Impact of overlapping newer generation drug-eluting stents on clinical and angiographic outcomes: pooled analysis of five trials from the international Global RESOLUTE Program

BACKGROUND Overlapping first generation sirolimus- and paclitaxel-eluting stents are associated with persistent inflammation, fibrin deposition and delayed endothelialisation in preclinical models, and adverse angiographic and clinical outcomes--including death and myocardial infarction (MI)--in clinical studies. OBJECTIVES To establish as to whether there are any safety concerns with newer generation drug-eluting stents (DES). DESIGN Propensity score adjustment of baseline anatomical and clinical characteristics were used to compare clinical outcomes (Kaplan-Meier estimates) between patients implanted with overlapping DES (Resolute zotarolimus-eluting stent (R-ZES) or R-ZES/other DES) against no overlapping DES. Additionally, angiographic outcomes for overlapping R-ZES and everolimus-eluting stents were evaluated in the randomised RESOLUTE All-Comers Trial. SETTING Patient level data from five controlled studies of the RESOLUTE Global Clinical Program evaluating the R-ZES were pooled. Enrollment criteria were generally unrestrictive. PATIENTS 5130 patients. MAIN OUTCOME MEASURES 2-year clinical outcomes and 13-month angiographic outcomes. RESULTS 644 of 5130 patients (12.6%) in the RESOLUTE Global Clinical Program underwent overlapping DES implantation. Implantation of overlapping DES was associated with an increased frequency of MI and more complex/calcified lesion types at baseline. Adjusted in-hospital, 30-day and 2-year clinical outcomes indicated comparable cardiac death (2-year overlap vs non-overlap: 3.0% vs 2.1%, p=0.36), major adverse cardiac events (13.3% vs 10.7%, p=0.19), target-vessel MI (3.9% vs 3.4%, p=0.40), clinically driven target vessel revascularisation (7.7% vs 6.5%, p=0.32), and definite/probable stent thrombosis (1.4% vs 0.9%, p=0.28). 13-month adjusted angiographic outcomes were comparable between overlapping and non-overlapping DES. CONCLUSIONS Overlapping newer generation DES are safe and effective, with comparable angiographic and clinical outcomes--including repeat revascularisation--to non-overlapping DES.

Clinical and intravascular imaging outcomes at 1 and 2 years after implantation of absorb everolimus eluting bioresorbable vascular scaffolds in small vessels. Late lumen enlargement: does bioresorption matter with small vessel size? Insight from the ABSORB cohort B trial

BACKGROUND The long-term results after second generation everolimus eluting bioresorbable vascular scaffold (Absorb BVS) placement in small vessels are unknown. Therefore, we investigated the impact of vessel size on long-term outcomes, after Absorb BVS implantation. METHODS In ABSORB Cohort B Trial, out of the total study population (101 patients), 45 patients were assigned to undergo 6-month and 2-year angiographic follow-up (Cohort B1) and 56 patients to have angiographic follow-up at 1-year (Cohort B2). The pre-reference vessel diameter (RVD) was <2.5 mm (small-vessel group) in 41 patients (41 lesions) and ≥2.5 mm (large-vessel group) in 60 patients (61 lesions). Outcomes were compared according to pre-RVD. RESULTS At 2-year angiographic follow-up no differences in late lumen loss (0.29±0.16 mm vs 0.25±0.22 mm, p=0.4391), and in-segment binary restenosis (5.3% vs 5.3% p=1.0000) were demonstrated between groups. In the small-vessel group, intravascular ultrasound analysis showed a significant increase in vessel area (12.25±3.47 mm(2) vs 13.09±3.38 mm(2) p=0.0015), scaffold area (5.76±0.96 mm(2) vs 6.41±1.30 mm(2) p=0.0008) and lumen area (5.71±0.98 mm(2) vs 6.20±1.27 mm(2) p=0.0155) between 6-months and 2-year follow-up. No differences in plaque composition were reported between groups at either time point. At 2-year clinical follow-up, no differences in ischaemia-driven major adverse cardiac events (7.3% vs 10.2%, p=0.7335), myocardial infarction (4.9% vs 1.7%, p=0.5662) or ischaemia-driven target lesion revascularisation (2.4% vs 8.5%, p=0.3962) were reported between small and large vessels. No deaths or scaffold thrombosis were observed. CONCLUSIONS Similar clinical and angiographic outcomes at 2-year follow-up were reported in small and large vessel groups. A significant late lumen enlargement and positive vessel remodelling were observed in small vessels.

