up.”

Among all three analyzed trials, 2,358 patients were randomly assigned to angioplasty with a biodegradable polymer DES (sirolimus-eluting = 1,501; biolimus-eluting = 857), while 1,704 patients were treated with a durable polymer SES (all sirolimus-eluting).

At the four-year follow-up point, the researchers found that the risk of target lesion revascularization (the study’s primary efficacy endpoint) was significantly lower among those patients treated with a biodegradable polymer DES than for those treated with a durable polymer DES (hazard ratio [HR] 0.82, 95 percent confidence interval [CI] 0.68-0.98, P=0.029). In addition, the risk of having a blood clot, called stent thrombosis (the study’s primary safety endpoint), was also significantly lower for those patients treated with a biodegradable polymer DES compared to those treated with a durable polymer DES (HR 0.56, 95 percent CI 0.35-0.90, P=0.015). This was driven by a lower risk of very late stent thrombosis (clots occurring more than one year after angioplasty) for the biodegradable polymer group (HR 0.22, 95 percent CI 0.08-0.61, P=0.004).

Furthermore, the incidence of heart attack late after stenting was lower for patients treated with biodegradable polymer versus durable polymer stents (HR 0.59, 95 percent CI 0.73-0.95, P=0.031).

While the arrival of DES has allowed interventionalists to provide treatment for more complex patients, concerns have arisen about the stents’ long-term safety, particularly concerning stent thrombosis. As a result, the polymer coating on the first-generation stents was targeted as an area for improvement. Specifically, the durable polymer remains in the coronary artery wall beyond the time when its useful function is served. This may cause delayed healing and a hypersensitivity reaction, leading to inflammation and stent thrombosis.

As a potential solution to these problems, new-generation stents with a bioabsorbable polymer were created. This polymer, which fully degrades and leaves a bare-metal stent in place, has been suggested to shorten healing time and cause less inflammation and subsequent stent thrombosis.

“These findings show that biodegradable polymer DES can provide better long-term safety and efficacy,” said Byrne. “This advantage, coupled with a shortened healing time compared with durable polymer DES, means that biodegradable polymer stents look to become an important tool for the interventional cardiologist in everyday practice.”

The current analysis was industry independent, supported in part by a grant from the Swiss National Science Foundation, and conducted at the ISAR Research Center in Munich, Germany, and the Clinical Trials Unit in Bern, Switzerland.

This study was simultaneously published in the European Heart Journal and was released online at the time of presentation.

The results offer a promising outlook for Boston Scientific’s Synergy DES, now in development. It uses the same platform stent as the Ion and Promus, but instead of a duable polymer it uses abluminal biodegradable polymer containing everolimus. The company presented its first-in-man study at TCT 2011 and hopes to begin its EVOLVE II U.S. Food and Drug Administration (FDA) investigational decive exemption trial later this year.

For more information: www.acc.org

Biosensensors BioMatrix Flex was among the stents included in this study. It uses an abluminal, biodegradable polymer as a carrier for its BA9 drug.

http://www.dicardiology.com/article/biodegradable-polymer-des-reduce-stent-thrombosis-rates

First Patient Enrolled in Dissolving Drug-Polymer Coronary Stent Trial

February 21, 2011 – The first patient has been enrolled the DESSOLVE II study to support CE mark for a coronary stent that uses a bioresorbable drug polymer. The MiStent drug-eluting coronary stent system (MiStent DES), by Micell Technologies.

The trial involves treatment of patients with de novo lesions in the native coronary arteries. Stefan Verheye, M.D., Ph.D. at Middelheim Hospital, Antwerp, Belgium enrolled the first patient in the study.

The MiStent DES employs supercritical fluid technology, which applies a precisely controlled absorbable polymer – active drug (sirolimus) matrix onto a cobalt-chromium stent. The polymer dissolves and releases the drug into the surrounding tissue in a controlled manner, designed to optimize dosing of the drug throughout the affected artery. In preclinical trials, the drug completely elutes and the polymer is eliminated from the stent within 45 to 60 days in-vivo, resulting in a bare-metal stent.

DESSOLVE II is a prospective, controlled, 2:1 unbalanced randomized, multicenter study of approximately 270 patients. Patients will be enrolled at 26 clinical sites in Europe, New Zealand and Australia. Candidates for the trial are patients with documented stable or unstable angina pectoris or ischemia. The primary endpoint is superiority of MiStent DES in minimizing in-stent late lumen loss at nine months, compared to Medtronic’s Endeavor DES, as measured with angiography in treated de-novo lesions ranging in diameter from 2.5 to 3.5 mm and amenable to treatment with a maximum 23 mm long stent.

Along with secondary clinical endpoints such as major adverse cardiac events and revascularization rates, the extent of stent coverage and re-endothelialization, via optical coherence tomography (OCT), and endothelial function (vasomotor response) will be evaluated in a subgroup of patients at nine months.

“Drug-eluting stents have significantly improved and expanded our ability to treat coronary atherosclerotic lesions compared to bare-metal stents,” said William Wijns, M.D., Cardiovascular Center, Aalst, Belgium, and principal investigator of the study. “However, cardiologists are still looking for options to improve safety and outcomes. The MiStent DES may address some of these issues directly. Based on recent GLP animal data, the polymer and drug are gone from the stent within 45 to 60 days. This may reduce the risk of late-stent thrombosis related to long-term exposure to DES nonerodible polymers. Given the relatively short residence time of polymer on the stent, MiStent DES may allow for a shorter duration of dual antiplatelet therapy and be a safer choice for noncompliant patients. These performance-enhancing properties are what interventional cardiologists are looking for in a new drug-eluting stent.”

For more information: www.micell.com

http://www.dicardiology.com/article/first-patient-enrolled-dissolving-drug-polymer-coronary-stent-trial

Part III

Stent Flexibility versus Stent Concertina Effect

Stent flexibility versus concertina effect: mechanism of an unpleasant trade-off in stent design and its implications for stent selection in the cath-lab.

Foin N, Di Mario C, Francis DP, Davies JE.

Abstract

The “concertina effect”, longitudinal deformation of the proximal segments of a deployed stent when force is applied from a guide catheter or other equipment, is a recently recognised problem which seems to particularly affect more recent stent designs. Until now, flexibility and deliverability have been paramount aims in stent design. Developments have focused on optimizing these features which are commonly evaluated by clinicians and demanded by regulatory bodies. Contemporary stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. These design evolutions may, however, simultaneously reduce longitudinal strength and have the unintended effect of inducing some risk of longitudinal compression of the stent (the “concertina effect”) during difficult clinical cases. Progress in stent design and elimination of restenosis by drug coating has improved PCI outcome and enabled new applications. Here we discuss design trade-offs that shaped evolution and improvement in stent design, from early bare metal designs to the latest generation of drug eluting stent (DES) platforms. Longitudinal strength was not recognised as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Clinicians could be more guarded in their assumption that changes in technology are beneficial in all clinical situations. Sometimes a silent trade-off may have taken place, adopting choices that are favourable for the vast majority of patients but exposing a few patients to unintended hazard.

Int J Cardiol. 2013 Apr 15;164(3):259-61. doi: 10.1016/j.ijcard.2012.09.143. Epub 2012 Oct 22.

http://www.ncbi.nlm.nih.gov/pubmed/23084111

Stent “Concertina:” Stent Design Does Matter

On-Hing Kwok, MBBS

From the Cardiac Catheterization & Intervention Center, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong.

ABSTRACT: The development of modern coronary stent platforms has transformed the landscape of interventional cardiology. Contemporary coronary stents are much more deliverable than older-generation stents. However, longitudinal deformation has emerged as a “new” complication in modern coronary stent platforms. Although most reported cases of longitudinal stent deformation involve mechanical or technical mishaps, it appears that it is more frequently associated with a particular stent design: the “offset peak-to-peak” stent design. This review summarizes the latest data around stent performance. Within this context, two clinical cases where longitudinal deformation was observed in the absence of any mechanical mishaps are also presented. Collectively, this evidence suggests that stent design may be a major determinant of stent performance.

SOURCE

Journal Cardiology, Volume 25 – Issue 6 – June 2013

Key words: longitudinal deformation, stent design, stent concertina, drug-eluting stent

Over the past decades, stent design and material has undergone significant evolution. The introduction of the drug-eluting stent (DES) has also made “drug delivery” another major determinant in modern stent design.¹

Coronary stent design. The majority of early coronary stents were made of stainless steel. These designs were associated with variable basic manufacture, cell geometry, and strut thickness.² Use of alloys such as cobalt chromium and platinum chromium has enabled stents to have thinner struts, while maintaining strength and radioopacity.³ Thin-strut stents improve deliverability and conformability. However, there is limited evidence suggesting that thinner struts may result in less vessel wall damage and hence less risk of restenosis.^4-6 Although thin-strut DESs have never been shown to have lower restenosis rates than thick-strut DESs, the trend of thinner strut platforms has triggered innovative designs to maintain stent radial strength. The development of longer, thinner, more flexible, and easier-to-deliver stent platforms made percutaneous coronary intervention (PCI) possible even in the most tortuous anatomy and calcified vessels.⁷ However, longitudinal stent strength may be compromised with these modern designs.³ Stent design requires careful consideration of several performance characteristics, including crimped and expanded stent flexibility, shortening upon expansion, trackability, scaffolding, radioopacity, longitudinal strength, radial strength, and recoil.⁸

Stent longitudinal flexibility and deliverability prior to deployment, and vessel conformability after deployment, are widely dependent on the number, orientation, shape, thickness, and material of the crests and links.⁹ These parameters also determine the longitudinal strength of the stent, defined as maintenance of intact stent architecture upon exposure to compressing or elongating forces.⁹ Alteration of any one feature of a stent platform will undoubtedly impact other aspects of stent performance and may result in clinical complications. For instance, thinner struts improve deliverability, but reduce radio-opacity of the cobalt chromium stents. In addition, reduction of the number of fixed links between cells or alteration of their geometry may enhance flexibility and conformability, but as a consequence may compromise longitudinal strength.⁷

Although stent flexibility may be influenced by a variety of factors, it has been shown that stent longitudinal integrity, defined by the number of links between hoops, correlates with stent stiffness. In addition, the alignment of the links with the long axis of the stent may also be an important factor for longitudinal integrity.⁹

Architectural design differences are major factors affecting resistance against longitudinal compression. The peak-to-peak or peak-to-valley strut architectures of platforms result in variation between the longitudinal stiffness and strength of stents. It is highly likely that the occurrence of longitudinal deformation is dependent on a particular stent design.¹⁰

Longitudinal stent deformation. Until recently, the longitudinal strength of coronary stents has never been considered a standard parameter of stent performance. However, recent evidence identified longitudinal compression, or postdeployment stent shortening, as a newly observed complication. Longitudinal stent deformation is defined as the distortion or shortening of a stent in the longitudinal axis following successful stent deployment.³ This phenomenon describes the effect of a longitudinal compression force on the stent rings, causing them to nest or concertinate.⁸

PCI procedures involve multiple and complex techniques that may increase the risk for longitudinal stent compression. These include the use of extra-support guide catheters, aggressive guide catheter manipulation (deep-seat), mother and child catheter systems, multiple balloon postdilations, bifurcation stent techniques, and adjunctive devices such as intravascular ultrasound (IVUS), distal protection devices, etc.⁷ In a clinical setting, longitudinal compression may occur in various situations (Table 1),⁸ and it may simply represent an angiographic detection of an exceptional PCI complication. Protrusion of struts into the lumen and extensive malapposition of struts due to longitudinal deformation may result in disruption of flow and increasing the risk of stent thrombosis. Moreover, longitudinal deformation of a DES may result in uneven drug delivery and increase the risk for in-stent restenosis (ISR).⁹

Clinical reports of longitudinal deformation. Hanratty and Walsh recently described 3 cases where longitudinal compression of a previously deployed stent resulted in stent deformation. Two cases were detected angiographically, while 1 was detected on adjunctive imaging. The complication was first reported with the Promus Element (Boston Scientific) platform. However, Hanratty and Walsh noted that this phenomenon has since been observed with all modern DES platforms. They concluded that such deformation could potentially result in a suboptimal technical result for the medium- to long-term and increase the risk for stent thrombosis and ISR if left undetected.⁷

References

1. Htay T, Liu MW. Drug-eluting stent: a review and update. Vasc Health Risk Manag. 2005;1(4):263-276.

2. Colombo A, Stankovic G, Moses JW. Selection of coronary stents. J Am Coll Cardiol. 2002;40(6):1021-1033.

3. Williams PD, Mamas MM, Morgan K, et al. Longitudinal stent deformation — a retrospective analysis of frequency and mechanisms. EuroIntervention. 2012;8(2):267-274. Epub AOP 2011.

4. Pache J, Kastrati A, Mehilli J, et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol. 2003;41(8):1283-1288.

5. Moreno R, Jimenez-Valero S, Sanchez-Recalde A. Periprocedural (30-day) risk of myocardial infarction after drug-eluting coronary stent implantation: a meta-analysis comparing cobalt-chromium and stainless steel drug-eluting coronary stents. EuroIntervention. 2011;6(8):1003-1010.

6. Kastrati A, Mehilli J, Dirschinger J, et al. Strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation. 2001;103(23):2816-2821.

7. Hanratty CG, Walsh SJ. Longitudinal compression: a “new” complication with model coronary stent platforms — a time to think beyond deliverability. EuroIntervention. 2011;7(7):872-877. Epub AOP 2011.

8. Prabhu S, Schikorr T, Mahmoud T, Jacobs J, Potgieter A, Simonton C. Engineering assessment of the longitudinal compression behavior of contemporary coronary stents. EuroIntervention. 2012;8(2):275-281.

9. Ormiston JA, Webber B, Webster MWI. Stent longitudinal integrity — bench insights into a clinical problem. JACC Cardiovasc Interv. 2011;4(12):1310-1317.

10. Mortier P, De Beule M. Stent design back in the picture: an engineering perspective on longitudinal stent compression. EuroIntervention. 2011;7(7):773-776.

11. Stone GW, Teirstein PS, Meredith IT, et al; PLATINUM Trial Investigators. A prospective randomised evaluation of a novel everolimus-eluting coronary stent: the PLATINUM trial. J Am Coll Cardiol. 2011;57(16):1700-1708.

12. Pitney M, Pitney K, Jepson N, et al. Major stent deformation/pseudofracture of 7 Crown Endeavor/Micro Driver stent platform: incidence and causative factors. EuroIntervention. 2011;7(2):256-262.

13. Finet G, Rioufol G. Coronary stent longitudinal deformation by compression: is this a new global stent failure, a specific failure of a particular stent design, or simply an angiographic detection of an exceptional complication. Eurointervention. 2012;8(2):177-181. Epub AOP 2011.

Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no conflicts of interest regarding the content herein.

Manuscript submitted September 12, 2012, provisional acceptance given October 31, 2012, final version accepted January 14, 2013.

Address for correspondence: On-Hing Kwok, MBBS, FRCP, FACC, FSCAI, Cardiology Center, 6/F Li Shu Fan Building, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong. Email: vohkwok@hksh.com

SOURCE

J INVASIVE CARDIOL 2013;25(6):E114-E119

Part IV

Stent Thrombosis Through the Generations of Stent Design

A recent retrospective analysis provided further valuable information on the frequency and mechanisms of longitudinal stent deformation. The study involved 4455 interventional cases performed during a 4-year period. Stent deformation occurred in a total of 9 cases (0.2%) and affected 0.097% of stents deployed. In 6 cases, the Promus Element stent was involved, and there was 1 case each involving Endeavor (Medtronic), Biomatrix (Biosensors Interventional Technologies), and Taxus Liberté (Boston Scientific) stents. Stent deformation varied from 0% in several stent types to 0.86% in the case of Promus Element.³ It was virtually unseen in the Cypher and Xience (Abbott Vascular) platforms. Longitudinal stent deformation is probably not a “class effect,” but highly dependent on a particular stent design.

http://www.invasivecardiology.com/articles/stent-“concertina”-stent-design-does-matter

Author(s):

Lawrence Rajan, MD and David J. Moliterno, MD

From the Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky.

Stent thrombosis (ST), while infrequent, remains a dreaded complication of percutaneous coronary revascularization because of the associated rates of

major myocardial infarction (60%-70%) and
early mortality (20%-25%).¹

As coronary stents became more widely used in clinical practice during the late 1990s to treat acute vessel closure and to reduce restenosis, the emergence of ST redirected the efforts of the cardiology community to mitigate or eliminate this potentially catastrophic event. Advances in

stent design and strut thinness,
the advent of drug-eluting stent (DES) options, and
more potent antithrombotic therapy

have been substantial influences on ST.

DESs have been associated with higher ST rates as compared to their bare-metal counterparts, particularly when utilized among high-risk groups and high-risk lesions.

More recently, early meta-analyses of smaller studies have suggested

reduced ST rates with newer-generation DESs versus prior versions.² Similarly, observations from a randomized trial suggested
lower ST rates with the newer-generation everolimus-eluting stent (<1%) compared to rates for the older-generation paclitaxel-eluting stent (3%).³

So while this uncommon but catastrophic complication persists in contemporary practice, its low frequency has made it difficult to study, particularly in the real-world setting.

In the current issue of the Journal of Invasive Cardiology, Dores et al have analyzed the outcome data from a large-volume, single-center prospective registry evaluating the incidence of definite ST.⁴ The study consisted of 3806 patients who underwent percutaneous coronary intervention between January 2003 and December 2010. In the registry, a total of 2388 patients (62.7%) were treated with first-generation DESs (sirolimus-eluting and paclitaxel-eluting stents), while 1418 patients (37.3%) were treated with second-generation DESs (everolimus-eluting and zotarolimus-eluting stents). The overall occurrence of Academic Research Consortium (ARC)-defined definite ST at 12 months was 1.2% (46 events). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, Dores et al concluded that the

use of first-generation DESs was associated with a 2.4-fold increase in the risk of definite ST. Among the cases receiving a first-generation DES,
the risk of ST was higher for paclitaxel-eluting versus sirolimus-eluting stents.

The observations from Dores et al are consistent with prior reports, in that the rates of definite ST are low and decreasing in recent years. As can be seen in Dores’s Figure 3 considering annual frequency of definite ST, the numerically highest years were 2003 and 2004, and over the most recent years, rates have averaged closer to 1%. Questions will remain in the field of ST, some of which will require large-scale registry data to help consider their relevance and possible answers.

The underlying challenge remains how to afford to study such low-frequency events with multifactorial and variable etiologies. Beyond the events during the interventional procedure and device utilized (ie, type of DES), many other factors that affect the rate of ST (eg, patient genotype and phenotype) are still being unraveled. Considerable research has gone into finding predictive subsets for those at increased risk for ST.⁵ Among identified factors are the timing and acuity of presentation. Patients presenting with an ACS are known to be more vulnerable to early ST than patients with chronic stable disease. The initial plaque rupture of ACS triggers a prothrombotic avalanche of events, from platelet activation to local thrombus formation and occlusion, spasm, and distal embolization of microcirculatory debris.⁶ It is interesting to note in the Dores et al. registry that patients receiving second-generation DESs more often presented with an ACS, making their observations reassuring that ST rates can be kept low with evolving care strategies.

In an analysis of the ACUITY trial, which particularly enrolled patients with ACS,⁷ early ST occurred with similar frequency after anticoagulation with either heparin plus glycoprotein IIb/IIIa inhibitors or bivalirudin (with or without IIb/IIIa inhibitors), and not surprisingly was predicted by diffuse atherosclerosis, suboptimal angiographic results, and inadequate pharmacotherapy. Such patients also had a higher incidence of renal insufficiency and insulin-dependent diabetes mellitus. The ACUITY subanalysis found that the rate of ST within 30 days was 1.4%, significantly higher than the 0.3%-0.5% ST rates reported among patients with stable coronary artery disease.

Among the most critical factors in mitigating the risk of ST are adequate and consistent dual-antiplatelet therapy (DAPT). A remarkable interpatient variability in the antiplatelet response to clopidogrel has been well documented. The frequency of

clopidogrel hyporesponsiveness has been reported among as many as 30% of patients undergoing PCI, yet the clinical relevance of antiplatelet responsivity is modest,⁸ again since the factors related to ST are many.
Loss-of-function alleles have been identified for clopidogrel metabolism, and these have been associated with an increased risk of adverse cardiovascular events, including ST.
Among patients with ACS, the need for more rapid and potent pharmacological suppression of platelet reactivity in the prevention of early ST is highlighted in clinical trials testing newer antiplatelet therapies.

In a landmark trial,

prasugrel, a more potent, consistent, and faster-acting third-generation thienopyridine has shown a significant reduction in overall ST rates compared to clopidogrel (1.1% vs 2.4%).⁹ Similarly,
ticagrelor, an oral, reversible, direct-acting inhibitor of the ADP receptor P2Y12 that has a more rapid onset and greater potency of platelet inhibition than clopidogrel was recently studied in a large clinical trial.
In the Platelet Inhibition and Patient Outcomes (PLATO) study, there was a significant reduction in ST in the ticagrelor group vs the clopidogrel group, with definite ST rates of 1.3% and 1.9%, respectively.¹⁰

It is becoming clear that there has been a generational improvement in DESs that has reduced the risk of ST. This has been paralleled by advances in DAPT regimens and interventional techniques that have collectively reduced the risk of ST. While the field will continue to search for answers to the

optimum duration of DAPT, and whether this is dependent on
stent type and
acuity of patient presentation,

DES polymers, design characteristics, and the antiproliferative drugs will also continue to evolve. Understanding incremental improvements in techniques, devices, and drugs will remain quite challenging as the rate of ST slowly moves closer to zero.

References

1. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15):1967-1971.

2. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379(9824):1393-1402.

3. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet. 2010;375(9710):201-209.

