Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study.

Efforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant-naïve patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 ± 12.4, 45.7% female, mean follow-up 1.9 ± 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced ≤ 90 days after incident AF in 13,221 patients (48.1%): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0% in 5/2014, and OAC prescriptions for CHA2DS2VASc score ≥ 2 (guideline adherence) increased from 41.2% to 65.5%. Persistence with OAC declined over 12 months to 63.6% for VKA and 79.2% for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc ≥ 2 was significantly greater for NOAC (83.0%) than VKA (65.3%, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden.

Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013.

OBJECTIVE: To determine whether the incidence of atrial fibrillation (AF) is static or rising in the UK. DESIGN: Among the cohort of all individuals aged ≥45 years in the UK Clinical Practice Research Datalink (CPRD) (linked to hospital discharges) we identified incident non-valvular AF cases between 2001 and 2013. Overall and annual AF incidence rates were calculated and standardised to the UK population. RESULTS: The cohort of 2.23 million individuals included 91,707 patients with incident AF. The overall standardised AF incidence rate was 6.7 (95% CI 6.7 to 6.8) per 1000 person-years, increasing exponentially with age and higher in men of all ages. There was a small increase in the standardised incidence of AF in the last decade from 5.9 (5.8 to 6.1)/1000 person-years in 2001 to 6.9 (6.8 to 7.1)/1000 person-years in 2013, mostly attributable to subjects aged >80 years with a non-primary hospital discharge diagnosis of AF. Standardised incidence rates of AF among white patients was 8.1 (8.1 to 8.2)/1000 person-years, compared with 5.4 (4.6 to 6.3) for Asians and 4.6 (4.0 to 5.3) for black patients. AF diagnosis was first made in general practice in 39% of incident AF. CONCLUSIONS: The incidence of AF in the UK has increased gradually in the last decade, with more than 200 000 first-ever non-valvular AF cases expected in 2015. This increase is only partly due to population ageing, though the principal increase has been in the elderly hospitalised for a reason other than AF.

iPhone ECG screening by practice nurses and receptionists for atrial fibrillation in general practice: the GP-SEARCH qualitative pilot study.

BACKGROUND: Atrial fibrillation (AF) is often asymptomatic and substantially increases stroke risk. A single-lead iPhone electrocardiograph (iECG) with a validated AF algorithm could make systematic AF screening feasible in general practice. METHODS: A qualitative screening pilot study was conducted in three practices. Receptionists and practice nurses screened patients aged ≥65 years using an iECG (transmitted to a secure website) and general practitioner (GP) review was then provided during the patient's consultation. Fourteen semi-structured interviews with GPs, nurses, receptionists and patients were audio-recorded, transcribed and analysed thematically. RESULTS: Eighty-eight patients (51% male; mean age 74.8 ± 8.8 years) were screened: 17 patients (19%) were in AF (all previously diagnosed). The iECG was well accepted by GPs, nurses and patients. Receptionists were reluctant, whereas nurses were confident in using the device, explaining and providing screening. DISCUSSION: AF screening in general practice is feasible. A promising model is likely to be one delivered by a practice nurse, but depends on relevant contextual factors for each practice.

Cardiac troponin-T and the prediction of acute and long-term mortality after acute pulmonary embolism.

BACKGROUND: Although cardiac troponin elevation during acute pulmonary embolism (PE) predicts in-hospital death, its long-term prognostic significance, and the role of troponin-T concentration in this prediction, is unknown. Moreover, its use in acute PE in elderly populations with multiple comorbidities is not well described. METHODS: Consecutive patients presenting with confirmed PE to a tertiary hospital between 2000 and 2007 with troponin-T measured were identified retrospectively and their outcomes tracked from a state-wide death registry. RESULTS: There were 577 patients, (47% male) with a mean age (± standard deviation) of 70.1 ± 15.2 years, of whom 19 died during index admission. Of the 558 patients who survived to discharge, 186 patients died during a mean follow-up of 3.8 ± 2.4 years. There were 187 (32%) patients with elevated troponin-T (≥ 0.01 µg/L). Troponin-T concentration was significantly and independently associated with in-hospital and long-term mortality whether analyzed as a continuous or categorical variable (p<0.001). However, different cut-points were required to optimally predict in-hospital and post-discharge long-term mortality in multivariate analysis. Troponin-T ≥ 0.01 µg/L was not an independent predictor of in-hospital or post-discharge survival. A cut-point of troponin-T ≥ 0.03 µg/L was required to independently predict in-hospital death (p=0.03), and troponin-T ≥ 0.1 µg/L was required to independently predict long-term mortality (hazard ratio 2.3, 95% confidence interval 1.4-3.8, p=0.001). CONCLUSIONS: Troponin-T elevation during acute PE shows a concentration-dependent relationship with acute and long-term outcome. Concentrations of troponin-T well above the threshold for detection may be required to independently contribute to prediction of outcome in elderly populations with acute PE.