A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.

BACKGROUND Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. OBJECTIVE To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). METHODS All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. RESULTS Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. CONCLUSION Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

Intracoronary Optical Coherence Tomography and Histology of Overlapping Everolimus-Eluting Bioresorbable Vascular Scaffolds in a Porcine Coronary Artery Model

OBJECTIVES: This study sought to assess the vascular response of overlapping Absorb stents compared with overlapping newer-generation everolimus-eluting metallic platform stents (Xience V [XV]) in a porcine coronary artery model. BACKGROUND: The everolimus-eluting bioresorbable vascular scaffold (Absorb) is a novel approach to treating coronary lesions. A persistent inflammatory response, fibrin deposition, and delayed endothelialization have been reported with overlapping first-generation drug-eluting stents. METHODS: Forty-one overlapping Absorb and overlapping Xience V (XV) devices (3.0 × 12 mm) were implanted in the main coronary arteries of 17 nonatherosclerotic pigs with 10% overstretch. Implanted coronary arteries were evaluated by optical coherence tomography (OCT) at 28 days (Absorb n = 11, XV n = 7) and 90 days (Absorb n = 11, XV n = 8), with immediate histological evaluation following euthanasia at the same time points. One animal from each time point was evaluated with scanning electron microscopy alone. A total of 1,407 cross sections were analyzed by OCT and 148 cross sections analyzed histologically. RESULTS: At 28 days in the overlap, OCT analyses indicated 80.1% of Absorb struts and 99.4% of XV struts to be covered (p < 0.0001), corresponding to histological observations of struts with cellular coverage of 75.4% and 99.6%, respectively (p < 0.001). Uncovered struts were almost exclusively related to the presence of "stacked" Absorb struts, that is, with a direct overlay configuration. At 90 days, overlapping Absorb and overlapping XV struts demonstrated >99% strut coverage by OCT and histology, with no evidence of a significant inflammatory process, and comparable % volume obstructions. CONCLUSIONS: In porcine coronary arteries implanted with overlapping Absorb or overlapping XV struts, strut coverage is delayed at 28 days in overlapping Absorb, dependent on the overlay configuration of the thicker Absorb struts. At 90 days, both overlapping Absorb and overlapping XV have comparable strut coverage. The implications of increased strut thickness may have important clinical and design considerations for bioresorbable platforms.

Natural history of optical coherence tomography-detected non-flow-limiting edge dissections following drug-eluting stent implantation

Aims: Angiographic evidence of edge dissections has been associated with a risk of early stent thrombosis. Optical coherence tomography (OCT) is a high-resolution technology detecting a greater number of edge dissections -particularly non-flow-limiting- compared to angiography. Their natural history and clinical implications remain unclear. The objectives of the present study were to assess the morphology, healing response, and clinical outcomes of OCT-detected edge dissections using serial OCT imaging at baseline and at one year following drug-eluting stent (DES) implantation. Methods and results: Edge dissections were defined as disruptions of the luminal surface in the 5 mm segments proximal and distal to the stent, and categorised as flaps, cavities, double-lumen dissections or fissures. Qualitative and quantitative OCT analyses were performed every 0.5 mm at baseline and one year, and clinical outcomes were assessed. Sixty-three lesions (57 patients) were studied with OCT at baseline and one-year follow-up. Twenty-two non-flow-limiting edge dissections in 21 lesions (20 patients) were identified by OCT; only two (9%) were angiographically visible. Flaps were found in 96% of cases. The median longitudinal dissection length was 2.9 mm (interquartile range [IQR] 1.6-4.2 mm), whereas the circumferential and axial extensions amounted to 1.2 mm (IQR: 0.9-1.7 mm) and 0.6 mm (IQR: 0.4-0.7 mm), respectively. Dissections extended into the media and adventitia in seven (33%) and four (20%) cases, respectively. Eighteen (82%) OCT-detected edge dissections were also evaluated with intravascular ultrasound which identified nine (50%) of these OCT-detected dissections. No stent thrombosis or target lesion revascularisation occurred up to one year. At follow-up, 20 (90%) edge dissections were completely healed on OCT. The two cases exhibiting persistent dissection had the longest flaps (2.81 mm and 2.42 mm) at baseline. Conclusions: OCT-detected edge dissections which are angiographically silent in the majority of cases are not associated with acute stent thrombosis or restenosis up to one-year follow-up.

