Publications by authors named "Stefan Andreas"

77 Publications

Inhaled therapy reduces COPD mortality.

ERJ Open Res 2020 Oct 30;6(4). Epub 2020 Nov 30.

Dept of Pulmonary Medicine, University Hospital Essen - Ruhrlandklinik, Essen, Germany.

https://bit.ly/35jbEiN.
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http://dx.doi.org/10.1183/23120541.00634-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701338PMC
October 2020

[Contract of the German Health Insurance AOK Hessen Concerning Prolonged Weaning-Methods and First Experiences].

Dtsch Med Wochenschr 2020 09 9;145(19):e108-e115. Epub 2020 Sep 9.

Lungenfachklinik Immenhausen, 34376 Immenhausen.

Introduction: In recent years, the number of patients requiring mechanical ventilation has increased steadily. In some cases, weaning is not successful. These patients depend on home mechanical ventilation and intensive outpatient care. Surprisingly, most of these patients were never treated in a weaning center. Thus, weaning might still be possible in at least some of them. Health insurance companies have recognized this problem.

Methods: AOK Hessen, a major health insurance company in the German federal state of Hesse, identified some starting points for improvement after having surveyed their patients in ambulant intensive care. Principal points for future measures are expertise of the treating medical center (weaning experience, weaning center), establishment of new centers for homecare ventilation for long term therapy of these patients and a coordinated follow up.

Results: Centers for homecare ventilation are wards with a non-hospital atmosphere affiliated to a weaning center. The main focus here is not weaning itself but daily physical and speech therapy. Patients in home care ventilation centers have time (up to 6 months) to improve their physical and mental strength. Afterwards, depending to their development, they can be transferred to the weaning center again.

Discussion: In this paper, we introduce the concept of the home care ventilation centers. Initial data suggests that home care ventilation centers can contribute to successful weaning.
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http://dx.doi.org/10.1055/a-1207-7731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515656PMC
September 2020

A Post Hoc Holter ECG Analysis of Olodaterol and Formoterol in Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1955-1965. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Background: Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 µg) versus placebo.

Methods: We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2-4 COPD from four studies (1222.11-14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 µg) versus placebo.

Results: No statistically significant (P>0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed.

Conclusion: Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD.

Trial Registration: ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).
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http://dx.doi.org/10.2147/COPD.S246353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428408PMC
August 2020

No Influence on Cardiac Arrhythmia or Heart Rate from Long-Term Treatment with Tiotropium/Olodaterol versus Monocomponents by Holter ECG Analysis in Patients with Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1945-1953. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Background: Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.

Methods: We analyzed Holter ECG data from a representative subset of patients (N=506) from the two pooled replicate studies (TONADO 1 and 2) assessing tiotropium/olodaterol 5/5 µg therapy versus tiotropium 5 µg or olodaterol 5 µg monotherapy, inhaled once daily (two single inhalations) using the Respimat Soft Mist™ inhaler device. Additionally, major adverse cardiac events (MACE) with tiotropium/olodaterol were assessed versus the respective monotherapies.

Results: After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 µg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 µg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 µg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 µg (-0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.

Conclusion: Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.

Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).
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http://dx.doi.org/10.2147/COPD.S246350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429402PMC
August 2020

Absence of Adverse Effects of Tiotropium/Olodaterol Compared with the Monocomponents on Long-Term Heart Rate and Blood Pressure in Patients with Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1935-1944. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Introduction: Long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are established maintenance bronchodilator treatments for chronic obstructive pulmonary disease (COPD) with the potential to increase heart rate (HR) and impact blood pressure (BP). While previous studies indicate that HR and BP are not negatively influenced by tiotropium or olodaterol monotherapy, the effect of tiotropium/olodaterol has not been evaluated. We report a post hoc analysis of the effect of dual bronchodilation with tiotropium/olodaterol versus monocomponents on HR and BP in patients with moderate-to-very-severe COPD included in the large TONADO study.

Methods: The TONADO trials (1237.5 [NCT01431274] and 1237.6 [NCT01431287]) were two replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials that compared tiotropium/olodaterol (5/5 μg and 2.5/5 μg) with tiotropium (5 μg and 2.5 μg) and olodaterol (5 μg) in patients with moderate-to-very-severe COPD. Patients with cardiovascular comorbidities were included. Changes in HR and systolic/diastolic BP were measured before and after dosing with the study medication at each visit (baseline, Week 12, Week 24 and Week 52).

