Publications

Objectives To investigate the impact of ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) on clinical outcomes after percutaneous coronary intervention (PCI) in patients with established cardiovascular disease (CVD) who were enrolled in the Global Leaders Trial. Background The impact of prolonged monotherapy with P2Y12 inhibitors after PCI in patients with CVD is undetermined. Methods GLOBAL LEADERS was a randomized, superiority, all-comers trial comparing one-month DAPT with ticagrelor and aspirin followed by 23-month ticagrelor monotherapy (experimental treatment) with standard 12-month DAPT followed by 12-month aspirin monotherapy (reference treatment) in patients treated with a biolimus A9-eluting stent. The cohort was stratified according to those with- and without established CVD, defined as a history of ≥1 prior myocardial infarction (MI), PCI, coronary artery bypass operation, stroke or peripheral vascular disease. The degree of CVD was defined according to the number of vascular territories effected (1, 2, ≥3). The primary endpoint was a composite of all-cause death or new Q-wave MI at 2-years. Secondary endpoints were the patient orientated composite endpoint (POCE) of death, stroke, MI and any revascularization; definite stent thrombosis and net adverse cardiovascular events a composite of POCE and BARC 3 or 5 bleeding. Results Amongst the 15,761 patients included in this cohort were 6693 patients (42.5%) with- and 9068 patients without established CVD. Patients with CVD were older, and had significantly higher rates of diabetes, hypertension, and hypercholesterolaemia (P<0.01). The incidence of the primary endpoint was significantly higher in patients with established CVD (5.1% vs. 3.3%, P<0.001) as were all secondary endpoints and their individual components. There was a trend for a reduction in the primary endpoint in patients with established CVD receiving the experimental treatment (4.6% vs. 5.6%, HR0.82 [0.66–1.02], p=0.07), which was not seen in those without prior CVD (3.2% vs. 3.3%, HR 0.95 [0.76–1.19, p=0.66; p(interaction)=0.37). Compared with patients without CVD the incidence of the primary and second endpoints and all their individual components, other than BARC 3/5 bleeding, rose significantly with an increasing degree of CVD. In an unadjusted model, compared with patients without CVD, the hazard ratio for the primary endpoint rose from 1.5 (1.21–1.81) to 3.0 (2.32–4.00) in patients with one and three territories of CVD, respectively. Similar rises were seen in models adjusted by age (1.3 [1.01–1.60] to 2.56 [1.94–3.38]) and age, left ventricular ejection fraction, clinical presentation and anti-platelet strategy (1.4 [1.10–1.68] to 2.26 [1.69–3.02]). Conclusions PCI outcomes are poorer in patients with increasing degrees of CVD compared to those without. Prolonged monotherapy with ticagrelor does not mitigate this risk suggesting a greater need to focus on modifiable risk factors

Abstract Sirtuin-1 (SIRT1) and SIRT6, NAD + -dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H 2 O 2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.

To determine the costs of a procedure, the total costs of the department that provides the service must be considered and, in addition, the direct cost of the specific procedure. Applying this principle to the cost accounting of angioplasty and bypass surgery results in a direct, i.e. procedural, cost, including the initial hospital stay, of respectively 8694 Dfl and 20 987 Dfl. A review of the follow-up data for the first year after the original intervention revealed a 2% reintervention rate for bypass surgery, while this percentage was 29% for angioplasty. Adding the first year costs involved with reinterventions to the procedural costs results in a 1-year cost of angioplasty and bypass operation of 13 625 Dfl and 21 363 Dfl, respectively. It is concluded that because of reinterventions in the first year, a mark up of 57% on the procedural cost of angioplasty must be added to cover 1-year costs, while for bypass surgery this is only 1%. Nevertheless, the 1-year cost for angioplasty is still 36% less than for bypass surgery. As reinterventions after PTC A may stay considerably higher than for CABG for several years, the mark-up percentages will be substantially higher for longer time spans. This may tend to equalize the total costs of PTC A and CABG over time spans of perhaps 5–8 years. Sufficient data are not available to verify this statement. Clinicians must realize that choosing the most appropriate procedure is not only a matter of medical assessment but also a matter of cost effectiveness. CABG can be seen as an 'investment decision' while PTC A tends to become a decision with characteristics of 'maintenance planning'!