A novel comparative research platform designed to determine the functional significance of tree species diversity in European forests

One of the current advances in functional biodiversity research is the move away from short-lived test systems towards the exploration of diversity-ecosystem functioning relationships in structurally more complex ecosystems. In forests, assumptions about the functional significance of tree species diversity have only recently produced a new generation of research on ecosystem processes and services. Novel experimental designs have now replaced traditional forestry trials, but these comparatively young experimental plots suffer from specific difficulties that are mainly related to the tree size and longevity. Tree species diversity experiments therefore need to be complemented with comparative observational studies in existing forests. Here we present the design and implementation of a new network of forest plots along tree species diversity gradients in six major European forest types: the FunDivEUROPE Exploratory Platform. Based on a review of the deficiencies of existing observational approaches and of unresolved research questions and hypotheses, we discuss the fundamental criteria that shaped the design of our platform. Key features include the extent of the species diversity gradient with mixtures up to five species, strict avoidance of a dilution gradient, special attention to community evenness and minimal covariation with other environmental factors. The new European research platform permits the most comprehensive assessment of tree species diversity effects on forest ecosystem functioning to date since it offers a common set of research plots to groups of researchers from very different disciplines and uses the same methodological approach in contrasting forest types along an extensive environmental gradient. (C) 2013 Elsevier GmbH. All rights reserved.

Correlating the Ancient Maya and Modern European Calendars with High-Precision AMS 14C Dating

The reasons for the development and collapse of Maya civilization remain controversial and historical events carved on stone monuments throughout this region provide a remarkable source of data about the rise and fall of these complex polities. Use of these records depends on correlating the Maya and European calendars so that they can be compared with climate and environmental datasets. Correlation constants can vary up to 1000 years and remain controversial. We report a series of high-resolution AMS C-14 dates on a wooden lintel collected from the Classic Period city of Tikal bearing Maya calendar dates. The radiocarbon dates were calibrated using a Bayesian statistical model and indicate that the dates were carved on the lintel between AD 658-696. This strongly supports the Goodman-Martinez-Thompson (GMT) correlation and the hypothesis that climate change played an important role in the development and demise of this complex civilization.

Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: An optical coherence tomography study

BACKGROUND Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. METHODS AND RESULTS A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). CONCLUSION Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo.

Initiation and continuation of randomized trials after the publication of a trial stopped early for benefit asking the same study question: STOPIT-3 study design

BACKGROUND Randomized control trials (RCTs) stopped early for benefit (truncated RCTs) are increasingly common and, on average, overestimate the relative magnitude of benefit by approximately 30%. Investigators stop trials early when they consider it is no longer ethical to enroll patients in a control group. The goal of this systematic review is to determine how investigators of ongoing or planned RCTs respond to the publication of a truncated RCT addressing a similar question. METHODS/DESIGN We will conduct systematic reviews to update the searches of 210 truncated RCTs to identify similar trials ongoing at the time of publication, or started subsequently, to the truncated trials ('subsequent RCTs'). Reviewers will determine in duplicate the similarity between the truncated and subsequent trials. We will analyze the epidemiology, distribution, and predictors of subsequent RCTs. We will also contact authors of subsequent trials to determine reasons for beginning, continuing, or prematurely discontinuing their own trials, and the extent to which they rely on the estimates from truncated trials. DISCUSSION To the extent that investigators begin or continue subsequent trials they implicitly disagree with the decision to stop the truncated RCT because of an ethical mandate to administer the experimental treatment. The results of this study will help guide future decisions about when to stop RCTs early for benefit.

Polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives (oxygenated PAHs, azaarenes) in soils along a climosequence in Argentina

We evaluated the effects of soil properties and climate on concentrations of parent and oxygenated polycyclic aromatic compounds (PAHs and OPAHs) and azaarenes (AZAs) in topsoil and subsoil at 20 sites along a 2100-km north (N)–south (S) transect in Argentina. The concentrations of Σ29PAHs, Σ15OPAHs and Σ4AZAs ranged 2.4–38 ng g− 1, 0.05–124 ng g− 1 and not detected to 0.97 ng g− 1, respectively. With decreasing anthropogenic influence from N to S, low molecular weight PAHs increasingly dominated. The octanol–water partitioning coefficients correlated significantly with the subsoil to topsoil concentration ratios of most compounds suggesting leaching as the main transport process. Organic C concentrations correlated significantly with those of many compounds typical for atmosphere–soil partitioning. Lighter OPAHs were mainly detected in the S suggesting biological sources and heavier OPAHs in the N suggesting a closer association with parent-PAHs. Decreasing alkyl-naphthalene/naphthalene and 9,10-anthraquinone (9,10-ANQ)/anthracene ratios from N to S indicated that 9,10-ANQ might have originated from low-temperature combustion.

Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study

AIM The effect of long-term high-intensity statin therapy on coronary atherosclerosis among patients with acute ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to quantify the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of STEMI patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS Between September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-IVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients were treated with high-intensity rosuvastatin (40 mg/day) throughout 13 months and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRA. The primary IVUS end-point was the change in per cent atheroma volume (PAV). After 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 3.29 to 1.89 mmol/L (P < 0.001), and high-density lipoprotein cholesterol (HDL-C) levels had increased from 1.10 to 1.20 mmol/L (P < 0.001). PAV of the non-IRA decreased by -0.9% (95% CI: -1.56 to -0.25, P = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Per cent necrotic core remained unchanged (-0.05%, 95% CI: -1.05 to 0.96%, P = 0.93) as did the number of RF-IVUS defined thin cap fibroatheromas (124 vs. 116, P = 0.15). CONCLUSION High-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-infarct-related arteries without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

Increasing incidence of canine leptospirosis in Switzerland.

A marked increase in canine leptospirosis was observed in Switzerland over 10 years with a peak incidence of 28.1 diagnosed cases/100,000 dogs/year in the most affected canton. With 95% affected dogs living at altitudes <800 m, the disease presented a seasonal pattern associated with temperature (r2 0.73) and rainfall (r2 0.39), >90% cases being diagnosed between May and October. The increasing yearly incidence however was only weakly correlated with climatic data including number of summer (r2 0.25) or rainy days (r2 0.38). Serovars Australis and Bratislava showed the highest seropositivity rates with 70.5% and 69.1%, respectively. Main clinical manifestations included renal (99.6%), pulmonary (76.7%), hepatic (26.0%), and hemorrhagic syndromes (18.2%), leading to a high mortality rate (43.3%). Similar to the human disease, liver involvement had the strongest association with negative outcome (OR 16.3). Based on these data, canine leptospirosis presents similar features and severity as the human infection for which it therefore can be considered a model. Its re-emergence in a temperate country with very high incidence rates in canines should thus be viewed as a warning and emphasize the need for increased awareness in other species.

Incidence and Imaging Outcomes of Acute Scaffold Disruption and Late Structural Discontinuity After Implantation of the Absorb Everolimus-Eluting Fully Bioresorbable Vascular Scaffold: Optical Coherence Tomography Assessment in the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions).