4. Dores H, Raposo L, Teles RC, et al. Stent thrombosis with second versus first generation drug eluting stents in real world coronary percutaneous intervention. J Invasive Cardiol. 2013;25(7):330-336.

5. Holmes DR Jr, Kereiakes DJ, Garg S, et al. Stent thrombosis. J Am Coll Cardiol. 2010;56(17):1357-1365.

6. Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30(7):1282-1292.

7. Aoki J, Lansky AJ, Mehran R, et al. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation. 2009;119(5):687-698.

8. Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning.” A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010;56(4):321-341.

9. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.

10. Wallentin L, Becker RC, Budaj A, et al; the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2009;361(11):1045-1057.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Address for correspondence: David J. Moliterno, MD, Department of Internal Medicine, The University of Kentucky, 900 S. Limestone Avenue, 329 Wethington Building, Lexington, KY 40536-0200. Email: moliterno@uky.edu

Journal of invasive Cardiology, Volume 25 – Issue 7 – July 2013

http://www.invasivecardiology.com/articles/stent-thrombosis-through-generations

Stent Thrombosis With Second- Versus First-Generation Drug-Eluting Stents in Real-World Percutaneous Coronary Intervention: Analysis of 3806 Consecutive Procedures From a Large-Volume Single-Center Prospective Registry

Stent thrombosis (ST) is a serious and often fatal event limiting the efficacy of percutaneous coronary intervention (PCI). The pathophysiology of ST is multifactorial, and underlying causes including stent-, procedure-, lesion-, and patient-related factors seem to play different roles at different time points after the index procedure.^1,2 When compared to first-generation (1^stGEN) drug-eluting stents (DESs), newer DESs have been associated with a lower rate of ST in several randomized clinical trials, subsequent meta-analyses, and also in some registries, such as the recently published Swedish Coronary Angiography and Angioplasty Registry (SCAAR).^3-7 New, second-generation (2^ndGEN) DESs have been developed with improved design and materials, both of which may contribute to overcome some of the limitations of the older DESs. Decreased strut thickness — resulting in higher flexibility, conformability, and deliverability — and optimized polymer biocompatibility and drug delivery kinetics have been shown to contribute to a low late-loss rate and to a lower thrombotic risk.¹ Despite the evidence pointing in this direction, most of the data comes from post hoc analysis and meta-analysis, mainly because studies defining ST as a primary endpoint are scarce.

We aimed to assess whether or not the systematic use of a 2^ndGEN DES, relative to the 1^stGEN DES, translates into a higher safety rate in a real-world population where DES implantation was indicated. For that purpose, we conducted an analysis of a single-center prospective registry, evaluating the incidence of definite ST, as defined by the Academic Research Consortium (ARC), at 12 months of follow-up as the primary outcome measure.

Author(s):

Helder Dores, MD, Luís Raposo, MD, Rui Campante Teles, MD, Carina Machado, MD, Sílvio Leal, MD, Pedro Araújo Gonçalves, MD, Henrique Mesquita Gabriel, MD, Manuel Sousa Almeida, MD, Miguel Mendes, MD

Abstract

Background and Aims. When compared to their first-generation (1^stGEN) counterparts, second-generation (2^ndGEN) drug-eluting stents (DESs) have been associated with better clinical outcomes in randomized clinical trials, namely by reducing the rates of stent thrombosis (ST). Our goal was to investigate whether or not the broad use of newer devices would translate into higher safety in a real-world population. For that purpose, we compared the occurrence of definite ST at 12 months between two patient subsets from a large-volume single-center registry, according to the type of DES used. Total mortality was a secondary endpoint.

Methods and Results. Between January 2003 and December 2010, a total of 3806 patients were submitted to percutaneous coronary intervention (PCI) with only 1^stGEN or 2^ndGEN DES: 2388 patients (62.7%) were treated with 1^stGEN DES only (sirolimus-eluting stent [SES] = 1295 [34.0%]; paclitaxel-eluting stent [PES] = 943 [24.8%]; both stent types were used in 150 patients) and 1418 patients (37.3%) were treated with 2^ndGEN DESs only. The total incidence of definite ST (as defined by the Academic Research Consortium) at 12 months was 1.2% (n = 46). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, the use of 1^stGEN DES was associated with a significant 2.4-fold increase in the risk of definite ST (95% confidence interval [CI], 1.05-5.42; P=.039) at 12 months; adjusted risk was higher with PES (hazard ratio [HR], 3.6; 95% CI, 1.48-8.70; P=.005) than with SES (HR, 2.3; 95% CI, 0.92-5.65; P=.074). Total mortality (3.7% vs 3.5%) did not differ significantly between groups (adjusted HR, 1.2; 95% CI, 0.81-1.84, P=.348).

Conclusions. Our data suggest that in the real-world setting of contemporary PCI, the unrestricted use of newer 2^ndGEN DESs translates into an improvement in PCI safety (relative to 1^stGEN DESs), with a significantly lower risk of definite ST at 12 months.

Journal of Invasive Cardiology Volume 25 – Issue 7 – July 2013

J INVASIVE CARDIOL 2013;25(7):330-336

Key words: stent thrombosis, drug-eluting stent

http://www.invasivecardiology.com/articles/stent-thrombosis-second-versus-first-generation-drug-eluting-stents-real-world-percutaneous

Part V

Stent Thrombosis in Randomized Trials of Drug-Eluting Stents:

Reappraisal of the Synthesis of Evidence!

Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents

Laura Mauri, M.D., Wen-hua Hsieh, Ph.D., Joseph M. Massaro, Ph.D., Kalon K.L. Ho, M.D., Ralph D’Agostino, Ph.D., and Donald E. Cutlip, M.D.

N Engl J Med 2007; 356:1020-1029February 12, 2007DOI: 10.1056/NEJMoa067731

http://www.nejm.org/doi/full/10.1056/NEJMoa067731?goback=%2Egde_675087_member_263490750

EDITORIAL on bare-metal stents (BMS) vs sirolimus-eluting stents (SES)

With full interest, we read the article “Stent thrombosis in randomized clinical trials (RCT) of drug-eluting stents (DES)” by Mauri L et al, previously published in the New England Journal of Medicine in 2007 [1]. The authors concluded that “The incidence of stent thrombosis (ST) did not differ significantly between patients with DES and those with bare-metal stents (BMS) in RCT, although the power to detect small differences in rates was limited” [1].  I have the following concerns. First and foremost, ST in the BMS groups occurred more frequently among patients who underwent intervening target lesion revascularization (TLR) versus those who did not [1]. And since brachytherapy was the standard of care for treatment of restenosis at that time, it was used more frequently in patients with restenosis following BMS (9 out of 11 patients with BMS who underwent intervening TLR and subsequently developed definite/probable ST), in whom restenosis occurred more frequently and more diffusely, compared with DES [1]. In an observational study, brachytherapy was associated with a high risk of late (thrombotic) total occlusion of the index vessel at 6-month angiographic follow-up [2]. In that study, the mean time from brachytherapy to late total occlusion was 5.4 ± 3.2 months [2]. Therefore, brachytherapy may constitute selection bias for devices with higher rates of restenosis, by increasing the risk of late ST following intervening procedures for these devices. This might explain the much higher rate of late (beyond 30 days to 1 year) definite/probable ST following BMS compared with sirolimus-eluting stents (SES) (1% versus 0.1%, respectively), which was obviously responsible for the higher overall rate of definite/probable ST following BMS compared with SES at 4-year follow-up (1.7% versus 1.5%, respectively, p=0.7) [1]. It is worth mentioning that

BMS was associated with a lower rate of very late (beyond 1 year) definite/probable ST compared with SES (0.4% versus 0.9%, respectively) [1]. Second,
the study included 4 RCT of SES published from 2002 to 2004, and 4 RCT of paclitaxel-eluting stents (PES) published from 2003 to 2005, all of which were published before the Academic Research Consortium (ARC) report that put forward the current standard definitions of ST [3].

Thus, the ARC definitions were applied to all of these trials retrospectively, and therefore, might have missed some of the ST events.

Third, the study enrolled 878 patients with SES versus 870 treated with the corresponding BMS, 1400 patients with PES versus 1397 treated with the corresponding BMS; thus, it was clearly underpowered for detection of a difference in rare-by-nature events such as ST. Forth, the
RCT included in the study were the earliest RCT of SES and PES; hence, they enrolled relatively low-risk patient, lesion, and clinical subsets, that do not reflect real-world practice.
Finally, the individual databases of RCT of PES were managed by Boston Scientific, which might introduce another source of bias!

References

1. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020-9.

2. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol. 2000;36:65-8.

3. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.

Part VI

Duration of Dual Antiplatelet Therapy following Zotarolimus-Eluting Stents and A New Strategy for Discontinuation of Dual Antiplatelet Therapy

Dr. Pearlman: Drug eluting stents decrease in stent stenosis from endothelial exuberant growth at the cost of increased propensity to thrombosis, offset by prolonged use of dual anti platelet medication. The net effect depends on compliance which if good results in net decrease. The risk has increased due to drug eluting stent prevalence, but that is offset by management with dual anti platelet agents, so the net incidence is reduced. There have been a number of presentations based on angioscopy showing thrombus inside bare metal and drug eluting stents that supported the general concensus also supported by TIMI trials that stent thrombosis is promoted by metal stents until they endothelialize, and that drug-eluting stents impede the endothelialization “too well” prolonging that issue, so minimal dual platelet agent duration in practice is 3 months for BMS, 6-12 months for DES, but benefit fades to 2% at 1 year, 1% at 2 years at which point risk-benefit is unconvincing and many stop plavix, while some insist it is a lifetime medication.

With full interest, we read the article “Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents (ZES)” by Kandzari DE, et al [1]. The authors concluded that “Among patients treated with ZES, late-term events of death, myocardial infarction (MI), stroke, and stent thrombosis (ST) do not significantly differ between patients taking 6 months dual antiplatelet therapy (DAPT) compared with continuation beyond 1 year” [1].
I have the following concerns. First, although the authors claimed that their study was based on a pooled analysis of patients who received ZES in 5 ‘clinical trials’; actually, 2 out of 5 were not ‘trials’. One was a registry of direct stenting with ZES [2], and the other was a study of pharmacokinetics of ABT 578 in a subset of the ENDEAVOR II trial, that was not published in a medical journal [3]! Second, patients were classified by “DAPT adherence according to the most recent report of compliance with aspirin and thienopyridine”. Evidence supports that premature discontinuation clopidogrel is the most powerful independent predictor of late ST [4].

There is no evidence, however, that stopping aspirin predisposes to ST following drug-eluting stent implantation. Third, follow-up of DAPT adherence was done at 30 days, 6 months, then annually for 3 years. Reporting DAPT adherence based on “the last reported follow-up interval of compliance with both aspirin and clopidogrel” does not reflect the actual duration of clopidogrel received in any of the comparison groups. Forth, in the second comparison of “6 months on/24 months off” (on DAPT at 6 but not at 24 months) versus “≥24 months” (on DAPT at 6 and 24 months)”, the first group included, by definition, patients who were also on DAPT at 12 months (but not at 24 months). Thus, it cannot be taken to reflect a comparison between 6-month DAPT and 24-month DAPT! Fifth, the ENDEAVOR II and ENDEAVOR III trials were published in 2006, before the publication of ARC report [5,6]. Therefore, the ARC definitions of ST were applied retrospectively in many patients, which might explain the absence of ‘probable’ ST in all comparison groups, in all time points. Sixth, major bleeding was defined exclusively as “any hemorrhagic event that required blood product transfusion”. This might explain why such rates were 0% in all groups, in all time points. Finally, the study involved low-risk patient and lesion subsets, and was statistically underpowered for rare events such as ST, cardiac death, or MI.

References
1. Kandzari DE, Barker CS, Leon MB, et al. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents. JACC Cardiovasc Interv 2011;4:1119-28.
2. Schultheiss HP, Grube E, Kuck KH, et al. Endeavor II Continued Access Investigators. Safety of direct stenting with the Endeavor stent: results of the Endeavor II continued access registry. EuroIntervention 2007;3:76–81.
3. Pharmacokinetics of ABT-578 in patients from Endeavor stent: results from a subset of a double-blind, randomized, multicenter (ENDEAVOR-II) trial. In: The ENDEAVOR II Study 30-Day Pharmacokinetic Report. Abbot Park, IL: Abbott Laboratories, 2004.
4. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.
5. Fajadet J, Wijns W, Laarman GJ, et al. ENDEAVOR II Investigators. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798–806.
6. Kandzari DE, Leon MB, Popma JJ, et al. ENDEAVOR III Investigators. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440–7.
SOURCE
interventions.onlinejacc.org <http://interventions.onlinejacc.org> interventions.onlinejacc.org <http://interventions.onlinejacc.org>

A New Strategy for Discontinuation of Dual Antiplatelet Therapy

With interest, we read the article “A New Strategy for Discontinuation of Dual Antiplatelet Therapy: REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation (RESET) Trial” by Kim B-K, et al [1]. The authors concluded that Endeavor zotarolimus-eluting stent (E-ZES) with 3-month dual antiplatelet therapy (DAPT) was noninferior to other drug-eluting stents (DES) with 12-month DAPT (standard therapy) with respect to the occurrence of the primary endpoint (a composite of cardiovascular death, myocardial infarction (MI), stent thrombosis (ST), target vessel revascularization (TVR), or bleeding at 1 year) [1].  I have the following concerns. First, the study design was defective since the comparator group should have been composed of patients who received the same stent (E-ZES) and took DAPT for 12 months. Moreover, the comparator group was not homogeneous, since it was composed of patients who received sirolimus-eluting stents (SES, Cypher, 28.5%), everolimus-eluting stents (EES, Xience, 30%), and ZES with a biocompatible polymer (R-ZES, Resolute, 41.5%). This would further complicate the comparison since it dilutes the results of the comparator group by mixing first- (Cypher) with second-generation (Xience and Resolute) DES. Further confusion was added with the unjustified stratified randomization of the comparator group: patients with Diabetes mellitus (DM) and those with acute coronary syndrome (ACS) were assigned to R-ZES; those with short lesions to SES; those with long lesions to EES. Second, whereas the trial compared two regimens (short versus long) of DAPT following DES, the primary endpoint adopted by the authors included ischemia-driven TVR; an event completely unrelated to the safety or efficacy of a DAPT regimen. Third, the authors could not explain why the event rates were very low (cardiovascular death 0.2%, MI 0.2%, ARC definite/probable ST 0.2%) compared with previous reports of the E-ZES at a similar time point: ENDEAVOR II trial (total death 1.2%, MI 2.7%, ST 0.5% at 9 months); ENDEAVOR IV trial (cardiac death 0.5%, MI 1.6%, ARC definite/probable ST 0.9% at 12 months) [2,3]. Forth, unexpectedly, both TVR and ST rates in patients with DM who received E-ZES were lower than the rates for the whole E-ZES group! And in the ACS subgroup, patients who received the standard therapy (R-ZES) had rates of cardiovascular death 0%, MI 0%, and ST 0%, at 12 months! And surprisingly, in the subset of short lesions, despite the shorter duration of DAPT, bleeding rates were higher with E-ZES + 3-month DAPT versus standard therapy (0.6% versus 0%)! Fifth, based on the current low 12-month rates of primary composite endpoint (4.7%) compared with the figure used for statistical power calculation (10-11%), the trial was underpowered for the primary endpoint. Additionally, the non-inferiority margin of 4% was very wide for the 12-month rates of primary endpoint (4.7%). Finally, enrollment of 2117 patients in 26 centers over 20 months speaks of a low enrollment rate of 4.1 patients/center/month, that reflects an overt selection bias.

References  

1. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60:1340-8.

2. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798-806.

3. Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the ENDEAVOR zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions 12-month outcomes from the ENDEAVOR IV trial.

SOURCE

J Am Coll Cardiol 2010;55:543-54.

content.onlinejacc.org content.onlinejacc.org

http://digitalreprints.elsevier.com/i/85787/6

Conclusions

by Larry H Bernstein, MD, FCAP

This has been a six part discussion on the progress of stent design, and the decreasing problem of stent thrombosis, which evades elimination with a tradeoff in greater utility and somewhat greater risk. However, the risk of thrombotic events has become low enough that accurate comparisons of stent technologies, method of placement, and antithrombotic techniques to avoid thrombotic complications is burdened by statistical power limitations. In addition to the issue of sample size, there is an issue of patient characteristics that probably confer increased risk.

In the first part we found that stent placement is done in 15-20% of cases at a bifurcation site, where it is most favorable for plaque buildup from turbulent flow and shear stress. Recall that Routledge et al. (1) presented 2-year outcome data of 477 patients treated for bifurcation coronary disease with provisional side branch T-stenting using drug-eluting stents (DES), and they concluded that a systematic approach is feasible for 90% of the patients, with acceptable efficacy and safety profiles. There are several inherent problems that encumbered any analysis. These were: numerous anatomic configurations of bifurcation types, with the concern for late complications, restenosis, and its frequency, leading to the dilemma of placing two stents versus one stent, and then another as a side branch, if needed. The study (1) did indicate that provisional stenting is feasible in 90% of all patients, and those who received a second stent in the side branch, 28%, had similar long-term outcomes as those treated with 1 stent. The outcome of this study is similar to that of the Nordic Bifurcation study, which observed no difference in outcomes at 6 months’ follow-up between 1 and 2 stents (9). As for technique, the latest Nordic Bifurcation Stent Technique study, comparing the culotte and crush techniques, reported low rates of angiographic restenosis and major adverse cardiac events for both techniques (10). However, kissing balloon was shown to be critical in preventing restenosis. Provisional T-stenting offers several advantages compared with other bifurcation techniques. It seems to be the simplest and is associated with favorable long-term outcomes. It has also been shown that side branches and osteal disease are most problematic and that dedicated devices will have a role in left main disease.

The next issue for consideration is the use of biodegradable drug-eluting stents versus durable polymer DES. Biodegradable polymer DES resulted in lower rates than durable polymer DES of

target lesion revascularization (hazard ratio [HR] 0.82, 95 percent confidence interval [CI] 0.68-0.98, P=0.029).
definite stent thrombosis (the study’s primary safety endpoint), (HR 0.56, 95 percent CI 0.35-0.90, P=0.015).
very late stent thrombosis (clots occurring more than one year after angioplasty) for the biodegradable polymer group (HR 0.22, 95 percent CI 0.08-0.61, P=0.004).
cardiac death and heart attack (HR 0.59, 95 percent CI 0.73-0.95, P=0.031).

The third topic for consideration is the tradeoff between stent flexibility versus the concertina effect. Longitudinal strength was not recognized as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. However, this design results in reduced longitudinal strength with the unintended effect of inducing some risk of longitudinal compression of the stent (the “concertina effect”). While contemporary coronary stents are much more deliverable than older-generation stents, longitudinal deformation has emerged as a “new” complication in modern coronary stent platforms. This is more frequently associated with a particular stent design: the “offset peak-to-peak” stent design. Thin-strut stents improve deliverability and conformability. There is only limited evidence that thinner struts may result in less vessel wall damage reducing risk of restenosis. The trend of thinner strut platforms has triggered innovative designs to maintain stent radial strength. The development of longer, thinner, more flexible, and easier-to-deliver stent platforms made percutaneous coronary intervention (PCI) possible even in the most tortuous anatomy and calcified vessels. Longitudinal stent deformation, the distortion or shortening of a stent in the longitudinal axis is the effect of a longitudinal compression force on the stent rings, causing them to nest or concertinate.

The fourth question is the effect of stent design on stent thrombosis. A recent retrospective analysis provided further valuable information on the frequency and mechanisms of longitudinal stent deformation. The study involved 4455 interventional cases performed during a 4-year period. Stent deformation occurred in a total of 9 cases (0.2%) and affected 0.097% of stents deployed. Longitudinal stent deformation is probably not a “class effect,” but highly dependent on a particular stent design.

Stent thrombosis (ST), while infrequent, remains a dreaded complication of percutaneous coronary revascularization because of the associated rates of

major myocardial infarction (60%-70%) and
early mortality (20%-25%).1

the emergence of ST redirected the efforts of the cardiology community to mitigate or eliminate this potentially catastrophic event by

stent design and strut thinness,
the advent of drug-eluting stent (DES) options, and
more potent antithrombotic therapy

DESs have been associated with higher ST rates as compared to their bare-metal counterparts, particularly when utilized among high-risk groups and high-risk lesions.

The overall occurrence of Academic Research Consortium (ARC)-defined definite ST at 12 months was 1.2% (46 events). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, Dores et al concluded that the

use of first-generation DESs was associated with a 2.4-fold increase in the risk of definite ST. Among the cases receiving a first-generation DES,
the risk of ST was higher for paclitaxel-eluting versus sirolimus-eluting stents.

It should not be a surprise that patients presenting with an ACS are known to be more vulnerable to early ST than patients with chronic stable disease. The initial plaque rupture of ACS triggers a prothrombotic avalanche of events, from platelet activation to local thrombus formation and occlusion, spasm, and distal embolization of microcirculatory debris.6 It is interesting to note in the Dores et al. registry that patients receiving second-generation DESs more often presented with an ACS, making their observations reassuring that ST rates can be kept low. Patients who had early ST were characterized by diffuse atherosclerosis, angiography, inadequate pharmacotherapy, and had a higher incidence of renal insufficiency and insulin-dependent diabetes mellitus. The ACUITY subanalysis found that the rate of ST within 30 days was 1.4%, significantly higher than the 0.3%-0.5% ST rates reported among patients with stable coronary artery disease.

Among the most critical factors in mitigating the risk of ST are adequate and consistent dual-antiplatelet therapy (DAPT). Among patients with ACS, the need for more rapid and potent pharmacological suppression of platelet reactivity in the prevention of early ST is highlighted in clinical trials testing newer antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) study, there was a significant reduction in ST in the ticagrelor group vs the clopidogrel group, with definite ST rates of 1.3% and 1.9%, respectively.