Results: Overall, 3,100 patients were included in this analysis. Over 52 weeks, small changes from baseline in mean HR (<2 beats per minute [bpm]) and small changes from pre- to post-dose (<1 bpm) were evident at different time points. There was a non-significant increase from baseline in mean diastolic and systolic BP (<2 mmHg) observed over 52 weeks of treatment. The short-term (1 hour pre- to 1 hour post-dose) mean changes in systolic and diastolic BP over 52 weeks in the tiotropium/olodaterol 5/5 µg group were comparable with those observed for the monocomponents at all time points.

Conclusion: There were no differences in HR or BP among patients on tiotropium/olodaterol when compared with monocomponents. This supports the already demonstrated cardiovascular safety profile of tiotropium/olodaterol as long-acting maintenance bronchodilator treatment for COPD, including patients with cardiovascular comorbidities.
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http://dx.doi.org/10.2147/COPD.S246348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428407PMC
August 2020

Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry.

Eur Respir J 2020 08 13;56(2). Epub 2020 Aug 13.

German Center for Lung Research (DZL), Germany.

Objective: There is a paucity of observational data on antifibrotic therapy for idiopathic pulmonary fibrosis (IPF). We aimed to assess the course of disease of IPF patients with and without antifibrotic therapy under real-life conditions.

Methods: We analysed data from a non-interventional, prospective cohort study of consecutively enrolled IPF patients from 20 interstitial lung disease expert centres in Germany. Data quality was ensured by automated plausibility checks, on-site monitoring, and source data verification. Propensity scores were applied to account for known differences in baseline characteristics between patients with and without antifibrotic therapy.

Results: Among the 588 patients suitable for analysis, the mean±sd age was 69.8±9.1 years, and 81.0% were male. The mean±sd duration of disease since diagnosis was 1.8±3.4 years. The mean±sd value at baseline for forced vital capacity (FVC) and diffusion capacity () were 68.6±18.8% predicted and 37.8±18.5% predicted, respectively. During a mean±sd follow-up of 1.2±0.7 years, 194 (33.0%) patients died. The 1-year and 2-year survival rates were 87% 46% and 62% 21%, respectively, for patients with without antifibrotic therapy. The risk of death was 37% lower in patients with antifibrotic therapy (hazard ratio 0.63, 95% CI 0.45; 0.87; p=0.005). The results were robust (and remained statistically significant) on multivariable analysis. Overall decline of FVC and was slow and did not differ significantly between patients with or without antifibrotic therapy.

Conclusions: Survival was significantly higher in IPF patients with antifibrotic therapy, but the course of lung function parameters was similar in patients with and without antifibrotic therapy. This suggests that in clinical practice, premature mortality of IPF patients eventually occurs despite stable measurements for FVC and .
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http://dx.doi.org/10.1183/13993003.02279-2019DOI Listing
August 2020

Abscopal effect in lung cancer: three case reports and a concise review.

Immunotherapy 2019 12;11(17):1445-1461

Department of Pneumology & Cardiology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Over the past 40 years, reports on the abscopal effect following conventional radiation have been relatively rare, especially in less immunogenic tumors such as lung cancer. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we present three illustrative case reports from our own institution and previous published cases of the abscopal effect in patients with non-small cell lung cancer, treated with immune checkpoint inhibitors and radiotherapy. We also present a concise review of the clinical and experimental literature on the abscopal effect in non-small cell lung cancer.
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http://dx.doi.org/10.2217/imt-2019-0105DOI Listing
December 2019

Time-updated resting heart rate predicts mortality in patients with COPD.

Clin Res Cardiol 2020 Jun 16;109(6):776-786. Epub 2019 Nov 16.

Department of Internal Medicine V - Pulmonology, Allergology, Critical Care Medicine, Saarland University Medical Centre, Saarland University Hospital, 66421, Homburg/Saar, Germany.

High resting heart rate (RHR) is associated with higher mortality in the general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). In particular, the time-updated RHR (most recent value before the event) appears informative. This is the first study to investigate the association of time-updated RHR with mortality in COPD. We compared the baseline and time-updated RHR related to survival in 2218 COPD patients of the German COSYCONET cohort (COPD and Systemic Consequences-Comorbidities Network). Patients with a baseline RHR > 72 beats per minute (bmp) had a significantly (p = 0.049) higher all-cause mortality risk (adjusted hazard ratio (HR) of 1.37 (1.00-1.87) compared to baseline RHR ≤ 72 bpm. The time-updated RHR > 72 bpm was markedly superior (HR 1.79, 1.30-2.46, p = 0.001). Both, increased baseline and time-updated RHR, were independently associated with low FEV1, low TLCO, a history of diabetes, and medication with short-acting beta agonists (SABAs). In conclusion, increased time-updated RHR is associated with higher mortality in COPD independent of other predictors and superior to baseline RHR. Increased RHR is linked to lung function, comorbidities and medication. Whether RHR is an effective treatment target in COPD, needs to be proven in controlled trials.
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http://dx.doi.org/10.1007/s00392-019-01572-1DOI Listing
June 2020

Prevalence of cardiac comorbidities, and their underdetection and contribution to exertional symptoms in COPD: results from the COSYCONET cohort.