<h3>Background:</h3> Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease. <h3>Objectives:</h3> To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I–IV) compared with age-matched control subjects, smokers with normal lung function and never smokers. <h3>Methods:</h3> The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB). <h3>Results:</h3> The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2–15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD. <h3>Conclusion:</h3> The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.

Abstract Background and Aims The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention in patients with acute coronary syndrome remains uncertain. This analysis examined the temporal patterns of ischaemic and bleeding risks of early aspirin withdrawal compared with DAPT. Methods NEO-MINDSET randomized 3410 acute coronary syndrome patients undergoing successful percutaneous coronary intervention with drug-eluting stents within 4 days of hospital admission to either potent P2Y12 inhibitor monotherapy (prasugrel or ticagrelor) or standard DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. This prespecified landmark analysis examined early (0–30 days) and late (31–365 days) follow-up events. Co-primary outcomes were (i) the composite of all cause death, myocardial infarction, stroke, or urgent target-vessel revascularization (ischaemic outcome) and (ii) Bleeding Academic Research Consortium type 2, 3, or 5 bleeding. Results At 30 days, the composite ischaemic outcome occurred in 3.3% of patients receiving monotherapy vs 1.8% with DAPT (risk difference 1.5%, 95% confidence interval .4%–2.6%; P = .006). Bleeding occurred in .6% vs 1.5% (risk difference −.8%, 95% confidence interval -1.5%–.1%; P = .018). In the landmark analysis between Days 31 and 365, ischaemic outcome rates were similar between study groups (3.8% each; P = .977), while bleeding remained less frequent with monotherapy (1.3% vs 3.5%; risk difference -2.2%, 95% confidence interval -3.2%–1.1%; P &amp;gt; .001). Conclusions This prespecified 30-day landmark analysis suggests an excess of ischaemic risk with monotherapy vs DAPT in the first 30 days but not thereafter, whereas an aspirin-free strategy was consistently associated with fewer bleeding events within and after 30 days.

Background Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. Methods APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. Results A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A1c (HbA1c) 7.2%, body mass index 29.5 kg/m2, and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. Conclusions APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.

Asthma is an inflammatory airway disease characterized by airway eosinophilia, in which CCL11 (eotaxin) plays a crucial role. The aim of study is to determine the elevation of CCL11 levels in bronchoalveolar lavage fluid (BALF), blood, exhaled breath condensate (EBC) and sputum in asthma patients and to identify which medium yields the most significant change in CCL11 level.The databases of PubMed, Embase and Cochrane Centre Register of Controlled Trials were systematically searched from inception to September 2013. Controlled clinical trials that focused on CCL11 concentrations in asthma patients and controls, and their correlations with other asthma indicators were obtained. Data were analysed using Stata 12.0.Thirty studies were included in this investigation. CCL11 levels in blood, EBC and sputum were significantly higher in asthma patients than in healthy subjects. Sputum CCL11 concentrations were significantly elevated in unstable asthma patients versus stable asthma patients and in uncontrolled asthma patients versus partially controlled asthma patients. CCL11 levels in sputum and blood were negatively correlated with the lung function as measured by FEV1% predicted, and were positively correlated with BALF, EBC and sputum eosinophil counts. Similarly, CCL11 concentrations were positively correlated with eosinophil cationic protein in EBC, blood and sputum as well as with interleukin-5 in sputum and fractional exhaled nitric oxide in EBC. Steroid treatment had no significant effect on CCL11 levels.CCL11 is a potentially useful biomarker for the diagnosis and assessment of asthma severity and control, especially in sputum. CCL11 is crucial in eosinophil chemoattraction and activation in asthma pathogenesis. Further studies using anti-CCL11 approaches are needed to confirm a role for CCL11 in asthma pathogenesis particularly in patients with more severe disease.