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

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Affective pathology and quality of life at chronic heart failure patient’s with sex-taking account during antidepressant therapy

In order to determine the severity of affective pathology by sex, with further assessment of the dynamics of the clinical status and quality of life in chronic heart failure (CHF) patient’s during therapy, including the antidepressant escitalopram (Selectra) 117 patients were examined. Methods: HADS scale and Zung; questionnaire MLHFQ; SACS scale. From the respondents patients were selected with chronic heart failure in combination with increased levels of anxiety and depression, which in addition to traditional treatment of CHF were receiving escitalopram (Selectra) for two months at a dose of 20 mg per day. All patients underwent a test of 6-minute walk, echocardiography. Statistical analysis of results was carried out using Statistica 6.0. Results: In women with CHF severity of affective pathology was 1.8 higher than in men, largely due to anxiety. In men with CHF reduced QoL is mainly due to its physical component, while in women changes all three aspects of QOL. Regardless of gender in patients with chronic heart failure, coupled with anxiety and depression treatment, including escitalopram (Selectra), accompanied by improved affective status, indicators of QOL, as well as decrease the severity of clinical symptoms of cardiac decompensation. For women compared with men positive changes in the indices of QOL during therapy with antidepressants were more pronounced.С целью определения выраженности аффективной патологии с умётом пола с дальнейшей оценкой динамики клинического состояния и качества жизни у больных с хронической сердечной недостаточностью (ХСН) на фоне терапии, включающей антидепрессант зсциталопрам (Селектра) обследовано 117 пациентов. Методы: шкалы HADS и Цунга; опросник MLHFQ; шкала ШОКС. Из опрошенных были выбраны пациенты с ХСН в сочетании с повышенным уровнем тревоги и депрессии, которые помимо традиционного лечения ХСН получали зсциталопрам (Селектра) в течение двух месяцев в дозе до 20 мг в сутки. Всем больным проводился тест 6-минутной ходьбы (ТШХ), эхокардиографическое исследование (ЗХО-КГ). Статистическая обработка результатов проводилась с помощью программы Statistica 6.0. Результаты: У женщин с ХСН выраженность аффективной патологии в 1,8 выше, чем у мужчин, в большей степени за счёт тревоги. У мужчин с ХСН снижение КЖ в основном обусловлено его физическим компонентом, в то время как у женщин изменяются все три аспекта КЖ. Независимо от пола больных с ХСН, сочетающейся с тревогой и депрессией, лечение, включающее зсциталопрам (Селектра), сопровождается улучшением аффективного статуса, показателей КЖ, а также уменьшением выраженности клинической симптоматики сердечной декомпенсации. У женщин в сравнении с мужчинами позитивные изменения показателей КЖ на фоне терапии антидепрессантом более выражены

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broaderinvolvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Nutritional status and the risk of cardiovascular events. Results of a 6-year prospective follow-up of the ESSE-RF study cohort

Research data indicate an increase in the risk of cardiovascular events (CVEs) with unhealthy diet.Aim. To assess the impact of diet on the development of cardiovascular events in the Russian population.Material and methods. The prospective cohort included representative samples of 10 Russian regions (n=17175, 6767 men and 10408 women aged 25-64 years), examined in 2012-2014 as part of the ESSE-RF study. The diet was studied by the frequency of consumption of the main food groups. The vital status of the cohort was clarified every 2 years. The follow-up period was 6 years. Kaplan-Meier survival curves were used to analyze survival, and the Cox proportional hazards model was used to assess the risk of CVEs.Results. Analysis of Kaplan-Meier curves showed better survival before the CVEs in the general population with daily consumption of cottage cheese (p=0,0029), cheese (p=0,00017), red meat (p=0,036) and the presence of the healthy eating model in the diet (p=0,013). A decrease in survival before the CVE onset was noted with excess salt intake (ESI) in the diet (p=0,0038) and the habit of adding salt to food (p=0,0032).Among men, a decrease in survival before the CVE onset was noted with ESI (p=0,018) and the habit of adding salt to food (p=0,047), and an increase — with regular consumption of red meat (p=0,00027). Among women, daily consumption of red meat (p=0,038), cheese (p=0,026), cottage cheese (p=0,019), as well as rare consumption of fatty dairy products (sour cream/cream) (p=0,04) delay the CVE onset. In the general population, in a univariate Cox proportional hazards analysis, daily cheese consumption and healthy eating model significantly reduce the risk of CVEs — 0,74 (0,61-0,89) and 0,78 (0,65-0,94), respectively, and excess salt and adding salt to food increase the CVE risk — 1,33 (1,12-1,59) and 1,33 (1,111,58), respectively. However, after introducing correction for socio-demographic indicators and risk factors, the significance is lost. In men, adding salt to food significantly increases the risk of cardiovascular events as follows: odds ratio 1,34 (1,04-1,73). Other eating habits are significant only in univariate analysis and lose their significance after introducing corrections.Conclusion. Adding salt to food significantly increases the risk of cardiovascular events among men of active working age

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Non-High Density Lipoprotein Cholesterol: A Modern Benchmark for Assessing Lipid Metabolism Disorders

Aim. To perform a population analysis of Non-High Density Lipoprotein Cholesterol level (non-HDL-c) in Russian population and to evaluate its association with cardiovascular events.Material and Methods. The material consisted of results obtained from 11 regions of the ESSE-RF1 Study and from 4 regions of the ESSE-RF2 Study. Study protocols were identical. The studies were performed in 2012-2014 and 2017, respectively. Endpoints were assessed in 19041 people aged 35-64 years. The median follow-up was 6.5 years in ESSE RF (1) and 3.8 years in ESSE RF(2). Analysis was performed for three lipid variables: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-HDLC in two samples: the general population sample and the same sample without individuals with coronary heart disease (CHD), myocardial infarction (MI) and/or stroke history and not taking statins (the population sample of "without a history of cardiovascular diseases [CVD]". The analysis of nonlinear associations was performed using the generalized additive Cox model. The combined cardiovascular endpoint was represented by cardiovascular death and nonfatal MI and stroke. Traditional and laboratory FRs, socio-demographic parameters were analyzed. The significance level for all tested hypotheses was set to be 0.05.Results. The prevalence of elevated non-HDL-C level (&gt;3.7 mmol/l) was found to be 74.6%. No gender differences were found: there was 74.6% for men and 74.5% for women. Both mean values and prevalence of elevated non-HDL-C were increased with age in women, and its level was slightly decreased in men after 55 years old. Almost all analyzed RFs were significantly associated with elevated non-HDL-C in these two population samples. In both samples elevated total CH and elevated LDL-C were associated with all-cause mortality after correction for all RFs. On the contrary, the non-HDL-C was associated with CVD combined end pints. It has been shown that the risk of these end points increases uniformly with increase in levels of non HDL cholesterol, no nonlinear associations were found.Conclusion. The results of a population-based analysis of non-HDL-C performed in the Russian population for the first time confirmed that elevated non-HDL-C levels contribute significantly to determining the risk of cardiovascular events in the medium term. It can be assumed that the new risk scales (SCORE2 and SCORE OP) proposed by the European Society of Cardiology and the European Society of Preventive Cardiology, which include non-HDL C instead of TC, will allow adequate assessment of 10-year cardiovascular risk for Russians. However, continued monitoring of endpoints in order to obtain stable associations is required