Inhaled pan-selectin antagonist Bimosiamose attenuates airway inflammation in COPD.

Selectins, a family of cell adhesion molecules, are involved in leukocyte extravasation to sites of inflammation. We investigated the safety and efficacy of the inhaled pan-selectin antagonist Bimosiamose in patients with chronic obstructive pulmonary disease (COPD). 77 COPD patients (mean forced expiratory volume in 1 s, 57% pred.) were enrolled in a cross-over, double-blind, randomized, Placebo-controlled, multi-center trial. Bimosiamose (10 mg) or Placebo was inhaled twice daily via the breath actuated nebulizer Akita2 Apixneb™ for 28 days on top of standard bronchodilator therapy. Efficacy was assessed by measurement of inflammatory parameters in induced sputum (differential cell count, interleukin-8, matrix-metalloproteinase-9, myeloperoxidase) and lung function at day 28 of both treatment periods. The total adverse event ratio of Bimosiamose compared to Placebo treatment was balanced. Compared to Placebo, treatment with Bimosiamose led to a decrease of the interleukin-8 concentration (-9.49 ng/mL, 95%CI -18.8 to -2.7 ng/mL, p = 0.008), for the neutrophil count a difference of -0.368 × 10(6) cells/mL (95%CI -1.256 to 0.407 × 10(6)/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 10(6) cells/mL (95%CI -0.365 to -0.044 × 10(6) cells/mL, p = 0.012). Most lung function parameters showed a small numeric increase. Inhalation of Bimosiamose for 28 days was safe and well tolerated in patients with COPD. It led to an attenuation of airway inflammation (EudraCT 2009-017257-35; NCT ID: NCT01108913).

Efficacy of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects--a double blind, randomized, placebo-controlled, cross-over clinical trial.

Selectins, a family of cell adhesion molecules, are involved in the activation and extravasation of leukocytes in inflammatory diseases. Inhalation of ozone induces an inflammation of the airways, which is dominated by neutrophils. We investigated the effect of repeated inhalations of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomized, cross-over study Bimosiamose (10 mg bid) was inhaled via a breath actuated nebulizer (AKITA2 APIXNEB(®)) for 4 days. Treatment was followed by inhalation of ozone (250 ppb) for 3 h with intermittent exercise. Induced sputum was collected 3 h post ozone challenge for analysis of cellular and non-cellular composition. 18 subjects were randomized and completed the study. All treatments were safe and well tolerated. Compared to placebo Bimosiamose reduced the numbers of sputum neutrophils by 40% (p = 0.068) and concentrations of interleukin-8 and matrix-metalloproteinase-9 in sputum supernatant by 35% (p = 0.004) and 46% (p = 0.022), respectively. Inhalation of Bimosiamose showed favourable anti-inflammatory effects on ozone-induced airway inflammation in healthy volunteers. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with chronic obstructive pulmonary disease. (ClinTrialgov Ident: NCT01108913).

Is patient self-report an adequate tool for monitoring cardiovascular conditions in patients with hypercholesterolemia?

BACKGROUND: To determine the accuracy of patient self-reports of specific cardiovascular diagnoses and to identify individual patient characteristics that influence the accuracy. METHODS: This investigation was conducted as a part of the randomized controlled ORBITAL study. Patients with hypercholesterolemia were enrolled in 1961 primary-care centers all over Germany. Self-reported questionnaire data of 7640 patients were compared with patients' case report forms (CRFs) and medical records on cardiovascular diseases, using kappa statistics and binomial logit models. RESULTS: kappa values ranged from 0.89 for diabetes to 0.04 for angina. The percentage of overreporting varied from 1% for diabetes to 17% for angina, whereas the percentage of underreporting varied from 8.0% for myocardial infarction to 57% for heart failure. Individual characteristics such as choice of individual general practitioner, male gender and age were associated with the accuracy of self-report data. CONCLUSION: Since the agreement between patient self-report and CRFs/medical records varies with specific cardiovascular diagnoses in patients with hypercholesterolemia, the adequacy of this tool seems to be limited. However, the authors recommend additional data validation for certain patient groups and consideration of individual patient characteristics associated with over- and underreporting.

