Abstract Background The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart ...disease (VHD) is of substantial interest. Objectives This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. Methods Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. Results After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio HR: 1.40; 95% confidence interval CI:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction pint = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57). Conclusions The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation ENGAGE AF-TIMI 48; NCT00781391 )
Summary Background Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in ...subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43–1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045). Interpretation This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. Funding None.
Summary
Despite decades of clinical and laboratory research, relatively little has been accomplished concerning the pathogenesis as well as the identification of risk factors for thrombosis and ...bleeding in myeloproliferative disorders. In polycythaemia vera, the pro‐thrombotic effect of an elevated haematocrit is well established. In contrast, thrombocytosis per se has not been similarly incriminated in essential thrombocythaemia. In both conditions, advanced age and the presence of a prior event identify thrombosis‐prone patients. There is increasing evidence to suggest an additional role by leucocytes that might partly explain the antithrombotic effects of myelosuppressive therapy. A substantial minority of affected patients display reduced levels of high molecular weight von Willebrand protein in the plasma during extreme thrombocytosis and it is believed that this might explain the bleeding diathesis of such patients. Recent controlled studies support the therapeutic value of hydroxyurea and aspirin in essential thrombocythaemia and polycythaemia vera, respectively. The current communication will address the incidence, phenotype, pathogenesis, risk factors, prevention, and treatment of both thrombosis and haemorrhage in these disorders.
Natural killer (NK) cells, like B and T lymphocytes, are potent effector cells that are crucial for immunity to tumors and infections. These effector responses must be controlled to avoid inadvertent ...attack against normal self. Yet, the mechanisms that guide NK cell tolerance differ from those guiding T and B cell tolerance. Here, we discuss how NK cells are licensed by self-MHC class I molecules through their inhibitory receptors which results in NK cell functional competence to be triggered through their activation receptors. We discuss recent data with respect to issues related to licensing, thereby providing a framework for unifying concepts on NK cell education.
Recent advances in stable isotope measurements now allow for detailed investigations of the sources, transformations, and deposition of reactive nitrogen (N) species. Stable isotopes show promise as ...a complementary tool for apportioning emissions sources that contribute to deposition and also for developing a more robust understanding of the transformations that can influence these isotope ratios. Methodological advances have facilitated the unprecedented examination of the isotopic composition of reactive N species in the atmosphere and in precipitation including nitrogen oxides (NOx = nitric oxide (NO) + nitrogen dioxide (NO2)), atmospheric nitrate (NO3−), nitric acid (HNO3), ammonia (NH3), and ammonium (NH4+). This isotopic information provides new insight into the mechanisms of transformation and cycling of reactive N in the atmosphere and moreover helps resolve the contribution of multiple NOx and NH3 emission sources to deposition across landscapes, regions, and continents. Here, we highlight the current state of knowledge regarding the isotopic ratios of NOx and NH3 emission sources and chemical alterations of isotopic ratios during atmospheric transformations. We also highlight illustrative examples where isotopic approaches are used and review recent methodological advances. While these highlights are not an exhaustive review of the literature, we hope they provide a glimpse of the potential for these methods to help resolve knowledge gaps regarding total N deposition to Earth surfaces. We conclude with promising opportunities for future research in the short-, medium-, and long-term.
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•Isotopes of reactive nitrogen species can aid in understanding emissions sources and chemical transformations that contribute to reactive nitrogen deposition.•Methodological advances have ushered in an unprecedented examination of reactive nitrogen isotope chemistry.•Here, we review advances in methods, applications, and gains in knowledge during the past decade.•We conclude with promising opportunities for future research in the short, medium-, and long-term.
Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or ...lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD)‐related kinase LRRK2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT‐III component CHMP4B, thereby favouring ESCRT‐mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 gain‐of‐function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin‐3. Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD.
Synopsis
Leucine‐rich repeat kinase 2 (LRRK2) has been linked to neurodegenerative and inflammatory diseases but it is unknown how LRKK2 activation occurs in these pathological conditions. Here, pathogen‐ or drug‐induced endomembrane damage is found to activate LRRK2 in macrophages, which in turn controls recruitment of membrane repair factors.
LRRK2 is activated upon endomembrane damage.
Endomembrane damage triggers LRRK2‐mediated phosphorylation of Rab8A.
Rab8A and ESCRT component CHMP4B are recruited to damaged endolysosomes in a LRRK2‐dependent manner.
In the absence of LRRK2 and Rab8A, damaged endolysosomes are disposed through lysophagy.
Macrophages from patients harbouring LRRK2 G2019S or R1441C mutation show accumulation of damaged endolysosomes.
LRRK2 phosphorylation of Rab8A GTPase promotes its co‐translocation with ESCRT component CHMP4B to damaged endolysosomes for their repair.
Red blood cell rupture (hemolysis) activates innate immunity and inflammation by releasing heme. Sundaram et al.
implicate the immune sensor NLRP12 in hemolytic disease, showing that it controls ...necrotic cell death induction in response to heme combined with pathogen-associated molecules.
Summary Background New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage ...and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events. Methods We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0–3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30–50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov , number NCT00781391. Findings Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0–48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35–0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL SD 45·8 to 34·6 ng/mL 30·9) and 35% (from 24·5 ng/mL 22·7 to 16·0 ng/mL 14·5) and mean anti-FXa activity by 25% (from 0·85 IU/mL 0·76 to 0·64 IU/mL 0·54) and 20% (from 0·44 IU/mL 0·37 to 0·35 IU/mL 0·28) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction =0·85, lower dose pinteraction =0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction =0·002). Interpretation These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. Funding Daiichi-Sankyo Pharma Development.
Transcatheter aortic valve replacement has emerged as a promising therapy for treatment of severe aortic stenosis. Although it has been shown that these valves can be safely delivered and implanted, ...studies of valve longevity are lacking because of the infancy of the technology. Particularly, the effects of stent crimping on the valve's leaflets have not yet been sufficiently investigated. In this study, we have characterized the effects of crimping on pericardial leaflets in time and through the depth of the tissue.
To test the structural changes at the surface and deep layers of bovine pericardial leaflets, scanning electron microscopy and second-harmonic generation microscopy were used. An uncrimped tissue sample was imaged, followed by imaging a segment of tissue after crimping in a stented transcatheter valve, immediately after, at 20 minutes, and 60 minutes after crimping. The crimping experiment was performed for multiple crimping sizes (ie, 14F, 16F, and 18F). We defined a damage index that quantifies the level of leaflet structural changes as a result of crimping.
Based on the calculated damage indices and analyses of the raw images, it was determined that crimping does measurable damage to the leaflet tissue that persists with time.
Significant tissue damage was observed at the surface layers of the leaflets. In the deeper tissue layers, damage was substantial for 14F crimping; however, it became less significant but still visible for larger collapse profiles. Crimping may induce substantial structural damage to pericardial leaflets that does not improve with time.
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