Kai M. Beeh

Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

BACKGROUNDnTreatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.nnnMETHODSnIn a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.nnnRESULTSnA total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.nnnCONCLUSIONSnThese results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

Minimal clinically important differences in pharmacological trials.

The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St Georges Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term minimum worthwhile incremental advantage to describe this parameter.

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.

BACKGROUNDnThe most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA).nnnMETHODSnWe conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1).nnnRESULTSnAfter 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo.nnnCONCLUSIONSnTreatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).

c‐erbB‐2 Expression in small‐cell lung cancer is associated with poor prognosis

Small‐cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c‐erbB‐2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c‐terminal domain of c‐erbB‐2. A clear‐cut positive expression of c‐erbB‐2 was observed in 13% of patients. Surprisingly, c‐erbB‐2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional‐hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I–IV), the most relevant clinical parameters. Similarly, a significant association between c‐erbB‐2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron‐specific enolase (NSE), gender and age (p = 0.033). Interestingly, c‐erbB‐2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II–IV), median survival of patients with undetectable c‐erbB‐2 expression was 274 days compared with only 23 days for patients with clear‐cut positive c‐erbB‐2 immunohistochemistry (p = 0.0031; log‐rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c‐erbB‐2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c‐erbB‐2 is expressed in more than 10% of SCLC. Expression of c‐erbB‐2 is an independent prognostic factor of survival. The effect of c‐erbB‐2 expression seems to become more important in advanced stages of the disease. Since c‐erbB‐2 is a therapeutical target in other types of cancer, further studies to identify the role of c‐erbB‐2 in SCLC are clearly warranted.

The short, the long and the "ultra-long": why duration of bronchodilator action matters in chronic obstructive pulmonary disease.

Bronchodilators are the cornerstone of symptomatic treatment for all chronic obstructive pulmonary disease (COPD) severity stages when administered on a regular basis to prevent or reduce symptoms and exacerbations. The principal inhaled bronchodilator treatments are beta-2 agonists and anticholinergics, used singularly or in combination. There is good evidence that regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. Long-acting agents include the twice-daily beta-2 agonists formoterol and salmeterol, the once-daily anticholinergic tiotropium, and, more recently, the once-daily beta-2 agonist indacaterol. Long-acting bronchodilators have been shown to improve multiple clinical outcomes in COPD in comparison to short-acting agents including lung function, symptoms, dyspnea, quality of life, and exacerbations. Studies of head-to-head comparisons of long-acting bronchodilators are scant but indicate superior bronchodilation of tiotropium over salmeterol, while preliminary data from trials with the novel once-daily beta-2 agonist indacaterol indicate superior bronchodilation and clinical efficacy over twice-daily long-acting beta-2 agonists and at least equipotent bronchodilation as once-daily tiotropium. These recent therapeutic developments in COPD represent a change of paradigm with a shift from short-acting bronchodilators with multiple dosing per day to reduced dosing frequency and prolonged duration of action including once-daily treatment. This review summarizes relevant data and landmark studies comparing the efficacy of short-acting versus longer-acting bronchodilators in COPD, including new data for once-daily indacaterol, and discusses potential mechanism underlying the improved efficacy of long-acting versus short-acting bronchodilators.

Sputum levels of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1, and their ratio correlate with airway obstruction in lung transplant recipients: relation to tumor necrosis factor-α and interleukin-10

BACKGROUNDnChronic transplant rejection is characterized by progressive narrowing of small airways caused by matrix remodeling and fibrosis. Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix.nnnMETHODSnTo clarify the contribution of MMPs and TIMPs to airway inflammation in patients after lung transplantation (LTx), we used enzyme immunoassays to measure induced sputum concentrations of MMP-9, TIMP-1, and controlling cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 of 30 LTx patients and 15 control subjects.nnnRESULTSnSputum concentrations of MMP-9, TIMP-1, the MMP-9:TIMP-1 ratio, and TNF-alpha were higher in LTx patients than in control subjects (p < 0.04, all comparisons). The MMP-9, MMP-9:TIMP-1, and TNF-alpha levels were also significantly higher in LTx patients with chronic rejection compared with those with stable organ function (p < 0.03, all comparisons), whereas IL-10 levels were higher in the latter group (p = 0.05). In all LTx patients, MMP-9 and the MMP-9:TIMP-1 ratio were negatively correlated with forced expiratory volume in 1 second values (rho = -0.47, p = 0.01, and rho = -0.53, p = 0.003, respectively). We found that MMP-9 positively correlated with sputum neutrophils and TNF-alpha whereas MMP-9 and TIMP-1 did not correlate with IL-10.nnnCONCLUSIONSnThese data underline the possible contribution of proteases such as MMP-9 to chronic transplant rejection, and suggest that an imbalance of MMP-9 and TIMP-1 may be involved in the pathogenesis of airway obstruction after LTx. We found that MMP-mediated inflammation seems to be controlled by TNF-alpha whereas IL-10 might elicit anti-inflammatory effects through different pathways.