Impact of a compliance program on cholesterol control: results of the randomized ORBITAL study in 8108 patients treated with rosuvastatin.

AIM: To determine whether a compliance-enhancing program could increase the level of lipid control in patients treated with rosuvastatin. METHODS AND RESULTS: A total of 8108 patients (56% men, mean age 59 years; 44% women, mean age 63 years) with low-density lipoprotein cholesterol (LDL-C) >or=115 mg/dl if statin-naive or else >or=125 mg/dl were randomized to rosuvastatin 10 mg daily either with or without a compliance-enhancing program for 12 months. Patients not achieving the goal after 3 months were uptitrated to rosuvastatin 20 mg daily thereafter. At 3, 6, and 12 months, rosuvastatin plus compliance initiatives were similarly effective to rosuvastatin alone in terms of 1998 European LDL-C goal of less than 115 mg/dl achievement (72 vs. 70%, 71 vs. 69%, 68 vs. 68%) and changes in the lipid profile. Significant differences were observed in the subgroup of statin-naive patients at 3 and 6 months (80 vs. 76% and 78 vs. 73%, P<0.01). The frequency of adverse events and relevant changes in laboratory data were consistent with the known safety profile of rosuvastatin. CONCLUSION: Rosuvastatin 10/20 mg daily enables the majority of patients to achieve LDL-C less than 115 mg/dl within 3 months. The compliance-enhancing program was only effective in statin-naive patients at early time points, but had no overall effect over 12 months.

Nighttime heartburn in patients with gastroesophageal reflux disease under routine care.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disorder. The aim of our study was to describe the prevalence of nighttime heartburn and its associations with esophagitis, Barrett's esophagus, and extra-esophageal symptoms. METHODS: Data were collected as part of the ongoing Progression of Gastroesophageal Reflux Disease (ProGERD) study. Based on endoscopy results, patients were categorized as having nonerosive GERD, erosive GERD, or Barrett's esophagus. ORs and 95% CIs derived from logistic regression analysis were calculated for the association between nighttime heartburn and GERD complications. RESULTS: The overall prevalence of nighttime heartburn for at least 1 of 3 years was 49%, and 21% of patients reported nighttime heartburn in all 3 years. According to multivariate analysis, chronic nighttime heartburn was associated with globus sensation (OR 1.79, 95% CI 1.29-2.47) and erosive GERD (OR 1.67, 95% CI 1.29-2.15). Compared to continuous proton pump inhibitor (PPI) intake, noncontinuous PPI therapy (OR 2.26, 95% CI 1.73-2.96) and medication other than PPIs (OR 2.46, 95% CI 1.67-3.62) were also associated with chronic nighttime heartburn. CONCLUSIONS: The prevalence of nighttime heartburn in GERD patients under routine care was high, even in patients on continuous PPI therapy. Nighttime heartburn was not associated with Barrett's esophagus or most extra-esophageal symptoms.

Economic assessment of adjustable maintenance treatment with budesonide/formoterol in a single inhaler versus fixed treatment in asthma.

OBJECTIVES: To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma. METHODS: In this prospective, randomised, open-label, parallel-group, multicentre trial conducted in Germany, patients with asthma received budesonide/formoterol 160 microg/4.5 microg in a single inhaler (Symbicort Turbuhaler with two inhalations twice daily for a 4-week run-in period. Patients were then randomised to either adjustable maintenance dosing (one inhalation twice daily, stepping up to four inhalations twice daily for 1 week if asthma worsened; n=1679) or fixed dosing (two inhalations twice daily; n=1618) for 12 weeks. The primary efficacy variable was the change in health-related quality of life (HR-QOL), measured using the Asthma Quality of Life Questionnaire (standardised) during the randomised treatment period. Resource utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs (year 2001 values). RESULTS: Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the randomised treatment period. However, overall, patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group (mean: 2.63 vs 3.82 inhalations; p<0.001). Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing (mean: 221 euro vs 292 euro; p<0.001). This pattern was maintained when patients were stratified into those with peak expiratory flow (PEF) of 60% to <80% predicted normal and those with PEF of>/=80% predicted normal and when total costs were considered. CONCLUSION: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing.