This brings us to ST in randomized trials of DES. There was a much higher rate of late (beyond 30 days to 1 year) definite/probable ST following BMS compared with sirolimus-eluting stents (SES) (1% versus 0.1%, respectively). BMS was associated with a lower rate of very late (beyond 1 year) definite/probable ST compared with SES (0.4% versus 0.9%, respectively) [1]. The different overall rate of definite/ probable ST following BMS compared with SES is nearly equal at 4-year follow-up (1.7% versus 1.5%, respectively), is indeterminate (p=0.7) [1]. The study was underpowered for detection of a difference in rare-by-nature events such as ST.

Finally, Dr. Pearlman analyzes the published studies concerning whether there should be a reduction in the length of dual antiplatelet therapy to six months. Drug eluting stents decrease in stent stenosis from endothelial exuberant growth at the cost of increased propensity to thrombosis, offset by prolonged use of dual anti-platelet medication. The risk has increased due to drug eluting stent prevalence, but that is offset by management with dual anti platelet agents, so the net incidence is reduced. Stent thrombosis is promoted by metal stents until they endothelialize, but drug-eluting stents impede the endothelialization, so minimal dual platelet agent duration in practice is 3 months for BMS, 6-12 months for DES, but benefit fades to 2% at 1 year, 1% at 2 years at which point risk-benefit is unconvincing. Evidence supports that premature discontinuation clopidogrel is the most powerful independent predictor of late ST.

So here we have the status in a nutshell.

ST has driven the design of stents to be simpler to insert effectively, with a clear goal to minimize ST
The stent designs have resulted in thinner, and multi-segmented longer insertions as needed.
The result of improved stent design has been an effect of local vessel distortion.
The standard of practice is provisional T-branch DES
The use of dual antiplatelet therapy for not less than 1 year is determined by the time required for endothelialization of the artery.
There is a risk difference incurred by ACS versus stable disease, and by adequacy of antithrombotic therapy prior to an acute event.

AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B).

Posted in Biomedical Measurement Science, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Frontiers in Cardiology and Cardiovascular Disorders, Health Law & Patient Safety, Interviews with Scientific Leaders, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Massachusetts Niche Suppliers and National Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Origins of Cardiovascular Disease, PCI, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, tagged American College of Cardiology, American Heart Association, Boston University School of Medicine, Cardiac surgery, Conventional PCI, Coronary artery disease, Massachusetts Department of Public Health, myocardial infarction, New England Journal of Medicine, Percutaneous coronary intervention, surgery on July 17, 2013| 2 Comments »

AHA, ACC Change in Requirement for Surgical Support: Class IIb -> Class III, Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, Level of Evidence B).

Larry H Bernstein, MD, FCAP, Author, Curator, Volumes 1,2,3,4,5,6 Co-Editor and Author, Volume Two & Five, Co-Editor and Justin Pearlman, MD, PhD, FACC, Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases

Article ID #68: AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B). Published on 7/17/2013

WordCloud Image Produced by Adam Tubman

Voice of content consultant: Justin Pearlman, MD, PhD, FACC

The American Heart Association (AHA) and the American College of Cardiology (ACC) have convened teams of experts to summarize evidence and opinion regarding a wide range of decisions relevant to cardiovascular disease. The system accounts for some of the short comings of “evidence based medicine” by allowing for expert opinion in areas where evidence is not sufficient. The main argument for evidence-based medicine is the existence of surprises, where a plausible decision does not actually appear to work as desired when it is tested. A major problem with adhesion to evidence based medicine is that it can impede adaptation to individual needs (we are all genetically and socially/environmentally unique) and impede innovation. Large studies carry statistical weight but do not necessary consider all relevant factors. Commonly, the AFFIRM trial is interpreted as support that rate control suffices for most atrial fibrillation (AFIB), but half of those randomized to rhythm control were taken off anticoagulation without teaching patients to check their pulse daily for recurrence of AFIB. Thus the endorsed “evidence” may have more to do with the benefits of anticoagulation for both persisting and recurring AFIB and rhythm control may yet prove better than rate control. However, with wide acceptance of a particular conclusion, randomizing to another treatment may be deemed unethical, or may simply not get a large trial due to lack of economic incentive, leaving only the large trial products as the endorsed options. A medication without patent protection, such as bismuth salts for H Pylori infection, lacks financial backing for large trials.

The American Heart Association Evidence-Based Scoring System
Classification of Recommendations

● Class I: Conditions for which there is evidence, general

agreement, or both that a given procedure or treatment is

useful and effective.

● Class II: Conditions for which there is conflicting evidence,

a divergence of opinion, or both about the usefulness/

efficacy of a procedure or treatment.

● Class IIa: Weight of evidence/opinion is in favor of

usefulness/efficacy.

● Class IIb: Usefulness/efficacy is less well established by

evidence/opinion.

● Class III: Conditions for which there is evidence, general

agreement, or both that the procedure/treatment is not useful/

effective and in some cases may be harmful.

Level of Evidence

● Level of Evidence A: Data derived from multiple randomized

clinical trials

● Level of Evidence B: Data derived from a single randomized

trial or nonrandomized studies

● Level of Evidence C: Consensus opinion of experts

Circulation 2006 114: 1761 – 1791.

Assessment of Coronary Artery Disease by Cardiac Computed Tomography

A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology

Reported by Chris Kaiser, Cardiology Editor, MedPage 7/2013

Action Points

Patients with indications for nonemergency PCI who presented at hospitals without on-site cardiac surgery, were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery or at a hospital with on-site cardiac surgery.
The rates of death, myocardial infarction, repeat revascularization, and stroke did not differ significantly between the groups.
Community hospitals without surgical services can safely perform percutaneous coronary intervention (PCI) in low-risk patients — and not refuse higher-risk patients either, the MASS COMM trial found.

Summary

The co-primary endpoint of major adverse cardiac events (MACE) at 30 days occurred at a rate of 9.5% in the 10 hospitals without surgical backup versus 9.4% in the seven hospitals with onsite surgery (P<0.001 for noninferiority), Alice K. Jacobs, MD, of Boston University School of Medicine, and colleagues found.
The other co-primary endpoint of MACE at 12 months was also significant, occurring in 17.3% of patients in hospitals without backup versus 17.8% in centers with surgical services (P<0.001 for non-inferiority), they reported in the study published online by the New England Journal of Medicine. The findings were also reported at the American College of Cardiology meeting.

Study Characteristics and Results

Primary Endpoints

death
myocardial infarction
repeat revascularization
stroke

no significant differences between the two groups at 30 days and at 12 months.

Rate of stent thrombosis at 30 days

similar in both groups (0.6% versus 0.8%) and at 12 months (1.1% versus 2.1%).

Jacobs and colleagues noted that the 2011 PCI guidelines lacked evidence to fully support nonemergent PCI without surgical backup (class IIb, level of evidence B).

CPORT – E trial

Even though those guidelines came out before the results of the CPORT-E trial were published, CPORT-E trial showed similar non-inferiority at 9 months between centers that perform PCI with or without surgical backup in a cohort of nearly 19,000 non-emergent patients. The CPORT-E results were published in the March 2012 issue of the New England Journal of Medicine, and in May three cardiology organizations published an update to cath lab standards allowing for PCI without surgical.

MASS COMM study

To further the evidence, Jacobs and colleagues in 2006 had designed and carried out the Randomized Trial to Compare Percutaneous Coronary Intervention between Massachusetts Hospitals with Cardiac Surgery On-Site and Community Hospitals without Cardiac Surgery On-Site (MASS COMM) in collaboration with the Massachusetts Department of Public Health who collaborated to obtain “evidence on which to base regulatory policy decisions about performing non-emergent PCI in hospitals without on-site cardiac surgery.”

Hospitals without backup surgery were required to perform at least 300 diagnostic catheterizations per year, and operators were mandated to have performed a minimum of 75 PCI procedures per year.
The researchers randomized 3,691 patients to each arm in a 3:1 ratio (without/with backup). The median follow-up was about 1 year.
The median age of patients was 64, one-third were women, and 92% were white. Both groups had similar median ejection fractions at baseline (55%).
The mean number of vessels treated was 1.17 and most patients (84%) had one vessel treated. The mean number of lesions treated was 1.45 and most patients (67%) had one lesion treated.

The indications for PCI were:

1. ST-segment elevated MI (>72 hours before PCI of infarct-related or non–infarct-related artery — 19% and 17%

2. Unstable angina — 45% and 47%

3. Stable angina — 27% and 28%

4. Silent ischemia — 5% and 6%

5. Other — 2.5% and 2.8%

Regarding secondary endpoints, both groups had similar rates of emergency CABG and urgent or emergent PCI at 30 days. Results at 30 days and 12 months were similar for rates of ischemia-driven target-vessel revascularization and target-lesion revascularization. Other endpoints as well were similar at both time points, including

all-cause death
repeat revascularization
stroke
definite or probable stent thrombosis
major vascular complications

Researchers adjusted for a 1.3 greater chance of MACE occurring at a randomly selected hospital compared with another randomly selected hospital and found

the relative risks at 30 days and 12 months “were consistent with those of the primary results” (RR 1.02 and 0.98, respectively).

However, they cautioned that new sites perhaps should be monitored as they gain experience.

A prespecified angiographic review of 376 patients who were in the PCI-without-backup arm and 87 in the other arm showed no differences in

rates of procedural success,
proportion with complete revascularization, or
the proportion of guideline-indicated appropriate lesions for PCI.

Such results show consistent practice patterns between the groups, they noted.

The study had several limitations including the

loss of data for 13% of patients, the
exclusion of some patients for certain clinical and anatomical features, and
not having the power to detect non-inferiority in the separate components of the primary endpoint, researchers wrote.

Cardio Notes: Score Predicts PCI Readmission

Published: Jul 15, 2013

By Chris Kaiser, Cardiology Editor, MedPage Today

A simple calculation of patient variables before PCI may help stem the tide of readmission within the first month. Also this week, two blood pressure drugs that benefit diabetics and imaging cardiac sympathetic innervation.

Pre-PCI Factors Predict Return Trip

A new 30-day readmission risk prediction model for patients undergoing percutaneous coronary intervention (PCI) showed it’s possible to predict risk using only variables known before PCI, according to a study published online in Circulation: Cardiovascular Quality and Outcomes.

After multivariable adjustment, the 10 pre-PCI variables that predicted 30-day readmission were older age (mean age 68 in this study), female sex, insurance type (Medicare, state, or unknown), GFR category (less than 30 and 30-60 mL/min per 1.73m²), current or history of heart failure, chronic lung disease, peripheral vascular disease, cardiogenic shock at presentation, admit source (acute and non-acute care facility or emergency department), and previous coronary artery bypass graft surgery.

Additional significant variables post-discharge that predicted 30-day readmission were beta-blocker prescribed at discharge, post-PCI vascular or bleeding complications, discharge location, African American race, diabetes status and modality of treatment, any drug-eluting stent during the index procedure, and extended length of stay.

A risk score calculator using the pre-PCI variables will be available online soon, according to Robert W. Yeh, MD, MSc, of Massachusetts General Hospital in Boston, and colleagues.

RELATED ARTICLES

Ischemic Preconditioning Reduces Myocardial Necrosis in Elective PCI – TCTMD (pharmaceuticalintelligence.com)
Too much blood: Researchers fear the ‘gift of life’ may sometimes endanger it (o.canada.com)
Representatives of The Valley Hospital Heart and Vascular Institute Recognized by the American Heart Association (paramuspost.com)

English: Patient Positioning for a Left Anterior Thoracotomy (Photo credit: Wikipedia)

A coronary angiogram that shows the LMCA, LAD and LCX. (Photo credit: Wikipedia)

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Mitral Valve: Repair and Replacement, PCI, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, tagged Cardiogenic Shock, Cleveland Clinic, Conventional PCI, Doctor of Philosophy, Food and Drug Administration, IABP, Intra-aortic balloon pump, Left ventricle, New England Journal of Medicine, Percutaneous coronary intervention, Sutter Medical Center, Thoratec, Thrombus, Ventricular assist device on July 17, 2013| 2 Comments »

Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)

Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)

Author: Larry H Bernstein, MD, FCAP
And
Curator: Justin D Pearlman, MD, PhD, FACC

Article ID #67: Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical). Published on 7/17/2013

WordCloud Image Produced by Adam Tubman

UPDATED on 12/2/2013 – HeartMate II – LVAD

http://www.nytimes.com/2013/11/28/business/3-hospital-study-links-heart-device-to-blood-clots.html?pagewanted=1&_r=0&emc=eta1

Hospital Studies Link Heart Device to Clots

David Maxwell for The New York Times

Dr. Randall Starling, right, said that he could only speculate about the reason for the rapid rise in early blood clots.

By BARRY MEIER

Published: November 27, 2013

Doctors at the Cleveland Clinic began to suspect in 2012 that something might be wrong with a high-tech implant used to treat patients with advanced heart failure like former Vice President Dick Cheney.

Thoratec Corportation

The HeartMate II is a left ventricular assist device, which contains a pump that continuously pushes blood through the heart.

The number of patients developing potentially fatal blood clots soon after getting the implant seemed to be rising. Then early this year, researchers completed a check of hospital records and their concern turned to alarm.

The data showed that the incidence of blood clots among patients who got the device, called the HeartMate II, after March 2011 was nearly four times that of patients who had gotten the same device in previous years. Patients who developed pump-related clots died or needed emergency steps like heart transplants or device replacements to save them.

“When we got the data, we said, ‘Wow,’ ” said Dr. Randall C. Starling, a cardiologist at Cleveland Clinic.

On Wednesday, The New England Journal of Medicine posted a study on its website detailing the findings from the Cleveland Clinic and two other hospitals about the device. The HeartMate II belongs to a category of products known as a left ventricular assist device and it contains a pump that continuously pushes blood through the heart.

The abrupt increase in pump-related blood clots reported in the study is likely to raise questions about whether its manufacturer, Thoratec Corporation, modified the device, either intentionally or accidentally. By March, the Cleveland Clinic had informed both Thoratec and the Food and Drug Administration about the problems seen there, Dr. Starling said.

Officials at Thoratec declined to be interviewed. But in a statement, the company, which is based in Pleasanton, Calif., said that the HeartMate II had been intensively studied and used in more 16,000 patients worldwide with excellent results. It added that the six-month survival rate of patients who received the device had remained consistently high.

“Individual center experience with thrombosis varies significantly, and Thoratec actively partners with clinicians at all centers to minimize this risk,” the company said in a statement.

Thoratec and other cardiologists also pointed to a federally funded registry that shows a smaller rise in the rate of blood clots, or thrombosis, among patients getting a HeartMate II than the one reported Wednesday by the three hospitals. In the registry, which is known as Intermacs, the rate of pump-related blood clot associated with the HeartMate II rose to about 5 percent in devices implanted after May 2011 compared with about 2 percent in previous years.

The data reported on Wednesday in The New England Journal of Medicine found rates of clot formation two months after a device’s implant had risen to 8.4 percent after March 2011 from 2.2 percent in earlier years. Researchers also suggested in the study that the Intermacs registry might not capture all cases of pump-related blood clots, such as when patients gets emergency heart transplants after a clot forms.

Not only did the rate of blood clots increase, but the clots also occurred much sooner than in the past, according to the study. After March 2011, the median time before a clot was 2.7 months, compared with 18.6 months in previous years. In addition to the Cleveland Clinic, the report on Wednesday included data from Duke University and Washington University in St. Louis.

All mechanical heart implants are prone to producing blood clots that can form on a device’s surface. And experts say that the rate of blood clot formation can be affected by a variety of factors like changes in the use of blood-thinning drugs or the health of a patient.

In a telephone interview, Dr. Starling described the Thoratec officials as cooperative, adding that they have been looking into the problem since March to understand its cause. He said that he could only speculate about the reason for the rapid rise in early blood clots but believed it was probably device-related.

“My belief is that it is something as subtle as a change in software that affects pump flow or heat dissipation near a bearing,” said Dr. Starling, who is a consultant to Thoratec.

Asked about his comments, Thoratec responded that it had yet to determine the reason for even the smaller rise in blood clots seen in the federally funded database. “We have performed extensive analysis on HeartMate II and have not identified any change that would cause the increase observed in the Intermacs registry,” the company said.

In a statement, the F.D.A. said that it was reviewing the findings of the study. “The agency shares the authors concerns about the possibility of increased pump thrombosis,” the F.D.A. said in a statement.

The fortunes of Thoratec, which has been a favorite of Wall Street investors, may depend on its ability to find an answer to the apparent jump in pump-related blood clots. Over the last two years, the company’s stock has climbed from about $30 a share to over $43 a share. In trading Wednesday, Thoratec stock closed at $42.12 a share, up 61 cents. (The New England Journal of Medicine article was released after the stock market closed.)

The HeartMate II has been a lifesaver for many patients like Mr. Cheney in the final stages of heart failure, who got his device in 2010, sustaining them until they get a heart transplant or permanently assisting their heart. Dr. Starling said that he planned to keep using the HeartMate II in appropriate patients at the Cleveland Clinic because those facing death from heart failure had few options.

But the company has also been pushing to expand the device’s use beyond patients who face imminent death from heart failure. For example, the F.D.A. approved a clinical trial for patients with significant, but less severe, heart failure to receive a HeartMate II to compare their outcomes with patients who take drugs for the same condition. Researchers at the University of Michigan Medical Center who are leading the trial said on Wednesday that, based on the lower rates of blood clots seen in the Intermacs registry, they are planning to move forward with the trial.

Dr. Starling and researchers at the Cleveland Clinic tried this spring to get The New England Journal of Medicine to publish a report about the findings at that hospital, but the publication declined, saying the data might simply represent the experience of one facility. As a result, Dr. Starling contacted Duke University and Washington University for their data. When analyzed, it mirrored events at the Cleveland Clinic, he said.

The problems seen with the HeartMate II at the three hospitals were continuing as recently as this summer, when researchers paused the collection of data to prepare Wednesday’s study. The study also noted that a preliminary analysis of data provided by a fourth hospital, the University of Pennsylvania, showed the same pattern of blood clot formation, but that the data had been submitted too late for full analysis.

SOURCE

http://www.nytimes.com/2013/11/28/business/3-hospital-study-links-heart-device-to-blood-clots.html?pagewanted=1&_r=0&emc=eta1

This article presents the following four Sections:

I. Impella LD – ABIOMED, Inc.

II. IABP VS. Percutaneous LVADS

III. Use of the Impella 2.5 Catheter in High-Risk Percutaneous Coronary Intervention

IV. PROTECT II Study – Experts Discussion

This account is a vital piece of recognition of very rapid advances in cardiothoracic interventions to support cardiac function mechanically by pump in the situation of loss of contractile function and circulatory output sufficient to sustain life, as can occur with the development of cardiogenic shock. This has been mentioned and its use has been documented in other portions of this series. On the one hand, PCI has a long and steady history in the development of interventional cardiology. This necessitated the availability of thoracic-surgical operative support. The situation is changed, and is more properly, conditional.

I. Impella LD – ABIOMED, Inc.

This micro-axial blood pump can be inserted into the left ventricle via open chest procedures. The Impella LD device has a 9 Fr catheter-based platform and a 21 Fr micro-axial pump and is inserted through the ascending aorta, across the aortic and mitral valves and into the left ventricle. It requires minimal bedside support and a 9 Fr single-access point requires no priming outside the body.

Impella Recover LD/LP 5.0

The Impella Recover miniaturized impeller pump located within a catheter. The Impella Recover LD/LP 5.0 Support System has been developed to address the need for ventricular support in patients who develop heart failure after heart surgery (called cardiogenic shock) and who have not responded to standard medical therapy. The system is designed to provide immediate support and restore hemodynamic stability for a period of up to 7 days. Used as a bridge to therapy, it allows time for developing a definitive treatment strategy.

http://www.texasheartinstitute.org/Research/Devices/impella.cfm

The Pump

The Impella Recover LD 5.0 showing implantation via direct placement into the left ventricle.

Insert B – location in LV

The Impella Recover system is a miniaturized impeller pump located within a catheter. The device can provide support for the left side of the heart using either the

Recover LD 5.0 (implanted via direct placement into the left ventricle) or the
Recover LP 5.0 LV (placed percutaneously through the groin and positioned in the left ventricle).

The microaxial pump of the Recover LP/LD 5.0 can pump up to 4.5 liters per minute at a speed of 33,000 rpm. The pump is located at the distal end of a 9 Fr catheter.

II. IABP VS. Percutaneous LVADS

An intra-aortic balloon pump (IABP) remains the method of choice for mechanical assistance1 in patients experiencing LV failure because of its

proven hemodynamic capabilities,
prompt time to therapy, and
low complication rates.

Percutaneous left ventricular assist devices (pLVADs), such as described above, represent an emerging option for partial or total circulatory support2 and several studies have compared the and efficacy of these devices with intra-aortic balloon pump (IABP) (IABP.)