Int J Chron Obstruct Pulmon Dis 2019 20;14:2163-2172. Epub 2019 Sep 20.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the Center for Lung Research (DZL), Munich, Germany.

Background: A substantial prevalence of cardiovascular disease is known for COPD, but detection of its presence, relationship to functional findings and contribution to symptoms remains challenging. The present analysis focusses on the cardiovascular contribution to COPD symptoms and their relationship to the patients' diagnostic status, medication and echocardiographic findings.

Methods: Patients from the COPD cohort COSYCONET with data on lung function, including FEV, residual volume/total lung capacity (RV/TLC) ratio, diffusing capacity TLCO, and echocardiographic data on left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), medical history, medication, modified British Medical Research Council dyspnea scale (mMRC) and Saint Georges Respiratory Questionnaire (SGRQ) were analyzed.

Results: A total of 1591 patients (GOLD 0-4: n=230/126/614/498/123) fulfilled the inclusion criteria. Ischemic heart disease, myocardial infarction or heart failure were reported in 289 patients (18.2%); 860 patients (54%) received at least one cardiovascular medication, with more than one in many patients. LVEF<50% or LVEDD>56 mm was found in 204 patients (12.8%), of whom 74 (36.3%) had neither a cardiovascular history nor medication. Among 948 patients (59.6%) without isolated hypertension, there were 21/55 (38.2%) patients with LVEF<50% and 47/88 (53.4%) with LVEDD>56 mm, who lacked both a cardiac diagnosis and medication. LVEDD and LVEF were linked to medical history; LVEDD was dependent on RV/TLC and LVEF on FEV. Exertional COPD symptoms were best described by mMRC and the SGRQ activity score. Beyond lung function, an independent link from LVEDD on symptoms was revealed.

Conclusion: A remarkable proportion of patients with suspicious echocardiographic findings were undiagnosed and untreated, implying an increased risk for an unfavorable prognosis. Cardiac size and function were dependent on lung function and only partially linked to cardiovascular history. Although the contribution of LV size to COPD symptoms was small compared to lung function, it was detectable irrespective of all other influencing factors. However, only the mMRC and SGRQ activity component were found to be suitable for this purpose.
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http://dx.doi.org/10.2147/COPD.S209343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759215PMC
April 2020

Decline of COPD exacerbations in clinical trials over two decades - a systematic review and meta-regression.

Respir Res 2019 Aug 16;20(1):186. Epub 2019 Aug 16.

Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

Background: An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials.

Methods: We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (p).

Results: Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); p <  0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the "placebo" group, also yielded consistent results.

Conclusions: In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed.

Registration: PROSPERO 2018 CRD4218118823.
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http://dx.doi.org/10.1186/s12931-019-1163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697937PMC
August 2019

Morbidity and mortality in patients with cardiovascular risk factors and obstructive sleep apnoea: results from the DIAST-CHF cohort.

Respir Med 2019 Jul - Aug;154:127-132. Epub 2019 Jun 21.

Clinic and Policlinic for Cardiology, University Hospital Leipzig, Leipzig, Germany; Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; German Cardiovascular Research Center, partner site Göttingen, Germany. Electronic address:

Study Objectives: Aim of the study was to investigate the association between obstructive sleep apnoea (OSA) and cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors.

Methods: In this prospective study, 378 patients of the DIAST-CHF cohort were screened for OSA by home polygraphy. Inclusion criteria were risk factors for diastolic heart failure, such as hypertension, diabetes mellitus, atherosclerotic disease, or history of chronic heart failure. Patients were followed up after 1, 2, 5, 9 and 10 years for the occurrence of major adverse cardiac and cerebrovascular events (MACE and MACCE).

Results: 344 patients were included in the analysis, of which 60% were diagnosed with OSA (apnoea-hypopnoea index ≥5/h). Overall mortality was higher in the OSA group (14.9% vs. 5.9%; p = 0.007), but significance disappeared after adjustment for age and sex (hazard ratio (HR) 1.89, 95% confidence interval (CI) 0.86-4.16, p = 0.12). There was no significant difference in the occurrence of MACE or MACCE in patients with OSA compared to those without OSA (MACE: 31% vs. 30%; p = 0.61; MACCE: 32% vs. 30%; p = 0.53).

Conclusion: We did not find evidence of an adverse effect of OSA on cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors.
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http://dx.doi.org/10.1016/j.rmed.2019.06.019DOI Listing
August 2020

Impact of EMT in stage IIIB/IV NSCLC treated with erlotinib and bevacizumab when compared with cisplatin, gemcitabine and bevacizumab.