OBJECTIVES This study sought to describe the frequency and clinical impact of acute scaffold disruption and late strut discontinuity of the second-generation Absorb bioresorbable polymeric vascular scaffolds (Absorb BVS, Abbott Vascular, Santa Clara, California) in the ABSORB (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) cohort B study by optical coherence tomography (OCT) post-procedure and at 6, 12, 24, and 36 months. BACKGROUND Fully bioresorbable scaffolds are a novel approach to treatment for coronary narrowing that provides transient vessel support with drug delivery capability without the long-term limitations of metallic drug-eluting stents. However, a potential drawback of the bioresorbable scaffold is the potential for disruption of the strut network when overexpanded. Conversely, the structural discontinuity of the polymeric struts at a late stage is a biologically programmed fate of the scaffold during the course of bioresorption. METHODS The ABSORB cohort B trial is a multicenter single-arm trial assessing the safety and performance of the Absorb BVS in the treatment of 101 patients with de novo native coronary artery lesions. The current analysis included 51 patients with 143 OCT pullbacks who underwent OCT at baseline and follow-up. The presence of acute disruption or late discontinuities was diagnosed by the presence on OCT of stacked, overhung struts or isolated intraluminal struts disconnected from the expected circularity of the device. RESULTS Of 51 patients with OCT imaging post-procedure, acute scaffold disruption was observed in 2 patients (3.9%), which could be related to overexpansion of the scaffold at the time of implantation. One patient had a target lesion revascularization that was presumably related to the disruption. Of 49 patients without acute disruption, late discontinuities were observed in 21 patients. There were no major adverse cardiac events associated with this finding except for 1 patient who had a non-ischemia-driven target lesion revascularization. CONCLUSIONS Acute scaffold disruption is a rare iatrogenic phenomenon that has been anecdotally associated with anginal symptoms, whereas late strut discontinuity is observed in approximately 40% of patients and could be viewed as a serendipitous OCT finding of a normal bioresorption process without clinical implications. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856).

Bioresorbable vascular scaffold treatment induces the formation of neointimal cap that seals the underlying plaque without compromising the luminal dimensions: a concept based on serial optical coherence tomography data.

Aims: To evaluate the implications of an Absorb bioresorbable vascular scaffold (Absorb BVS) on the morphology of the superficial plaques. Methods and results: Forty-six patients who underwent Absorb BVS implantation and 20 patients implanted with bare metal stents (BMS) who had serial optical coherence tomographic examination at baseline and follow-up were included in this analysis. The thin-capped fibroatheromas (TCFA) were identified in the device implantation regions and in the adjacent native coronary segments. Within all regions, circumferential locations of TCFA and calcific tissues were identified, and the neointimal thickness was measured at follow-up. At six to 12-month follow-up, only 8% of the TCFA detected at baseline were still present in the Absorb BVS and 27% in the BMS implantation segment (p=0.231). Sixty percent of the TCFA in native segments did not change their phenotype at follow-up. At short-term follow-up, significant reduction in the lumen area of the BMS was noted, which was higher compared to that reported in the Absorb BVS group (-2.11±1.97 mm2 vs. -1.34±0.99 mm2, p=0.026). In Absorb BVS, neointima tissue continued to develop at midterm follow-up (2.17±0.48 mm2 vs. 1.38±0.52 mm2, p<0.0001) and covered the underlying tissues without compromising the luminal dimensions (5.93±1.49 mm2 vs. 6.14±1.49 mm2, p=0.571) as it was accommodated by the expanded scaffold (8.28±1.74 mm2 vs. 7.67±1.28 mm2, p<0.0001). Conclusions: Neointimal tissue develops following either Absorb BVS or BMS implantation and shields lipid tissues. The neointimal response in the BMS causes a higher reduction of luminal dimensions compared to the Absorb BVS. Thus, Absorb BVS may have a value in the invasive re-capping of high-risk plaques.