Despite some randomized controlled trials demonstrating better hemodynamic profiles for pLVADs compared with IABP, there is no difference in 30-day survival or trend toward a reduced 30-day mortality rate associated with pLVADs. Patients treated with pLVADs tended to have a

higher incidence of leg ischemia and
device related bleeding.3

Further, no differences have been detected in the overall use of

positive inotropic drugs or
vasopressors in patients with pLVADs.4,5

However, pLVADs may increase their use for patients not responding to

PCI,
fluids,
inotropes, and
IABP

Therefore, the decision making process on how to treat requires an integrated stepwise approach. A pLVAD might be considered on the basis of

anticipated individual risk,
success rates, and for
postprocedural events.6

Potential Algorithm for Device Selection during High-Risk PCI

Potential Algorithm for Device Selection during Cardiogenic Shock

Until an alternative modality, characterized by improved efficacy and safety features compared with IABP, is developed, IABP remains the cornerstone of temporary circulatory support.2

Device Comparison for Treatment of Cardiogenic Shock: traditional intra-aortic balloon therapy with Impella 2.5 percutaneous ventricular assist device

1. Percutaneous LVADs in AMI complicated by cardiogenic shock. H Thiele, et al. EHJ 2007;28:2057-2063
2. Cardiogenic shock current concepts and improving outcomes. H R Reynolds et al. Circulation 2008 ;117 :686-697
3. Percutaneous left ventricular assist devices vs. IABP counterpulsation for treatment of cardiogenic shock. J M Cheng, et al. EHJ doi:10.1093/eurheart/ehp292
4. A randomized clinical trial to evaluate the safety and efficacy of a pLVAD vs. IABP for treatment of cardiogenic shock caused by MI. M Seyfarth, et al. JACC 2008;52:1584-8
5. A randomized multicenter clinical study to evaluate the safety and efficacy of the tandem heart pLVAD vs. conventional therapy with IABP for treatment of cardiogenic shock.
6. Percutaneous LVADs in AMI complicated by cardiogenic shock. H Thiele, et al. EHJ 2007;28:2057-2063

III. Use of the Impella 2.5 Catheter in High-Risk Percutaneous Coronary Intervention

Brenda McCulloch, RN, MSN

Sutter Heart and Vascular Institute, Sutter Medical Center, Sacramento, California

Crit Care Nurse 2011; 31(1): e1-e16 http://dx.doi.org/10.4037/ccn2011293

Abstract

The Impella 2.5 is a percutaneously placed partial circulatory assist device that is increasingly being used in high-risk coronary interventional procedures to provide hemodynamic support. The Impella 2.5 is able to unload the left ventricle rapidly and effectively and increase cardiac output more than an intra-aortic balloon catheter can. Potential complications include bleeding, limb ischemia, hemolysis, and infection. One community hospital’s approach to establishing a multidisciplinary program for use of the Impella 2.5 is described.

Patients who undergo high-risk percutaneous coronary intervention (PCI), such as procedures on friable saphenous vein grafts or the left main coronary artery, may have an intra-aortic balloon catheter placed if they require hemodynamic support during the procedure. Currently, the intra-aortic balloon pump (IABP) is the most commonly used device for circulatory support. A newer option that is now available for select patients is the Impella 2.5, a short-term partial circulatory support device or percutaneous ventricular assist device (VAD).

In this article, I discuss the Impella 2.5, review indications and contraindications for its use, delineate potential complications of the Impella 2.5, and discuss implications for nursing care for patients receiving extended support from an Impella 2.5. Additionally, I share our experiences as we developed our Impella program at our community hospital. Routine management of patients after PCI is not addressed.

IABP Therapy: Background

decreases after-load,
decreases myocardial oxygen consumption,
increases coronary artery perfusion, and
modestly enhances cardiac output.1,2

The IABP cannot provide total circulatory support. Patients must have some level of left ventricular function for an IABP to be effective.

Optimal hemodynamic effect from the IABP is dependent on:

the balloon’s position in the aorta,
the blood displacement volume,
the balloon diameter in relation to aortic diameter,
the timing of balloon inflation in diastole and deflation in systole, and
the patient’s own blood pressure and vascular resistance.3,4

Impella 2.5 Catheter – ABIOMED, Inc.

Effect

reduces myocardial oxygen consumption,
improves mean arterial pressure, and
reduces pulmonary capillary wedge pressure.2

The Impella 2.5 has been used for

hemodynamic support during high-risk PCI and for
hemodynamic support of patients with

myocardial infarction complicated by cardiogenic shock or ventricular septal defect,
cardiomyopathy with acute decompensation,
postcardiotomy shock,
off-pump coronary artery bypass grafting surgery, or
heart transplant rejection and
as a bridge to the next decision.9

The Impella provides a greater increase in cardiac output than the other IABP provides. In one trial5 in which an IABP was compared with an Impella in cardiogenic shock patients, after 30 minutes of therapy, the cardiac index (calculated as cardiac output in liters per minute divided by body surface area in square meters) increased by 0.5 in the patients with the Impella compared with 0.1 in the patients with an IABP.

Unlike the IABP, the Impella does not require timing, nor is a trigger from an electrocardiographic rhythm or arterial pressure needed (Table 1). The device received 510(k) clearance from the Food and Drug Administration in June 2008 for providing up to 6 hours of partial circulatory support. In Europe, the Impella 2.5 is approved for use up to 5 days. Reports of longer duration of therapy in both the United States and Europe have been published.8,9

Clinical Research and Registry Findings

Abiomed has sponsored several trials, including PROTECT I, PROTECT II, RECOVER I, RECOVER II, and ISAR-SHOCK.
The PROTECT I study was done to assess the safety and efficacy of device placement in patients undergoing high-risk PCI.10

Twenty patients who had

poor ventricular function (ejection fraction =35%) and had
PCI on an unprotected left main coronary artery or the
last remaining patent coronary artery or graft.

The device was successfully placed in all patients, and the duration of support ranged from 0.4 to 2.5 hours. Following this trial, the Impella 2.5 device received its 510(k) approval from the Food and Drug Administration.

The ISAR-SHOCK trial was done to evaluate the safety and efficacy of the Impella 2.5 versus the IAPB in patients with cardiogenic shock due to acute myocardial infarction.5 Patients were randomized to support from an IABP (n=13) or an Impella (n=12).

The trial’s primary end point of hemodynamic improvement was defined as improved cardiac index at 30 minutes after implantation.

Improvements in cardiac index were greater with the Impella (P=.02).
The diastolic pressure increased more with Impella (P=.002).
There was a nonsignificant difference in the MAP (P=.09), as was the use of inotropic agents and vasopressors similar in both groups of patients.

Device Design: Impella 2.5 Catheter

The Impella 2.5 catheter contains a nonpulsatile microaxial continuous flow blood pump that pulls blood from the left ventricle to the ascending aorta, creating increased forward flow and increased cardiac output. An axial pump is one that is made up of impellar blades, or rotors, that spin around a central shaft; the spinning of these blades is what moves blood through the device.13

The Impella 2.5 catheter has 2 lumens. A tubing system called the Quick Set-Up has been developed for use in the catheterization laboratory. It is a single tubing system that bifurcates and connects to each port of the catheter. This arrangement allows rapid initial setup of the console so that support can be initiated quickly. When the Quick Set-Up is used, the 10% to 20% dextrose solution used to purge the motor is not heparinized. One lumen carries fluid to the impellar blades and continuously purges the motor to prevent the formation of thrombus. The proximal port of this lumen is yellow. The second lumen ends near the motor above the level of the aortic valve and is used to monitor aortic pressure.
The components required to run the device are assembled on a rolling cart and include the power source, the Braun Vista infusion pump, and the Impella console. The Impella console powers the microaxial blood pump and monitors the functioning of the device, including the purge pressure and several other parameters. The console can run on a fully charged battery for up to 1 hour.

Placement of the Device

The Impella 2.5 catheter is placed percutaneously through the common femoral artery and advanced retrograde to the left ventricle over a guidewire. Fluoroscopic guidance in the catheterization laboratory or operating room is required. After the device is properly positioned, it is activated and blood is rapidly withdrawn by the microaxial blood pump from the inlet valve in the left ventricle and moved to the aorta via the outlet area, which sits above the aortic valve in the aorta.

If the patient tolerates the PCI procedure and hemodynamic instability does not develop, the Impella 2.5 may be removed at the end of the case, or it can be withdrawn, leaving the arterial sheath in place, which can be removed when the patient’s activated clotting time or partial thromboplastin time has returned to near normal levels. For patients who become hemodynamically unstable or who have complications during the PCI (eg, no reflow, hypotension, or lethal arrhythmias), the device can remain in place for continued partial circulatory support, and the patient is transported to the critical care setting.

Potential Complications of Impella Therapy

The most commonly reported complications of Impella 2.5 placement and support include

limb ischemia,
vascular injury, and
bleeding requiring blood transfusion.6,9

Hemolysis is an inherent risk of the axial construction, and results in transfusions.5,10

Hemolysis can be mechanically induced when red blood cells are damaged as they pass through the microaxial pump. Other potential complications include

aortic valve damage,
displacement of the distal tip of the device into the aorta,
infection, and
sepsis.
Device failure, although not often reported, can occur.

Patients on Impella 2.5 support who may require

interrogation of a permanent pacemaker or
implantable cardioverter defibrillator

present an interesting situation. In order for the interrogator to connect with the permanent pacemaker or implantable cardioverter defibrillator, the Impella console must be turned off for a few seconds while the signal is established. As soon as the signal has been established, Impella support is immediately restarted.

Impella 2.5 Console Management

The recommended maximum performance level for continuous use is P8. At P8, the flow rate is 1.9 to 2.6 L/min and the motor is turning at 50000 revolutions per minute. When activated, the console is silent. No sound other than alarms is audible during Impella support, unlike the sound heard with an IABP. Ten different performance levels ranging from P0 to P9 are available. As the performance level increases, the flow rate and number of revolutions per minute increase. At maximum performance (P9), the pump rotates at 50000 revolutions per minute and delivers a flow rate of 2.1 to 2.6 L/min. P9 can be activated only for 5-minute intervals when the Impella 2.5 is in use.

IV. PROTECT II Study – Experts Discussion

the use of the Impella support device and the intraortic balloon pump for high-risk percutaneous coronary intervention

DR. SMALLING: Well, the idea about the PROTECT trial is that it would show that using the Impella device to support high-risk angioplasty was not inferior to utilizing the balloon pump for the same patient subset. Ejection fraction’s were in the 30%–35% range. Supposedly last remaining vessel or left main disease or left-main plus three-vessel disease and low EF; so I think that was the screening for entry into the trial.

major adverse cardiac event endpoints

Acute myocardial infarction,
mortality,
bleeding,

mortality was the same. Their endpoints really didn’t show that much difference. In subgroup analysis, they felt that they Impella may have had a little advantage over balloon pump.

DR. KERN: So do you think this study would tip the interventionalist to move in one direction or the other for high-risk angioplasty?

DR. SMALLING: That’s an interesting concept, you know? One has to get to: What is really a high-risk angioplasty. I think you and I are both old enough to remember that back in the mid-’80s, we determined that high-risk angioplasty was a patient with an ejection fraction of 25% or less, with a jeopardy score over 6. The EFs were a little higher. And, I guess, based on our prior experience with other support devices — like, for instance, CPS and then, later on, the Tandem Heart — there really was not an advantage of so-called more vigorous support systems. And so, the balloon pump served as well.

DR. SMALLING:

Those of us that have looked carefully at what it can really do, I think it may get one liter a minute at most, maybe more.1-6 But I think, for all intents and purposes, it doesn’t support at a very vigorous level. So I think personally, if I had someone I was really worried about, I would opt for something more substantial like, for instance, a Tandem Heart device.

DR. KERN: I think this is a really good summary of the study and the. Are there any final thoughts for those of us who want to read the PROTECT II study when it comes out?

DR. SMALLING: We have to consider a $20,000, $25,000 device. Is that really necessary to do something that we could often do without any support at all, or perhaps with a less costly device like a balloon pump.

DR. KERN: We’re going to talk for a few minutes about the PROTECT II study results that were presented here in their form. And Ron, I know you’ve been involved with following the work of the PROTECT II investigators. Were you a trial site for this study?

DR. WAKSMAN: No, actually, we were not, but we have a lot of interest in high-risk PCI and using devices to make this safe — mainly safe — and also effective. We were not investigators, but we did try to look, based on the inclusion/exclusion criteria, on our own accord with the balloon pump. If you recall, this study actually was comparing balloon time to the Impella device for patients who are high-risk PCI.

The composite endpoint was very complicated. They added like probably nine variables there, which is unusual for a study design. … They basically estimated that the event rate on the balloon pump would be higher than what we thought it should be. So we looked at our own data, and we found out that the actual — if you go by the inclusion/exclusion criteria and their endpoints — the overall event rate in the balloon pump would be much lower than they predicted and built in their sample size.

DR. KERN: And, so, the presentation of the PROTECT II trial, was it presented as a positive study or a negative study.

DR. WAKSMAN: Overall the study did not meet the endpoint. So the bottom line, you can call it the neutral study, which is a nice way to say it.

if you go and do all those analyses, you may find some areas that you can tease a P value, but I don’t think that this has any scientific value, and people should be very careful. We’re not playing now with numbers or with statistics, this is about patient care. You’re doing a study — the study, I think, has some flaws in the design to begin with — and we actually pointed that out when we were asked to participate in the study. But if the study did not meet the endpoint, then I think all those subanalyses, subgroups, you extract from here, you add to there, and you get a P value, that means nothing. So we have to be careful when we interpret this, other than as a neutral study that you basically cannot adopt any of the … it did not meet the hypothesis, that’s the bottom line.

A first-in-man study of the Reitan catheter pump for circulatory support in patients undergoing high-risk percutaneous coronary intervention.

Smith EJ, Reitan O, Keeble T, Dixon K, Rothman MT.
Department of Cardiology, London Chest Hospital, United Kingdom.
Catheter Cardiovasc Interv. 2009 Jun 1;73(7):859-65.
http://dx.doi.org/10.1002/ccd.21865.

To investigate the safety of a novel percutaneous circulatory support device during high-risk percutaneous coronary intervention (PCI).

BACKGROUND:

The Reitan catheter pump (RCP) consists of a catheter-mounted pump-head with a foldable propeller and surrounding cage. Positioned in the descending aorta the pump creates a pressure gradient, reducing afterload and enhancing organ perfusion.

METHODS:

Ten consecutive patients requiring circulatory support underwent PCI; mean age 71 +/- 9; LVEF 34% +/- 11%; jeopardy score 8 +/- 2.3. The RCP was inserted via the femoral artery. Hemostasis was achieved using Perclose sutures. PCI was performed via the radial artery. Outcomes included in-hospital death, MI, stroke, and vascular injury. Hemoglobin (Hb), free plasma Hb (fHb), platelets, and creatinine (cre) were measured pre PCI and post RCP removal.

RESULTS:

The pump was inserted and operated successfully in 9/10 cases (median 79 min). Propeller rotation at 10,444 +/- 1,424 rpm maintained an aortic gradient of 9.8 +/- 2 mm Hg. Although fHb increased,

there was no significant hemolysis (4.7 +/- 2.4 mg/dl pre vs. 11.9 +/- 10.5 post, P = 0.04, reference 20 mg/dl).
Platelets were unchanged (pre 257 +/- 74 x 10(9) vs. 245 +/- 63, P = NS).
Renal function improved (cre pre 110 +/- 27 micromol/l vs. 99 +/- 28, P = 0.004).

All PCI procedures were successful with no deaths or strokes, one MI, and no vascular complications following pump removal.

CONCLUSIONS:

The RCP can be used safely in high-risk PCI patients.

Travis gets booster device to help his heart pump blood (usatoday.com)
Opening Blocked Arteries With PTCA (heartdisease.answers.com)
Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty (emberbranch.wordpress.com)
Boston Scientific launches stent-placing device (bizjournals.com)
Unclogging Heart Arteries Via Wrists On The Rise; Minimizes Bleeding Complications (hngn.com)
Dual Antiplatelet Therapy Following Coronary Stent Implantation Associated With Significant Improvement (medindia.net)

Todd J. Brinton, MD and Peter J. Fitzgerald, MD, PhD, Chapter 14: VENTRICULAR ASSIST TECHNOLOGIES

http://www.sis.org/docs/2006Yearbook_Ch14.pdf

Follow-up on Tomosynthesis

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Imaging-based Cancer Patient Management, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged 2d mammography, 3d mammography, biomarkers, breast cancer, breast cancer screening, Cancer - General, Cancer screening, companion diagnostics, dense breast tissue, imaging based screening, imaging biomarkers, Medical imaging, Medical technology, personalised treatment, Personalized medicine, research, tomosynthesis on July 11, 2013| 2 Comments »

Follow-up on Tomosynthesis

Writer & Curator: Dror Nir, PhD

Tomosynthesis, is a method for performing high-resolution limited-angle (i.e. not full 360⁰ rotation but more like ~50⁰) tomography. The use of such systems in breast-cancer screening is steadily increasing following the clearance of such system by the FDA on 2011; see my posts – Improving Mammography-based imaging for better treatment planning and State of the art in oncologic imaging of breast.

Many radiologists expects that Tomosynthesis will eventually replace conventional mammography due to the fact that it increases the sensitivity of breast cancer detection. This claim is supported by new peer-reviewed publications. In addition, the patient’s experience during Tomosynthesis is less painful due to a lesser pressure that is applied to the breast and while presented with higher in-plane resolution and less imaging artifacts the mean glandular dose of digital breast Tomosynthesis is comparable to that of full field digital mammography. Because it is relatively new, Tomosynthesis is not available at every hospital. As well, the procedure is recognized for reimbursement by public-health schemes.

A good summary of radiologist opinion on Tomosynthesis can be found in the following video:

Recent studies’ results with digital Tomosynthesis are promising. In addition to increase in sensitivity for detection of small cancer lesions researchers claim that this new breast imaging technique will make breast cancers easier to see in dense breast tissue. Here is a paper published on-line by the Lancet just a couple of months ago:

***Integration of 3D digital mammography with* *tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study***

Stefano Ciatto†, Nehmat Houssami, Daniela Bernardi, Francesca Caumo, Marco Pellegrini, Silvia Brunelli, Paola Tuttobene, Paola Bricolo, Carmine Fantò, Marvi Valentini, Stefania Montemezzi, Petra Macaskill , Lancet Oncol. 2013 Jun;14(7):583-9. doi: 10.1016/S1470-2045(13)70134-7. Epub 2013 Apr 25.

Background Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening.

Methods Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar’s test.

Findings 7292 women were screened (median age 58 years [IQR 54–63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0.0001). Cancer detection rates were 5·3 cancers per 1000 screens (95% CI 3.8–7.3) for 2D only, and 8.1 cancers per 1000 screens (6.2–10.4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens (1.7–4.2). 395 screens (5.5%; 95% CI 5.0–6.0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0·0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17.2% (95% CI 13.6–21.3) without missing any of the cancers detected in the study population.

Interpretation Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening.

Funding National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.

Introduction

Although controversial, mammography screening is the only population-level early detection strategy that has been shown to reduce breast-cancer mortality in randomised trials.^1,2 Irrespective of which side of the mammography screening debate one supports,^1–3 efforts should be made to investigate methods that enhance the quality of (and hence potential benefit from) mammography screening. A limitation of standard 2D mammography is the superimposition of breast tissue or parenchymal density, which can obscure cancers or make normal structures appear suspicious. This short coming reduces the sensitivity of mammography and increases false-positive screening. Digital breast tomosynthesis with 3D images might help to overcome these limitations. Several reviews^4,5 have described the development of breast tomosynthesis technology, in which several low-dose radiographs are used to reconstruct a pseudo-3D image of the breast.^4–6

Initial clinical studies of 3D mammography, ^6–10 though based on small or selected series, suggest that addition of 3D to 2D mammography could improve cancer detection and reduce the number of false positives. However, previous assessments of breast tomosynthesis might have been constrained by selection biases that distorted the potential effect of 3D mammography; thus, screening trials of integrated 2D and 3D mammography are needed.⁶

We report the results of a large prospective study (Screening with Tomosynthesis OR standard Mammography [STORM]) of 3D digital mammography. We investigated the effect of screen-reading using both standard 2D and 3D imaging with tomosynthesis compared with screening with standard 2D digital mammography only for population breast-cancer screening.

Methods

Study design and participants

STORM is a prospective population-screening study that compares mammography screen-reading in two sequential phases (figure)—2D only versus integrated 2D and 3D mammography with tomosynthesis—yielding paired results for each screening examination. Women aged 48 years or older who attended population-based screening through the Trento and Verona screening services, Italy, from August, 2011, to June, 2012, were invited to be screened with integrated 2D and 3D mammography. Participants in routine screening mammography (once every 2 years) were asymptomatic women at standard (population) risk for breast cancer. The study was granted institutional ethics approval at each centre, and participants gave written informed consent. Women who opted not to participate in the study received standard 2D mammography. Digital mammography has been used in the Trento breast-screening programme since 2005, and in the Verona programme since 2007; each service monitors outcomes and quality indicators as dictated by European standards, and both have published data for screening performance.11,12

Procedures

All participants had digital mammography using a Selenia Dimensions Unit with integrated 2D and 3D mammography done in the COMBO mode (Hologic, Bedford, MA, USA): this setting takes 2D and 3D images at the same screening examination with a single breast position and compression. Each 2D and 3D image consisted of a bilateral two-view (mediolateral oblique and craniocaudal) mammogram. Screening mammograms were interpreted sequentially by radiologists, first on the basis of standard 2D mammography alone, and then by the same radiologist (on the same day) on the basis of integrated 2D and 3D mammography (figure). Thus, integrated 2D and 3D mammography screening refers to non-independent screen reading based on joint interpretation of 2D and 3D images, and does not refer to analytical combinations. Radiologists had to record whether or not to recall the participant at each screen-reading phase before progressing to the next phase of the sequence. For each screen, data were also collected for breast density (at the 2D screen-read), and the side and quadrant for any recalled abnormality (at each screen-read). All eight radiologists were breast radiologists with a mean of 8 years (range 3–13 years) experience in mammography screening, and had received basic training in integrated 2D and 3D mammography. Several of the radiologists had also used 2D and 3D mammography for patients recalled after positive conventional mammography screening as part of previous studies of tomosynthesis.8,13

Mammograms were interpreted in two independent screen-reads done in parallel, as practiced in most population breast-screening programs in Europe. A screen was considered positive and the woman recalled for further investigations if either screen-reader recorded a positive result at either 2D or integrated 2D and 3D screening (figure). When previous screening mammograms were available, these were shown to the radiologist at the time of screen-reading, as is standard practice. For assessment of breast density, we used Breast Imaging Reporting and Data System (BI-RADS)¹⁴ classification, with participants allocated to one of two groups (1–2 [low density] or 3–4 [high density]). Disagreement between readers about breast density was resolved by assessment by a third reader.