Oncol Lett 2019 Jun 15;17(6):4891-4900. Epub 2019 Mar 15.

Department of Thoracic Oncology, University Hospital Heidelberg and Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, D-69126 Heidelberg, Germany.

The aim of the present study was to assess the expression of epithelial-mesenchymal transition biomarkers (E-cadherin and vimentin) and their potential significance as prognostic markers in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) enrolled in the INNOVATIONS trial, receiving treatment with either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). The tumor tissues of 104 patients were retrospectively analyzed using immunohistochemistry to assess the expression of E-cadherin and vimentin. The distribution between the treatment arms was 46 patients in the EB-arm and 58 in the PGB-arm. Comparing the treatment arms according to E-cadherin and vimentin expression, the analysis revealed that progression-free survival (PFS) was increased in the PGB treatment group when compared with EB treatment in patients with low expression of E-cadherin [hazard ratio (HR)=0.353; 95% confidence interval (CI) 0.189- 0.658; log-rank P=0.0007] and in those with high expression of vimentin [HR=0.276 (95% CI, 0.115- 0.659), log-rank P=0.0021]. In patients that exhibited high E-cadherin and were negative for vimentin, there was no difference in the PFS between the PGB and EB treatment groups. In conclusion, in non-squamous NSCLC with downregulated E-cadherin and upregulated vimentin, the efficacy of chemotherapy with PGB was superior compared with EB; but the same effect was not observed in patients with high E-cadherin and low vimentin. Although increased PFS was observed in patients with PGB treatment compared with EB treatment in the whole analysis populations, in the subgroup of patients with the mesenchymal phenotype, no prognostic or predictive value of either biomarker could be identified. The potential role of bevacizumab in overcoming chemotherapy resistance in the population with the mesenchymal phenotype has to be further explored.
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http://dx.doi.org/10.3892/ol.2019.10153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507446PMC
June 2019

Monitoring efficacy of checkpoint inhibitor therapy in patients with non-small-cell lung cancer.

Immunotherapy 2019 06;11(9):769-782

LKI Lungenfachklinik Immenhausen, Immenhausen, Germany.

Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab.  A total of 51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.
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http://dx.doi.org/10.2217/imt-2019-0039DOI Listing
June 2019

Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis.

Cell Death Differ 2019 12 8;26(12):2740-2757. Epub 2019 May 8.

Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany.

Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues. Analysis of TAp73 mutant animals revealed that TAp73 regulates Foxj1, Rfx2, Rfx3, axonemal dyneins Dnali1 and Dnai1, plays a pivotal role in the generation of MCCs in male and female reproductive ducts, and contributes to fertility. However, the function of MCCs in the brain appears to be preserved despite the loss of TAp73, and robust activity of cilia-related networks is maintained in the absence of TAp73. Notably, TAp73 loss leads to distinct changes in ciliogenic microRNAs: miR34bc expression is reduced, whereas the miR449 cluster is induced in diverse multiciliated epithelia. Among different MCCs, choroid plexus (CP) epithelial cells in the brain display prominent miR449 expression, whereas brain ventricles exhibit significant increase in miR449 levels along with an increase in the activity of ciliogenic E2F4/MCIDAS circuit in TAp73 mutant animals. Conversely, E2F4 induces robust transcriptional response from miR449 genomic regions. To address whether increased miR449 levels in the brain maintain the multiciliogenesis program in the absence of TAp73, we deleted both TAp73 and miR449 in mice. Although loss of miR449 alone led to a mild ciliary defect in the CP, more pronounced ciliary defects and hydrocephalus were observed in the brain lacking both TAp73 and miR449. In contrast, miR449 loss in other MCCs failed to enhance ciliary defects associated with TAp73 loss. Together, our study shows that, in addition to the airways, TAp73 is essential for generation of MCCs in male and female reproductive ducts, whereas miR449 and TAp73 complement each other to support multiciliogenesis and CP development in the brain.
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http://dx.doi.org/10.1038/s41418-019-0332-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224178PMC
December 2019

The clinical course of idiopathic pulmonary fibrosis and its association to quality of life over time: longitudinal data from the INSIGHTS-IPF registry.

Respir Res 2019 Mar 15;20(1):59. Epub 2019 Mar 15.

Medizinische Klinik und Poliklinik V, Klinikum der LMU, Munich, Germany.

Background: Quality of life (QoL) is profoundly impaired in patients with idiopathic pulmonary fibrosis (IPF). However, data is limited regarding the course of QoL. We therefore analysed longitudinal data from the German INSIGHTS-IPF registry.

