clinical conundrums in antithrombotic therapy management a delphi consensus panel

Abstract Background Anticoagulants are recommended for the prevention of stroke/systemic embolism for most patients with atrial fibrillation (AF) and for the treatment of patients with venous thromboembolism (VTE). Regulatory-driven randomized trials, however, typically exclude extreme patient scenarios involving, for instance, severe bleeding, ischaemic risk, frailty or renal impairment, despite their common occurrence in clinical practice. Uncertainty in the management of such cases leads to a high degree of variability in therapeutic approaches. Consensus conferences or panels may provide insights and help bridge the gaps that separate clinical guidelines from real-world practice. In the present study, a description of challenging AF and VTE patients was submitted to a large panel of experts to investigate areas of common or divergent management. Method A modified-Delphi method was used to obtain consensus among 178 Italian AF and VTE specialists. A questionnaire was sent on the appropriateness of anticoagulant therapy in AF and VTE cases, including CHA 2 DS 2 -VASc=1, comorbid coronary artery disease, frailty, advanced age, risk of falling, prior haemorrhagic stroke, and low- or intermediate-risk pulmonary embolism. Strategies to improve guideline adherence were also investigated. Results All participants completed the questionnaire. Consensus was reached on many, but not all cases, leaving uncertainty on some debated topics (conundrums) where decisions are unsupported by clinical studies or driven by controversial results. Conclusions The indications emerging from this large panel of experts may help guide the management of challenging AF or VTE cases. Studies are needed addressing treatment options in those cases for whom no consensus was reached

Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials

ObjectiveThe role of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.Design and methodsAll available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with GLP-1 receptor agonists (exenatide and liraglutide), with a duration>12 weeks were meta-analysed for HbA1c, body mass index, hypoglycaemia and other adverse events.Results and conclusionsA total of 21 RCTs (six of which unpublished), enrolling 5429 and 3053 patients (with GLP-1 receptor agonists and active comparator or placebo respectively), was retrieved and included in the analysis. GLP-1 receptor agonists determine a significant improvement of HbA1c in comparison with placebo (−1.0 (−1.1, −0.8),P<0.001), with a low risk of hypoglycaemia. There is no evidence of increased cardiovascular risk with the use of GLP-1 receptor agonists. GLP-1 receptor agonists, which induce weight loss, are associated with gastrointestinal side effects. GLP-1 receptor agonists are effective in reducing HbA1c and postprandial glucose. In patients failing to sulphonylureas and/or metformin, GLP-1 receptor agonists are similarly effective as insulin. Available data suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for once-a-day administration, are comparable with those of exenatide bis in die

Heart failure with mid-range ejection fraction: Current evidence and uncertainties

Heart failure (HF) with mid-range ejection fraction (HFmrEF) has been conceptualized by the European Society of Cardiology guidelines with the aim of stimulating research to fill a gap in knowledge: whether such a condition exists as a distinct pathophysiological and clinical entity, or it is just a residual category of ejection fraction indeed is still a matter of debate. Current evidence suggests that HFmrEF represents up to one fifth of patients with HF, who may ultimately result in an intermediate clinical phenotype, as for age and gender, with an intermediate prevalence of comorbidities. Nevertheless, a strong connection exists with HF with reduced ejection fraction, since ischemic aetiology is common in both categories, conveying relevant implications for prognosis and therapeutic response. Little is known about its pathophysiology: mild systolic impairment may be not enough and advocating diastolic dysfunction may be an oversimplification. An increasing amount of data is clarifying how many of HFmrEF patients are the results of deteriorating or recovering hearts, thus underscoring that aetiology may be, more than EF, the key to understand this new category. Sparse evidence points toward a potential benefit of common HF therapies in those patients, but further research is still needed

Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of −1.0 [−1.3; −0.6] kg/m2. Considering the average BMI at baseline (32.4 kg/m2) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction

Biomarkers of Alzheimer's Disease: From Central Nervous System to Periphery?

Alzheimer's Disease (AD) is the most frequent form of dementia and represents one of the main causes of disability among older subjects. Up to now, the diagnosis of AD has been made according to clinical criteria. However, the use of such criteria does not allow an early diagnosis, as pathological alterations may be apparent many years before the clear-cut clinical picture. An early diagnosis is even more valuable to develop new treatments, potentially interfering with the pathogenetic process. During the last decade, several neuroimaging and cerebrospinal fluid (CSF) parameters have been introduced to allow an early and accurate detection of AD patients, and, recently, they have been included among research criteria for AD diagnosis. However, their use in clinical practice suffers from limitations both in accuracy and availability. The increasing amount of knowledge about peripheral biomarkers will possibly allow the future identification of reliable and easily available diagnostic tests

Antithrombotic therapy in acute coronary syndrome: undertreatment of elderly?

The appropriate use of dual antiplatelet therapy (DAPT) in elderly patients with acute coronary syndrome (ACS) is largely debated. Due to the "demographic transition" in western countries, the elderly represent a growing percentage of patients admitted to hospitals for ACS, and among this high risk setting population most of early and late adverse outcomes occur. The presence of several concomitant "comorbidities" complicate the management strategy of both medical or invasive treatment and the clinical decision making process is challenging. Moreover, elderly people are constantly underrepresented in clinical trials and studies. As a result, there is no specific evidence about the optimal antithrombotic therapy in elderly and no specific recommendations are mentioned in the current ACS guidelines. Currently, the best practice for old people is still rudimentary and principally extrapolated from general cardiovascular guidelines. The management of elderly patients should be based on the evaluation of ischemic and hemorrhagic risk, life expectancy, comorbidities and parameters that are not included in the scores recommended by the current guidelines such as frailty and disability. In the era of "precision medicine", the evaluation of bleeding and ischaemic risk in elderly patients must be a dynamic process because of the risk changing over time. A"tailored therapy by individualized medicine" is the key of management strategy

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Events: A Meta-Analysis of Randomized Clinical Trials

Objective. Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists. Design and Methods. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events. Results. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50–1.08), P = .12 (0.85 (0.50–1.45), P = .55, and 0.69 (0.40–1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25–0.83), P = .009, and 1.05 (0.63–1.76), P = .84, respectively. Conclusions. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect

Neurocognitive profile of patients with continuous flow Left Ventricular Assist Device

The increase of severe heart failure and the consequent reduction of the organ availability for transplantation has led to, in recent years, the introduction of the LVAD as replacement therapy to heart transplantation. Severe Heart Failure patients show cognitive deficits in various domains especially in executive functions, memory and speed of proceedings, due to different neurophysiopathological processes including chronic hypoperfusion and subsequent damage to hippocampal and para-hippocampal cortical areas. It is also known that these deficits improve after heart transplantation. We carried out a literature review selecting studies that analyzed the cognitive changes in patients with severe heart failure after implantation of the Continuous Flow Left Ventricular Assist Device. According to the inclusion criteria, we selected four studies since 2005 that presented a comprehensive neurocognitive assessment. The results show that the cognitive profile, with the implantation of LVAD improves in memory and executive domains, and this improvements results stable in short- medium time. The effects would also be independent of the type of flow produced by the device (pulsatile vs continuous). We believe that further studies are required to explore the relationship between LVAD and cognitive function in severe heart failure