Our primary outcomes were the number of cancers detected, the number of cancers detected per 1000 screens, the number and percentage of false positive recalls, and the incremental cancer detection rate attributable to integrated 2D and 3D mammography screening. We compared the number of cancers that were detected only at 2D mammography screen-reading and those that were detected only at 2D and 3D mammography screen-reading; we also did this analysis for false positive recalls. To explore the potential effect of integrated 2D and 3D screening on false-positive recalls, we also estimated how many false-positive recalls would have resulted from using a hypothetical conditional false-positive recall approach; – i.e. positive integrated 2D and 3D mammography as a condition of recall (screening recalled at 2D mammography only would not be recalled). Pre-planned secondary analyses were comparison of outcome measures by age group and breast density.

Outcomes were assessed by excision histology for participants who had surgery, or the complete assessment outcome (including investigative imaging with or without histology from core needle biopsy) for all recalled participants. Because our study focuses on the difference in detection by the two screening methods, some cancers might have been missed by both 2D and integrated 2D and 3D mammography; this possibility could be assessed at future follow-up to identify interval cancers. However, this outcome is not assessed in the present study and does not affect estimates of our primary outcomes – i.e. comparative true or false positive detection for 2D-only versus integrated 2D and 3D mammography.

Statistical analysis

The sample size was chosen to provide 80% power to detect a difference of 20% in cancer detection, assuming a detection probability of 80% for integrated 2D and 3D screening mammography and 60% for 2D only screening, with a two-sided significance threshold of 5%. Based on the method of Lachenbruch¹⁵ for estimating sample size for studies that use McNemar’s test for paired binary data, a minimum of 40 cancers were needed. Because most screens in the participating centres were incident (repeat) screening (75%–80%), we used an underlying breast-cancer prevalence of 0·5% to estimate that roughly 7500–8000 screens would be needed to identify 40 cancers in the study population.

We calculated the Wilson CI for the false-positive recall ratio for integrated 2D and 3D screening with conditional recall compared with 2D only screening.¹⁶ All of the other analyses were done with SAS/STAT (version 9.2), using exact methods to compute 95 CIs and p-values.

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (NH) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

7292 participants with a median age of 58 years (IQR 54–63, range 48–71) were screened between Aug 12, 2011, and June 29, 2012. Roughly 5% of invited women declined integrated 2D and 3D screening and received standard 2D mammography. We present data for 7294 screens because two participants had bilateral cancer (detected with different screen-reading techniques for one participant). We detected 59 breast cancers in 57 participants (52 invasive cancers and seven ductal carcinoma in-situ). Of the invasive cancers, most were invasive ductal (n=37); others were invasive special types (n=7), invasive lobular (n=4), and mixed invasive types (n=4).

Table 1 shows the characteristics of the cancers. Mean tumour size (for the invasive cancers with known exact size) was 13.7 mm (SD 5.8) for cancers detected with both 2D alone and integrated 2D and 3D screening (n=29), and 13.5 mm (SD 6.7) for cancers detected only with integrated 2D and 3D screening (n=13).

Of the 59 cancers, 39 were detected at both 2D and integrated 2D and 3D screening (table 2). 20 cancers were detected with only integrated 2D and 3D screening compared with none detected with only 2D screening (p<0.0001; table 2). 395 screens were false positive (5.5%, 95% CI 5.0–6.0); 181 occurred at both screen-readings, and 141 occurred at 2D screening only compared with 73 at integrated 2D and 3D screening (p<0.0001; table 2). These differences were still significant in sensitivity analyses that excluded the two participants with bilateral cancer (data not shown).

5.3 cancers per 1000 screens (95% CI 3.8–7.3; table 3) were detected with 2D mammography only versus 8.1 cancers per 1000 screens (95% CI 6.2–10.4) with integrated 2D and 3D mammography (p<0.0001). The incremental cancer detection rate attributable to integrated 2D and 3D screening was 2.7 cancers per 1000 screens (95% CI 1.7–4.2), which is 33.9% (95% CI 22.1–47.4) of the cancers detected in the study population. In a sensitivity analysis that excluded the two participants with bilateral cancer the estimated incremental cancer detection rate attributable to integrated 2D and 3D screening was 2.6 cancers per 1000 screens (95% CI 1.4–3.8). The stratified results show that integrated 2D and 3D mammography was associated with an incrementally increased cancer detection rate in both age-groups and density categories (tables 3–5). A minority (16.7%) of breasts were of high density (category 3–4) reducing the power of statistical comparisons in this subgroup (table 5). The incremental cancer detection rate was much the same in low density versus high density groups (2.8 per 1000 vs 2.5 per 1000; p=0.84; table 3).

Overall recall—any recall resulting in true or false positive screens—was 6.2% (95% CI 5.7–6.8), and the false-positive rate for the 7235 screens of participants who did not have breast cancer was 5.5% (5.0–6.0). Table 6 shows the contribution to false-positive recalls from 2D mammography only, integrated 2D and 3D mammography only, and both, and the estimated number of false positives if positive integrated 2D and 3D mammography was a condition for recall (positive 2D only not recalled). Overall, more of the false-positive rate was driven by 2D mammography only than by integrated 2D and 3D, although almost half of the false-positive rate was a result of false positives recalled at both screen-reading phases (table 6). The findings were much the same when stratified by age and breast density (table 6). Had a conditional recall rule been applied, we estimate that the false-positive rate would have been 3.5% (95% CI 3.1–4.0%; table 6) and could have potentially prevented 68 of the 395 false positives (a reduction of 17.2%; 95% CI 13.6–21.3). The ratio between the number of false positives with integrated 2D and 3D screening with conditional recall (n=254) versus 2D only screening (n=322) was 0.79 (95% CI 0.71–0.87).

Discussion

Our study showed that integrated 2D and 3D mammography screening significantly increases detection of breast cancer compared with conventional mammography screening. There was consistent evidence of an incremental improvement in detection from integrated 2D and 3D mammography across age-group and breast density strata, although the analysis by breast density was limited by low number of women with breasts of high density.

One should note that we investigated comparative cancer detection, and not absolute screening sensitivity. By integrating 2D and 3D mammography using the study screen-reading protocol, 1% of false-positive recalls resulted from 2D and 3D screen-reading only (table 6). However, significantly more false positives resulted from 2D only mammography compared with integrated 2D and 3D mammography, both overall and in the stratified analyses. Application of a conditional recall rule would have resulted in a false-positive rate of 3.5% instead of the actual false-positive rate of 5.5%. The estimated false positive recall ratio of 0.79 for integrated 2D and 3D screening with conditional recall compared with 2D only screening suggests that integrated 2D and 3D screening could reduce false recalls by roughly a fifth. Had such a condition been adopted, none of the cancers detected in the study would have been missed because no cancers were detected by 2D mammography only, although this result might be because our design allowed an independent read for 2D only mammography whereas the integrated 2D and 3D read was an interpretation of a combination of 2D and 3D imaging. We do not recommend that such a conditional recall rule be used in breast-cancer screening until our findings are replicated in other mammography screening studies—STORM involved double-reading by experienced breast radiologists, and our results might not apply to other screening settings. Using a test set of 130 mammograms, Wallis and colleagues⁷ report that adding tomosynthesis to 2D mammography increased the accuracy of inexperienced readers (but not of experienced readers), therefore having experienced radiologists in STORM could have underestimated the effect of integrated 2D and 3D screen-reading.

No other population screening trials of integrated 2D and 3D mammography have reported final results (panel); however, an interim analysis of the Oslo trial¹⁷ a large population screening study has shown that integrated 2D and 3D mammography substantially increases detection of breast cancer. The Oslo study investigators screened women with both 2D and 3D mammography, but randomised reading strategies (with vs without 3D mammograms) and adjusted for the different screen-readers,¹⁷whereas we used sequential screen-reading to keep the same reader for each examination. Our estimates for comparative cancer detection and for cancer detection rates are consistent with those of the interim analysis of the Oslo study.¹⁷ The applied recall methods differed between the Oslo study (which used an arbitration meeting to decide recall) and the STORM study (we recalled based on a decision by either screen-reader), yet both studies show that 3D mammography reduces false-positive recalls when added to standard mammography.

An editorial in The Lancet¹⁸ might indeed signal the closing of a chapter of debate about the benefits and harms of screening. We hope that our work might be the beginning of a new chapter for mammography screening: our findings should encourage new assessments of screening using 2D and 3D mammography and should factor several issues related to our study. First, we compared standard 2D mammography with integrated 2D and 3D mammography the 3D mammograms were not interpreted independently of the 2D mammograms therefore 3D mammography only (without the 2D images) might not provide the same results. Our experience with breast tomosynthesis and a review⁶ of 3D mammography underscore the importance of 2D images in integrated 2D and 3D screen-reading. The 2D images form the basis of the radiologist’s ability to integrate the information from 3D images with that from 2D images. Second, although most screening in STORM was incident screening, the substantial increase in cancer detection rate with integrated 2D and 3D mammography results from the enhanced sensitivity of integrated 2D and 3D screening and is probably also a result of a prevalence effect (ie, the effect of a first screening round with integrated 2D and 3D mammography). We did not assess the effect of repeat (incident) screening with integrated 2D and 3D mammography on cancer detection it might provide a smaller effect on cancer detection rates than what we report. Third, STORM was not designed to measure biological differences between the cancers detected at integrated 2D and 3D screening compared with those detected at both screen-reading phases. Descriptive analyses suggest that, generally, breast cancers detected only at integrated 2D and 3D screening had similar features (eg, histology, pathological tumour size, node status) as those detected at both screen-reading phases. Thus, some of the cancers detected only at 2D and 3D screening might represent early detection (and would be expected to receive screening benefit) whereas some might represent over-detection and a harm from screening, as for conventional screening mam mography.1,19 The absence of consensus about over-diagnosis in breast-cancer screening should not detract from the importance of our study findings to applied screening research and to screening practice; however, our trial was not done to assess the extent to which integrated 2D and 3D mammography might contribute to over-diagnosis.

The average dose of glandular radiation from the many low-dose projections taken during a single acquisition of 3D mammography is roughly the same as that from 2D mammography.^6,20–22 Using integrated 2D and 3D entails both a 2D and 3D acquisition in one breast compression, which roughly doubles the radiation dose to the breast. Therefore, integrated 2D and 3D mammography for population screening might only be justifiable if improved outcomes were not defined solely in terms of improved detection. For example, it would be valuable to show that the increased detection with integrated 2D and 3D screening leads to reduced interval cancer rates at follow-up. A limitation of our study might be that data for interval cancers were not available; however, because of the paired design we used, future evaluation of interval cancer rates from our study will only apply to breast cancers that were not identified using 2D only or integrated 2D and 3D screening. We know of two patients from our study who have developed interval cancers (follow-up range 8–16 months). We did not get this information from cancer registries and follow-up was very short, so these data should be interpreted very cautiously, especially because interval cancers would be expected to occur in the second year of the standard 2 year interval between screening rounds. Studies of interval cancer rates after integrated 2D and 3D mammography would need to be randomised controlled trials and have a very large sample size. Additionally, the development of reconstructed 2D images from a 3D mammogram²³ provides a timely solution to concerns about radiation by providing both the 2D and 3D images from tomosynthesis, eliminating the need for two acquisitions.

We have shown that integrated 2D and 3D mammography in population breast-cancer screening increases detection of breast cancer and can reduce false-positive recalls depending on the recall strategy. Our results do not warrant an immediate change to breast-screening practice, instead, they show the urgent need for randomised controlled trials of integrated 2D and 3D versus 2D mammography, and for further translational research in breast tomosynthesis. We envisage that future screening trials investigating this issue will include measures of breast cancer detection, and will be designed to assess interval cancer rates as a surrogate endpoint for screening efficacy.

Contributors

SC had the idea for and designed the study, and collected and interpreted data. NH advised on study concepts and methods, analysed and interpreted data, searched the published work, and wrote and revised the report. DB and FC were lead radiologists, recruited participants, collected data, and commented on the draft report. MP, SB, PT, PB, PT, CF, and MV did the screen-reading, collected data, and reviewed the draft report. SM collected data and reviewed the draft report. PM planned the statistical analysis, analysed and interpreted data, and wrote and revised the report.

Conflicts of interest

SC, DB, FC, MP, SB, PT, PB, CF, MV, and SM received assistance from Hologic (Hologic USA; Technologic Italy) in the form of tomosynthesis technology and technical support for the duration of the study, and travel support to attend collaborators’ meetings. NH receives research support from a National Breast Cancer Foundation (NBCF Australia) Practitioner Fellowship, and has received travel support from Hologic to attend a collaborators’ meeting. PM receives research support through Australia’s National Health and Medical Research Council programme grant 633003 to the Screening & Test Evaluation Program.

References

1 Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380: 1778–86.

2 Glasziou P, Houssami N. The evidence base for breast cancer screening. Prev Med 2011; 53: 100–102.

3 Autier P, Esserman LJ, Flowers CI, Houssami N. Breast cancer screening: the questions answered. Nat Rev Clin Oncol 2012; 9: 599–605.

4 Baker JA, Lo JY. Breast tomosynthesis: state-of-the-art and review of the literature. Acad Radiol 2011; 18: 1298–310.

5 Helvie MA. Digital mammography imaging: breast tomosynthesis and advanced applications. Radiol Clin North Am 2010; 48: 917–29.

6 Houssami N, Skaane P. Overview of the evidence on digital breast tomosynthesis in breast cancer detection. Breast 2013; 22: 101–08.

7 Wallis MG, Moa E, Zanca F, Leifland K, Danielsson M. Two-view and single-view tomosynthesis versus full-field digital mammography: high-resolution X-ray imaging observer study. Radiology 2012; 262: 788–96.

8 Bernardi D, Ciatto S, Pellegrini M, et al. Prospective study of breast tomosynthesis as a triage to assessment in screening. Breast Cancer Res Treat 2012; 133: 267–71.

9 Michell MJ, Iqbal A, Wasan RK, et al. A comparison of the accuracy of film-screen mammography, full-field digital mammography, and digital breast tomosynthesis. Clin Radiol 2012; 67: 976–81.

10 Skaane P, Gullien R, Bjorndal H, et al. Digital breast tomosynthesis (DBT): initial experience in a clinical setting. Acta Radiol 2012; 53: 524–29.

11 Pellegrini M, Bernardi D, Di MS, et al. Analysis of proportional incidence and review of interval cancer cases observed within the mammography screening programme in Trento province, Italy. Radiol Med 2011; 116: 1217–25.

12 Caumo F, Vecchiato F, Pellegrini M, Vettorazzi M, Ciatto S, Montemezzi S. Analysis of interval cancers observed in an Italian mammography screening programme (2000–2006). Radiol Med 2009; 114: 907–14.

13 Bernardi D, Ciatto S, Pellegrini M, et al. Application of breast tomosynthesis in screening: incremental effect on mammography acquisition and reading time. Br J Radiol 2012; 85: e1174–78.

14 American College of Radiology. ACR BI-RADS: breast imaging reporting and data system, Breast Imaging Atlas. Reston: American College of Radiology, 2003.

15 Lachenbruch PA. On the sample size for studies based on McNemar’s test. Stat Med 1992; 11: 1521–25.

16 Bonett DG, Price RM. Confidence intervals for a ratio of binomial proportions based on paired data. Stat Med 2006; 25: 3039–47.

17 Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology 2013; published online Jan 3. http://dx.doi.org/10.1148/ radiol.12121373.

18 The Lancet. The breast cancer screening debate: closing a chapter? Lancet 2012; 380: 1714.

19 Biesheuvel C, Barratt A, Howard K, Houssami N, Irwig L. Effects of study methods and biases on estimates of invasive breast cancer overdetection with mammography screening: a systematic review. Lancet Oncol 2007; 8: 1129–38.

20 Tagliafico A, Astengo D, Cavagnetto F, et al. One-to-one comparison between digital spot compression view and digital breast tomosynthesis. Eur Radiol 2012; 22: 539–44.

21 Tingberg A, Fornvik D, Mattsson S, Svahn T, Timberg P, Zackrisson S. Breast cancer screening with tomosynthesis—initial experiences. Radiat Prot Dosimetry 2011; 147: 180–83.

22 Feng SS, Sechopoulos I. Clinical digital breast tomosynthesis system: dosimetric characterization. Radiology 2012; 263: 35–42.

23 Gur D, Zuley ML, Anello MI, et al. Dose reduction in digital breast tomosynthesis (DBT) screening using synthetically reconstructed projection images: an observer performance study. Acad Radiol 2012; 19: 166–71.

A very good and down-to-earth comment on this article was made by Jules H Sumkin who disclosed that he is an unpaid member of SAB Hologic Inc and have a PI research agreement between University of Pittsburgh and Hologic Inc.

“ The results of the study by Stefano Ciatto and colleagues¹ are consistent with recently published prospective,^2,3 retrospective,⁴ and observational⁵ reports on the same topic. The study¹ had limitations, including the fact that the same radiologist interpreted screens sequentially the same day without cross-balancing which examination was read first. Also, the false-negative findings for integrated 2D and 3D mammography, and therefore absolute benefit from the procedure, could not be adequately assessed because cases recalled by 2D mammography alone (141 cases) did not result in a single detection of an additional cancer while the recalls from the integrated 2D and 3D mammography alone (73 cases) resulted in the detection of 20 additional cancers. Nevertheless, the results are in strong agreement with other studies reporting of substantial performance improvements when the screening is done with integrated 2D and 3D mammography.

I disagree with the conclusion of the study with regards to the urgent need for randomised clinical trials of integrated 2D and 3D versus 2D mammography. First, to assess differences in mortality as a result of an imaging-based diagnostic method, a randomised trial will require several repeated screens by the same method in each study group, and the strong results from all studies to date will probably result in substantial crossover and self-selection biases over time. Second, because of the high survival rate (or low mortality rate) of breast cancer, the study will require long follow-up times of at least 10 years. In a rapidly changing environment in terms of improvements in screening technologies and therapeutic interventions, the avoidance of biases is likely to be very difficult, if not impossible. The use of the number of interval cancers and possible shifts in stage at detection, while appropriately accounting for confounders, would be almost as daunting a task. Third, the imaging detection of cancer is only the first step in many management decisions and interventions that can affect outcome. The appropriate control of biases related to patient management is highly unlikely. The arguments above, in addition to the existing reports to date that show substantial improvements in cancer detection, particularly with the detection of invasive cancers, with a simultaneous reduction in recall rates, support the argument that a randomised trial is neither necessary nor warranted. The current technology might be obsolete by the time results of an appropriately done and analysed randomised trial is made public.”

In order to better link the information given by “scientific” papers to the context of daily patients’ reality I suggest to spend some time reviewing few of the videos in the below links:

The following group of videos is featured on a website by Siemens. Nevertheless, the presenting radiologists are leading practitioners who affects thousands of lives every year – What the experts say about tomosynthesis. – click on ECR 2013
Breast Tomosynthesis in Practice – part of a commercial ad of the Washington Radiology Associates featured on the website of Diagnostic Imaging. As well, affects thousands of lives in the Washington area every year.

The pivotal questions yet to be answered are:

What should be done in order to translate increase in sensitivity and early detection into decrease in mortality?
What is the price of such increase in sensitivity in terms of quality of life and health-care costs and is it worth-while to pay?

An article that summarises positively the experience of introducing Tomosynthesis into routine screening practice was recently published on AJR:

Implementation of Breast Tomosynthesis in a Routine Screening Practice: An Observational Study

Stephen L. Rose¹, Andra L. Tidwell¹, Louis J. Bujnoch¹, Anne C. Kushwaha¹, Amy S. Nordmann¹ and Russell Sexton, Jr.¹

Affiliation: ¹ All authors: TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090.

Citation: American Journal of Roentgenology. 2013;200:1401-1408

ABSTRACT :

OBJECTIVE. Digital mammography combined with tomosynthesis is gaining clinical acceptance, but data are limited that show its impact in the clinical environment. We assessed the changes in performance measures, if any, after the introduction of tomosynthesis systems into our clinical practice.

MATERIALS AND METHODS. In this observational study, we used verified practice- and outcome-related databases to compute and compare recall rates, biopsy rates, cancer detection rates, and positive predictive values for six radiologists who interpreted screening mammography studies without (n = 13,856) and with (n = 9499) the use of tomosynthesis. Two-sided analyses (significance declared at p < 0.05) accounting for reader variability, age of participants, and whether the examination in question was a baseline were performed.

RESULTS. For the group as a whole, the introduction and routine use of tomosynthesis resulted in significant observed changes in recall rates from 8.7% to 5.5% (p < 0.001), nonsignificant changes in biopsy rates from 15.2 to 13.5 per 1000 screenings (p = 0.59), and cancer detection rates from 4.0 to 5.4 per 1000 screenings (p = 0.18). The invasive cancer detection rate increased from 2.8 to 4.3 per 1000 screening examinations (p = 0.07). The positive predictive value for recalls increased from 4.7% to 10.1% (p < 0.001).

CONCLUSION. The introduction of breast tomosynthesis into our practice was associated with a significant reduction in recall rates and a simultaneous increase in breast cancer detection rates.