Methods: Clinical status and QoL were assessed at enrollment and subsequently at 6- to 12-months intervals. A range of different QoL questionnaires including the St. George's Respiratory Questionnaire (SGRQ) were used.

Results: Data from 424 patients were included; 76.9% male; mean age 68.7 ± 9.1 years, mean FVC% predicted 75.9 ± 19.4, mean DL% predicted 36.1 ± 15.9. QoL worsened significantly during follow-up with higher total SGRQ scores (increased by 1.47 per year; 95% CI: 1.17 to 1.76; p < 0.001) and higher UCSD-SOBQ scores and lower EQ-5D VAS and WHO-5 scores. An absolute decline in FVC% predicted of > 10% was associated with a significant deterioration in SGRQ (increasing by 9.08 units; 95% CI: 2.48 to 15.67; p = 0.007), while patients with stable or improved FVC had no significantly change in SGRQ. Patients with a > 10% decrease of DL predicted also had a significant increase in SGRQ (+ 7.79 units; 95% CI: 0.85 to 14.73; p = 0.028), while SQRQ was almost stable in patients with stable or improved DL. Patients who died had a significant greater increase in SGRQ total scores (mean 11.8 ± 18.6) at their last follow-up visit prior to death compared to survivors (mean 4.2 ± 18.9; HR = 1.03; 95% CI: 1.01 to 1.04; p < 0.001). All QoL scores across the follow-up period were significantly worse in hospitalised patients compared to non-hospitalised patients, with the worst scores reported in those hospitalised for acute exacerbations.

Conclusions: QoL assessments in the INSIGHTS-IPF registry demonstrate a close relationship between QoL and clinically meaningful changes in lung function, comorbidities, disease duration and clinical course of IPF, including hospitalisation and mortality.
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http://dx.doi.org/10.1186/s12931-019-1020-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420774PMC
March 2019

Adjuvant treatment patterns and outcomes in patients with stage IB-IIIA non-small cell lung cancer in France, Germany, and the United Kingdom based on the LuCaBIS burden of illness study.

Lung Cancer 2018 10 10;124:310-316. Epub 2018 Aug 10.

GSK, Rue de l'Institut, 89, Rixensart 1330, Belgium. Electronic address:

Objectives: To inform health-technology assessments of new adjuvant treatments, we describe treatment patterns in patients with complete resection of stage IB-IIIA non-small cell lung cancer (NSCLC) in France, Germany, and the United Kingdom (UK).

Materials And Methods: Data were collected via medical record abstraction. Patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC, diagnosed between 01 January 2009 and 31 December 2011. Median follow-up was 26 months. Adjuvant treatment patterns and clinical outcomes were summarized descriptively.

Results: Among the 831 patients studied, 239 (29%) had stage IB disease, 179 (22%) had stage IIA disease, 165 (20%) had stage IIB disease, and 248 (30%) had stage IIIA disease. Adjuvant systemic therapy was received by 402 patients (48.4%), (France, 61.8%; Germany, 51.9%; UK, 33.4%). Use of adjuvant therapy increased with increasing stage of disease. Cisplatin/vinorelbine and carboplatin/vinorelbine were the most frequently prescribed adjuvant regimens. Median disease-free survival was 48.0 months (95% confidence interval [CI] 42.3-not estimable); the 25th percentile was 13.2 months (95% CI, 11.0-15.3). 204 patients (24%) died during the follow-up period. The median overall survival was not reached, the 25th percentile was 31.2 months (95% CI 26.8-36.0 months). 272 patients (33%) had disease recurrence during the follow-up period. For 86 of those patients, the first recurrence was local or regional with no distant metastasis and 14 had further progression to metastatic disease during the follow-up time. For the other 186 patients, the first recurrence involved distant metastases. A total of 200 patients had metastatic disease at any time during study follow-up.

Conclusions: Less than half the patients with stage IB-IIIA NSCLC in this observational study received adjuvant systemic therapy. A high rate of first recurrence with distant metastatic disease was observed, emphasising the need for more effective systemic adjuvant therapies in this population.
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http://dx.doi.org/10.1016/j.lungcan.2018.07.042DOI Listing
October 2018

Effect of long-acting β-agonists olodaterol and formoterol on heart rate and blood pressure in chronic obstructive pulmonary disease patients.

Pulm Pharmacol Ther 2018 10 2;52:1-6. Epub 2018 Aug 2.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg, Marburg, Germany.

Background: Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD), and elevated heart rate reflects increased cardiovascular risk over time, which is associated with unfavourable neurohumoral activation. Long-acting β-agonists (LABAs) are established treatments in COPD, but potentially increase heart rate. We report a post hoc pooled analysis of the effect of olodaterol (5 or 10 μg) or formoterol (12 μg) on heart rate and blood pressure (BP) in Global Initiative for Chronic Obstructive Lung Disease Stage 2-4 COPD patients.

