Search

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention‐to‐treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention‐to‐treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per‐protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time‐varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all‐cause mortality or nonfatal Q‐wave myocardial infarction at 2 years. At 2‐year follow‐up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per‐protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75–1.03; P =0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79–1.26; P =0.99). The per‐protocol and intention‐to‐treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01813435.

Objectives: Right ventricular (RV) failure post left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality. A novel RV multi-plane imaging method using two-dimensional echocardiography and electronic plane rotation (MPE) was used to quantify RV function prior to LVAD implantation and to identify potential added value in this patient population. Methods: In twenty-five end-stage heart failure patients (age 58.9 ± 6.8 years, 76% male), systolic function of four different RV walls (lateral, anterior, inferior and inferior coronal) were evaluated from one focussed apical view using MPE. Results: Feasibility of tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (RV-S') measurements were high (84–100%), with lower TAPSE values measured in the inferior (14.2 ± 4.6 mm) and inferior coronal (12.3 ± 5.0 mm) walls compared to the lateral (16.3 ± 4.5 mm) and anterior walls (16.0 ± 4.5 mm). RV wall longitudinal strain (RV-LS) measurement was most feasible in the lateral wall (80%; mean: –12.1 ± 4.2%). TAPSE and RV-LS values were significantly reduced in patients compared to matched healthy individuals (p =

Background We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens. Methods GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75-100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75-100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01813435, and is closed to new participants, with followup completed. Findings Between July 1, 2013, and Nov 9, 2015, 15 968 participants were randomly assigned, 7980 to the experimental group and 7988 to the control group. At 2 years, 304 (3.81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4.37%) participants in the control group (rate ratio 0.87 [95% CI 0. 75-1. 01]; p=0.073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0.93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2.04% vs 2.12%; rate ratio 0.97 [95% CI 0. 78-1. 20]; p=0.77). Interpretation Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention. Copright (C) 2018 Elsevier Ltd. All rights reserved. European Clinical Research Institute; Biosensors International; AstraZeneca; Medicines Company; Canada Research Chairs Programme

Pharmacokinetic modeling has a long history that originates from tracers or indicators that were injected into the bloodstream and needed direct contact with a sensor to be detected. Examples of these approaches are provided by the Fick method [1], requiring blood sampling to assess the oxygen saturation, or thermodilution [2, 3], where a catheter is inserted in the central circulation to measure the blood temperature. Pharmacokinetic modeling has a long history that originates from tracers or indicators that were injected into the bloodstream and needed direct contact with a sensor to be detected. Examples of these approaches are provided by the Fick method [1], requiring blood sampling to assess the oxygen saturation, or thermodilution [2, 3], where a catheter is inserted in the central circulation to measure the blood temperature. Modeling was adopted to deal with noisy data and to provide a physiological interpretation of the measurements. Since the introduction of the first indicators, accuracy and complexity of the adopted models have shown terrific development, supported by increasing computing capabilities. Model fitting computations that only few decades ago could take several days, today can be solved in a split of a second. This chapter introduces the fundamental knowledge on pharmacokinetic modeling, establishing the basis for the modern developments applied to contrast-enhanced imaging.

This book provides a comprehensive survey of the pharmacokinetic models used for the quantitative interpretation of contrast-enhanced imaging. It discusses all the available imaging technologies and the problems related to the calibration of the imaging system and accuracy of the estimated physiological parameters. Enhancing imaging modalities using contrast agents has opened up new opportunities for going beyond morphological information and enabling minimally invasive assessment of tissue and organ functionality down to the molecular level. In combination with mathematical modeling of the contrast agent kinetics, contrast- enhanced imaging has the potential to provide clinically valuable additional information by estimating quantitative physiological parameters. The book presents the broad spectrum of diagnostic possibilities provided by quantitative contrast-enhanced imaging, with a particular focus on cardiology and oncology, as well as novel developments in the area of quantitative molecular imaging along with their potential clinical applications. Given the variety of available techniques, the choice of the appropriate imaging modality and the most suitable pharmacokinetic model is often challenging. As such, the book provides a valuable technical guide for researchers, clinical scientists, and experts in the field who wish to better understand and properly apply tracer-kinetic modeling for quantitative contrast-enhanced imaging.

The main characteristic distinguishing intravascular contrast agents lies in their inability to pass across the vascular wall and leave the blood pool. Therefore, while being unsuitable for visualization and quantification of permeability and leakage into the interstitial space, these agents are especially suitable to analyze the vascular architecture and intravascular flow. The main characteristic distinguishing intravascular contrast agents lies in their inability to pass across the vascular wall and leave the blood pool. Therefore, while being unsuitable for visualization and quantification of permeability and leakage into the interstitial space, these agents are especially suitable to analyze the vascular architecture and intravascular flow. The size of the contrast-agent molecules is the distinguishing factor. While large size molecules cannot pass through the gaps between the vascular layers made of endothelial cells, smaller molecules can pass and leak into the extravascular space. In general, only molecules larger than few hundred nanometers can stay intravascular. Most contrast agents are therefore extravascular, unless specific binding to larger molecular complexes is realized. The only contrast agents which remain naturally intravascular are UCAs, as they are made of microbubbles with size larger than that of the endothelial gaps, even in the case of increased vascular permeability due to angiogenesis, i.e., the formation of a dense, irregular microvascular network in relation to cancer growth or other inflammatory processes (see Sect. 3.3.2). Therefore, although MR blood pool agents are also briefly treated, this chapter is mostly dedicated to UCAs, because of their intravascular nature.

