Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Seemingly Unrelated Mixed-Effects Biomass Models for Black Locust in West Poland

Information about tree biomass is important not only in the assessment of wood resources but also in the process of preparing forest management plans, as well as for estimating carbon stocks and their flow in forest ecosystems. The study aimed to develop empirical models for determining the dry mass of the aboveground parts of black locust trees and their components (stem, branches, and leaves). The research was carried out based on data collected in 13 stands (a total of 38 sample trees) of black locust located in western Poland. The model system was developed based on multivariate mixed-effect models using two approaches. In the first approach, biomass components and tree height were defined as dependent variables, while diameter at breast height was used as an independent variable. In the second approach, biomass components and diameter at breast height were dependent variables and tree height was defined as the independent variable. Both approaches enable the fixed-effect and cross-model random-effect prediction of aboveground dry biomass components of black locust. Cross-model random-effect prediction was obtained using additional measurements of two extreme trees, defined as trees characterized by the smallest and largest diameter at breast height in sample plot. This type of prediction is more precise (root mean square error for stem dry biomass for both approaches equals 77.603 and 188.139, respectively) than that of fixed-effects prediction (root mean square error for stem dry biomass for both approaches equals 238.716 and 206.933, respectively). The use of height as an independent variable increases the possibility of the practical application of the proposed solutions using remote data sources

Spin transition and relaxation dynamics coupled to a crystallographic phase transition in a polymeric iron(II) spin-crossover system

a b s t r a c t The spin-crossover compound [Fe(bbtr) 3 ](ClO 4 ) 2 (bbtr = 1,4-di(1,2,3-triazol-1-yl)butane) forms a polymeric hexagonal sheet structure. It shows an abrupt thermal spin transition with 13 K wide hysteresis around 105 K, as evidenced by single crystal optical spectroscopy. The transition temperature for the thermal high-spin?low-spin transition on cooling as well as the relaxation kinetics just below T c ; depend upon the history of the sample. This is typical for a nucleation and growth mechanism and domain formation. In contrast, the high-spin?low-spin relaxation following the light-induced population of the high-spin state at low temperatures is governed by the intersystem crossing process

Role of Fe–N–C Geometry Flip-Flop in Bistability in Fe(tetrazol-2-yl)₄(C₂H₅CN)₂‑Type Core Based Coordination Network

[Fe­(ebtz)₂(C₂H₅CN)₂]­(ClO₄)₂ was prepared in the reaction of 1,2-di­(tetrazol-2-yl)­ethane (ebtz) with Fe­(ClO₄)₂·6H₂O in propionitrile. The compound crystallizes as a one-dimensional (1D) network, where bridging of neighboring iron­(II) ions by two ebtz ligand molecules results in formation of a [Fe­(ebtz)₂]_∞ polymeric skeleton. The 1D chains are assembled into supramolecular layers with axially coordinated nitrile molecules directed outward. The complex in the high spin (HS) form reveals a very rare feature, namely, a bent geometry of the Fe–N–C­(propionitrile) fragment (149.1(3)° at 250 K). The HS to low spin (LS) HS→LS transition triggers reorientation of the propionitrile molecule resulting in accommodation of a typical linear geometry of the Fe–N–C­(nitrile) fragment. The switching of the propionitrile molecule orientation in relation to the coordination octahedron is associated with increase of the distance between the supramolecular layers. When the crystal is in the LS phase, raising the temperature does not cause reduction of the distance between supramolecular layers, which contributes to further stabilization of the more linear geometry of Fe–N–C­(C₂H₅) and the LS form of the complex. Thus, a combination of Fe–N–C­(C₂H₅) geometry lability and lattice effects contributes to the appearance of hysteretic behavior (<i>T</i>_1/2^↓ ≈ 112 K, <i>T</i>_1/2^↑ ≈ 141 K)

Spin transition and relaxation dynamics coupled to a crystallographic phase transition in a polymeric iron(II) spin-crossover system

The spin-crossover compound [Fe(bbtr)3](ClO4)2 (bbtr = 1,4-di(1,2,3-triazol-1-yl)butane) forms a polymeric hexagonal sheet structure. It shows an abrupt thermal spin transition with 13 K wide hysteresis around 105 K, as evidenced by single crystal optical spectroscopy. The transition temperature for the thermal high-spin→low-spin transition on cooling as well as the relaxation kinetics just below Tc↓ depend upon the history of the sample. This is typical for a nucleation and growth mechanism and domain formation. In contrast, the high-spin→low-spin relaxation following the light-induced population of the high-spin state at low temperatures is governed by the intersystem crossing process

Empirical equations for estimating aboveground biomass of Betula pendula growing on former farmland in central Poland

We determined empirical models for estimating total aboveground as well as stem, branches, and foliage dry biomass of young (age up to 16 years) silver birch (Roth.) growing on the post-agricultural lands. Two sets of allometric models for trees with a height below or above 1.3 m (small and large trees respectively) were developed. Simplified models were elaborated based exclusively on appropriate tree diameter (diameter at ground level for small trees, diameter at breast height for large trees), while expanded models also included tree height. Total aboveground biomass was estimated as the sum of biomass of all tree components. To assure additivity of the developed equations, the seemingly unrelated regression approach for the final model fitting was used. Expanded models in both tree groups were characterized by a better fit to the data (Rfor total aboveground biomass for small and large trees equaled 0.8768 and 0.9752, respectively). Diameter at breast height appeared to be a better predictor than diameter at ground level â simplified models had better fit for large trees (R for total aboveground biomass equals 0.9611) than for small ones (Râ=â0.7516). The developed equations provide biomass predictions consistent with available Latvian, Estonian, Finnish, Swedish, and Norwegian models for silver birch.Betula pendula 2 2