Methods: Four randomised, double-blind, placebo-controlled, Phase III studies were analysed. Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit.

Results: At each study visit, the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo. Systolic and diastolic BP were decreased with all treatments. Short-term (pre-dose to 40 min post-dose) effects of drug administration on heart rate were small and similar for all treatment arms (between -3 and +1 beats per minute).

Conclusion: Heart rate and BP were not adversely influenced in this study involving long-term administration of olodaterol or formoterol in patients with moderate-to-severe COPD. This supports the cardiovascular safety of LABAs in COPD maintenance treatment.
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http://dx.doi.org/10.1016/j.pupt.2018.08.002DOI Listing
October 2018

Economic burden of resected (stage IB-IIIA) non-small cell lung cancer in France, Germany and the United Kingdom: A retrospective observational study (LuCaBIS).

Lung Cancer 2018 10 9;124:298-309. Epub 2018 Jun 9.

GSK, Rixensart, Belgium. Electronic address:

Objectives: New adjuvant treatments are being developed for patients with resected non-small cell lung cancer (NSCLC). Due to scarcity of real-world data available for treatment costs and resource utilization, health technology and cost-effectiveness assessments can be limited. We estimated the burden and cost-of-illness associated with completely resected stage IB-IIIA NSCLC in France, Germany and the United Kingdom (UK).

Materials And Methods: Eligible patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC between August 2009 and July 2012. Patients (living or deceased) were enrolled at clinical sites by a systematic sampling method. Data were obtained from medical records and patient surveys. Direct, indirect and patient out-of-pocket expenses were estimated by multiplying resource use by country-specific unit costs. National annual costs were estimated based on disease prevalence data available from published sources.

Results: 39 centers provided data from 831 patients of whom patient surveys were evaluable in 306 patients. Median follow-up was 26 months. The mean total direct costs per patient during follow-up were: €19,057 (France), €14,185 (Germany), and €8377 (UK). The largest cost drivers were associated with therapies received (€12,375 France; €3694 UK), and hospitalization/emergency costs (€7706 Germany). Monthly direct costs per patient were the highest during the distant metastasis/terminal illness phase in France (€15,562) and Germany (€6047) and during the adjuvant treatment period in the UK (€2790). Estimated mean total indirect costs per patient were: €696 (France), €2476 (Germany), and €1414 (UK). Estimates for the annual national direct cost were €478.4 million (France), €574.6 million (Germany) and €325.8 million (UK).

Conclusion: To our knowledge, this is the first comprehensive study describing the burden of illness for patients with completely resected stage IB-IIIA NSCLC. The economic burden was substantial in all three countries. Treatment of NSCLC is associated with large annual national costs, mainly incurred during disease progression.
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http://dx.doi.org/10.1016/j.lungcan.2018.06.007DOI Listing
October 2018

ERCC1 assessment in upfront treatment with and without cisplatin-based chemotherapy in stage IIIB/IV non-squamous non-small cell lung cancer.

Med Oncol 2018 Jun 15;35(7):106. Epub 2018 Jun 15.

Department of Thoracic Oncology, University Hospital Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Röntgenstr. 1, 69126, Heidelberg, Germany.

Prior studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The aim of this study was to assess the impact of ERCC1 on survival for patients with stage IIIB/IV non-squamous NSCLC (NS-NSCLC) enrolled in the INNOVATIONS trial, thus receiving as treatment either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). We retrospectively analyzed tumor tissue of 72 patients using immunohistochemistry to assess the expression of ERCC1. The distribution between treatment arms was equal (36 patients each). Two different H scores were calculated and correlated with survival. In ERCC1-positive patients, no significant difference in terms of progression-free survival (PFS) between treatment arms has been detected. ERCC1-negative patients benefited from PGB compared to EB arm (H score: HR = 0.377, 95% CI [0.167-0.849], p = 0.0151; modified H score: HR = 0.484, 95% CI [0.234-1.004], p = 0.0468). With respect to the scoring system, in the EB-arm, a significant superior PFS turned out in ERCC1-positive patients when employing the H-score (HR = 0.430, 95% CI [0.188-0.981], p = 0.0397; median 4.9 vs. 3.9 months), but not with the modified H-score. Our findings support the hypothesis that NS-NSCLC displaying a low ERCC1 expression might benefit from cisplatin-based chemotherapy. High expression indicated better PFS in the EB arm supporting the prognostic impact. However, as impact of ERCC1-assessment even might depend on scoring systems differences, the need in standardization of assessment methodology is emphasized.
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http://dx.doi.org/10.1007/s12032-018-1169-5DOI Listing
June 2018

The association of cardiovascular autonomic dysfunction and the prediction of COPD can be explained by neurohumoral activation.