Contrast-enhanced imaging combines into a powerful diagnostic tool all the diagnostic insight provided by standard anatomical imaging along with the interpretation of the transport kinetics of detectable tracers, referred to as “contrast agents.” These are substances that comply with all the safety requirements to be injected into the bloodstream and subsequently detected by dedicated sensors. Contrast-enhanced imaging is a powerful diagnostic tool combining all the diagnostic insight provided by standard anatomical imaging along with the interpretation of the transport kinetics of detectable tracers, referred to as “contrast agents.” These are substances that comply with all the safety requirements to be injected into the bloodstream and subsequently detected by dedicated sensors. Originally, the detection of an injected tracer required physical contact with a sensor, usually positioned on a catheter tip. A typical example is provided by thermodilution measurements, making use of a thermistor [1, 2]. An alternative option consisted of drawing blood and performing the sensing outside the body. An example is provided by lithium dilution systems [3]. By any of these solutions, the tracer concentration can be sampled at few locations only, depending on the number of adopted catheters. Moreover, the invasiveness of these methods represents an important limiting factor, excluding the use of dilution principles in outpatients, outside the intensive care unit or operating theater. The possibility of detecting tracers without contact, but just using imaging technology, has opened up new immense possibilities for the diagnostic use of contrast agents. When the concentration of these agents can be measured in space and time, it provides valuable inputs for the identification of pharmacokinetic models enabling the assessment of physiological and functional parameters of diagnostic relevance. Obviously, this requires coping with complex, technical problems, ranging from the calibration of the imaging system and its ability to provide an accurate estimation of the contrast-agent concentration, up to the spatiotemporal resolution of the imaging system and the identifiability of the proposed pharmacokinetic models. These complex problems have different solutions depending on the adopted imaging technology and contrast agent, which rely on different physical principles for detection and quantification. Before discussing use and quantification of contrast agents, in this chapter we first provide a brief survey of the adopted imaging technology: magnetic resonance imaging (MRI), ultrasound (US), X-ray computed tomography (CT), and nuclear scintigraphy. This provides the technological basis for contrast-enhanced imaging. While MRI, US, and X-ray imaging do not require the use of contrast agents to produce diagnostic images, nuclear imaging, referred to as scintigraphy, generates images by detection of the radiation released by decaying radioisotopes, which must be injected in the bloodstream. Because of this, scintigraphy represents historically the first imaging technology integrating imaging with contrast enhancement and pharmacokinetic modeling. At the end of this chapter, the use of contrast enhancement by the other imaging technologies will also be introduced, along with its clinical implication and perspectives. Being injected in the body, contrast agents have strict requirements not only in terms of detectability, but especially in terms of safety. These will be briefly discussed in Sect. 1.2 along with the growing market share of contrast-enhanced imaging, motivated by the additional diagnostic possibilities provided by contrast-enhanced functional imaging.

The aim of this post hoc analysis from the RESPOND (Repositionable Lotus Valve System-Post-Market Evaluation of Real World Clinical Outcomes) post-market study was to assess the final implantation depth on the contrast aortogram after Lotus valve (Boston Scientific, Marlborough, Massachusetts) transcatheter aortic valve replacement (TAVR) and to correlate with permanent pacemaker implantation (PPI) and paravalvular leak (PVL).Contrast aortography allows for the assessment of implantation depth and PVL during and after TAVR. Previous reports suggested an association between final device position and rates of PPI and PVL.The RESPOND study was a prospective, open-label, single-arm study in 41 centers evaluating outcomes after Lotus TAVR in routine clinical practice. Aortograms were collected at the Erasmus Medical Center and analyzed by researchers who were blinded to clinical outcomes. The primary analysis correlated implantation depth with PPI and PVL and required aortograms in a coaxial projection. The relation between implantation depth and need for PPI was assessed by multivariate logistic regression, adjusting for pre-defined confounders. A secondary analysis compared PVL analysis by contrast aortography with transthoracic echocardiography (TTE) performed by the independent core laboratory.A total of 724 angiographic studies were included in this analysis. Mean Lotus implantation depth was 6.67 ± 2.19 mm. The overall PPI rate was 35%. PPI rate was lower with shallow implants (6.5 mm: 21% vs. ≥6.5 mm: 41%; p 0.001). After adjustment for confounders, implantation depth independently predicted need for PPI (odds ratio per 1-mm increment in depth: 1.200; 95% confidence interval: 1.091 to 1.319; p = 0.002). More than trivial PVL was present in 23% by contrast aortography and in 8% by TTE. Implantation depth was not correlated with PVL by contrast aortography or TTE (p = 0.342 and p = 0.149, respectively). PVL grading by contrast aortography and TTE was concordant in 77%.In this post hoc analysis of the RESPOND study PPI was highly correlated with implantation depth, whereas PVL was not. Higher Lotus implantation may reduce need for PPI.