Economic evaluation of a compliance-enhancing intervention in patients with hypercholesterolemia: design and baseline results of the Open Label Primary Care Study: Rosuvastatin Based Compliance Initiatives To Achievements of LDL Goals (ORBITAL) study.

BACKGROUND: Previous studies investigating the effectiveness of compliance programs in patients with cardiovascular risk factors have been inconclusive and have not included economic analyses. The primary aim of this Open Label Primary Care Study: Rosuvastatin Based Compliance Initiatives To Achievements of LDL Goals (ORBITAL) study is to determine the long-term cost-effectiveness of a compliance-enhancing intervention in patients with hypercholesterolemia (HC). Secondary objectives include the assessment of compliance, cardiovascular events, and health-related quality of life. STUDY DESIGN: A total of 7598 patients (56% men, age 60 +/- 10 years, and 44% women, 64 +/- 10 years) with HC requiring statin therapy according to the Second Joint European Guidelines were recruited at presentation to 1961 primary care physicians in Germany. Patients were randomized to rosuvastatin therapy with or without a compliance-enhancing program (including standardized contacts between the study center and patients, 9 mailings, 6 telephone calls, and access to a Web page and hotline) for 12 months. Following the intervention phase, there will be a 24-month observational period with patients receiving usual care. Baseline and 6-monthly follow-up assessments are to be obtained from patients and their physicians using standardized questionnaires to evaluate medical and economic parameters. Cumulative direct and indirect disease-related costs (including resource utilization for ambulatory, hospital, rehabilitative, and nursing care, medication, physiotherapy, and transportation, and loss of productivity) will be compared applying a societal perspective. CONCLUSIONS: The results of this ORBITAL study will provide a basis to develop cost-effective compliance strategies and eventually improve medical care for patients with HC.

Productivity loss as a major component of disease-related costs in patients with hypercholesterolemia in Germany.

OBJECTIVE: Hypercholesterolemia is a common risk factor for cardiovascular diseases; however, there are only few data available on associated costs. The objective of this study is, therefore, to analyse direct and indirect costs in patients with hypercholesterolemia and to determine predictors of costs. METHODS: The ORBITAL Study is a randomised controlled trial evaluating the effectiveness of a compliance-enhancing program in patients with statin therapy. Consecutive patients eligible for statin therapy according to the Joint European Guidelines were enrolled nationwide in 1961 primary care practices in Germany. For the present cost-of-illness analysis, patients were asked retrospectively about medical resource use and employment status in the 6 months preceding enrollment. The perspective chosen was societal. Factors associated with costs were determined using linear regression. RESULTS: A total of 7,640 patients (56% men, mean age 60 +/- 10 years, and 44% women, 64 +/- 10 years) were included. Of these patients, 32% were employed, 17% had a history of myocardial infarction, 7% a history of stroke, 58% had hypertension, and 29% diabetes. Total disease-related costs amounted to a mean of 2,498 +/- 4,898 Euros per patient over 6 months, comprising direct (44%) and indirect (56%) costs. Disease-related early retirement was responsible for 42% of costs, followed by hospital visits (19%), medication (15%), workdays lost (14%), physician visits (5%), outpatient therapy (2%), and rehabilitation (2%). In multivariable analyses, factors associated with direct costs included coronary interventions, risk stratum, and medical history. Factors associated with indirect costs included disease-related early retirement, other socio-economic and lifestyle factors, coronary interventions, risk stratum, and medical history. CONCLUSION: The considerable economic burden associated with hypercholesterolemia indicates the need to assess long-term cost-effectiveness of health care programs in patients with this disorder.

Association of body mass index with heartburn, regurgitation and esophagitis: results of the Progression of Gastroesophageal Reflux Disease study.

