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      Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study

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          We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium, tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

          This was a multicentre, randomised, double-blind, placebo- and active-controlled, 26-week trial. Patients (n = 2144) were randomised (2:2:2:2:1) to receive once-daily QVA149 (indacaterol 110 μg/glycopyrronium 50 μg), indacaterol 150 μg, glycopyrronium 50 μg, open-label tiotropium 18 μg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV 1) at week 26 for QVA149 versus its monocomponents. Secondary end-points included dyspnoea, health status, rescue medication use and safety.

          Trough FEV 1 at week 26 was significantly improved (p<0.001) with QVA149 compared with indacaterol and glycopyrronium (least squares mean (LSM) differences 0.07 L and 0.09 L, respectively), tiotropium and placebo (LSM differences 0.08 L and 0.20 L, respectively); these beneficial effects were sustained throughout the 26-week study. QVA149 significantly improved dyspnoea and health status versus placebo (p<0.001 and p = 0.002, respectively) and tiotropium (p = 0.007 and p = 0.009, respectively) at week 26. All treatments were well tolerated.

          Dual bronchodilation with once-daily QVA149 demonstrated superior and clinically meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator, with a safety and tolerability profile similar to placebo, supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting β 2-agonist combinations for the treatment of COPD.


          Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD http://ow.ly/p3H5E

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          Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.

          The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p
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            Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

            Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions. Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. After a detailed screening of 103 articles, 17 trials enrolling 13,645 [corrected] patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 134 of 6984 [corrected] patients (1.9%) [corrected] receiving inhaled anticholinergics and 83 of 6661 [corrected] patients (1.2%) receiving control therapy (RR, 1.60 [corrected] [95% confidence interval {CI}, 1.22-2.10]; [corrected] P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.35]; [corrected] P < .001, I(2) = 0%). Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.
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              Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis.

              beta-Adrenergic agonists exert physiologic effects that are the opposite of those of beta-blockers. beta-Blockers are known to reduce morbidity and mortality in patients with cardiac disease. beta(2)-Agonist use in patients with obstructive airway disease has been associated with an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death. To assess the cardiovascular safety of beta(2)-agonist use in patients with obstructive airway disease, defined as asthma or COPD. A meta-analysis of randomized placebo-controlled trials of beta(2)-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. Longer duration trials were included in the analysis if they reported at least one adverse event. Adverse events included sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death. Thirteen single-dose trials and 20 longer duration trials were included in the study. A single dose of beta(2)-agonist increased the heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to placebo. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95% CI, 0.76 to 3.6). beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic stimulation, that beta(2)-agonists may precipitate ischemia, congestive heart failure, arrhythmias, and sudden death.

                Author and article information

                Eur Respir J
                Eur. Respir. J
                The European Respiratory Journal
                European Respiratory Society (442 Glossop Road, Sheffield, S10 2PX, UK )
                December 2013
                30 May 2013
                : 42
                : 6
                : 1484-1494
                [1 ]Dept of Medicine, University of Cape Town , Cape Town, South Africa
                [2 ]Pulmonary Research Institute of Southeast Michigan , Livonia, MI
                [5 ]Novartis Pharmaceuticals Corporation , East Hanover, NJ, USA
                [3 ]London Chest Hospital , Barts Health NHS Trust, London
                [4 ]Novartis Horsham Research Centre , Horsham, UK
                Author notes
                E.D. Bateman, Division of Pulmonology, Dept of Medicine, University of Cape Town, George Street, Mowbray 7700, Cape Town, South Africa. E-mail: Eric.Bateman@ 123456uct.ac.za
                ©ERS 2013

                ERJ Open articles are open access and distributed under the terms of the ( Creative Commons Attribution Licence 3.0>)

                Original Article

                Respiratory medicine


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