Here are the facts in tables and pictures from this article

Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

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Heart Transplant (HT) Indication for Heart Failure (HF) – Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers:

Center for Heart Failure @Cleveland Clinic, and
Transplant Center @Mayo Clinic

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 10/15/2013

http://archive.is/5kQgj

JACC Volume 62, Issue 16, October 2013 >

Practice Guideline | October 2013

2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Clyde W. Yancy, MD, MSc, FACC, FAHA; Mariell Jessup, MD, FACC, FAHA; Biykem Bozkurt, MD, PhD, FACC, FAHA; Javed Butler, MBBS, FACC, FAHA; Donald E. Casey, MD, MPH, MBA, FACP, FAHA; Mark H. Drazner, MD, MSc, FACC, FAHA; Gregg C. Fonarow, MD, FACC, FAHA; Stephen A. Geraci, MD, FACC, FAHA, FCCP; Tamara Horwich, MD, FACC; James L. Januzzi, MD, FACC; Maryl R. Johnson, MD, FACC, FAHA; Edward K. Kasper, MD, FACC, FAHA; Wayne C. Levy, MD, FACC; Frederick A. Masoudi, MD, MSPH, FACC, FAHA; Patrick E. McBride, MD, MPH, FACC; John J.V. McMurray, MD, FACC; Judith E. Mitchell, MD, FACC, FAHA; Pamela N. Peterson, MD, MSPH, FACC, FAHA; Barbara Riegel, DNSc, RN, FAHA; Flora Sam, MD, FACC, FAHA; Lynne W. Stevenson, MD, FACC; W.H. Wilson Tang, MD, FACC; Emily J. Tsai, MD, FACC; Bruce L. Wilkoff, MD, FACC, FHRS

[+] Author Information

J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019

This article has THREE Parts:

Part One: National Organizations Addressing the Heart Transplant (HT) Indication for Heart Failure (HF)

Part Two: Procedure Outcomes of Heart Transplant (HT) Indication for Heart Failure (HF)

Center for Heart Failure @Cleveland Clinic, and
Transplant Center @Mayo Clinic

Part Three: Research on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF)

Center for Heart Failure @Cleveland Clinic, and
Transplant Center @Mayo Clinic

Part One

National Organizations Addressing the

Heart Transplant (HT) Indication for Heart Failure (HF)

The Clinical Deliberation of the Heart Failure Diagnosis and the Heart Transplant Treatment Decision

have taken central stage as it is related to

patient safety
prolongation of life
quality of life post procedure
procedure outcomes, and
cost of care for the patient diagnosed with Heart Failure

VIEW VIDEO – Sudden Cardiac Death in Heart Failure

http://theheart.medscape.org/viewarticle/803124

We present below four National institutions with pubic mandate to promote all Healthcare aspects of Cardiovascular Diseases.

A. 2020 Vision of the Heart Failure Society of America (HFSA)

Special Communication: The Heart Failure Society of America in 2020: A Vision for the Future

Journal of Cardiac Failure Vol. 18 No. 2 2012 written by BARRY H. GREENBERG, MD,1,3 INDER S. ANAND, MD, PhD,2 JOHN C. BURNETT JR, MD,2,3 JOHN CHIN, MD,2,3 KATHLEEN A. DRACUP, RN, DNSc,3 ARTHUR M. FELDMAN, MD, PhD,3 THOMAS FORCE, MD,2,3 GARY S. FRANCIS, MD,3 STEVEN R. HOUSER, PhD,2 SHARON A. HUNT, MD,2 MARVIN A. KONSTAM, MD,3 JOANN LINDENFELD, MD,2,3 DOUGLAS L. MANN, MD,2,3 MANDEEP R. MEHRA, MD,2,3 SARA C. PAUL, RN, DNP, FNP,2,3 MARIANN R. PIANO, RN, PhD,2 HEATHER J. ROSS, MD,2 HANI N. SABBAH, PhD,2 RANDALL C. STARLING, MD, MPH,2 JAMES E. UDELSON, MD,2 CLYDE W. YANCY, MD, MSc,3 MICHAEL R. ZILE, MD,2 AND BARRY M. MASSIE, MD2,3

From the 1Chair, ad hoc Committee for Strategic Development, Heart Failure Society of America; 2Member of Executive Council, Heart Failure Society of America and 3Member, ad hoc Committee for Strategic Development, Heart Failure Society of America.

They write:

The preceding 2 decades had been marked by unprecedented insights into the underlying pathophysiology of cardiac dysfunction that were paralleled by therapeutic advances that, for the first time, were shown to clearly improve outcomes in heart failure patients. At the same time, heart failure prevalence was rapidly increasing throughout the world because of the aging of the population, improved survival of patients with myocardial infarction and other cardiac conditions, and inadequate treatment of common risk factors such as hypertension.

More recently the Heart Failure Society successfully promoted establishment of Advanced Heart Failure and Transplant Cardiology as an American Board of Internal Medicine recognized secondary subspecialty of cardiology developed a board review course to help physicians prepare for the certification examination for the new subspecialty and created a national heart failure review course.

The Society has Advocacy goals, membership goals – to increase by 10% per year for 3 years from all disciplines of Heart Failure.

Education Goals:

The Heart Failure Society of America will be recognized for its innovative approaches to educating and content dissemination on heart failure targeting

healthcare professionals and patients
Grow and enhance the annual meeting through innovative approaches
Continue board review course
Increase web-based programs for patients and health care providers
Enhance the website as a portal for information dissemination for health care professionals and patients
Grow and enhance the relevance and value of the Journal of Cardiac Failure

Journal of Cardiac Failure Vol. 18 No. 2 2012

B. American Heart Association Research on the National Cost of Care of Heart Failure

Conceptual analysis of projection done by the AHA regarding the increase in the Cost of Care for the the American Patient in Heart Failure were developed in the following two articles:

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States -A Policy Statement From the American Heart Association (Aviva Lev-Ari)

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems (Justin Pearlman, Larry H Bernstein and Aviva Lev-Ari)

C. National Heart, Lung, And Blood Institute (NHLBI)’s Ten year Strategic Research Plan

Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes (Larry H Bernstein and Aviva Lev-Ari)

National Heart, Lung, And Blood Institute Working Group identified the most urgent knowledge gaps in Heart Transplantation Research. These gaps require to address the following 4 specific research directions:

enhanced phenotypic characterization of the pre-transplant population
donor-recipient optimization strategies
individualized immunosuppression therapy, and
investigations of immune and non-immune factors affecting late cardiac allograft outcomes.

D. Donor-Recipient Optimization Strategies – 33,640 Cases in the United Network for Organ Sharing database – Organ Donor’s Age is BEST predictor for survival after Heart Transplant

IF the donor age is in the 0- to 19-year-old group the median survival of 11.4 years follows the Heart Transplant.

The effect of ischemic time on survival after heart transplantation varies by donor age: An analysis of the United Network for Organ Sharing database

The Journal of Thoracic and Cardiovascular Surgery ● February 2007

J Thorac Cardiovasc Surg 2007;133:554-9

Mark J. Russo, MD, MS,a,b Jonathan M. Chen, MD,a Robert A. Sorabella, BA,a Timothy P. Martens, MD,a

Mauricio Garrido, MD,a Ryan R. Davies, MD,a Isaac George, MD,a Faisal H. Cheema, MD,a Ralph S. Mosca, MD,a Seema Mital, MD,c Deborah D. Ascheim, MD,b,d Michael Argenziano, MD,a Allan S. Stewart, MD,a Mehmet C. Oz, MD,a and Yoshifumi Naka, MD, PhDa

Objectives:

(1) To examine the interaction of donor age with ischemic time and their effect on survival and

(2) to define ranges of ischemic time associated with differences in survival.

Methods: The United Network for Organ Sharing provided de-identified patientlevel data. The study population included 33,640 recipients undergoing heart transplantation between October 1, 1987, and December 31, 2004. Recipients were divided by donor age into terciles: 0 to 19 years (n 10,814; 32.1%), 20 to 33 years (11,410, 33.9%), and 34 years or more (11,416, 33.9%). Kaplan-Meier survival functions and Cox regression were used for time-to-event analysis. Receiver operating characteristic curves and stratum-specific likelihood ratios were generated to compare 5-year survival at various thresholds for ischemic time.

Results: In univariate Cox proportional hazards regression, the effect of ischemic time on survival varied by donor age tercile: 0 to 19 years (P .141), 20 to 33 years (P .001), and 34 years or more (P .001). These relationships persisted in multivariable regression. Threshold analysis generated a single stratum (0.37-12.00 hours) in the 0- to 19-year-old group with a median survival of 11.4 years. However, in the 20- to 33-year-old-group, 3 strata were generated: 0.00 to 3.49 hours (limited), 3.50 to 6.24 hours (prolonged), and 6.25 hours or more (extended), with median survivals of 10.6, 9.9, and 7.3 years, respectively. Likewise, 3 strata were generated in the group aged 34 years or more: 0.00 to 3.49 (limited), 3.50 to 5.49 (prolonged), and 5.50 or more (extended), with median survivals of 9.1, 8.5, and 6.3 years, respectively.

Conclusions: The effect of ischemic time on survival after heart transplantation is dependent on donor age, with greater tolerance for prolonged ischemic times among grafts from younger donors. Both donor age and anticipated ischemic time must be considered when assessing a potential donor.

J Thorac Cardiovasc Surg 2007;133:554-9

Part Two

Procedures Outcomes of Heart Transplant (HT) Indication for Heart Failure (HF)

Center for Heart Failure @Cleveland Clinic, and
Transplant Center @Mayo Clinic

Center for Heart Failure @Cleveland Clinic: Institution Profile

Heart failure (sometimes called congestive heart failure or ventricular dysfunction) means your heart muscle is not functioning as well as it should. Either the left ventricle (lower chamber of the heart) is not contracting with enough force (systolic heart failure), or the ventricles are stiff and do not relax and fill properly (diastolic heart failure). The treatment of heart failure requires a specialized multidisciplinary approach to manage the overall patient care plan.

The George M and Linda H Kaufman Center for Heart Failure is one of the premier facilities in the United States for the care of people with heart failure.

The Kaufman Center Heart Failure Intensive Care was the recipient of the Beacon Award of Excellence for continuing improvements in providing the highest quality of care for patients. With over 6,000 ICUs in the Unites States, the Center joins a distinguished group of just 300 to receive this honor that recognizes the highest level of standards in patient safety and quality in acute and critical care.

In 2011, Cleveland Clinic received the American Heart Association’s Get With The Guidelines Heart Failure GOLD Plus Certification for improving the quality of care for heart failure patients. Gold Plus distinction recognizes hospitals for their success in using Get With The Guidelines treatment interventions. This quality improvement program provides tools that follow proven, evidence-based guidelines and procedures in caring for heart failure patients to prevent future hospitalizations.

http://my.clevelandclinic.org/heart/departments-centers/heart-failure.aspx

The Kaufman Center for Heart Failure Team brings together clinicians that specialize in cardiomyopathies and ischemic heart failure. The team includes physicians and nurses from Cardiovascular Medicine, Cardiothoracic Surgery, Radiology, Infectious Disease, Immunology, Pathology, Pharmacy, Biothetics and Social Work with expertise in diagnostic testing, medical and lifestyle management, surgical procedures, and psychosocial support for patients with:

Please note Hypertrophic Cardiomyopathy is treated by our Hypertrophic Cardiomyopathy Center.

Patients at Cleveland Clinic Kaufman Center for Heart Failure have available to them the full array of diagnostic testing, treatments and specialized programs.

»Services Provided for Heart Failure Patients
»Specialized Programs for Heart Failure
http://my.clevelandclinic.org/heart/departments-centers/heart-failure.aspx

Outcomes of Heart Failure and Heart Transplant @Cleveland Clinic

1,570 Number of heart transplants performed at Cleveland Clinic since inception of the Cardiac Transplant Program in 1984.

The survival rates among patients who have heart transplants at Cleveland Clinic exceeds the expected rates. Of the 150 transplant centers in the United States, Cleveland Clinic is one of only three that had better-than-expected one-year survival rates in 2011.

Ventricular Assist Device Volume 2007 – 2011

2007 – N = 23

2008 – N = 48

2009 – N = 76

2010 – N = 51

2011 – N = 56

Mechanical circulatory support (MCS) devices are used in patients with heart failure to preserve heart function until transplantation (bridge-to-transplant) or as a final treatment option (destination therapy). Cleveland Clinic has more than 20 years of experience with MCS devices for both types of therapy.

LVAD In-Hospital Mortality 2007 – 2011

Cleveland Clinic continues to make improvements to reduce mortality rates among patients who are placed on mechanical circulatory support. The mortality rate among patients who have a left ventricular assist device (LVAD) has been drastically reduced over the past five years.5% in 2011

VAD Mortality 2011

The mortality rate among Cleveland Clinic patients placed on ventricular assist devices (VADs) was much lower than expected in 2011. Observed 10%, Expected 17.5%

Heart Failure – National Hospital Quality Measures

This composite metric, based on four heart failure hospital quality process measures developed by the Centers for Medicare and Medicaid Services (CMS), shows the percentage of patients who received all the recommended care for which they were eligible. Cleveland Clinic has set a target of UHC’s 90th percentile.

Cleveland Clinic, 2010 (N = 1,194) 93.9%

Cleveland Clinic, 2011 (N = 1,163) 96.9%

UHC Top Decile, 2011 99.2%

SOURCE

University HealthSystem Consortium (UHC) Comparative Database, January through November 2011 discharges.

The Centers for Medicare and Medicaid Services (CMS) calculates two heart failure outcome measures: all-cause mortality and all-cause readmission rates, each based on Medicare claims and enrollment information. Cleveland Clinic’s performance appears below.

Heart Failure All-Cause 30-Day Mortality (N = 762) July 2008 – June 2011

Cleveland Clinic 9.2%

National Average 11.6%

Heart Failure All-Cause 30-Day Readmission (N = 1,029) July 2008 – June 2011

Cleveland Clinic 27.3%

National Average 24.7%

SOURCE:

hospitalcompare.hhs.gov

Cleveland Clinic’s heart failure risk-adjusted 30-day mortality rate is below the national average; the difference is statistically significant. Our heart failure risk-adjusted readmission rate is higher than the national average; that difference is also statistically significant. To further reduce this rate, a multidisciplinary team was tasked with improving transitions from hospital to home or post-acute care facility. Specific initiatives have been implemented in each of these focus areas: communication, education and follow-up.

http://my.clevelandclinic.org/Documents/outcomes/2011/outcomes-hvi-2011.pdf

Lung and Heart-Lung Transplant

In 2011, 51% of lung transplant patients were from outside the state of Ohio.

Cleveland Clinic surgeons transplanted 111 lungs in 2011. Our Lung and Heart-Lung Transplant

Program is the leader in Ohio and among the best programs in the country.

July 2010 – June 2011

160 Performed in 2009

Liver-Lung

Heart-Lung

Double Lung

Single Lung

53.5% Idiopathic

Primary Disease of Lung Transplant Recipients (N = 101)

Source: Scientific Registry of Transplant Recipients. March 2011. Ohio, Lung Centers, Cleveland Clinic. Table 7

Cleveland Clinic surgeons transplanted 111 lungs in 2011. Our Lung and Heart-Lung Transplant Program is the leader in Ohio and among the best programs in the country.

July 2010 – June 2011

53.5% Idiopathic Pulmonary Fibrosis (N = 54)

26.7% Emphysema/Chronic Obstructive Pulmonary Disease (N = 27)

9.9% Cystic Fibrosis (N = 10)

6.9% Idiopathic Pulmonary Arterial Hypertension (N = 7)

3.0% Other (N = 3)

Peripheral Vascular Diseases

Lower Extremity Interventional

Procedure Volume

2011

Angioplasty 451

Atherectomy 74

Stenting 260

Thrombolysis 91

Lower Extremity Surgery Volume and Mortality (N = 303)

A total of 229 lower extremity bypass surgeries were performed in 2011. The 30-day

mortality rate was 0 percent. Cleveland Clinic’s vascular surgeons have expertise in this area

and strive to use autologous vein grafts.

2011 Volume

Bypass 229

Thrombectomy 74

2011 30-Day Mortality (%)

Bypass 0%

Noninvasive Vascular Lab Ultrasound Study Distribution (N = 36,775)

2011

The Noninvasive Vascular Laboratory provides service seven days a week to diagnose arterial and

venous disorders throughout the vascular tree and for follow-up after revascularization procedures,

such as bypass grafts and stents. In 2011, 36,775 vascular lab studies were performed.

47% Venous Duplex (N = 17,284)

36% Arterial Duplex (N = 13,239)

17% Physiologic Testing (N = 6,252)

http://my.clevelandclinic.org/Documents/outcomes/2011/outcomes-hvi-2011.pdf

Transplant Center @Mayo Clinic: Heart Transplant Procedures Outcomes

Mayo Clinic History

Dr. W.W. Mayo

Drs. William (left) and Charles Mayo

Mayo Clinic developed gradually from the medical practice of a pioneer doctor, Dr. William Worrall Mayo, who settled in Rochester, Minn., in 1863. His dedication to medicine became a family tradition when his sons, Drs. William James Mayo and Charles Horace Mayo, joined his practice in 1883 and 1888, respectively.

From the beginning, innovation was their standard and they shared a pioneering zeal for medicine. As the demand for their services increased, they asked other doctors and basic science researchers to join them in the world’s first private integrated group practice.

Although the Mayo doctors were initially viewed as unconventional for practicing medicine through this teamwork approach, the benefits of a private group practice were undeniable.

As the success of their method of practice became evident, so did its acceptance. Patients discovered the advantages to a “pooled resource” of knowledge and skills among doctors. In fact, the group practice concept that the Mayo family originated has influenced the structure and function of medical practice throughout the world.

Along with its recognition as a model for integrated group practice, “the Mayos’ Clinic” developed a reputation for excellence in individual patient care. Doctors and students came from around the world to learn new techniques from the Mayo doctors, and patients came from around the world for diagnosis and treatment. What attracted them was not only technologically advanced medicine, but also the caring attitude of the doctors.

Through the years, Mayo Clinic has nurtured and developed its founders’ style of working together as a team. Shared responsibility and consensus still provide the framework for decision making at Mayo.

That teamwork in medicine is carried out today by more than 55,000 doctors, nurses, scientists, students and allied health staff at Mayo Clinic locations in the Midwest, Arizona and Florida.

http://www.mayoclinic.org/history/

http://www.mayoclinic.org/tradition-heritage-artifacts/2-1.html

2013 – Transplant Center @ Mayo Clinic:

Alternative Solutions to Treatment of Heart Failure

Mayo Clinic, with transplant services in Arizona, Florida and Minnesota, performs more transplants than any other medical center in the world. Mayo Clinic has pre-eminent adult and pediatric transplant programs, offering cardiac, liver, kidney, pancreas and bone marrow transplant services. Since performing the first clinical transplant in 1963, Mayo’s efforts to continually improve and expand organ transplantation have placed Mayo at the leading edge of clinical and basic transplant research worldwide. Research activities in the Transplant Center at Mayo Clinic have contributed significantly to the current successful outcomes of organ transplantation.

Transplant research articles

VIEW VIDEO on LVAD

http://www.mayoclinic.org/transplant-center/transplant-surgery-techniques.html

VIEW VIDEO on Mayo Clinic Heart Attack Study

People who survive a heart attack face the greatest risk of dying from sudden cardiac death (SCD) during the first month after leaving the hospital, according to a long-term community study by Mayo Clinic researchers of nearly 3,000 heart attack survivors.
Sudden cardiac death can happen when the hearts electrical system malfunctions; if treatment — cardiopulmonary resuscitation and defibrillation — does not happen fast, a person dies.
After that first month, the risk of sudden cardiac death drops significantly — but rises again if a person experiences signs of heart failure. The research results appear in the Nov. 5 edition of Journal of the American Medical Association.
Veronique Roger, M.D., a Mayo Clinic cardiologist provides an overview of the study and it’s findings.
For more information on heart attacks, click on the following link:http://www.mayoclinic.org/heart-attack/

VIEW VIDEO on Mayo Clinic Regenerative Medicine Consult Service – Stem Cell Transplantation post MI

In a proof-of-concept study, Mayo Clinic investigators have demonstrated that induced pluripotent stem (iPS) cells can be used to treat heart disease. iPS cells are stem cells converted from adult cells. In this study, the researchers reprogrammed ordinary fibroblasts, cells that contribute to scars such as those resulting from a heart attack, converting them into stem cells that fix heart damage caused by infarction. The findings appear in the current online issue of the journal Circulation.
Timothy Nelson, M.D., Ph.D., first author on the Mayo Clinic study, talks about the study and it’s findings.

Heart Transplant: Volumes and success measures Transplant Center@ Mayo Clinic

Mayo Clinic doctors’ experience and integrated team approach results in transplant outcomes that compare favorably with national averages. Teams work with transplant recipients before, during and after surgery to ensure the greatest likelihood of superior results.

Volumes and statistics are maintained separately for the three Mayo Clinic locations. Taken together or separately, transplant recipients at Mayo Clinic enjoy excellent results.

Volumes

Arizona

More than 100 heart transplants have been completed since the program began in 2005.

Florida

Surgeons at Mayo Clinic in Florida have performed more than 167 heart transplants and eight heart-lung transplants since the program began in 2001. Mayo surgeons have performed combined transplants, such as heart-kidney and heart-lung-liver transplants.

Minnesota

Mayo Clinic’s outcomes for heart transplantation compare favorably with national norms. Doctors at Mayo Clinic in Minnesota have transplanted more than 450 adult and pediatric patients, including both isolated heart transplants and combined transplants such as heart-liver, heart-kidney and others.

