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McGarvey L.,Queen's University of Belfast | Niewoehner D.,Minneapolis VA Health Care System | Magder S.,McGill University | Sachs P.,Pulmonary Assoct. of Stamford | And 8 more authors.
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2015

The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 g) QD via Respimat®, formoterol 12 g twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 g, 883 received olodaterol 10 g, 885 received placebos, and 460 received formoterol 12 g BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 g (marketed and registered dose) and 10 g QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified. © 2015 © L. McGarvey, D. Niewoehner, S. Magder, P. Sachs, K. Tetzlaff, A. Hamilton, L. Korducki, U. Bothner, C. Vogelmeier, A. Koch, G. T. Ferguson.


Koch A.,University Hospital Bochum Bergmannsheil | Pizzichini E.,Federal University of Santa Catarina | Hamilton A.,Boehringer Ingelheim | Hart L.,Boehringer Ingelheim | And 3 more authors.
International Journal of COPD | Year: 2014

Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat® versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 μg, twice-daily formoterol 12 μg, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0-3 hours response, FEV1 trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George's Respiratory Questionnaire. Overall, 904 (Study 1222.13) and 934 (Study 1222.14) patients received treatment. Olodaterol significantly improved FEV1 area under the curve from 0-3 hours versus placebo in both studies (with olodaterol 5 μg, 0.151 L and 0.129 L; with olodaterol 10 μg, 0.165 L and 0.154 L; for all comparisons P,0.0001) and FEV1 trough responses versus placebo (0.053-0.085 L; P,0.01), as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for discontinuations) demonstrated statistical significance for olodaterol versus placebo. St George's Respiratory Questionnaire total score was significantly improved with olodaterol, but not formoterol, versus placebo. No safety signals were identified from adverse-event or other safety data. Once-daily olodaterol 5 μg and 10 μg is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy, with a satisfactory safety profile. © 2014 Koch et al.


PubMed | Queen's University of Belfast, k Pulmonary Research Institute of Southeast Michigan, McGill University, University of Marburg and 5 more.
Type: Clinical Trial, Phase III | Journal: COPD | Year: 2015

The novel long-acting 2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 g) QD via Respimat, formoterol 12 g twice daily (BID) via Aerolizer (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with 60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 g, 883 received olodaterol 10 g, 885 received placebos, and 460 received formoterol 12 g BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 g (marketed and registered dose) and 10 g QD delivered via Respimat are comparable to placebo and formoterol BID in this population, with no safety signals identified.


Mat Z.,University of Cologne | Grensemann B.,University of Cologne | Yakin Y.,University of Cologne | Knobloch J.,University of Cologne | And 3 more authors.
International Immunopharmacology | Year: 2012

Susceptibility to infections with gram-positive bacteria, which are an important trigger of exacerbations, is increased in COPD and asthma. Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates. The aim of this study was to evaluate the effects of lipoteichoic acid (LTA), a danger signal from gram-positive bacteria, on T cell cytokines related to bacterial infection defense in COPD and asthma. T cell populations within peripheral blood mononuclear cells (PBMCs) were ex-vivo activated towards T H2/T C2 subtypes and subsequently stimulated with LTA. IL-2 and IL-5 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers (NS), current smokers without airflow limitation (S), smokers with moderate to severe COPD and mild to moderate asthmatics (A) (each n = 10). IL-2 and IL-5 baseline levels were without differences between the cohorts. After T cell activation, IL-2 and IL-5 releases were increased in all cohorts, however, for IL-2 this increase was significantly higher in S and by trend in COPD compared to the other groups. LTA time-dependently suppressed IL-2 release in NS, S and COPD but not in A. LTA reduced IL-5 release in COPD and A but not in NS and S. Summarized, LTA reduces T H2/T C2 cytokines indicating immunosuppressive effects, which are dysregulated in COPD and asthma. This implies a misguided response to gram-positive bacterial infections, which might help to explain the increased susceptibility to bacterial infections in COPD and asthma. © 2012 Elsevier B.V. All rights reserved.