Screening Education And Recognition in Community pHarmacies of Atrial Fibrillation to prevent stroke in an ambulant population aged >=65 years (SEARCH-AF stroke prevention study): a cross-sectional study protocol.

BACKGROUND: Atrial fibrillation (AF) is associated with a high risk of stroke and may often be asymptomatic. AF is commonly undiagnosed until patients present with sequelae, such as heart failure and stroke. Stroke secondary to AF is highly preventable with the use of appropriate thromboprophylaxis. Therefore, early identification and appropriate evidence-based management of AF could lead to subsequent stroke prevention. This study aims to determine the feasibility and impact of a community pharmacy-based screening programme focused on identifying undiagnosed AF in people aged 65 years and older. METHODS AND ANALYSIS: This cross-sectional study of community-based screening to identify undiagnosed AF will evaluate the feasibility of screening for AF using a pulse palpation and handheld single-lead electrocardiograph (ECG) device. 10 community pharmacies will be recruited and trained to implement the screening protocol, targeting a total of 1000 participants. The primary outcome is the proportion of people newly identified with AF at the completion of the screening programme. Secondary outcomes include level of agreement between the pharmacist's and the cardiologist's interpretation of the single-lead ECG; level of agreement between irregular rhythm identified with pulse palpation and with the single-lead ECG. Process outcomes related to sustainability of the screening programme beyond the trial setting, pharmacist knowledge of AF and rate of uptake of referral to full ECG evaluation and cardiology review will also be collected. ETHICS AND DISSEMINATION: Primary ethics approval was received on 26 March 2012 from Sydney Local Health District Human Research Ethics Committee-Concord Repatriation General Hospital zone. Results will be disseminated via forums including, but not limited to, peer-reviewed publication and presentation at national and international conferences. CLINICAL TRIALS REGISTRATION NUMBER: ACTRN12612000406808.

The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein.

The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25µg/ml) decreased nitric oxide ((•)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10µg/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (O(2)(•-)) production. Gene expression for arginase-1, nuclear factor κB (NF-κB), interleukin-8, and tissue factor (TF) increased within 4h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24h. Therefore, in addition to modulating (•)NO bioavailability by stimulating O(2)(•-) production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, µg/ml) before (not after) SAA treatment ameliorated the Ca(2+) influx and O(2)(•-) production; decreased TF, NF-κB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (•)NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium.

Lack of widespread inflammation after contemporary PCI.

BACKGROUND: The inflammatory response to percutaneous coronary intervention (PCI) contributes to restenosis. However, it is not known if advances in PCI have attenuated this response. This study sought to determine the prevalence of systemic inflammation immediately after contemporary PCI, and to identify the predictors of the acute proinflammatory response to PCI. METHODS: Twenty seven consecutive eligible patients undergoing uncomplicated single lesion PCI were recruited. Clinical and procedural characteristics were collected. Neutrophil Mac-1 and plasma matrix metalloproteinase-9 (MMP-9) levels were measured by flow cytometry and ELISA. RESULTS: Overall, neutrophils were de-activated post-procedure [median (IQR) Mac-1: 329(277-555) versus 423 (273-533) MFI, p=0.011] but MMP-9 was unchanged [2.6 (1.8-5.1) versus 2.0 (1.5-3.8) ng/ml, p=ns]. There was a heterogeneous inflammatory response: Neutrophils were activated in 6 (22%) patients, whilst plasma MMP-9 rose in 10 (37%) patients. Twelve (44%) patients had either neutrophil activation or increased MMP-9 level post-procedure. There was no relationship between these two biomarkers. Lesion length predicted both neutrophil activation (OR, 95%CI: 19.0, 2.0-178.0, p=0.010) and increased MMP-9 (16.0, 1.5-17.2, p=0.022), and lesion complexity predicted the latter (9.6, 1.5-62.2, p=0.018). Presentation with an acute coronary syndrome, diabetes mellitus, receipt of drug-eluting stent, and stent diameter were not associated with an acute inflammatory response to PCI. CONCLUSIONS: In contrast to the balloon angioplasty era, widespread inflammation is absent in most patients after contemporary PCI. Lesion length and complexity predicted an inflammatory reaction, suggesting it to be primarily a response to vascular injury.

Incidence and determinants of myocardial infarction following percutaneous coronary interventions according to the revised Joint Task Force definition of troponin T elevation.

