Summary Background Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the ...effects of fibrates on major clinical outcomes. Methods We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. Findings We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0–18) for major cardiovascular events (p=0·048) and a 13% RR reduction (7–19) for coronary events (p<0·0001), but had no benefit on stroke (−3%, −16 to 9; p=0·69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, −8 to 7; p=0·92), cardiovascular mortality (3%, −7 to 12; p=0·59), sudden death (11%, −6 to 26; p=0·19), or non-vascular mortality (−10%, −21 to 0·5; p=0·063). Fibrates reduced the risk of albuminuria progression by 14% (2–25; p=0·028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1·21, 0·91–1·61; p=0·19), although increases in serum creatinine concentrations were common (1·99, 1·46–2·70; p<0·0001). Interpretation Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. Funding National Health and Medical Research Council of Australia.
Prediction models for gestational hypertension and preeclampsia have been developed with data and assumptions from developed countries. Their suitability and application for low resource settings ...have not been tested. This review aimed to identify and assess the methodological quality of prediction models for gestational hypertension and pre-eclampsia with reference to their application in low resource settings.
Using combinations of keywords for gestational hypertension, preeclampsia and prediction models seven databases were searched to identify prediction models developed with maternal data obtained before 20 weeks of pregnancy and including at least three predictors (Prospero registration CRD 42017078786). Prediction model characteristics and performance measures were extracted using the CHARMS, STROBE and TRIPOD checklists. The National Institute of Health quality assessment tools for observational cohort and cross-sectional studies were used for study quality appraisal.
We retrieved 8,309 articles out of which 40 articles were eligible for review. Seventy-seven percent of all the prediction models combined biomarkers with maternal clinical characteristics. Biomarkers used as predictors in most models were pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF). Only five studies were conducted in a low-and middle income country.
Most of the studies evaluated did not completely follow the CHARMS, TRIPOD and STROBE guidelines in prediction model development and reporting. Adherence to these guidelines will improve prediction modelling studies and subsequent application of prediction models in clinical practice. Prediction models using maternal characteristics, with good discrimination and calibration, should be externally validated for use in low and middle income countries where biomarker assays are not routinely available.
In the past two decades, the built environment emerged as a conceptually important determinant of obesity. As a result, an abundance of studies aiming to link environmental characteristics to ...weight-related outcomes have been published, and multiple reviews have attempted to summarise these studies under different scopes and domains. We set out to summarise the accumulated evidence across domains by conducting a review of systematic reviews on associations between any aspect of the built environment and overweight or obesity.
Seven databases were searched for eligible publications from the year 2000 onwards. We included systematic literature reviews, meta-analyses and pooled analyses of observational studies in the form of cross-sectional, case-control, longitudinal cohort, ecological, descriptive, intervention studies and natural experiments. We assessed risk of bias and summarised results structured by built environmental themes such as food environment, physical activity environment, urban-rural disparity, socioeconomic status and air pollution.
From 1850 initial hits, 32 systematic reviews were included, most of which reported equivocal evidence for associations. For food- and physical activity environments, associations were generally very small or absent, although some characteristics within these domains were consistently associated with weight status such as fast-food exposure, urbanisation, land use mix and urban sprawl. Risks of bias were predominantly high.
Thus far, while most studies have not been able to confirm the assumed influence of built environments on weight, there is evidence for some obesogenic environmental characteristics. Registration: This umbrella review was registered on PROSPERO under ID CRD42019135857.
Clinical prediction models are increasingly used to complement clinical reasoning and decision-making in modern medicine, in general, and in the cardiovascular domain, in particular. To these ends, ...developed models first and foremost need to provide accurate and (internally and externally) validated estimates of probabilities of specific health conditions or outcomes in the targeted individuals. Subsequently, the adoption of such models by professionals must guide their decision-making, and improve patient outcomes and the cost-effectiveness of care. In the first paper of this series of two companion papers, issues relating to prediction model development, their internal validation, and estimating the added value of a new (bio)marker to existing predictors were discussed. In this second paper, an overview is provided of the consecutive steps for the assessment of the model's predictive performance in new individuals (external validation studies), how to adjust or update existing models to local circumstances or with new predictors, and how to investigate the impact of the uptake of prediction models on clinical decision-making and patient outcomes (impact studies). Each step is illustrated with empirical examples from the cardiovascular field.
Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ ...agonists improve non-invasive tests of liver steatosis and fibrosis.
This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS).
LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study.
This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.
This is the introductory paper in a series of eight papers. In this series, we integrate the theoretical design options with the practice of conducting pragmatic trials. For most new market-approved ...treatments, the clinical evidence is insufficient to fully guide physicians and policy makers in choosing the optimal treatment for their patients. Pragmatic trials can fill this gap, by providing evidence on the relative effectiveness of a treatment strategy in routine clinical practice, already in an early phase of development, while maintaining the strength of randomized controlled trials. Selecting the setting, study population, mode of intervention, comparator, and outcome are crucial in designing pragmatic trials. In combination with monitoring and data collection that does not change routine care, this will enable appropriate generalization to the target patient group in clinical practice. To benefit from the full potential of pragmatic trials, there is a need for guidance and tools in designing these studies while ensuring operational feasibility. This paper introduces the concept of pragmatic trial design. The complex interplay between pragmatic design options, feasibility, stakeholder acceptability, validity, precision, and generalizability will be clarified. In this way, balanced design choices can be made in pragmatic trials with an optimal chance of success in practice.
Abstract
Aims
Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We ...aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research.
Methods and results
We sought exemplars based on literature reviews and expertise across the BigData@Heart Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health.
Conclusion
High volumes of inherently diverse (‘big’) EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.
Higher levels of physical activity are associated with a lower risk of cardiovascular events. Nevertheless, there is debate on the dose-response relationship of exercise and cardiovascular disease ...outcomes and whether high volumes of exercise may accelerate coronary atherosclerosis. We aimed to determine the relationship between lifelong exercise volumes and coronary atherosclerosis.
Middle-aged men engaged in competitive or recreational leisure sports underwent a noncontrast and contrast-enhanced computed tomography scan to assess coronary artery calcification (CAC) and plaque characteristics. Participants reported lifelong exercise history patterns. Exercise volumes were multiplied by metabolic equivalent of task (MET) scores to calculate MET-minutes per week. Participants' activity was categorized as <1000, 1000 to 2000, or >2000 MET-min/wk.
A total of 284 men (age, 55±7 years) were included. CAC was present in 150 of 284 participants (53%) with a median CAC score of 35.8 (interquartile range, 9.3-145.8). Athletes with a lifelong exercise volume >2000 MET-min/wk (n=75) had a significantly higher CAC score (9.4 interquartile range, 0-60.9 versus 0 interquartile range, 0-43.5;
=0.02) and prevalence of CAC (68%; adjusted odds ratio OR
=3.2; 95% confidence interval CI, 1.6-6.6) and plaque (77%; OR
=3.3; 95% CI, 1.6-7.1) compared with <1000 MET-min/wk (n=88; 43% and 56%, respectively). Very vigorous intensity exercise (≥9 MET) was associated with CAC (OR
=1.47; 95% CI, 1.14-1.91) and plaque (OR
=1.56; 95% CI, 1.17-2.08). Among participants with CAC>0, there was no difference in CAC score (
=0.20), area (
=0.21), density (
=0.25), and regions of interest (
=0.20) across exercise volume groups. Among participants with plaque, the most active group (>2000 MET-min/wk) had a lower prevalence of mixed plaques (48% versus 69%; OR
=0.35; 95% CI, 0.15-0.85) and more often had only calcified plaques (38% versus 16%; OR
=3.57; 95% CI, 1.28-9.97) compared with the least active group (<1000 MET-min/wk).
Participants in the >2000 MET-min/wk group had a higher prevalence of CAC and atherosclerotic plaques. The most active group, however, had a more benign composition of plaques, with fewer mixed plaques and more often only calcified plaques. These observations may explain the increased longevity typical of endurance athletes despite the presence of more coronary atherosclerotic plaque in the most active participants.
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