Authors:
Stefan Andreas

Eur Respir J 2018 06 7;51(6). Epub 2018 Jun 7.

Lungenfachklinik Immenhausen, Immenhausen, Germany.

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http://dx.doi.org/10.1183/13993003.00737-2018DOI Listing
June 2018

Airway obstruction and lung hyperinflation in COPD are linked to an impaired left ventricular diastolic filling.

Respir Med 2018 04 19;137:14-22. Epub 2018 Feb 19.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig Maximilians University, Comprehensive Pneumology Centre Munich (CPC-M), Member of the German Centre for Lung Research (DZL), Munich, Germany. Electronic address:

Aims: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases are thought to be linked through various factors. We aimed to assess the relationship between airway obstruction, lung hyperinflation and diastolic filling in COPD.

Methods: The study population was a subset of the COPD cohort COSYCONET. Echocardiographic parameters included the left atrial diameter (LA), early (E) and late (A) transmitral flow, mitral annulus velocity (e'), E wave deceleration time (E[dt]), and isovolumic relaxation time (IVRT). We quantified the effect of various predictors including forced expiratory volume in 1 s (FEV) and intrathoracic gas volume (ITGV) on the echocardiographic parameters by multiple linear regression and integrated the relationships into a path analysis model.

Results: A total of 615 COPD patients were included (mean FEV 52.6% predicted). In addition to influences of age, BMI and blood pressure, ITGV was positively related to e'-septal and negatively to LA, FEV positively to E(dt) (p < 0.05 each). The effect of predictors was most pronounced for LA, e'-septal and E(dt), and less for E/A, IVRT and E/e'. Path analysis was used to take into account the additional relationships between the echocardiographic parameters themselves, demonstrating that their associations with the predictors were maintained and robust.

Conclusions: Airway obstruction and lung hyperinflation were significantly associated with cardiac diastolic filling in patients with COPD, suggesting a decreased preload rather than an inherently impaired myocardial relaxation itself. This suggests that a reduction in obstruction and hyperinflation could help to improve cardiac filling.
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http://dx.doi.org/10.1016/j.rmed.2018.02.011DOI Listing
April 2018

Advance care planning in severe COPD: it is time to engage with the future.

ERJ Open Res 2018 Jan 16;4(1). Epub 2018 Feb 16.

Dept of Palliative Medicine, University Medical Center Göttingen, Göttingen, Germany.

http://ow.ly/Cshs30i8FS9.
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http://dx.doi.org/10.1183/23120541.00009-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814759PMC
January 2018

Increased Arterial Stiffness Might Be Caused by Sympathetic Activation.

Chest 2018 02;153(2):569

Respiratory Medicine/Cardiology, Lungenfachklinik Immenhausen, Immenhausen, Germany.

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http://dx.doi.org/10.1016/j.chest.2017.09.055DOI Listing
February 2018

Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: insights-IPF registry.

Respir Res 2017 07 14;18(1):139. Epub 2017 Jul 14.

Comprehensive Pneumology Center, Lungenforschungsambulanz, Klinikum der Universität München, München, Germany.

Background: The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline.

Methods: Six hundred twenty-three IPF patients with available QoL data (St George's Respiratory Questionnaire SGRQ, UCSD Shortness-of-Breath Questionnaire SoB, EuroQol visual analogue scale and index EQ-5D, Well-being Index WHO-5) were analysed. Mean age was 69.6 ± 8.7 years, 77% were males, mean disease duration 2.0 ± 3.3 years, FVC pred was 67.5 ± 17.8%, DL pred 35.6 ± 17%.

Results: Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms (NYHA; p < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity (as measured by GAP score, CPI, FVC and 6-min walk test; p < 0.05 each). Multivariate analyses showed a significant association between QoL (by SGRQ total) and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment.

Conclusions: Overall, IPF patients under real-life conditions have lower QoL compared to those in clinical studies. There is a meaningful relationship between QoL and various patient characteristics.

Trial Registration: The INSIGHTS-IPF registry is registered at Clinicaltrials.gov ( NCT01695408 ).
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http://dx.doi.org/10.1186/s12931-017-0621-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512739PMC
July 2017

Aclidinium bromide improves symptoms and sleep quality in COPD: a pilot study.

Eur Respir J 2017 06 22;49(6). Epub 2017 Jun 22.

Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.

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http://dx.doi.org/10.1183/13993003.00485-2017DOI Listing
June 2017

Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep.

Eur Respir J 2017 01 18;49(1). Epub 2017 Jan 18.