BACKGROUND: Elevations in troponin T (TnT) occur frequently following percutaneous coronary intervention (PCI) and are associated with an adverse prognosis. The Joint ESC/ACC/AHA/WHF Task Force have released a proposal for a universal definition of myocardial infarction (MI), including diagnostic criteria for PCI associated MI. This is based on a TnT cut-point of more than three times the 99th percentile (0.03 ng/ml), which better reflects the precision of the assay. Our study investigated the incidence and predictive factors of a PCI associated MI, using the revised definition. METHODS: 325 patients were studied following PCI with stenting. TnT was collected at both 8 and 18 h following PCI in patients with either stable or unstable angina and normal baseline TnT levels. Comparison was made of both clinical and procedural characteristics of patients with and without a rise in TnT following intervention, using cut points of 0.01 and 0.03 ng/ml. RESULTS: TnT was elevated > or = 0.03 ng/ml in 27% and > or = 0.01 ng/ml in 39% of patients following PCI. Troponin elevation was significantly more likely in those patients who experienced peri-procedural ischemic symptoms or EKG changes, or in whom abciximab was used. The variables associated with a troponin rise showed a greater difference between TnT positive and negative patients when using 0.03 ng/ml compared to 0.01 ng/ml, suggesting that this may be a better definition of PCI-related MI. CONCLUSIONS: Approximately one-quarter of low risk patients experience a procedural MI according to the revised definition. Rises in troponin were significantly associated with peri-procedural ischemic symptoms and EKG changes, and abciximab use, consistent with this level of TnT reflecting true myocardial necrosis.

Sleep disordered breathing in chronic heart failure.

Heart failure is a growing problem, placing an increasing burden on public health resources and continuing to exert a high toll in mortality and morbidity. Sleep disordered breathing (SDB) is also a major public health problem and is associated with an increased risk of fatal and non-fatal cardiovascular events. Current evidence suggests SDB, particularly central SDB, is more prevalent in patients with chronic heart failure (CHF) than in the general population, but is under-diagnosed as SDB symptoms are less prevalent in CHF. This is further hampered by the absence of a simple and accurate screening tool and limited access to sleep facilities to diagnose SDB in the large numbers of patients with CHF. The presence of SDB in patients with CHF imposes increased haemodynamic burdens and results in autonomic abnormalities. Central SDB is an independent marker of worse prognosis, and evidence is increasing that obstructive SDB is also associated with higher mortality in patients with CHF. Optimal treatment of central SDB in these patients remains uncertain. While evidence of efficacy of positive pressure ventilation is stronger in obstructive SDB, improvement in survival for patients with both CHF and SDB awaits definitive trials. This paper summarizes our current understanding of the pathophysiology of SDB in CHF, and the cardiovascular consequences, and reviews the evidence for the beneficial effects of treatment of SDB in patients with CHF.

Differences in management and outcome of ischemic and non-ischemic cardiomyopathy.

BACKGROUND: Ischemic and non-ischemic cardiomyopathy (ICM and NICM) both cause heart failure, but the different etiologies may result in differences in management and outcome, which were explored in this study. METHODS: Cohort study of 168 consecutive patients (90 ICM, 78 NICM) recruited from a tertiary referral heart failure clinic followed for 40+/-19 months. RESULTS: Patients with ICM were older than NICM with worse NYHA functional state but similar left ventricular ejection fraction (LVEF) and dimensions at baseline. Similar proportions (>80%) in both groups were on a beta-blocker and angiotensin-converting-enzyme inhibitor and/or angiotensin-II-receptor blocker (ACE inhibitor+/-ARB) by end of study. Mean LVEF improved in both groups over time (27.3+/-11.9% vs. 33.1+/-12.6%, p<0.05). Overall 40-month mortality was 17%. In univariate analysis of patients <80 years old, ICM, NYHA class, serum creatinine, ACE inhibitor+/-ARB, and amiodarone use were predictors of mortality, but only serum creatinine was significant in multivariate analysis, with a 2.9-fold relative risk of death (95%CI, 1.34-6.42, p<0.01) for creatinine >/=120 micromol/L compared to <120 micromol/L. CONCLUSIONS: Mortality of patients with cardiomyopathy remains high and is strongly related to serum creatinine. NICM patients were younger and showed greater improvement in symptoms and left ventricular function in long-term follow-up.

Autonomic abnormalities in congestive heart failure patients with sleep-disordered breathing.