Strauch J.,University Hospital Bochum Bergmannsheil | Scherner M.,University of Cologne | Haldenwang P.,University Hospital Bochum Bergmannsheil | Madershahian N.,University of Cologne | And 5 more authors.
Thoracic and Cardiovascular Surgeon | Year: 2012

Objective Transcatheter aortic valve implantation (TAVI) has been developed to minimize the operative trauma in high-risk patients. Patient selection for TAVI is still subject to debate and octogenarians are often regarded as high-risk patients. Methods In this single-center study, data of 169 octogenarians who received conventional AVR (90) or TAVI (79) have been analyzed retrospectively according to the endpoint definitions of the Valve Academic Research Consortium to answer the following questions: (a) Should patients due to their age of 80 years or older be considered as high risk? (b) Is the EuroSCORE a suitable tool for estimating mortality after AVR or TAVI in octogenarians? (c) Is TAVI the procedure of choice for octogenarians? Results TAVI patients showed higher comorbid conditions concerning an existing renal dysfunction (31 vs. 56%, p = 0.001), peripheral vascular disease (6 vs. 30%, p < 0.001), diabetes (19% vs. 49%, p < 0.001), a decreased ejection fraction (LVEF < 30%: 2 vs. 13%, p < 0.05), and pulmonary hypertension (23 vs. 48%; p < 0.005) with an increase of the perioperative risk represented by logistic EuroSCORE (AVR 11% ± 1.27 vs. TAVI 38% ± 1.35; p < 0.0005) and STS Score (7% ± 0.52 vs. 14% ± 0.56; p < 0.0005). All-cause and cardiovascular-cause in-hospital or 30-day mortality was 5.6% (n = 5) and 3.4% (n = 3) in the AVR cohort and 8.8% (n = 7) and 7.6% (n = 6) in TAVI-patients (p = 0.55; p = 0.31), respectively. The overall combined safety endpoint at 30 days was 22.2% (n = 20) in AVR patients and 29.1% (n = 23) with regard to the TAVI group (p = 38). Analysis of cerebrovascular complications, vascular complications, and pacemaker revealed no significant differences. In the AVR group, actuarial survival at 6 months and 1 and 2 years was 89, 78, and 74%, respectively. Data of the TAVI patients are only available for a follow-up of 6 months and revealed a survival of 85%. Conclusion AVR and TAVI in octogenarians show comparable results, but the analyzed cohorts differ significantly in their risk profile. The results indicate an overrated perioperative mortality using the EuroSCORE but on the other hand logistic EuroSCORE represents articulately the different risk profile of the two groups. For this reason, we consider the EuroSCORE still to be a useful tool for preoperative risk assessment. Moreover, octogenarians cannot per se be considered as "true high risko" patients. Differentiated clinical judgment is most important for reasonable decision making. © 2012 by Thieme Medical Publishers, Inc.


PubMed | University Hospital Bochum Bergmannsheil
Type: Comparative Study | Journal: The Thoracic and cardiovascular surgeon | Year: 2012

Transcatheter aortic valve implantation (TAVI) has been developed to minimize the operative trauma in high-risk patients. Patient selection for TAVI is still subject to debate and octogenarians are often regarded as high-risk patients.In this single-center study, data of 169 octogenarians who received conventional AVR (90) or TAVI (79) have been analyzed retrospectively according to the endpoint definitions of the Valve Academic Research Consortium to answer the following questions: (a) Should patients due to their age of 80 years or older be considered as high risk? (b) Is the EuroSCORE a suitable tool for estimating mortality after AVR or TAVI in octogenarians? (c) Is TAVI the procedure of choice for octogenarians?TAVI patients showed higher comorbid conditions concerning an existing renal dysfunction (31 vs. 56%, p = 0.001), peripheral vascular disease (6 vs. 30%, p < 0.001), diabetes (19% vs. 49%, p < 0.001), a decreased ejection fraction (LVEF < 30%: 2 vs. 13%, p < 0.05), and pulmonary hypertension (23 vs. 48%; p < 0.005) with an increase of the perioperative risk represented by logistic EuroSCORE (AVR 11% 1.27 vs. TAVI 38% 1.35; p < 0.0005) and STS Score (7% 0.52 vs. 14% 0.56; p < 0.0005). All-cause and cardiovascular-cause in-hospital or 30-day mortality was 5.6% (n = 5) and 3.4% (n = 3) in the AVR cohort and 8.8% (n = 7) and 7.6% (n = 6) in TAVI-patients (p = 0.55; p = 0.31), respectively. The overall combined safety endpoint at 30 days was 22.2% (n = 20) in AVR patients and 29.1% (n = 23) with regard to the TAVI group (p = 38). Analysis of cerebrovascular complications, vascular complications, and pacemaker revealed no significant differences. In the AVR group, actuarial survival at 6 months and 1 and 2 years was 89, 78, and 74%, respectively. Data of the TAVI patients are only available for a follow-up of 6 months and revealed a survival of 85%.AVR and TAVI in octogenarians show comparable results, but the analyzed cohorts differ significantly in their risk profile. The results indicate an overrated perioperative mortality using the EuroSCORE but on the other hand logistic EuroSCORE represents articulately the different risk profile of the two groups. For this reason, we consider the EuroSCORE still to be a useful tool for preoperative risk assessment. Moreover, octogenarians cannot per se be considered as true high risk patients. Differentiated clinical judgment is most important for reasonable decision making.

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