Laboratoire du sommeil explorations fonct. respire., Centre Hospitalier Universitaire Grenoble, Grenoble, France.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.
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http://dx.doi.org/10.1183/13993003.00959-2016DOI Listing
January 2017

Impact of Non-Invasive Ventilation on Sympathetic Nerve Activity in Chronic Obstructive Pulmonary Disease.

Lung 2017 02 16;195(1):69-75. Epub 2016 Nov 16.

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37099, Göttingen, Germany.

Purpose: Chronic obstructive pulmonary disease (COPD) is associated with elevated sympathetic nerve activity, which is probably linked to an increased cardiovascular risk, and may contribute to muscle dysfunction by heightened muscle vasoconstrictor drive. We hypothesized that resistive unloading of respiratory muscles by intermittent non-invasive ventilation (NIV) reduces sympathetic tone at rest and during subsequent handgrip exercise in patients with COPD.

Methods: Muscle sympathetic nerve activity (MSNA) in the peroneal nerve, heart rate, blood pressure, CO, and SpO were continuously recorded in 5 COPD patients with intermittent NIV and 11 control COPD patients without NIV. Static and dynamic handgrip exercises were performed before and after NIV.

Results: At baseline, heart rate-adjusted MSNA (bursts/100 heart beats) did not differ between groups. NIV did not significantly affect MSNA levels at rest. However, during handgrip exercises directly following NIV, MSNA was lower than before, which was significant for dynamic handgrip (67.00 ± 3.70 vs. 62.13 ± 4.50 bursts/100 heart beats; p = 0.035 in paired t test). In contrast, MSNA (non-significantly) increased in the control group during repeated dynamic or static handgrip. During dynamic handgrip, tCO was lower after NIV than before (change by -5.04 ± 0.68 mmHg vs. -0.53 ± 0.64 in the control group; p = 0.021), while systolic and diastolic blood pressure did not change significantly.

Conclusions: NIV reduces sympathetic activation during subsequent dynamic handgrip exercise and thereby may elicit positive effects on the cardiovascular system as well as on muscle function in patients with COPD.
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http://dx.doi.org/10.1007/s00408-016-9965-1DOI Listing
February 2017

Cardiac impact of inhaled therapy in the largest randomised placebo-controlled trial in COPD history: have we reached the SUMMIT?

ERJ Open Res 2016 Apr 26;2(2). Epub 2016 May 26.

Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; Dept of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

http://ow.ly/p6Is300ffoc.
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http://dx.doi.org/10.1183/23120541.00055-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005175PMC
April 2016

Recommendations to improve smoking cessation outcomes from people with lung conditions who smoke.

ERJ Open Res 2016 Apr 27;2(2). Epub 2016 Apr 27.

Education for Health, Warwick, UK.

This study aimed to gain insight into the impact of lung conditions on smoking behaviour and smoking cessation, and identify recommendations for smoking cessation and professional-patient communications. The study was led by the European Lung Foundation in collaboration with the European Respiratory Society Task Force on "Statement on smoking cessation on COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit". A web-based observational cross-sectional questionnaire was developed from a patient-centered literature review. Topics covered were: cohort characteristics; perspectives on smoking cessation; interactions with healthcare professionals; and recommendations to improve cessation outcomes. The questionnaire was disseminated existing patient and professional networks and social media channels. The survey was available online for a period of 4 months in 16 languages. The data were analysed as a whole, not by country, with thematic analysis of the open responses. Common characteristics were: male (54%); age 40-55 years (39%); 11-20 cigarettes a day (39%); smokes within 30 min of waking (61%); and has made 1-5 cessation attempts in the previous 12 months (54%). 59% had tried cessation treatments, but, of these, 55% had not found any treatments helpful. Recommendations were: earlier intervention; discussion of the patient's smoking beliefs, behaviours and motivation; giving constructive advice; understanding addiction; informed decision-making; and treatment options. Areas for new and further research have been highlighted through exploring the smoking cessation perspectives and recommendations of people with lung conditions in Europe who smoke.
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http://dx.doi.org/10.1183/23120541.00009-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005168PMC
April 2016

Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial.

Tob Induc Dis 2016 8;14:26. Epub 2016 Aug 8.

Department of Cardiology and Pneumology, University Medical Centre Göttingen, D-37099 Göttingen, Germany.

Background: Varenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal.

Methods: In this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal).

Results: Regarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (-3.0 ± 3.3 vs.-3.9 ± 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 ± 1.0 vs.-1.8 ± 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 ± 1.2 vs.-1.1 ± 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015).

Conclusion: We did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome.
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http://dx.doi.org/10.1186/s12971-016-0091-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977756PMC
August 2016