BACKGROUND: The increasing prevalence of chronic heart failure is affecting patients' longevity, quality of life, and health resources, despite advances in management. Recognizing and treating comorbid illnesses is critical. Risk factors such as hypertension and diabetes are treated, but less importance is placed on the role of sleep apnea in heart failure. METHODS AND RESULTS: There is a discrepancy between the growing evidence on the potential adverse influence of sleep apnea on heart failure (and vice versa) and incorporating its treatment as part of the management strategy for chronic heart failure. Apneic episodes during sleep can lead to profound disturbances to the sympathetic and parasympathetic nervous system. CONCLUSIONS: This review explores the impact of sleep disordered breathing in patients with chronic heart failure, focusing on the autonomic nervous system.

Gene therapy for cardiovascular disease: the potential of VEGF.

The quest for new therapeutic options and the recent exponential explosion in our knowledge of genetics have led to active interest and research into gene therapy. One area of gene therapy that has generated much debate and controversy is the use of vascular endothelial growth factor (VEGF) for therapeutic angiogenesis for palliative intent, and for the prevention of restenosis following percutaneous revascularization in coronary and peripheral arterial disease. This review highlights the development in VEGF gene therapy in the last 12 to 18 months, particularly the results from randomized, double-blind, placebo-controlled phase I and II studies that have evolved from encouraging results from animal models and early pilot studies in humans.

Clinical trials of gene therapy for atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: To provide an update on clinical trials of gene therapy for atherosclerotic cardiovascular disease published since 1 August 2001 and summarize the general advantages and potential problems of gene transfer in these disorders. RECENT FINDINGS: There are two major areas in which gene therapy has entered clinical trials. The first is angiogenesis for coronary and peripheral arterial disease. Two relatively small placebo-controlled trials for coronary disease were reported, one using intramyocardial plasmid VEGF-2 gene, the other using intracoronary adenoviral FGF-4 gene. The VEGF-2 study in no-option patients showed reduced angina, and significant improvement in perfusion and function, whereas the FGF-4 study in less severely affected patients showed promising results in some subsets. In peripheral artery disease two phase 1 studies of adenoviral NV1FGF and VEGF showed some objective improvement in pain, ulcer size and ankle:brachial index in one study and endothelial function in the other. Both adenoviral and plasmid VEGF gene transfer at angioplasty increased vascularity in a phase 2 double-blind study. The other major area is the prevention of graft disease and restenosis using antisense oligodeoxynucleotides. E2F decoy led to a significant reduction in venous graft complications after ex-vivo transfection at the time of coronary bypass surgery, whereas the c-Myc oligodeoxynucleotide was ineffective in preventing in-stent coronary restenosis. SUMMARY: There are more reviews of gene therapy for atherosclerosis in the literature than publications with original data or trials, but in the past year the imbalance is being redressed, with some promising results from controlled studies.

Plasma vascular endothelial growth factor (VEGF) levels after intramuscular and intramyocardial gene transfer of VEGF-1 plasmid DNA.

The purpose of this study was to document the kinetics of vascular endothelial growth factor (VEGF) protein release into the systemic circulation after phVEGF gene transfer for therapeutic angiogenesis. VEGF plasma levels were measured by ELISA in 64 patients undergoing gene transfer of plasmid DNA: intramuscular in 34 patients with peripheral artery disease, and intramyocardial in 30 patients with coronary disease. Baseline plasma VEGF was highly variable and not normally distributed. After intramuscular gene transfer, median plasma VEGF rose slightly, although significantly, by 7 days (38 to 41 pg/ml, p < 0.05), but was not different from baseline at 14, 21, or 28 days. After intramyocardial gene transfer, median plasma VEGF levels were significantly elevated compared with baseline on days 2, 3, and 7 (39, 38, and 45 pg/ml, respectively, each p < 0.05 vs. baseline value of 21 pg/ml). Day 7 plasma levels did not differ significantly as a function of phVEGF dose, or between intramyocardial and intramuscular injections (1.8 and 1.3 times baseline levels, respectively, p = 0.6), despite an almost 10-fold difference in mean phVEGF dose. Intramuscular and intramyocardial phVEGF injections result in significant, although modest, elevations of circulating gene product for <14 days, with no relationship to injected dose. While a statistically significant increase in circulating VEGF level can provide evidence of successful gene transfer for groups of patients, interpretation of results for individual subjects is complicated by wide variation in baseline VEGF and low circulating levels compared with baseline after gene transfer.

Therapeutic angiogenesis for coronary artery disease.

A large body of evidence in animal models of ischemia shows that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization. Many cytokines have angiogenic activity; those that have been best studied in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger-scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein and have not yet shown significant improvement in exercise time or angina compared with placebo. Larger-scale placebo-controlled studies of gene transfer are in progress. Clinical studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor-cell or stem-cell supplementation, to provide safe and effective therapeutic myocardial angiogenesis. Determination of which growth factors or cells are required to optimize therapeutic neovascularization in an individual patient should be a goal of future research.