Success Measures

Heart Transplant Patient Survival — Adult

Arizona

Mayo Clinic Hospital
(Phoenix, AZ)

1-month survival: 97.50%(n=40) • 2009-2011
1-year survival: 94.63%(n=40) • 2009-2011
3-year survival: 82.22%(n=45) • 2006-2008
n = number of patients

National Average

1-month survival: 95.89%
1-year survival: 90.21%
3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

1-month survival: 95.08%(n=61) • 2009-2011
1-year survival: 91.50%(n=61) • 2009-2011
3-year survival: 81.82%(n=44) • 2006-2008
n = number of patients
**Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

1-month survival: 95.89%
1-year survival: 90.21%
3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

Minnesota

Saint Marys Hospital
(Mayo Clinic)

1-month survival: 95.83%(n=48) • 2009-2011
1-year survival: 95.83%(n=48) • 2009-2011
3-year survival: 82.61%(n=46) • 2006-2008
n = number of patients

National Average

1-month survival: 95.89%
1-year survival: 90.21%
3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart Transplant Patient Survival — Children

Minnesota

Saint Marys Hospital
(Mayo Clinic)

1-month survival: 100.00%(n=5) • 2009-2011
1-year survival: 100.00%(n=5) • 2009-2011
3-year survival: 60.00%(n=5) • 2006-2008
n = number of patients

National Average

1-month survival: 96.38%
1-year survival: 91.31%
3-year survival: 82.93%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart Donor Organ (Graft) Survival — Adult

Arizona

Mayo Clinic Hospital
(Phoenix, AZ)

1-month survival: 97.56%(n=41) • 2009-2011
1-year survival: 94.77%(n=41) • 2009-2011
3-year survival: 82.22%(n=45) • 2006-2008
n = number of patients

National Average

1-month survival: 95.71%
1-year survival: 89.91%
3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

Florida
Mayo Clinic Hospital**
(Jacksonville, FL)
1. 1-month survival: 95.08%(n=61) • 2009-2011
2. 1-year survival: 91.50%(n=61) • 2009-2011
3. 3-year survival: 80.00%(n=45) • 2006-2008
4. n = number of patients
5. **Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.
National Average
1. 1-month survival: 95.71%
2. 1-year survival: 89.91%
3. 3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

Minnesota

Saint Marys Hospital
(Mayo Clinic)

1-month survival: 93.88%(n=49) • 2009-2011
1-year survival: 93.88%(n=49) • 2009-2011
3-year survival: 82.61%(n=46) • 2006-2008
n = number of patients

National Average

1-month survival: 95.71%
1-year survival: 89.91%
3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart-Lung Transplant Patient Survival — Adult

Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

1-month survival: 0.00%(n=0) • 2009-2011
1-year survival: 0.00%(n=0) • 2009-2011
3-year survival: 0.00%(n=1) • 2006-2008
n = number of patients
**Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

1-month survival: 89.04%
1-year survival: 80.12%
3-year survival: 56.36%

Source: Scientific Registry of Transplant Recipients, July 2012

Minnesota

Saint Marys Hospital
(Mayo Clinic)

1-month survival: 100.00%(n=2) • 2009-2011
1-year survival: 100.00%(n=2) • 2009-2011
3-year survival: 100.00%(n=1) • 2006-2008
n = number of patients

National Average

1-month survival: 89.04%
1-year survival: 80.12%
3-year survival: 56.36%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart-Lung Donor Organ (Graft) Survival — Adult

Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

1-month survival: 0.00%(n=0) • 2009-2011
1-year survival: 0.00%(n=0) • 2009-2011
3-year survival: 0.00%(n=1) • 2006-2008
n = number of patients
**Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

1-month survival: 89.04%
1-year survival: 80.02%
3-year survival: 57.93%

Source: Scientific Registry of Transplant Recipients, July 2012

Minnesota

Saint Marys Hospital
(Mayo Clinic)

1-month survival: 100.00%(n=2) • 2009-2011
1-year survival: 100.00%(n=2) • 2009-2011
3-year survival: 100.00%(n=1) • 2006-2008
n = number of patients

National Average

1-month survival: 89.04%
1-year survival: 80.02%
3-year survival: 57.93%

Source: Scientific Registry of Transplant Recipients, July 2012

http://www.mayoclinic.org/heart-transplant/heart-transplant-success.html

Part Three

Research on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF)

Center for Heart Failure @Cleveland Clinic, and
Transplant Center @Mayo Clinic

The Editorial decision to focus on Research on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF) is covered in

Chapter 5 Invasive Procedures by Surgery versus Catheterization

and had yielded one Sub-Chapter (5.8) The Human Heart & Heart-Lung Transplant. This Sub-Chapter deals with

Heart Failure – Organ Transplant: The Human Heart & Heart-Lung Transplant,
Implantable Assist Devices and the Artificial Heart,

This Chapter 5 is in Volume Three in a forthcoming three volume Series of e-Books on Cardiovascular Diseases

Cardiovascular Diseases: Causes, Risks and Management

The Center for Heart Failure @Cleveland Clinic’s, and the Transplant Center @Mayo Clinic’s Institutions Profiles, Procedures Outcomes and Selection of their Research are now in:

Volume Three

Management of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

Leaders in Pharmaceutical Business Intelligence, Los Angeles

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed E-Book Series

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

5.8 The Human Heart & Heart-Lung Transplant, Implantable Assist Devices and the Artificial Heart

5.8.1 Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

Aviva Lev-Ari, PhD, RN

5.8.2. Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)

Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC

5.8.3 Mechanical Circulatory Assist Devices as a Bridge to Heart Transplantation or as “Destination Therapy“: Options for Patients in Advanced Heart Failure

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.4 Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.5 Orthotropic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.6 After Cardiac Transplantation: Sirolimus acts asimmunosuppressant Attenuates Allograft Vasculopathy

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.7 Prognostic Marker Importance of Troponin I in Acute Decompensated Heart Failure (ADHF)

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.8 Alternative Models of Artificial Hearts PENDING

Larry H. Bernstein, Justin D. Pearlman, and A. Lev-Ari

From other Sub-Chapters in Chapter 5:

5.6.1 The Cardio-Renal Syndrome (CRS) in Heart Failure (HF)

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.4.3 Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device:Abiomed’s Symphony | Comments

Aviva Lev-Ari, PhD, RN

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Atherogenic Processes & Pathology, CABG, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Frontiers in Cardiology and Cardiovascular Disorders, Heart Transplant, Heart-Lung Transplant, HTN, Interviews with Scientific Leaders, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Medical Devices R&D and Inventions, Mitral Valve: Repair and Replacement, Origins of Cardiovascular Disease, PCI, Pharmacotherapy of Cardiovascular Disease, Scientist: Career considerations, Statistical Methods for Research Evaluation, Stents & Tools, Valves & Tools, tagged cardiothoracic surgery, Cardiovascular disease, Isaac George, John Benjamin Murphy, surgery, William James Mayo on July 8, 2013| 2 Comments »

Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

Author and Curator: Aviva Lev-Ari, PhD, RN

Article ID #65: Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications. Published on 7/8/2013

WordCloud Image Produced by Adam Tubman

Two components of an Emerging Profile of a Young Cardiothoracic Surgeon were researched by the Author for the case of Dr. Isaac George, Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center , New York, NY.

The two components being:

1. the Cardiothoracic Surgery Theater

2. the Scientific Publications

I noted with interest Dr. George’s second publication, to be about a very well known surgeon in the US and Europe, John Benjamin Murphy. written by Dr. George and two other colleagues, George I, Hardy MA, Widmann WD. published in Curr Surg. 2004 Sep-Oct;61(5):439-41.

Dr. Murphy, is best remembered for the eponymous clinical sign that is used in evaluating patients with acute cholecystitis. His career spanned general surgery, orthopedics, neurosurgery, and cardiothoracic surgery, which helped him to gain international prominence in the surgical profession. Mayo Clinic co-founder William James Mayo called him “the surgical genius of our generation.”

http://en.wikipedia.org/wiki/John_Benjamin_Murphy

^{[Musana, Kenneth and Steven H. Yale (May 2005). “John Benjamin Murphy (1857–1916)”. Clinical Medicine & Research. Retrieved 2008-05-16.]}

I assume that Dr. Murphy’s contributions to Thoracic surgery were of interest to Dr. George to inspire him to write on the subject and elect that Specialty in Surgery.

Murphy was first in the U.S. to induce (1898) artificial immobilization and collapse of the lung in treatment of pulmonary tuberculosis. He was a pioneer in the use of bone grafting and made contributions to the understanding and management of ankylosis as well as independently proposing artificial pneumothorax to manage unilateral lung disease in tuberculosis.

Journal of the American Medical Association, Chicago, 1911, 57: 1.

SOURCE Whonamedit? A dictionary of medical eponyms, John Benjamin Murphy

I came across Dr. Isaac George’s name while researching clinical indications for Inhaled Nitric Oxide in June 2013, upon the recent publication of Leaders in Pharmaceutical Business Intelligence FIRST e-Book on Amazon (Biomed e-Books) [Kindle Edition]

Perspectives on Nitric Oxide in Disease Mechanisms
http://www.amazon.com/dp/B00DINFFYC

Dr. George’s article on Outcomes After Inhaled Nitric Oxide Therapy was particularly useful in my own research on the topic,

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions

Being myself in Analytics and quantitative model design, 1976-2004, I found of particular interest the range of quantitative methodologies used in the following article by Isaac George, assuming that his days at MIT, came very handy in 2006:

George, Isaac, Xydas, Steve, Topkara, Veli K., Ferdinando, Corrina, Barnwell, Eileen C., Gableman, Larissa, Sladen, Robert N., Naka, Yoshifumi, Oz, Mehmet C.
Clinical Indication for Use and Outcomes After Inhaled Nitric Oxide Therapy
Ann Thorac Surg 2006 82: 2161-2169

As a result of studying this article, I became aware that it has impacted favorably my 6/2013, Editorial decision, for a forthcoming book on Cardiovascular Disease in 2013. The Editorial decision regarding the selection and representation of prominent Cardiothoracic Surgery Theater in the US, and my personal decision to select a Young Cardiothoracic Surgeon

Dr. Isaac George, Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY

Education Profile and Medical Training of a Cardiac Surgeon

Isaac George, MD

Positions and Appointments
2012-present		Attending Surgeon, Heart Valve Center
2012-present		NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY
2012-present		Assistant Professor of Surgery
2012-present		Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center , New York, NY

Clinical Specialties

Adult aortic and mitral valve surgery
Transcatheter aortic and mitral valve implantation
Hybrid coronary artery bypass surgery
Complex aortic surgery
Complex valvular surgery
Heart failure and transplant surgery
Reoperative cardiac surgery
Thoracic aortic endograft implantation

Research Interests

Director, Cardiac Surgery Research Lab

1. Regulation of myostatin signaling in human cardiomyopathy

2. TGFB regulation in non-syndromic aortic aneurysm formation

3. Valve interstitial cell activation mechanisms after surgical and transcatheter valve replacement

4. Clinical outcomes after valve and hybrid surgery

Education and Training
2011-2012		Interventional Cardiology/Hybrid Cardiac Surgery Fellowship
2011-2012		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2011		Ventricular Assist Device/Cardiac Transplant Fellowship, Minimally Invasive, Cardiac Surgery
2011		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2009-2011		Fellow, Cardiothoracic Surgery
2009-2011		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2008-2009		Post-Doctoral Clinical Fellow, Cardiothoracic Surgery
2008-2009		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2006-2008		Resident, General Surgery
2006-2008		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2004-2006		Research Fellow, Cardiothoracic Surgery
2004-2006		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2002-2004		Resident, General Surgery
2002-2004		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2001-2002		Internship, General Surgery
2001-2002		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
1997-2001		MD, Medicine
1997-2001		Duke University School of Medicine, Durham, NC
1993-1997		BS, Mechanical Engineering
1993-1997		Massachusetts Institute of Technology, Cambridge, MA

Board Certifications

American Board of Thoracic Surgery, 2012-
American Board of Surgery, 2008-
Certification, Pediatric Advanced Life Support, 2008-
Certification, Advanced Trauma Life Support, 2006-
MD, State of New York, 2005-
Certification, Advanced Cardiac Life Support/Basic Life Support, 2001-
United States Medical Licensing Examination Step 3, 2004
United States Medical Licensing Examination Step 2, 2001
United States Medical Licensing Examination Step 1, 2000

Professional Honors

2008 Blakemore Prize – Best Resident Research Award, Columbia University College of Physicians and Surgeons

2007 Blakemore Award – Best Resident Research Award, Columbia University College of Physicians and Surgeons

2006 Blakemore Award – Best Resident Research Award, Columbia University College of Physicians and Surgeons

2004 New Era Cardiac Surgery Conference Scholarship

1995 Pi Tau Sigma, Mechanical Engineering Honor Society

1993 Duke University Comprehensive Cancer Center Fellowship

Professional Societies and Committees

2011 Faculty, Transcatheter Cardiovascular Therapeutics (TCT) Annual Symposium

2010- Candidate Member, Society of Thoracic Surgeons

2010- Fellow-in-Training, American College of Cardiology, Surgeons Council

2005-06 American Society of Artificial Internal Organs

2004- Member, American Heart Association

1997-01 Member, American Medical Association

SOURCE http://asp.cpmc.columbia.edu/facdb/profile_list.asp?uni=ig2006&DepAffil=Surgery

The decision to focus on Cardiothoracic Surgery @Presbeterian as described in Dr. Isaac George’s research had yielded one Sub-Chapter (4.1) in Chapter 4

Cardiac Surgery, Cardiothoracic Surgical Procedures and Percutaneous Coronary Intervention (PCI)/Coronary Angioplasty – Heart and Cardiovascular Medical Devices in Use in Operating Rooms and in Catheterization Labs in the US

in Volume Three in a forthcoming three volume Series of e-Books on Cardiovascular Diseases

Cardiovascular Diseases: Causes, Risks and Management

This very Sub-Chapter represents milestones in Dr. Isaac George – Becoming a Cardiothoracic Surgeon: An Emerging Profile through Scientific Publications, This profile is now in:

Volume Three

Management of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

Leaders in Pharmaceutical Business Intelligence, Los Angeles

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed E-Book Series

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

Chapter 5 Invasive Procedures by Surgery versus Catheterization

5.1 Cardiothoracic Surgery

5.1.1 Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

Aviva Lev-Ari, PhD, RN

5.2: Catheter Interventions

5.2.2 Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.3: Transcatheter (Percutaneous) Valves

5.3.1 Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.3.2 Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.3.3 First case in the US: Valve-in-Valve (Aortic and Mitral) Replacements with Transapical Transcatheter Implants – The Use of Transfemoral Devices

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.4: Transcatheter (Percutaneous) Pumps

5.4.1 Ventricular Assist Device (VAD): Recommended Approach to the Treatment of Intractable Cardiogentic Shock

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.4.2 Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Content Analysis of Surgeon Isaac George, MD – Publications on PubMed

SOURCE

Original classification by Aviva Lev-Ari, PhD, RN, 7/8/2013

Title	Journal	Year	CABG Stent	Valves Bio material TAVR MVR	End stage HF AMI shock	Congen Genet	Animal Model	Heart & Heart-Lung Transpl
Stent exteriorization	CCI	13	X
Left Main Coronary	CCI	13		X
TAVR-MVR	JACC	13		X
Paravalvular	CVI	13		X
Cardiogenic Shock	Heart-Lung	12			X
Cheyne-Stokes	Chest	12			X
Myostatin	PlusOne	11				X
Aortic Root & RV	ATS	11		X
Beta-Adrenergic	CV Research	11					X
Erythropoietin LV Systolic	J CV Pharmacol	10					X
Myostatin & HF	Eur J Heart Failure	10			X
Stentless in valve conduit	ATS	09		X
BNP peptide- infusion-post MI	Am J Physiol- Heart Circ Physiology	09			X
Marginal donor heart	ATS	09						X
Device-surface & Immunogenic	J Thoracic CV Surg	08		X
Myocardial electromagnetic	J Cell Physiol	08			X
Clenbuterol- muscle-mass	J Heart- Lung Transplant	08			X
Bradycardic LV	J Pharmacol Exper Therap	07					X
Ischemia- post Heart Transplant	J Thoracic CV Surgery	07						X
Octogen CABG	ATS	07	X
Ventricular synchrony	Eup J Cardio-thoracic Surg	07					X
Inhaled NO	ATS	06			X	X
Adult heart-donor- to-pediatric	J Thoracic CV Surg	06						X
Clenbuterol on LVAD	J Heart-Lung Transplant	06		X
LV-CA stent	Heart Surg Forum	06					X
LVAD myocarditis	J Thoracic CV Surg	06		X
MI-Ischemia	Am J Physiol- Ht-Circ Physiol	06		X

It is the unique combination of Animal Model Research, Biomaterial, Surgical Procedures and Molecular Cardiology, N=33.

Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater

Isaac George, MD – Clinical Specialties

Adult aortic and mitral valve surgery
Transcatheter aortic and mitral valve implantation
Hybrid coronary artery bypass surgery
Complex aortic surgery
Complex valvular surgery
Heart failure and transplant surgery
Reoperative cardiac surgery
Thoracic aortic endograft implantation

VIDEOS on CardioThoracic Surgery @ Department of Cardiothoracic Surgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City

VIEW VIDEO on the new Heart Center @ Presbyterian Hospital

http://videos.nyp.org/videos/introduction-to-the-vivian-and-seymour-milstein-family-heart-center

VIEW VIDEO on the two Hybrid OR with Siemens Artis Zeego Technology

http://videos.nyp.org/videos/tour-a-hybrid-or-with-siemens-artis-zeego-technology

VIEW VIDEO on Mininally Invesive and Conventional Therapy for Aortic Dissection and Aneurysms – Hybrid Surgery Case

http://videos.nyp.org/videos/thoracic-innovations-in-minimally-invasive-and-conventional-therapy-for-aortic-dissection-and-aneurysms

VIEW VIDEO on Mitral Valve Repair and Replacement – Dr. Karl H. Krieger

Dr. Karl H. Krieger, the Vice Chairman of the Department of Cardiothoracic Surgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City, discusses treatment for Mitral Valve Disease. Specifically, Dr. Krieger compares the options of Mitral Valve Repair with Mitral Valve Replacement.

This video with Dr. Krieger is from a web cast at the Ronald O. Perelman Heart Institute at NewYork-Presbyterian.

VIEW VIDEO on Left Ventricular Assist Devices (LVADs) – Dr. Jonathan Chen

Dr. Jonathan Chen, the Site Chief for Pediatric Cardiac Surgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City, explains how Left Ventricular Assist Devices (LVADs) work and how they can benefit patients with heart failure.

LVADs are implantable devices that help the heart pump blood. They can be used as a temporary therapy, allowing patients’ hearts to rest while they recover from cardiac events such as heart attacks, or while they wait for hearts to become available for transplants. For some patients whose hearts are unlikely to recover and are not candidates for heart transplants, the devices may be used as a permanent therapy. Heart failure, especially in severe forms, can force patients to lead restricted lives because often even very limited physical activity, such as walking from one room to another, will leave them breathless.

Dr. Chen is a pediatric cardiothoracic surgeon, yet the information in the video is applicable to adult patients as well.

VIEW VIDEO on Transcatheter Aortic Valve Implantation @ Presbyterian Hospital

http://videos.nyp.org/videos/chapter-3-transcatheter-aortic-valve-implantation

Heart, Heart-Lung Transplantation @ Presbyterian Hospital

Organ transplantation that prolongs and dramatically improves quality of life is nearly a daily occurrence at Columbia University Medical Center.

The success of solid organ transplantation – with improved surgical techniques, replacement organ procurement, and medical management – is advancing each year. Many of these advances have resulted from scientific and clinical research conducted at Columbia University Medical Center.

A Brief History of Transplantation at Columbia

Transplantation: Where we’ve been, where we’re going

Eric A. Rose, MD, former chairman of the department of surgery, left center, performing the first successful pediatric heart transplant in 1984. Transplant pioneer Keith Reemtsma, MD, who is overseeing the operating field (top of photo).

When he transplanted a chimpanzee kidney into a human patient in the late 1960’s, the late Keith Reemtsma, MD, then Department of Surgery Chairman at Tulane University, revolutionized treatment of end-stage organ failure and initiated an era of unprecedented exploration into organ transplantation that would affect the lives of patients around the world.

Transferring to Columbia-Presbyterian Medical Center in 1971, Dr. Reemtsma recruited Mark A. Hardy, MD, who laid another cornerstone of organ transplant medicine by founding the program for dialysis and kidney transplantation. Dr. Hardy based the new program on the principle of collaborative clinical care between surgeons and nephrologists. During a time when renal transplant programs were managed by one or the other discipline but never by both simultaneously, the medical community regarded the concept as folly. Yet the program grew steadily, as did the program’s immune tolerance research initiatives to induce the transplant recipient’s body to accept a donor organ. This multidisciplinary cooperation also led to major contributions in immunogenetics, immunosuppression, and treatment of autoimmune diseases and lymphoma — and it ultimately became the overarching principle for all the NewYork-Presbyterian Hospital transplant services.

Mark A. Hardy, MD

Eric A. Rose, MD

Lloyd E. Ratner, MD

Colleagues universally give credit to Eric A. Rose, MD, who co-founded the heart transplantation program with Dr. Reemtsma, for his successful transformation of the program into the outstanding center it is today. A parade of achievements marks the history of the heart transplant program, including the first mechanical bridge-totransplantation using intra-aortic balloon pumps in the 1970’s, and the first successful pediatric heart transplant, performed by Dr. Rose in 1984. Under the guidance of Dr. Rose and his successors, the program has pioneered research in immunosuppressant medications, mechanical assist devices, and minimally invasive surgical procedures. It currently performs over 100 heart transplants yearly, with among the highest success rates in the nation.

Also in 2004, Lloyd E. Ratner, MD, succeeded Dr. Hardy as director of the renal and pancreas transplant program. One of the first to perform laparoscopic donor operations, Dr. Ratner has found creative solutions to overcome immune barriers to kidney transplantation. The program now routinely uses extended-criteria donor organs, performs transplants among incompatible donors, and is a leader in coordinating “donor swaps” to maximize availability of compatible donor organs. Since Dr. Ratner’s arrival, Columbia has been designated one of ten regional islet resource centers in the U.S. that isolate and transplant pancreatic cells to treat type 1 diabetes as part of a limited protocol controlled by the FDA. Recent progress in visualization of pancreatic islets using PET technology, under the guidance of Paul Harris, PhD, has been recognized by the scientific community as a milestone in this developing field.