Seasonal Distribution of COPD Exacerbations in the Prevention of Exacerbations With Tiotropium in COPD Trial

BACKGROUNDnThere is still a lack of data on the seasonality of exacerbations of COPD based on large randomized studies using COPD exacerbations as primary end points. The objective of this study was to assess the seasonal pattern of moderate and severe exacerbations and analyze the influence of associated baseline factors. We also determined the timing of second exacerbations and the potential impact of the 2009 influenza A(H1N1) pandemic on exacerbations.nnnMETHODSnAnalyses of exacerbation rates across treatment groups were adjusted for differing times on treatment by means of descriptive statistics based on the 1-year Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) trial, in which exacerbations were the primary end point.nnnRESULTSnOf the 7,376 patients who were randomized, a total of 4,411 exacerbations were reported in 2,691 patients. Mean monthly exacerbation rates during winter were 2.16-fold higher than during summer, regardless of baseline characteristics (age, sex, COPD severity, smoking status, BMI, inhaled corticosteroid use, cardiovascular comorbidity, concomitant cardiovascular medication). Second exacerbations after a previous event in October to March occurred 1 month earlier than during the warmer half of the season. The portion of exacerbation-related hospitalizations remained constant throughout the year. Most exacerbations were treated with antibiotics and reached a peak in the colder season. All-cause mortality showed a seasonal pattern similar to exacerbations. The 2009 A(H1N1) pandemic was not associated with an increase in exacerbation rates or deaths.nnnCONCLUSIONSnThis analysis presented a marked impact of season on exacerbation outcomes, antibiotic treatment, timing of second exacerbations, and all-cause mortality.

Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial

BackgroundThis study evaluated the effects of aclidinium bromide, a long-acting muscarinic antagonist indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), on exercise endurance, dyspnea, lung hyperinflation, and physical activity.MethodsIn this randomized, double-blind, crossover study, patients with stable COPD and moderate-to-severe airflow limitation received aclidinium 400xa0μg twice daily or placebo via Genuair®/Pressair®a for 3xa0weeks (2-week washout between treatment periods). The primary endpoint was change from baseline to Week 3 in endurance time, measured by constant work rate cycle ergometry testing at 75% peak incremental work rate. Changes from baseline in intensity of exertional dyspnea (Borg CR10 Scale®) and trough inspiratory capacity were secondary endpoints. Additional endpoints included changes from baseline in other spirometric, plethysmographic, and physical activity (assessed by objective accelerometer measurement) parameters. Efficacy endpoints were analyzed using an analysis of covariance model.ResultsIn total, 112xa0patients were randomized and treated (mean age 60.3xa0years; mean post-bronchodilator forced expiratory volume in 1xa0s 1.7xa0L [56.7% predicted]; mean endurance time 485.7xa0s). After 3xa0weeks, endurance time was significantly increased with aclidinium versus placebo (treatment difference 58.5xa0s; pu2009<u20090.05). At Weekxa03, aclidinium significantly reduced dyspnea intensity at isotime during exercise (treatment difference -0.63; pu2009<u20090.05) and improved trough inspiratory capacity (treatment difference 78xa0mL; pu2009<u20090.05) versus placebo. Significant improvements in spirometric, plethysmographic, and some physical activity parameters were observed with aclidinium versus placebo.ConclusionsThese results suggest that aclidinium significantly improves exercise endurance, exertional dyspnea, hyperinflation, and physical activity in patients with COPD.Trial registrationClinicalTrials.gov identifier: NCT01471171; URL: http://www.clinicaltrials.gov.

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial

BackgroundData examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.MethodsPost-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.ResultsIn total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.ConclusionThe frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.Trial registrationNCT00563381; Study identifier: BI 205.389.

Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function

BACKGROUND Sputum induction is a non-invasive procedure for measuring inflammatory processes of the lower respiratory tract. The aim of this study was to establish sputum cell counts and differentials in patients after lung transplantation (LTx), with or without chronic transplant rejection. METHODS Sputum induction was performed in 41 LTx patients (25 single LTx (sLTx), 16 double LTx (dLTx) and 15 healthy non-smoking volunteers. Sputum was processed according to standard protocols. Total cell count was calculated as mean (SE) cells × 106/ml sputum and cell differential (%) was evaluated after staining. Cellular profiles were correlated with lung function. RESULTS Total sputum cell counts were increased in sLTx (9 (1.9) cells × 106/ml, p=0.01) and dLTx patients (7.2 (1.5) × 106/ml, p=0.01) compared with healthy controls (2.6 (0.6) × 106/ml). There was also a marked sputum neutrophilia in both patient groups (59 (6)% and 62 (6)%, respectively, p<0.001v controls). Moreover, in both sLTx and dLTx patients with chronic transplant rejection there was an increased number of sputum neutrophils compared with patients with normal graft function (p<0.05 both comparisons), and neutrophils were inversely correlated with lung function (forced expiratory volume in one second (FEV1) % predicted): sLTx,r=–0.61, p=0.001; dLTx,r=–0.75, p=0.001, respectively). Sputum lymphocytes and eosinophils were similar in both groups. No relevant side effects occurred during sputum induction. CONCLUSIONS Sputum induction is a safe and non-invasive tool for monitoring lower respiratory tract inflammation in LTx patients. Both sLTx and dLTx patients with chronic rejection had increased sputum neutrophils compared with patients with normal transplant function. These data support findings of other authors highlighting a possible role for neutrophils in the pathogenesis of chronic transplant rejection.