BACKGROUND: Overweight and obesity are believed to be risk factors for gastroesophageal reflux disease (GERD). The aim of the present study was to analyze the impact of body mass index (BMI) on the severity and frequency of reflux symptoms and esophagitis in a large cohort of reflux patients. METHODS: As part of the Progression of Gastroesophageal Reflux Disease (ProGERD) study, 6215 patients with clinically assessed GERD were included in the present investigation (53% male, 52 +/- 14 years; 47% female, 56 +/- 14 years). Heartburn and regurgitation symptoms were assessed using the validated Reflux Disease Questionnaire. Endoscopies were performed and patients were subsequently classified as having non-erosive or erosive disease. To examine the association between BMI, GERD symptoms, and esophagitis, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using logistic regression models. RESULTS: In patients with GERD, higher BMI was associated with more frequent and more severe heartburn and regurgitation, as well as with esophagitis. The effects were more pronounced for regurgitation than for heartburn. The strongest association was between obesity and severity of regurgitation symptoms (women: OR 2.11, 95%CI 1.60-2.77; men: OR 2.15, 95%CI 1.59-2.90). Obese women, but not men, had an increased risk of severe esophagitis compared to women with normal weight (OR 2.51, 95%CI 1.53-4.12). CONCLUSIONS: In patients with GERD, higher BMI was associated with more severe and more frequent reflux symptoms and esophagitis.

Prospective follow-up data from the ProGERD study suggest that GERD is not a categorial disease.

OBJECTIVES: There is a controversy as to whether gastroesophageal reflux disease (GERD) exists as a spectrum of disease severity or as a categorial disease in three distinct groups: nonerosive (NERD) and erosive reflux disease (ERD) and Barrett's esophagus (BE). Aim of the study was to assess progression or regression of GERD over 2 yr in a large cohort of patients (N = 3,894) under routine clinical care in Germany, Austria, and Switzerland (ProGERD study). METHOD: Patients with predominant heartburn, with or without esophagitis, were recruited and classified according to endoscopic status at baseline, i.e., NERD, erosive reflux disease-Los Angeles (ERD-LA) grade A/B and ERD-LA grade C/D, and BE. After an initial treatment with esomeprazole, they were followed, regardless of their response. Medical therapy or endoscopy was initiated at the discretion of their primary care physician, in line with routine care. At 2 yr, endoscopy with biopsy was performed according to the protocol. RESULTS: After 2 yr, 25% of patients who had NERD at baseline progressed to LA A/B and 0.6% to LA C/D; 1.6% of patients who had LA A/B progressed to LA C/D and 61% regressed to NERD; 42% of patients who had LA C/D regressed to LA A/B and 50% regressed to NERD (all figures exclude patients with confirmed BE at baseline). At 2 yr, 22% of patients had been off medication for at least 3 months. Patients with ERD-LA grade C/D were at greatest risk of developing BE: 5.8% compared with 1.4% for ERD-LA grade A/B and 0.5% for NERD. CONCLUSION: GERD does not seem to be a categorial disease. Progression and regression between grades was observed in this large cohort of patients under routine clinical care.

Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD study initiative.

OBJECTIVES: Gastroesophageal reflux disease can be divided into three categories: nonerosive GERD (NERD), erosive GERD (ERD), and Barrett's esophagus. A shift among these categories rarely occurs. The aim of the present study was to elucidate potential patient-associated risk factors associated with ERD. METHODS: A total of 6,215 patients with troublesome heartburn were recruited to a large, prospective, multicenter open cohort study comprising an initial treatment phase and a 5-yr follow-up phase. Each center planned to recruit an equal number of patients with NERD and ERD. All patients underwent an interview based on standardized questionnaires, a physical examination, and endoscopy with biopsies. Data were analyzed by multiple logistic regression analysis. RESULTS: Risk factor analysis was performed on 5,289 patients (NERD: n = 2,834; ERD: n = 2,455), which was the intent-to-treat population excluding patients with suspected/proven complicated reflux disease. Stepwise regression analysis identified the following independent predictors of ERD: male gender, overweight, regular use of alcohol, a history of GERD >1 yr, and smoker or ex-smoker. A higher level of education and a positive Helicobacter pylori (H. pylori) status were associated with a lower risk of ERD. CONCLUSIONS: Some patient-associated factors increase the risk of erosive esophagitis as opposed to nonerosive reflux disease. However, no single factor or combination of factors is capable of predicting mucosal damage with clinically sufficient certainty. Thus, endoscopy is still required in all GERD patients if valid information on the state of the esophageal mucosa is needed.