NYPH/Columbia received UNOS approval for pancreatic transplantation in January 2008. Our premier kidney transplant program is facilitating rapid growth of the new pancreatic transplantation program, which overlaps both in its patient population and its surgical and medical expertise. The northeast region of the U.S. has been consistently underserved as far as access to pancreatic transplantation, with relatively few centers serving a disproportionately large metropolitan population. The expanding program at NewYork-Presbyterian now provides much-needed access to patients with end-stage pancreatic disease in New York state, particularly those with the most complex medical and surgical challenges.

Transplantation of cells, rather than organs, is emerging as a therapy with enormous potential. Transplantation of either a patient’s own or a foreign donor’s bone marrow cells, for example, offers hope of regenerating the heart so that patients with heart failure may be able to avoid heart transplantation.

In introducing the transplantation programs, it would be remiss to neglect mention of the yet another dimension in which they excel — education. Physician training is a top priority, and NYPH/Columbia has trained many of the greatest transplant surgeons over the last 20 years, including many of the leaders of transplant programs throughout the U.S.

http://columbiasurgery.org/transplant/history.html

Transplant Initiative

At NewYork-Presbyterian Hospital/Columbia University Medical Center, the Transplant Initiative (TI) has been launched to drive the growth of both clinical and research aspects of transplantation. This multi-year undertaking will involve Departments of Medicine, Pathology, Pediatrics, and Surgery and all of the solid organ transplantation programs, both adult and pediatrics. It is led by its Executive Director, Jean C. Emond, MD.

Although NYP/Columbia is already a national leader in clinical transplantation with respect to volume and patient outcomes, this initiative will further leverage the diverse expertise of its transplant scientists and clinicians.

Heart Transplantation

Approximately 2,200 heart transplants are now performed each year in more than 150 heart transplant centers in the United States. The surgeons and cardiologists of Columbia University Medical Center of NYPH have a long and distinguished history of advancing “standards of care” and the survival rates of our patients by using innovative surgical techniques, by applying our basic scientific research in immunosuppression to the clinical setting, and by inventing and perfecting life-sustaining cardiac assist devices that prolong life while waiting for organ availability.

Lung and Heart-Lung Transplantation

Columbia University Medical Center’s lung and heart-lung transplantation program, which began in 1985, is fast approaching its 200th transplant. Performing more than 30 transplants each year, the lung and heart-lung transplant teams have earned a national reputation for excellence. Our world-renowned transplantation researchers have helped lead the way to improvements in care that, nationwide, have increased the long-term survival rate for lung transplantation by 50% over the past seven years. Among those improvements are new immunosuppressive agents, new antibiotics, refined surgical techniques, and a more comprehensive understanding of follow-up care.

http://columbiasurgery.org/transplant/

It is the combination of basic research at the molecular cardiology level, biomaterial, surgical procedures and PUBLICATION of Cases and research results that found me in Dr. George’s territory as a renewed inspiration.

For Author’s training & experience @ MGH – Cardiac Floor – Ellison 11, BWH – CCU, Tower 3 – 12Fl, BIDMC – Acute Surgery, Farr 9, and Texas Heart Institute, Perfusion, Faulkner Hospital – ICU

http://pharmaceuticalintelligence.com/founder/scientific-and-medical-affairs-chronological-cv/

and in Part II, Section IV in

http://pharmaceuticalintelligence.com/2013/07/14/vascular-surgery-position-statement-in-2013-and-contributions-of-a-vascular-surgeon-at-peak-career-richard-paul-cambria-md-chief-division-of-vascular-and-endovascular-surgery-co-director-thoracic/

Surgeon Isaac George, MD – Training in the OR @ Presbyterian Hospital

2011-2012		Interventional Cardiology/Hybrid Cardiac Surgery Fellowship
2011-2012		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2011		Ventricular Assist Device/Cardiac Transplant Fellowship, Minimally Invasive, Cardiac Surgery
2011		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2009-2011		Fellow, Cardiothoracic Surgery
2009-2011		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2008-2009		Post-Doctoral Clinical Fellow, Cardiothoracic Surgery
2008-2009		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2006-2008		Resident, General Surgery
2006-2008		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2004-2006		Research Fellow, Cardiothoracic Surgery
2004-2006		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2002-2004		Resident, General Surgery
2002-2004		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY
2001-2002		Internship, General Surgery
2001-2002		New York Presbyterian Hospital – Columbia University Medical Center, New York, NY

SOURCE

http://asp.cpmc.columbia.edu/facdb/profile_list.asp?uni=ig2006&DepAffil=Surgery

Surgeon Isaac George, MD – Publications on PubMed

http://www.ncbi.nlm.nih.gov/pubmed

Select item 234757651.

Stent exteriorization facilitates surgical repair for large-bore sheath complications.

George I, Shrikhande G, Williams MR.

Catheter Cardiovasc Interv. 2013 Mar 8. doi: 10.1002/ccd.24918. [Epub ahead of print]

PMID:

23475765

[PubMed – as supplied by publisher]

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Select item 234131722.

Paradis JM, George I, Kodali S.

Catheter Cardiovasc Interv. 2013 Feb 14. doi: 10.1002/ccd.24865. [Epub ahead of print]

PMID:

23413172

[PubMed – as supplied by publisher]

Concomitant transcatheter aortic and mitral valve-in-valve replacements using transfemoral devices via the transapical approach: first case in United States.

Select item 233478683.

Paradis JM, Kodali SK, Hahn RT, George I, Daneault B, Koss E, Nazif TM, Leon MB, Williams MR.

JACC Cardiovasc Interv. 2013 Jan;6(1):94-6. doi: 10.1016/j.jcin.2012.07.018. No abstract available.

PMID:

23347868

[PubMed – in process]

Efficacy and safety of postdilatation to reduce paravalvular regurgitation during balloon-expandable transcatheter aortic valve replacement.

Select item 233398414.

Daneault B, Koss E, Hahn RT, Kodali S, Williams MR, Généreux P, Paradis JM, George I, Reiss GR, Moses JW, Smith CR, Leon MB.

Circ Cardiovasc Interv. 2013 Feb;6(1):85-91. doi: 10.1161/CIRCINTERVENTIONS.112.971614. Epub 2013 Jan 22.

PMID:

23339841

[PubMed – in process]

A stepwise progression in the treatment of cardiogenic shock.

Select item 226080345.

Pollack A, Uriel N, George I, Kodali S, Takayama H, Naka Y, Jorde U.

Heart Lung. 2012 Sep-Oct;41(5):500-4. doi: 10.1016/j.hrtlng.2012.03.007. Epub 2012 May 16.

PMID:

22608034

[PubMed – indexed for MEDLINE]

Transvenous phrenic nerve stimulation in patients with Cheyne-Stokes respiration and congestive heart failure: a safety and proof-of-concept study.

Select item 223022996.

Zhang XL, Ding N, Wang H, Augostini R, Yang B, Xu D, Ju W, Hou X, Li X, Ni B, Cao K, George I, Wang J, Zhang SJ.

Chest. 2012 Oct;142(4):927-34.

PMID:

22302299

[PubMed – in process]

Myostatin is elevated in congenital heart disease and after mechanical unloading.

Select item 219316167.

Bish LT, George I, Maybaum S, Yang J, Chen JM, Sweeney HL.

PLoS One. 2011;6(9):e23818. doi: 10.1371/journal.pone.0023818. Epub 2011 Sep 13.

PMID:

21931616

[PubMed – indexed for MEDLINE]

Aortic root and right ventricular outflow tract reconstruction using composite biological valved conduits after failed Ross procedure.

Select item 216199558.

Russo MJ, Easterwood R, Williams MR, George I, Stewart AS.

Ann Thorac Surg. 2011 Jun;91(6):e87-9. doi: 10.1016/j.athoracsur.2011.01.035.

PMID:

21619955

[PubMed – indexed for MEDLINE]

β-adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines.

Select item 214937019.

George I, Sabbah HN, Xu K, Wang N, Wang J.

Cardiovasc Res. 2011 Aug 1;91(3):447-55. doi: 10.1093/cvr/cvr106. Epub 2011 Apr 14.

PMID:

21493701

[PubMed – indexed for MEDLINE]

Erythropoietin derivate improves left ventricular systolic performance and attenuates left ventricular remodeling in rats with myocardial infarct-induced heart failure.

Select item 2088161410.

Xu K, George I, Klotz S, Hay I, Xydas S, Zhang G, Cerami A, Wang J.

J Cardiovasc Pharmacol. 2010 Nov;56(5):506-12. doi: 10.1097/FJC.0b013e3181f4f05a.

PMID:

20881614

[PubMed – indexed for MEDLINE]

Myostatin activation in patients with advanced heart failure and after mechanical unloading.

Select item 2034855011.

George I, Bish LT, Kamalakkannan G, Petrilli CM, Oz MC, Naka Y, Sweeney HL, Maybaum S.

Eur J Heart Fail. 2010 May;12(5):444-53. doi: 10.1093/eurjhf/hfq039. Epub 2010 Mar 27.

PMID:

20348550

[PubMed – indexed for MEDLINE]

Stentless bioprosthesis in a valved conduit: implications for pulmonary reconstruction.

Select item 1993228712.

George I, Shah JN, Bacchetta M, Stewart A.

Ann Thorac Surg. 2009 Dec;88(6):2022-4. doi: 10.1016/j.athoracsur.2009.04.145.

PMID:

19932287

[PubMed – indexed for MEDLINE]

Long-term effects of B-type natriuretic peptide infusion after acute myocardial infarction in a rat model.

Select item 1985873513.

George I, Xydas S, Klotz S, Hay I, Ng C, Chang J, Xu K, Li Z, Protter AA, Wu EX, Oz MC, Wang J.

J Cardiovasc Pharmacol. 2010 Jan;55(1):14-20. doi: 10.1097/FJC.0b013e3181c5e743.

PMID:

19858735

[PubMed – indexed for MEDLINE]

Prolonged effects of B-type natriuretic peptide infusion on cardiac remodeling after sustained myocardial injury.

Select item 1952537314.

George I, Morrow B, Xu K, Yi GH, Holmes J, Wu EX, Li Z, Protter AA, Oz MC, Wang J.

Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H708-17. doi: 10.1152/ajpheart.00661.2008. Epub 2009 Jun 12.

PMID:

19525373

[PubMed – indexed for MEDLINE]

Matching high-risk recipients with marginal donor hearts is a clinically effective strategy.

Select item 1932412915.

Russo MJ, Davies RR, Hong KN, Chen JM, Argenziano M, Moskowitz A, Ascheim DD, George I, Stewart AS, Williams M, Gelijns A, Naka Y.

Ann Thorac Surg. 2009 Apr;87(4):1066-70; discussion 1071. doi: 10.1016/j.athoracsur.2008.12.020.

PMID:

19324129

[PubMed – indexed for MEDLINE]

Association of device surface and biomaterials with immunologic sensitization after mechanical support.

Select item 1854438916.

George I, Colley P, Russo MJ, Martens TP, Burke E, Oz MC, Deng MC, Mancini DM, Naka Y.

J Thorac Cardiovasc Surg. 2008 Jun;135(6):1372-9. doi: 10.1016/j.jtcvs.2007.11.049.

PMID:

18544389

[PubMed – indexed for MEDLINE]

Myocardial function improved by electromagnetic field induction of stress protein hsp70.

Select item 1844681617.

George I, Geddis MS, Lill Z, Lin H, Gomez T, Blank M, Oz MC, Goodman R.

J Cell Physiol. 2008 Sep;216(3):816-23. doi: 10.1002/jcp.21461.

PMID:

18446816

[PubMed – indexed for MEDLINE]

Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure.

Select item 1837488418.

Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S.

J Heart Lung Transplant. 2008 Apr;27(4):457-61. doi: 10.1016/j.healun.2008.01.013.

PMID:

18374884

[PubMed – indexed for MEDLINE]

Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure.

Select item 1727719619.

Cheng Y, George I, Yi GH, Reiken S, Gu A, Tao YK, Muraskin J, Qin S, He KL, Hay I, Yu K, Oz MC, Burkhoff D, Holmes J, Wang J.

J Pharmacol Exp Ther. 2007 May;321(2):469-76. Epub 2007 Feb 2.

PMID:

17277196

[PubMed – indexed for MEDLINE]

The effect of ischemic time on survival after heart transplantation varies by donor age: an analysis of the United Network for Organ Sharing database.

Select item 1725859920.

Russo MJ, Chen JM, Sorabella RA, Martens TP, Garrido M, Davies RR, George I, Cheema FH, Mosca RS, Mital S, Ascheim DD, Argenziano M, Stewart AS, Oz MC, Naka Y.

J Thorac Cardiovasc Surg. 2007 Feb;133(2):554-9.

PMID:

17258599

[PubMed – indexed for MEDLINE]

Discharge to home rates are significantly lower for octogenarians undergoing coronary artery bypass graft surgery.

Bardakci H, Cheema FH, Topkara VK, Dang NC, Martens TP, Mercando ML, Forster CS, Benson AA, George I, Russo MJ, Oz MC, Esrig BC.

Ann Thorac Surg. 2007 Feb;83(2):483-9.

PMID:

17257973

[PubMed – indexed for MEDLINE]

Clinical indication for use and outcomes after inhaled nitric oxide therapy.

Select item 1712612922.

George I, Xydas S, Topkara VK, Ferdinando C, Barnwell EC, Gableman L, Sladen RN, Naka Y, Oz MC.

Ann Thorac Surg. 2006 Dec;82(6):2161-9.

PMID:

17126129

[PubMed – indexed for MEDLINE]

Effect of passive cardiac containment on ventricular synchrony and cardiac function in awake dogs.

Select item 1708176423.

George I, Cheng Y, Yi GH, He KL, Li X, Oz MC, Holmes J, Wang J.

Eur J Cardiothorac Surg. 2007 Jan;31(1):55-64. Epub 2006 Nov 1.

PMID:

17081764

[PubMed – indexed for MEDLINE]

Ray optics model for triangular hollow silicon waveguides.

Select item 1706858824.

Isaac G, Khalil D.

Appl Opt. 2006 Oct 10;45(29):7567-78.

PMID:

17068588

[PubMed]

Adult-age donors offer acceptable long-term survival to pediatric heart transplant recipients: an analysis of the United Network of Organ Sharing database.

Select item 1705994525.

Russo MJ, Davies RR, Sorabella RA, Martens TP, George I, Cheema FH, Mital S, Mosca RS, Chen JM.

J Thorac Cardiovasc Surg. 2006 Nov;132(5):1208-12.

PMID:

17059945

[PubMed – indexed for MEDLINE]

Effect of clenbuterol on cardiac and skeletal muscle function during left ventricular assist device support.

Select item 1696247026.

George I, Xydas S, Mancini DM, Lamanca J, DiTullio M, Marboe CC, Shane E, Schulman AR, Colley PM, Petrilli CM, Naka Y, Oz MC, Maybaum S.

J Heart Lung Transplant. 2006 Sep;25(9):1084-90.

PMID:

16962470

[PubMed – indexed for MEDLINE]

Delusional Misidentification Syndromes: Separate Disorders or Unusual Presentations of Existing DSM-IV Categories?

Select item 2097582827.

Atta K, Forlenza N, Gujski M, Hashmi S, Isaac G.

Psychiatry (Edgmont). 2006 Sep;3(9):56-61.

PMID:

20975828

[PubMed]

Direct left ventricle-to-coronary artery stent restores perfusion to chronic ischemic swine myocardium.

Select item 1680912728.

Yi GH, George I, He KL, Lee MJ, Cahalan P, Zhang G, Gu A, Klotz S, Burkhoff D, Wang J.

Heart Surg Forum. 2006;9(5):E744-9.

PMID:

16809127

[PubMed – indexed for MEDLINE]

Ventricular assist device use for the treatment of acute viral myocarditis.

Select item 1667861929.

Topkara VK, Dang NC, Barili F, Martens TP, George I, Cheema FH, Bardakci H, Ozcan AV, Naka Y.

J Thorac Cardiovasc Surg. 2006 May;131(5):1190-1. No abstract available.

PMID:

16678619

[PubMed – indexed for MEDLINE]

A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia.

Select item 1661713930.

George I, Yi GH, Schulman AR, Morrow BT, Cheng Y, Gu A, Zhang G, Oz MC, Burkhoff D, Wang J.

Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1126-37. Epub 2006 Apr 14.

PMID:

16617139

[PubMed – indexed for MEDLINE]

Predictors and outcomes of continuous veno-venous hemodialysis use after implantation of a left ventricular assist device.

Select item 1656396931.

Topkara VK, Dang NC, Barili F, Cheema FH, Martens TP, George I, Bardakci H, Oz MC, Naka Y.

J Heart Lung Transplant. 2006 Apr;25(4):404-8. Epub 2006 Feb 28.

PMID:

16563969

[PubMed – indexed for MEDLINE]

Select item 1547509032.

John Benjamin Murphy.

George I, Hardy MA, Widmann WD.

Curr Surg. 2004 Sep-Oct;61(5):439-41. No abstract available.

PMID:

15475090

[PubMed – indexed for MEDLINE]

Multiple-scattering lidar retrieval method: tests on Monte Carlo simulations and comparisons with in situ measurements.

Select item 1239618033.

Bissonnette LR, Roy G, Poutier L, Cober SG, Isaac GA.

Appl Opt. 2002 Oct 20;41(30):6307-24.

PMID:

12396180

[PubMed]

Discharge to home rates are significantly lower for octogenarians undergoing coronary artery bypass graft surgery.

Bardakci H, Cheema FH, Topkara VK, Dang NC, Martens TP, Mercando ML, Forster CS, Benson AA, George I, Russo MJ, Oz MC, Esrig BC.

Ann Thorac Surg. 2007 Feb;83(2):483-9.

PMID:

17257973

[PubMed – indexed for MEDLINE]

Clinical indication for use and outcomes after inhaled nitric oxide therapy.

Select item 1712612922.

George I, Xydas S, Topkara VK, Ferdinando C, Barnwell EC, Gableman L, Sladen RN, Naka Y, Oz MC.

Ann Thorac Surg. 2006 Dec;82(6):2161-9.

PMID:

17126129

[PubMed – indexed for MEDLINE]

Effect of passive cardiac containment on ventricular synchrony and cardiac function in awake dogs.

Select item 1708176423.

George I, Cheng Y, Yi GH, He KL, Li X, Oz MC, Holmes J, Wang J.

Eur J Cardiothorac Surg. 2007 Jan;31(1):55-64. Epub 2006 Nov 1.

PMID:

17081764

[PubMed – indexed for MEDLINE]

Ray optics model for triangular hollow silicon waveguides.

Select item 1706858824.

Isaac G, Khalil D.

Appl Opt. 2006 Oct 10;45(29):7567-78.

PMID:

17068588

[PubMed]

Adult-age donors offer acceptable long-term survival to pediatric heart transplant recipients: an analysis of the United Network of Organ Sharing database.

Select item 1705994525.

Russo MJ, Davies RR, Sorabella RA, Martens TP, George I, Cheema FH, Mital S, Mosca RS, Chen JM.

J Thorac Cardiovasc Surg. 2006 Nov;132(5):1208-12.

PMID:

17059945

[PubMed – indexed for MEDLINE]

Effect of clenbuterol on cardiac and skeletal muscle function during left ventricular assist device support.

Select item 1696247026.

George I, Xydas S, Mancini DM, Lamanca J, DiTullio M, Marboe CC, Shane E, Schulman AR, Colley PM, Petrilli CM, Naka Y, Oz MC, Maybaum S.

J Heart Lung Transplant. 2006 Sep;25(9):1084-90.

PMID:

16962470

[PubMed – indexed for MEDLINE]

Delusional Misidentification Syndromes: Separate Disorders or Unusual Presentations of Existing DSM-IV Categories?

Select item 2097582827.

Atta K, Forlenza N, Gujski M, Hashmi S, Isaac G.

Psychiatry (Edgmont). 2006 Sep;3(9):56-61.

PMID:

20975828

[PubMed]

Direct left ventricle-to-coronary artery stent restores perfusion to chronic ischemic swine myocardium.

Select item 1680912728.

Yi GH, George I, He KL, Lee MJ, Cahalan P, Zhang G, Gu A, Klotz S, Burkhoff D, Wang J.

Heart Surg Forum. 2006;9(5):E744-9.

PMID:

16809127

[PubMed – indexed for MEDLINE]

Ventricular assist device use for the treatment of acute viral myocarditis.

Select item 1667861929.

Topkara VK, Dang NC, Barili F, Martens TP, George I, Cheema FH, Bardakci H, Ozcan AV, Naka Y.

J Thorac Cardiovasc Surg. 2006 May;131(5):1190-1. No abstract available.

PMID:

16678619

[PubMed – indexed for MEDLINE]

A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia.

Select item 1661713930.

George I, Yi GH, Schulman AR, Morrow BT, Cheng Y, Gu A, Zhang G, Oz MC, Burkhoff D, Wang J.

Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1126-37. Epub 2006 Apr 14.

PMID:

16617139

[PubMed – indexed for MEDLINE]

Predictors and outcomes of continuous veno-venous hemodialysis use after implantation of a left ventricular assist device.

Select item 1656396931.

Topkara VK, Dang NC, Barili F, Cheema FH, Martens TP, George I, Bardakci H, Oz MC, Naka Y.

J Heart Lung Transplant. 2006 Apr;25(4):404-8. Epub 2006 Feb 28.

PMID:

16563969

[PubMed – indexed for MEDLINE]

Select item 1547509032.

John Benjamin Murphy.

George I, Hardy MA, Widmann WD.

Curr Surg. 2004 Sep-Oct;61(5):439-41. No abstract available.

PMID:

15475090

[PubMed – indexed for MEDLINE]

Multiple-scattering lidar retrieval method: tests on Monte Carlo simulations and comparisons with in situ measurements.

Select item 1239618033.

Bissonnette LR, Roy G, Poutier L, Cober SG, Isaac GA.

Appl Opt. 2002 Oct 20;41(30):6307-24.

PMID:

12396180

[PubMed]